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Hello, everyone. Thank you for joining us, and welcome to the BioMarin Third Quarter 2026 Conference Call. After today's prepared remarks, we will host a question-and-answer session. [Operator Instructions]

I will now hand the call over to BioMarin's Head of Investor Relations, Traci McCarty. Please go ahead.

Thank you, operator. To remind you, this nonconfidential presentation contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc., including expectations regarding BioMarin's financial performance, commercial products and potential future products in different areas of therapeutic research and development. Results may differ materially depending on the progress of BioMarin's product programs, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market and developments by competitors and those factors detailed in BioMarin's filings with the Securities and Exchange Commission, such as 10-Q, 10-K and 8-K reports.

In addition, we will use non-GAAP financial measures as defined in Regulation G during the call today. These non-GAAP measures should not be considered in isolation from, as substitutes for or superior to financial measures prepared in accordance with U.S. GAAP, and you can find the related reconciliations to U.S. GAAP in the earnings release and earnings presentation, both of which are available in the Investor Relations section of our website. Please note that our commentary on today's call will focus on non-GAAP financial measures unless otherwise indicated.

Beginning on Slide 3 and introducing BioMarin's management team joining today's call, Alexander Hardy, Chief Executive Officer; Cristin Hubbard, Chief Commercial Officer; Greg Friberg, Chief R&D Officer; and Brian Mueller, Chief Financial Officer. I will now turn the call over to Alexander to provide our quarterly highlights. Alexander?

Thank you, Traci, and thank you all for joining us today. Starting on Slide 5. Strong demand across our diversified portfolio of innovative therapies drove 32% year-over-year growth in the third quarter, surpassing $1 billion in quarterly revenues for the first time in our history. Also last week, we announced the addition of a new investigational Fabry asset to our clinical portfolio, recently renamed BMN 450, the fourth new asset added to our pipeline in 2026. This highlights the focused and deliberate expansion of BioMarin's clinical stage pipeline, BMN 450 has the potential to become the first subcutaneous enzyme therapy to treat people with Fabry and I will provide more detail in a moment.

Moving to our third quarter results. The metabolic conditions business delivered revenue growth of 44% compared to the third quarter of last year, driven by strong contributions from both GALAFOLD, POMBILITI and OPFOLDA. Together, they totaled more than $200 million in combined revenues in the quarter, while at the same time, the pace of Amicus cost synergies realization exceeded our expectations. We are energized by the addition of our Amicus colleagues, and we're working together to expand the reach of both GALAFOLD and POMBILITI and OPFOLDA, of bringing these therapies to more patients around the world. I am also pleased with the continued global expansion of VOXZOGO as the number of children treated increased by 17% worldwide.

Building on this momentum, we are pleased to share that May 30, 2027 is the PDUFA date for VOXZOGO for the treatment of hypochondroplasia, the first targeted therapy to potentially be approved for the indication and a potential seventh first in disease medicine for BioMarin. The team is well prepared for strong launches in hypochondroplasia in the U.S. and Europe, and we anticipate both regions will benefit from our global leadership in skeletal conditions. Before I turn the call over to Cristin, I want to say a few words about the work we are doing to expand our pipeline, including the most recent addition to our clinical portfolio.

BMN 450 is a Phase I/II compound that builds on our GALAFOLD experience and has the potential to expand the therapeutic reach to those with Fabry whose variants are not amenable with GALAFOLD. BMN 450 is a strategically compelling addition to our metabolic conditions BU, addressing treatment burden and a priority unmet need with a differentiated long-acting subcutaneous profile. It also reflects our growing commitment to the Fabry community, building on the Amicus acquisition as well as the expertise and relationships established with GALAFOLD.

In summary, we delivered strong financial results in the third quarter and made meaningful progress across every part of our business. In a moment, Brian will speak to some expected order timing dynamics and geopolitical headwinds that we are observing, resulting in today's updated guidance. In 2026, we have delivered on the strategic expansion of our innovative pipeline, including the addition of BMN 450, BMN 440 for hypophosphatasia, BMN 430 for a new syndrome and BMN 820 for FSGS. Our business development execution having delivered 5 deals in 2 years, demonstrates our capabilities across the value chain as a rare disease leader operating at scale.

Our commercial portfolio is now more diversified and more resilient following the successful acquisition of Amicus as well as our pipeline with the more recently acquired earlier stage assets. We look ahead with enthusiasm for what's to come as we advance the next wave of therapies from our clinical stage pipeline and to reporting on a number of key updates in 2027. Combined with the strength of our more diversified commercial portfolio, we are confident in our ability to create lasting value for patients and all of our stakeholders, and we look forward to updating you on our progress. I will now turn the call over to Cristin for more detail on our commercial performance. Cristin?

Thank you, Alexander. The third quarter again showed the strength and growing diversity of our portfolio. Our team stayed focused on expanding diagnosis, increasing access and helping more patients start and stay on therapy. Now turning to Slide 7. We have begun to implement the initiatives that we outlined last quarter for GALAFOLD and POMBILITI and OPFOLDA. For GALAFOLD, those levers are expanding diagnosis and treatment and deepening market penetration globally. For POMBILITI and OPFOLDA, there are increased patient switching and global market expansion complemented by improvements in diagnosis and treatment. New geographies take time. So this quarter, we focused on the fastest levers, finding and treating more patients in existing markets.

We are pleased with the progress we've made in a short amount of time. Both medicines delivered strong revenue in the quarter. GALAFOLD was $152 million, 10% higher than the $138 million Amicus reported for the third quarter of 2025. POMBILITI and OPFOLDA revenue was $49 million, 58% higher than the $31 million Amicus reported for the same period last year. The number of patients treated with GALAFOLD increased by approximately 13% year-over-year, with growth across both established and newer markets. For example, in the quarter, 1 international market increased patients on therapy by 20% year-over-year, reflecting the ongoing success of Family Cascades testing initiatives bolstered by expanding newborn screening programs.

The number of patients on POMBILITI and OPFOLDA increased by approximately 69% year-over-year. Switching continues to be supported by its differentiated clinical profile as we help physicians better identify disease progression on prior therapies. The expanding body of clinical and real-world evidence reinforces that profile including the 5-year PROPEL extension data presented at the World Muscle Society Congress in October, which Greg will speak to in a moment. We are also seeing an increasing penetration in Europe, where POMBILITI and OPFOLDA is now the market share leader in terms of patients on therapy in 4 markets. This leadership reflects the growing confidence in the profile of POMBILITI and OPFOLDA.

In the third quarter, we also began supporting patients in certain European markets who are affected by recent supply constraints for other Pompe therapies. We have released additional supply so that patients who need it can get treatment without interruption. As a result, patients who switched to POMBILITI and OPFOLDA during the quarter due to supply constraints represented a meaningful share of new patient starts in these markets. We would expect to see some additional patients in the fourth quarter due to supply constraints for the other Pompe therapies, with the revenue benefit from this dynamic building in 2027 and beyond.

Now we can't predict how long the constraints for other Pompe therapies will last where if it will result in material revenue increases from POMBILITI and OPFOLDA, but reliable supply from BioMarin could become a factor in treatment choice. Now turning to Slide 8. Total metabolic conditions revenue was $744 million and grew 44% year-over-year, driven largely by the first full quarter of GALAFOLD and POMBILITI and OPFOLDA. The number of patients on therapy grew across every one of our marketed metabolic conditions brands. Moving to the other products and metabolic conditions. The quarter reflected continued patient demand, along with the order timing patterns we have consistently described. Reflecting Palynziq's distinct product profile, patients on therapy increased 9% year-over-year globally, led by the adolescent launch in the U.S., and we observed minimal switching to Beach for analogs.

In fact, we've been pleased that some patients who switched to oral therapies have returned to PALYNZIQ treatment. Revenue grew 2% as the U.S. order timing normalized after a strong second quarter. It can take many months for a patient to titrate to a maintenance dose so we expect the adolescent revenue contribution to build into 2027 and beyond. Vimizim grew 18% year-over-year, benefiting from orders outside of the U.S. while Naglazyme revenue was lower as expected, following order timing benefits in the second quarter. Because order timing shifts between quarters, our full year metabolic conditions guidance is the best indicator of expected underlying performance.

Turning to Slide 9. In the third quarter, VOXZOGO revenue grew 12% year-over-year to $245 million despite a large order previously expected in Q3 now anticipated in Q4. Patient demand outpaced revenue in Q3 as the number of children treated with VOXZOGO globally increased approximately 17%. More than 75% of revenue in the third quarter was generated outside of the U.S. and we expect this segment to be a leading area of expansion in achondroplasia. We are pleased to share that we recently received approval to treat children with achondroplasia in 3 additional international markets with VOXZOGO.

Briefly on the U.S. Children under 2 represented the majority of new patient starts in the quarter and approximately 85% of the U.S. children remained on VOXZOGO as of the end of September based on our switching data. We served that the pace of switching trended downward each month during the third quarter. When we survey families about why they stay on VOXZOGO, they say it's because they are confident and is working for their child and because daily dosing has become an established well-tolerated routine. Further confidence for families and treaters comes from the growing body of clinical and real-world data supporting VOXZOGO's long-term safety and efficacy profile as reflected in the data package we submitted for full approval.

Beginning in the fourth quarter, we plan to focus our updates on VOXZOGO revenue rather than providing U.S. switching metrics. As VOXZOGO market mix changes with the anticipated launch for hypochondroplasia next year, along with continued international expansion in achondroplasia, U.S. switch data becomes less relevant to VOXZOGO's overall revenue performance. leadership in achondroplasia sets the foundation for a potential launch of VOXZOGO in hypochondroplasia, where we estimate a global total addressable patient population of approximately 14,000 children.

Our launch preparation is focused on 3 things. First, we are sharing the evidence. The first full Phase III results published in the New England Journal of Medicine evidence and presented as a late-breaking oral at SP showed statistically significant improvements in growth velocity, height and arm spend. Second, our medical affairs team is increasing diagnosis and patient identification, helped by the first international consensus recommendations for diagnosing hypochondroplasia published this quarter and by disease education that has reached more than 1,200 pediatric endocrinologists and geneticists in the U.S.

And third, we're laying the foundation for rapid access, engaging payers early on the pivotal data and building on VOXZOGO's established coverage and real-world experience in contemplation. With the potential addition of hypochondroplasia, we remain confident in VOXZOGO's durability. More than 5,000 infants and children in 58 countries have been treated with VOXZOGO and its evidence base continues to expand. Together with the potential of BMN 333 should data be supportive, these opportunities underpin our ambition to remain the leader in skeletal conditions. With that, I'll turn the call over to Greg for an R&D update.

Thank you, Cristin. Turning to Slide 11. We are quite pleased to have 4 new assets under development, having leveraged externally sourced innovation to add multiple new programs to our pipeline this year. These additions span preclinical through Phase III development setting the stage for some exciting potential updates in the coming quarters. Today, I have the opportunity to provide more details and talk about our newest addition, BMN 450, a potential first subcutaneous enzyme replacement therapy for Fabry disease, having just announced the license agreement last week.

I'm also excited to share a little more detail on BMN 440, the first potential oral treatment for hypophosphatasia. And finally, I'll review the 5-year outcome data for POMBILITI and OPFOLDA that were presented at the World Muscle Society further underscoring the benefit of this therapy for those with late onset Pompe disease. Now moving to Slide 12 and BMN 450, which we are thrilled to add to our growing clinical pipeline. It is an investigational long-acting ERT for Fabry disease and is designed to extend the half-life and improve stability relative to currently available ERTs. Approved ERTs for Fabry are all administered by intravenous infusion and BMN 450 has the potential to be the first subcutaneous ERT in the space, giving patients and physicians an option to reduce the treatment burden.

Importantly, we believe BMN 450 also has the potential to be mutation agnostic and to address a broader patient population than that of GALAFOLD, which is indicated for the estimated 35% to 50% of patients with amenable mutations. We are encouraged that in preclinical studies, BMN 450 demonstrated differentiated efficacy across key measures, including renal function, vascular health and peripheral nerve system outcomes, which may offer potential for an improved therapeutic profile. It has received orphan drug designation from the FDA and is currently in Phase I/II testing.

Entering at Phase I/II is fortuitous as it allows us to shape the program moving forward, including the selection of dosing and patient populations. We bring deep experience developing and manufacturing ERTs and the regulatory pathways for ERTs in Fabry are well established. Following the ongoing study, we will assume sole responsibility for subsequent clinical development, manufacturing and commercialization outside of Korea. We look forward to updating you as the program progresses.

Now turning to Slide 13 and BMN 440, which we added in the third quarter through the Alesta acquisition. Because of the disease and the mechanism may be new to many of you, I want to spend a moment on each. Hypophosphatasia, or HPP is a rare genetic condition caused by mutation in the ALPL gene that codes for the enzyme tissue nonspecific alkaline phosphatase. When this enzyme is deficient, inorganic pyrophosphate or PPI, accumulates upstream and acts as a direct inhibitor of bone mineralization leading to fractures and exerting both direct and indirect effects on muscle leading to weakness.

PPI reduction is known to track with clinical benefits on bone health and mobility in patients. BMN 440 is a direct inhibitor of the ENPP1 enzyme directly upstream of PPI and thus can be thought of as a substrate reduction therapy for HPP. Preclinical data support this approach at ASBMR in October data from a mouse model of later onset HPP showed that oral treatment with BMN 440 reduced PPI and normalized the phosphate to PPI ratio. It also improved bone mineralization, muscle strength and mobility measures. The promise of this approach is to deliver an oral alternative to ERT therapy for pediatric and adult onset HPP with the added potential to better address systemic symptoms that bone selective ERTs cannot.

This is especially important because adult onset patients are often affected by muscle weakness, pain and fatigue, more so than bone problems. At ASBMR in October, a study with adult HPP patients demonstrated that the burden of this condition in adults extends beyond the skeleton to physical functioning, fatigue, sleep and pain. There are no approved therapies for adult onset HPP in the U.S. or Europe. BMN 440 is now in a Phase I/IIa study in healthy volunteers and adults with HPP. We expect data in 2027 that will characterize pharmacokinetics, pharmacodynamics and safety, establishing initial human proof of mechanism and informing dose selection and design for our next study.

Turning to Slide 14. At the World Muscle Society Congress in October, we presented 5-year data for the PROPEL open-label extension study in adults with late onset Pompe disease. This analysis followed 82 people who received POMBILITI and OPFOLDA continuously from the start of Propel. Most had received prior enzyme replacement therapy, having received it for an average of 7.6 years per year previous to enrollment. Over 5 years on POMBILITI and OPFOLDA, motor function was maintained and pulmonary function remained relatively stable. In ERT-experienced patients, 6-minute walk distance was maintained while in the ERT-naive patients, it actually improved over time.

Reductions in creatine kinase, a marker of muscle damage or sustained for the duration and there were no new safety signals. These data support durable outcomes through 5 years in patients who had already been treated and add to the growing body of evidence supporting the rationale of switching to POMBILITI and OPFOLDA. Sustaining motor function and limiting pulmonary decline for 5 years in a progressive disease like late onset Pompe is quite clinically meaningful. As a reminder, POMBILITI and OPFOLDA is indicated in the U.S. for adults who are not improving on their current ERT therapy. So long-term results in this population are especially relevant. With that, I will turn the call over to Brian. Brian?

Thank you, Greg. Please refer to today's press release for detailed third quarter 2026 results, including reconciliations of GAAP to non-GAAP financial measures as well as our upcoming Form 10-Q. As Alexander and Cristin have already covered the key revenue details for Q3, I will cover the financial impact of our 2 recent business development transactions, some revenue timing and geopolitical dynamics that we are observing and the expected associated earnings per share impacts in 2026.

Turning to Slide 16. We were pleased that third quarter revenue exceeded $1 billion, a first for BioMarin. Also on revenue, beginning this quarter, royalty and other revenues include amounts earned from Ascendis under the global settlement that we announced in August. Third quarter results include the Alesta acquisition, which closed on August 31, and drove approximately $290 million of pretax expenses or approximately $1.48 per share on a pretax basis, mostly related to acquired in-process research and development or IP R&D. The impact of the Alesta charges on pretax income for Q3 and the full year results in a timing-related tax element between Q3 and Q4. As a result, Q3 includes a $0.24 earnings per share tax benefit that will normalize in Q4 and net to 0 for the full year.

We continue to expect the acquisition to reduce full year non-GAAP diluted earnings per share by approximately $1.55 as announced in our October Form 8-K. Non-GAAP diluted earnings per share during the quarter was $0.23, which reflects the IP R&D charges related to the Alesta acquisition. Also underlying results, revenue grew 32% year-over-year, while non-GAAP SG&A expense increased 12%. The non-GAAP SG&A increase primarily reflects the addition of Amicus, including the commercial teams that support GALAFOLD and POMBILITI and OPFOLDA.

Turning to Slide 17 and our updated full year 2026 guidance. We are updating our full year total revenue guidance range to between $3.8 billion and $3.9 billion. The driver of the change is order timing and not underlying patient demand. During the third quarter, a single international customer indicated they intend to defer multiple expected orders totaling approximately $70 million. Certain of these orders are already under contract for shipment, and we expect to fulfill the majority of the orders between late Q4 and Q1 2027. However, we cannot predict the exact timing. And while this type of order movement is normal for our large global business and one of the reasons that we don't guide quarterly the magnitude and timing uncertainty so close to year-end has led us to update full year guidance accordingly.

A second factor is the prolonged conflict in the Middle East. We have been managing through moderate disruption thus far in 2026. However, customer liquidity and customer cash flow disruption have increased over the last 2 months, we are sharing this dynamic today because on a full year basis, we are usually able to offset various headwinds and tailwinds in our business. However, with just 2 months to go in the year, there are less of those available. The expected order timing just discussed and the observed Middle East disruption are reflected in today's updated guidance. To be clear, this guidance change is not driven by patient demand in these markets and our updated guidance is based on timing of revenue between Q4 and next year.

The underlying business is performing strongly as underscored by third quarter results today. We're also updating non-GAAP diluted earnings per share guidance to a range of $2.80 to $3.10, reflecting the 2 business development transactions that were not included in our August guidance as well as the bottom line impact of today's updated revenue guidance. The Alesta acquisition reduces full year non-GAAP diluted earnings per share by approximately $1.55 and the BMN 450 license agreement reduces it by approximately $0.32. The Alesta impact reflects approximately $320 million of acquired IP R&D and ongoing operating expenses this year, including transaction and transition costs.

The BMN 450 impact reflects approximately $83 million of primarily upfront acquired IP R&D expense and ongoing operating expenses, which we expect to record in the fourth quarter. We recognize that the bridge from our Q2 to Q3 guidance is complex. Excluding the 2 recent business development deals and today's updated revenue guidance due to order timing, the midpoint of our updated earnings per share range is effectively unchanged from August, reflecting the delivery of our underlying business profitability goal. In summary, the third quarter reflected strong top line execution across a broader portfolio, and we continued investing in future value creation through the acquisition of new clinical assets.

At the same time, Amicus cost synergies are ahead of schedule, and we continue to expect approximately $220 million of non-GAAP cost synergies to be realized fully in 2028. Thank you for your attention. We will now open the call to your questions. Operator?

[Operator Instructions] Your first question is from the line of Jessica Fye with JPMorgan.

This is Adam on for Jess. I just wanted to ask, and sorry if I missed this, but the -- says you realize accelerated cost synergies in 3Q while maintaining the [ 229 ] target for 2028. Could you elaborate on that? And what should investors carry into the 2027 OpEx assumptions as we model that out?

Adam, this is Brian Mueller. Thanks for the question. And yes, you heard that accurately. We came out in the Q2 report in early August with our long-term views on the Amicus integration, we quantified the synergies and started to talk about the accretion of the deal in those metrics were partially dilutive post-acquisition here in 2026. Substantial accretion beginning next year in 2027 and then growing to full synergy realization in 2028. The integration is going really well. We're executing really proud of both the BioMarin and Amicus teams and now we're one team. And the cost synergies are ahead of schedule.

So we're not updating or quantifying any additional metrics at this time. We'll talk more about the '27 accretion when we guide to '27. But we can say that the cost synergies are ahead of schedule. We initially said that within the first calendar year post closing, the deal would be accretive. We can now pull that forward and be confident that the deal is accretive actually within 9 months. and still a quarter to go here, but I'll also share that we're currently tracking to even calendar year accretion in '26.

Your next question is from the line of Sean Laaman with Morgan Stanley.

The patient growth was around 69%, but you've acknowledged that uptake benefited from the competitor supply constraint. Alexander, can you quantify the underlying growth, excluding that disruption? And I might have missed it. And how many of those starts are likely to remain durable once competitor supply normalizes.

Thanks very much, Sean. I'm going to hand it over to Cristin.

Thanks much, Sean, for the question. This is Cristin. Yes, as you noted, the performance in the third quarter for POM OP was indeed strong. revenue up 58% and patients up 69% year-over-year relative to what Amicus reported in the same quarter. And I think what's really important to note on POM OP is that the switching really is based on the clinical profile of the medicine. Now we're watching this growing body of clinical and real-world evidence saw in the prepared remarks, the PROPEL extension study that Greg spoke to, which I think has been a really important momentum builder for us.

But as noted, we have also seen what we call a meaningful share of new patient starts based on the supply shortage we're hearing from other Pompe therapies. Now it's -- this is happening in certain European markets. We aren't sure how long this will last or the depth of the problem. But what we've done is worked really hard to ensure that we have additional supply so that we can not only support our patients that are on POMBILITI and OPFOLDA and not fold up, but importantly, any new patients that want to come on as a result of these shortages. So we really do think that this is an important moment for POMBILITI and OPFOLDA.

We're building great momentum, and it's just the beginning of some of the initiatives we put in place. I do want to note, however, that revenue growth will lag as we had many of these new starts in the quarter. So we will see that revenue build more into 2027 and beyond. But it's an exciting time for POMBILITI and OPFOLDA, and we're excited to carry with this momentum.

Your next question is from the line of Eliana Merle with Barclays.

Just on the achondroplasia base, something we've been hearing about recently. I guess, 1 of the more outspoken competitors in the space is just around the safety I've inhibiting FGFR2 in the developing brand and potential implications of that. I guess do you have any thought on the debate here and how this could play out commercially even just from a perception perspective. And then just second quick follow-up. For BMN 440, an interesting opportunity there, could you elaborate what would constitute proof of concept at the data next year.

This is Greg Friberg. I'll take a stab at both of those. Yes. With regard to -- I think the comment you made about FGFR2 inhibition in the brain. My ops are much more philosophical, which is direct development is hard. I think that when we are looking at small versus large molecules, they have their risks, they have their opportunities, they have their challenges. But really, this issue of whether or not a small molecule crossing the blood-brain barrier leads to any sort of untoward side effects. These are hypothetical at this point. I would just comment that the FDA has established guidance on how they look at this. They take structured processes, they evaluate the risk benefit of these drugs very carefully.

And we know that, that's incredibly important, particularly in children who are going to be on these treatment for multiple years. At the end of the day, Clinical data is the antidote to all of these potential concerns and really -- from that standpoint, we're quite proud of the data package that we have with VOXZOGO. We've got, as Cristin commented on, over 5,000 patients, 10,000 patient years, 50 countries, we know that the benefit risk profile is one that we can stand behind. It's one of the -- we like to say it's the best-in-class evidence package. That, of course, has given us the opportunity to put forward the full approval data package that has additional information that will be ruled on by the FDA with the February 28 PDUFA date.

I really can't speculate beyond that how the FDA will view this. But certainly, the idea of a chronic safety and efficacy package that we bring with VOXZOGO, we see that as a winning argument that we will be putting forward and continuing to publish on for patients and physicians.

With regard to your second question, 440 and the proof-of-concept data, we have an ongoing Phase I/II study right now. As a quick reminder, this is a single dose and a multidose study rolled together. It's in both healthy volunteers as well as the subset of HPP patients. And the data that we will have to present publicly next year will include both PK as well as what we're calling proof of mechanism data. So this is data. Again, looking at enzymatic activity and biomarker activity what will come thereafter once we've been able to select doses and schedules, will be a Phase II study that will look at harder clinical end points. More to come, but we're really excited about this opportunity.

As a quick reminder, as a small molecule, a substrate reduction therapy for HPP, the promise and the opportunity here isn't just that we have a more convenient therapy, but potentially one that also reaches compartments like the muscle and the bone that can affect in particularly the adults, the kind of side effects that are -- and adverse events from their disease that are really burdening them the most. That is muscle pain and limitations of mobility that again, some of the more bone targeting large molecules may not be able to.

Your next question is from the line of Cory Kasimov with Evercore ISI.

This is Adi on for Cory. We noticed the January PDUFA for pump in adolescent -- is that opportunity already included in your $1.2 billion peak sales outlook? Or would it be upside? And also more broadly, now that you've had more time to the acquired business, where else do you see the biggest opportunity to bring more Fabry and Pompe patients onto treatment beyond switching from existing therapies? .

So we do believe that there's a lot of opportunity here to continue to -- and did you ask specifically about POM OP or also GALAFOLD? Sorry, just so that I'm clear on the question, POM OP specifically.

Yes. For both of them. For POM OP, we noticed that SMD has already filed. So on both.

Yes. So we believe that opportunity is relatively small in the scheme of things. But we believe that the overall opportunity on POMBILITI and OPFOLDA is quite a bit bigger. In so much, as I just mentioned in the previous comments, we really are seeing momentum build for this therapy, not only is it the evidence that we're seeing but also importantly, just the experience. So where we see the opportunities where we can really help build this is certainly to share the real-world evidence as we generate it. Certainly, the adolescent is a catalyst opportunity, I should say, for POMBILITI and OPFOLDA. But really, as we continue to expand this not only in the kind of in the indications that we have today, as we geographically expand this as well. So the real switching opportunities here are to make sure that the data continue to be generated and that we educate on that meaningful data that we importantly empower both physicians and patients to understand when their current treatment might be waning or they might be -- they are doing as well on the treatment that they're on.

And so that they're advocating on their own behalf to ensure that they get that switch to happen. And then as I've mentioned, I think that this geographic expansion, given that POMBILITI and OPFOLDA is still in its early days, it's important that we continue to build momentum in countries not only where we are today, but importantly, in the countries we aren't yet. And so our regulatory team, our commercial teams in the field are preparing for this, which will help to build that growth into the future.

Your next question is from the line of Paul Matteis with Stifel.

I appreciate it. I wanted to ask a couple on BMN 333 data next year. Understanding that your thesis here is that you could show clinical superiority I was wondering what would be an outcome next year that would definitively derisk that profile and make you confident in going that path for a pivotal study. And then maybe just as a second question to that, let's say, this drug does show good clinical activity, but maybe the question around power for superiority looks a little bit riskier. Would you still forge ahead with maybe some sort of noninferiority or -- path?

Thanks, Paul, this is Greg. I'll tackle that one for you. With regard to the 333 study that's ongoing, just as a reminder for folks, we are running the Phase II portion of our combined Phase II/III program, which is looking at a variety of doses. In this case, it's 3 doses of 333. And looking at the AGV at 6 months, or greater and trying to determine how that compares to the control arm of VOXZOGO. That not only will be studied within the protocol, but also will be supplemented by a wealth of historic data again that we have at our disposal. .

Now again, it's not a question of whether a dose response exists, but it really is a question of the shape of that curve. We know that those 3 doses are going to give us significantly increased AUC exposures of free CNP and will allow us to test the hypothesis. So we have a basin model that's in place that will determine a posterior probability not only of those 3 doses, but really looking at it with regard to exposure response as well. And while we're not releasing what the math behind that model is we feel that, again, if we meet those criteria, we will have a good degree of confidence that moving forward with a superiority study, testing the winter dose against VOXZOGO is a very good bet.

That being -- as I said, again, what we know so far is, of course, that we've been able to get not only PK but increases in PD as well with the cyclic GMP. And we're quite confident, again, that we have the right molecule, and we're running the right study. just for posterity sake, since you're asking the question, should it not be achieved? Our Phase III study also will provide an opportunity to consider alternative hypotheses like noninferiority or less frequent dosing, and that would not materially slow down our development time lines. That's not our hypothesis. We think that we have the right study and the right molecule. We're looking forward to turn over the cards to that initial dose ranging study sometime next year.

So Greg, just to clarify, next year's readout is not really a growth velocity readout. It's more of a PK/PD readout. Is that right?

It is a growth velocity readout. In this case, the PD is AGV. It's 6 months or greater data.

Please clarify, Paul. Yes, I was going to say it's AGV indeed. So the PD is AGV. Technically, that's an intermediate endpoint and final is all type, which we're thrilled to again have for VOXZOGO would be the primary endpoint for full approval. But when I mentioned PK/PD, I meant exposure response with regard to AGV.

Your next question is from the line of Alex Hammond with Wolfe Research.

So since the fold acquisition, you've added BMN 440 as well as 450 both early-stage clinical assets -- is that now the template? Or would you use that $4 billion to $5 billion of firepower you expect in mid-2027 on other commercial or late-stage deal? I guess, after these deals, what gaps remain in your pipeline? .

Alex, thanks very much for your question. Yes, we're -- as you can tell, we're very excited about the deals we've done and to add 4 assets to our pipeline in 2026 so far. We continue to remain focused on clinical stage deals at the moment. So programs that fit with our capabilities around genetics, around regulatory expertise around manufacturing, around commercialization. Particularly, as you can tell, interested in assets that fit with our business units, skeletal conditions and metabolic conditions. But we're interested also in other genetic conditions, but clinical stage assets, absolutely. And we do -- as Brian said, we're -- the accretion has been very impressive, the implementation of the Amicus acquisition and our fire power is increasing. So we -- we will continue to do these clinical stage deals for the foreseeable future.

Your next question is from the line of Philip Nadeau with TD Cowen.

This is Rishi on for Phil. Really great progress. Two questions for me. First is -- so UV well was given a positive opinion from the CHMP of the EMA last month. So with the possible launch in Europe, or approval in Europe coming up. How do you anticipate this to play into the competitive dynamics with VOXZOGO as quantitatively as possible? And then my second question is you previously -- moving on to hypochondroplasia. You've previously given metrics on your efforts to increase diagnosis rates and age of -- and reduced age of diagnosis saying 90% increase in diagnosis rates, 70% reduction in the age of diagnosis. Just do you have any updates on those metrics now?

Thanks for the question, Rishi. So I'll take those. So -- in Europe, I can say that we are very much anticipating the launch there, have that into our plans. Our competitive readiness, of course, assumes that. We've not given guidance for the next year. And so at next point-- sorry, in the next year, we'll be able to provide more color on that, but I will say that we are ready for it, have it in our baseline plans and are looking forward to seeing what that looks like. Now on the second one on the HCH metrics, what we have shared is the real focus areas as we're nearing the launch. As you know, the PDUFA is coming in May in the U.S.

And we're really focused on right now sharing the Phase III data making sure that we're increasing diagnosis and then ensuring rapid access, so having the right conversations with payers. Now with regard to the specific metrics that you've asked for, we don't have an update on those today. But I will say that as we get closer to the launch timing, we very much will be sharing more on our plans and specifically the metrics that we'll be tracking and sharing as we move forward. So very excited about that as next year.

Your next question is from the line of Joon Lee with UBS.

The DMS 333 has a bit of a moving target as we're expecting longer follow-up data from the combination of people growth hormone and by year-end. What would you be most focused on? And how would you position 333 vis-a-vis the competition?

Thanks, Joon. This is Greg. Maybe I'll take a stab at that. Really, our thoughts with regard to the growth hormone combination are consistent with what we've been communicating in the last few quarters. I think the question is not whether adding growth hormone to an achondroplasia patients regimen would result in a spurt of additional growth. The question is whether or not that would be, number one, safe, of course, number two, whether or not it would be persistent, whether or not, again, that would be an increase that would continue over time. .

And of course, the larger question, which gets back to the root of why growth hormone is not typically used in achondroplasia patients to begin with is whether or not the final adult hide of these patients will be impacted. The concern, of course, is that growth plates may close prematurely over time. These are hypothetical risks, but it highlights the fact that additional data is needed. Now when you slice and dice the data every 3 to 6 months, it's hard to get a look at that. That being said, again, the last look at the data did suggest that perhaps those effects were starting to wane with the addition of growth hormone to CNP, our feeling 333 is that having a single agent, again, one that for remember, patients who are not growth hormone deficient, a single agent that gives you similar results would be preferable.

That is also consistent with the thesis of what we think that 333 can deliver. Again, higher levels of CNP, we're looking to optimize and have the best-in-class CNP that if there were a future state where combinations were available, you'd always want to combine with the best CNP anyways.

Your next question is from the line of Olivia Brayer with Cantor Fitzgerald.

Brian, on the updated revenue guidance, can you maybe just help us better understand what's happening with that single customers' ordering patterns not sure whether you're able to disclose which country it is. But do you still expect growth from VOXZOGO in 2027, no matter how that order timing actually shakes out, whether it be in late 4Q versus the early 1Q of 2027 time frame that you mentioned? And then on hypochondroplasia, congrats on the PDUFA. So assuming a summer launch, anything you guys can say at this point about how quickly you expect that to meaningfully contribute to Box over sales? And is that something that you think you'll be ready to quantify come January?

Thanks, Olivia, it's Brian. I'll start with your first question, and then I'll let Cristin comment on -- so first, for those of you that know the company well, quarterly order timing dynamics in our business is very common, something that we regularly manage through. We've got this diverse global business. 2/3 of it is outside of the United States. That international business is largely single payer national health care systems that tend to order large quantities on an inconsistent basis. But they roll up to this robust business that we have. And over the course of any given year, again, these dynamics are something that we consistently manage through. There are usually puts and takes over the course of the year, and we'll comment on those at the quarters and perhaps adjust expectations as necessary.

However, at this point in time, with this single customer that flagged their intention to defer these handful of orders that totaled $70 million for the fourth quarter. It was just large enough and uncertain enough for us to recognize the uncertainty in today's guidance update. But very important, as I mentioned a few moments ago, it's not tied to patient interest in the therapy. It's entirely timing. Some of the orders are contracted for shipment. It's just that the contract runs into January in that instance. So just timing before Q4 and Q1 and for the lack of offsets here. So we just wanted to share the update and take a measured approach here.

And Olivia, with regard to your second question about hypochondroplasia. So yes, very excited about this as we near into next year. And specifically, the team working on diagnosis and patient identification. Our medical affairs teams are out there now we're educating on the Phase III data that we have. We're educating on the condition itself. And what we're really working on, both in our customer interactions, but also using different sources of data and being able to switch some of that data together because we have more access to data in the U.S. We are working on identifying patients and offices and finding out where they actually are. So what we will do as we near the launch and we gear up for it early in next year, we will be sharing more about specifically what our expectations are around that and how we feel like we'll be able to deliver on it and report out on it as we move forward.

Okay. That's helpful. Can you guys actually comment on whether you expect VOXZOGO to grow in 2027? Or is it too early given the dynamics with the ordering patterns?

Yes. Thanks for the reminder, there Olivia. We do expect VOXZOGO to continue to grow in 2027. And there is an element which includes the hypo and launch offsetting some of the potential loss of share to current and additional potential competitors. But just a reminder that more 75% of the VOXZOGO business is outside of the U.S. continuing to launch in new markets. We're continuing to deeply penetrate some of those international markets. We will remain the only achondroplasia therapy with a label for patients, children under 2 years old. And that exclusivity over what we believe is at least the next couple of years with the importance of starting therapy is early for birth for the international treatment guidelines, that sets up this potential switch market. And so we've got a number of growth drivers and plan to continue to invest and grow VOXZOGO.

Your next question is from the line of Chris Raymond with Raymond James.

I wanted to maybe ask a similar question. The last one was asked maybe a little bit more explicitly. So Brian, I heard you say that there was a $70 million order from Q3 that got shifted. Full year '26 guidance was lower by $25 million. So the math, I guess, is it as simple as saying so Q4 should benefit by $45 million and I know you guys don't guide to '27 yet, but should we also then think then there's an additional benefit of $25 million in Q1 '27, just given the shift and you mentioned that it spans both Q4 and Q1 of next year.

And then maybe a follow-up to that question is on 333. Just hearing what you're saying about the option maybe to size the Phase III portion to look at non-inferiority what kinds of unmet needs are you thinking about addressing under that scenario if you have a Phase II data set that maybe points to noninferiority as the right way to go for 333.

Chris, this is Brian. I'll start. So first, just to clarify 1 element because I think you touched on some of the Q3 to Q4 dynamics as well. Just to be clear, Cristin mentioned an order that shifted from Q3 into Q4. That was, again, a single large international customer. And that order actually was VOXZOGO. So that's part of the VOXZOGO being a little less than expectations this quarter. That's again, a single order, but that one is planned for Q4. And it's different and not included in the $70 million that I referenced. That is another batch of orders that was previously expected in Q4, where the customer has now flagged that they may take delivery of those in Q1 or early '27. In the latter, the $70 million is the driver for today's guidance update. We took a risk-adjusted approach. We still have a chance to deliver some of these orders. So that's the lowering of the midpoint. But separate from that first item in Q3, hopefully, that helps. .

Yes, I just want to make sure I understand. So lowering VOXZOGO by $25 million for the full year. The assumption is that some of that will spill over into Q1. Is that correct? Can you just clarify?

Through this lowering of guidance, which allows and recognizes the uncertainty through some of the Q4 slippage, if you will. And by the way, a little more than half of that $70 million is VOXZOGO in this market. So yes, if those slip into about Q4 into Q1, they would benefit Q1 or early '27. But we'll talk more about '27 when we guide to '27 in these types of markets. If there's a -- if there's a timing deferral of a quarter, that could play forward into the next year where follow-on orders get delayed. So we're still building up the revenue plan for '27.

And Chris, this is Greg again. With regard to your 333 question, I think your question behind the question, of course, is what is the compelling value argument that we bring with 333 to the table. And we firmly believe that the superiority argument, the pharmacodynamics that we can bring forward, give us a chance again to demonstrate that there is more growth to be had and more pull-through to markers of health and wellness with a molecule like 333. Out of an abundance of politeness since I think it's 4 consecutive earnings calls that I've gotten a question about the noninferiority. I answered it. again, for directness stake, but we would believe that we would need to add something beyond simple convenience to make a value argument for what society would value from 333. .

Your next question is from the line of Joe Schwartz.

I have a couple of questions on 333. With only about 10 kids per arm in Phase II, what growth advantage over VOXZOGO would convince you that it's real. And how does the model you've used to power Phase III address the potential for growth velocity to plateau if it doesn't increase commensurate with the CGMP increases you've seen at some point over the curve.

Thanks, Joe. Let me answer the question this way. We believe that the size of the study that we put in place and the models that we're using, again, we'll be looking at AGV for the individual cohorts, but we will also have the ability to match that to exposure analysis that we're going to have more than enough statistical power based on our model to have comfort moving forward to Phase III. You had a second part of the question as well, though. Can you remind me?

Yes. I guess what it's getting at is that other CNPs have not seen growth move up in line with the G&P increases that have been seen because there's been a plateau. And I know that you're hoping that exposure plus more activity at the receptor might be able to move beyond that. But I'm just wondering how, if at all, the Phase III powering is planning for that potential to play out?

So the Phase II is powered off an effect size. Again, as I was mentioning, the Phase II will give us confidence that, yes, we have a dose that can reach it. And just to take a step back, the big question isn't whether there's a dose response relationship to increasing levels of free CNP. It's really about the shape of the curve where and if a plateau occurs, and of course, whether you can push your way up that curve. I think the direct answer to your question is we've picked 3 doses that give us sufficient increases in AUC for free CNP.

That's roughly 3x, 5x, 7x. That's again, probably a conservative estimate in terms of free CNP. These are doses that have not been tested in humans to this point. So again, that kind of spread of exposure, we do believe that we will definitively ask the question appropriately with this study that we've got the right reagent in 333 that can test that. Beyond that, I'm not going to get ahead of the data. We do think that, that data though will be incredibly informative and will help us identify whether that hypothesis holds true.

This concludes the Q&A portion of our call. I will now turn the call back to Alexander Hardy for closing remarks. Thank you.

Thank you, operator. We delivered another standout quarter with 32% top line growth and the first quarter in our history in which total revenue surpassed $1 billion. Our focused and deliberate expansion of BioMarin's clinical stage pipeline is delivering results with 4 new programs added in the last 12 months and spanning preclinical through Phase III development. We expect our leadership in skeletal conditions to support a strong launch of VOXZOGO for hypochondroplasia following its potential approval next May, which should mark BioMarin's seventh force disease medicine. As you look ahead with enthusiasm, we advance a next wave of therapies from our clinical stage pipeline, prepared to report on a number of key updates in 2027. .

Combined with the strength of our more diversified commercial portfolio, we're confident in our ability to create lasting value for patients and all of our stakeholders. Thank you for your continued support and look forward to keeping you updated on our progress.

This concludes today's call. Thank you for attending. You may now disconnect.

Good morning, everyone. I'm Sean Laaman, Head of U.S. SMID-cap biotech Equity Research here at Morgan Stanley, and welcome to our Global Healthcare Conference. Before we begin, I'll make you aware of some important disclosures. For those disclosures, see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. And if you have any questions, please reach out to your Morgan Stanley sales representative.

I welcome here today, President and CEO, Alexander Hardy; and EVP and CFO, Brian Mueller. Welcome to both of you. Alexander, I believe you wanted to make some introductory remarks before we kick off the formal Q&A part of the session. But thank you for your time today.

Thanks very much, Sean. Thanks very much for having us. Thanks to Morgan Stanley for hosting this. Yes, I just want to say a few things. We mainly want to hear the questions that you have and folks in the room. I'm very, very happy with our execution and how we're delivering over the last several quarters. To be able to perform strongly with the delivery of the business, at the same time, integrate a major acquisition simultaneously is really exciting, and it's a testament to the organization.

I think with the Amicus integration, we've added two additional significant growth drivers, further strengthening the growth profile of the business. We're showing that BioMarin is a rare disease company at scale. We've delivered, obviously, efficiency in profit and growth in profit margins. Now with Amicus, that translates to additional cash flow. We have this capability across all of the parts of our enterprise from research, development, manufacturing to commercialization when it comes to rare disease. And we have the balance sheet to act on that.

So even as we're integrating Amicus, we also just, obviously announced and closed an additional deal to bring in Alesta, ALE1, into our pipeline. We're really excited about that. So we're going to continue doing these sorts of deals of strengthening our pipeline, all positioned towards growth in the long run, leveraging our capabilities. And it's really an exciting time at BioMarin.

Sure. Great intro. I have a few questions on the Amicus deal. So just the core strategy behind it. Was it taking two assets that you think you could grow a lot more strongly? Is it synergies? Is it dilution of what exposure you think you might have on the changing competitive dynamic in VOXZOGO?

It's really all, but it's mainly the first two. I would say that the diversification of our growth was a sort of secondary benefit. It's not something that we were -- that was not our primary objective. We believe in VOXZOGO's growth with the pending hypochondroplasia approval, should the FDA approve it. We think that that's in good shape, and we're continuing to look at the second quarter, even with a competitor now in the market in the U.S., for a second quarter, we grew at obviously 20% in terms of patient growth.

But we really felt that Amicus was both value creating on the top line and on the bottom line. And I think you can see from our second quarter update that we're starting to realize that, projecting a $1.2 billion peak for POM-OPF and $1.4 billion peak for GALAFOLD in our hands. That's more than our geographic -- additional geographic footprint. It's the depth of our capabilities across those geographies. We really like what we saw as we got into the due diligence and the integration planning. And then on top of it, as a rare disease company operating at scale, the synergies on the bottom line, $200 million of non-GAAP expense savings.

So it does all of those three things. But I think the very cool thing is particularly on that top line, you don't see that many deals which offer a higher peak and a faster ramp. And I think you can be confident that BioMarin's capabilities, we can realize those additional revenue.

Sure. Yes. And I guess that some of the story that might be missed so far is just what we see on the bottom line and the compounding earnings that are going on in the background. And so just your confidence around achieving those savings from the acquisition? And how much of it is due to overlap? How much is just genuine better operations? And then how does that walk down to -- you've brought forward your leverage targets, like how that translates to balance sheet leverage and maybe being able to flex again on the BD side?

Excellent. I'll start off and hand over to you, Brian. So with regard to the synergies, I think you can feel also very confident around those. I mean, as you know, biotech P&L from an expense standpoint is very much on the head count -- disproportionate head count. And we made very quickly -- I was very impressed with the execution of the organization in terms of the integration planning and then implementation. We very quickly communicated to all Amicus employees, the future employment status. So there are about 505 Amicus employees. We're retaining in the long run about 192 of those. So therefore, those decisions are made, and those savings will be realized.

We -- so who are the 192 retained? Obviously, as we talked about, a very important part of this deal thesis is synergistic on the top line. So we wanted to maintain and then add to that growth rate on the revenue line for GALAFOLD and POM-OPF. So we primarily retained the commercial and the medical affairs team, so the customer-facing teams. And in fact, we'll be -- and we are investing even more in driving the growth of GALAFOLD and POM-OPF.

The bulk of the savings on the other hand, were on the G&A side, about 70% savings in G&A. And then the remainder was in R&D, where there are duplicate R&D functions. And maybe hand over to Brian for the next part.

Yes. Thanks, Alexander. Thanks for the question, Sean, and thanks for having us. So first, it was very important given the strong strategic rationale for the transaction that we developed an integration plan to fully realize the potential value from the transaction. And Alexander has already touched on some of those revenue and then the OpEx synergies.

So to be clear, as Alexander touched on, these are not high-level plans. We're executing in terms of the employees that we'll be retaining or not. Those folks have been notified at the operational level, whether -- process by process and department by department, we've got operational cutover plans.

The integration itself will take some time through this year, even into next year because some of the relevant systems and processes that we're cutting over are qualified and regulated, and that takes some time. That's why we point to 2028 as the first full year of realizing all of the synergies because again, most of the synergies will be realized in '27. In terms of '26 here in the third quarter, it's still mostly a full quarter of Amicus operating expenses, but we'll start to realize some of the synergies in the fourth quarter.

And then to your point about what it means, so we do believe the deal will be accretive within its first year with substantial accretion beginning next year and then growing when we get to that first full year of synergy realization in 2028. But the level of operating margin accretion, substantial cash flow generation, that's what enabled us to pull forward that deleveraging target by almost a year. When we announced the transaction in December of last year, we said we'd target less than 2.5x leverage within 2 years of the transaction. Now that's middle of next year. That will replenish pre-Amicus deal firepower for BioMarin, which will allow us to continue our cycle of investing in innovation. And then again, EPS, cash flow margin growth from there is substantial.

Sure.

So by the middle of next year then by -- just to be -- put a point on it, by the middle of '27, we'll have the same level of firepower as we had prior to the Amicus acquisition. So the ability to do up to a $5 billion acquisition. So we're continuing -- and we have, obviously, the firepower, we're doing deals right now. So we will continue to do deals. We obviously just did the Alesta deal, bringing ALE1 to our pipeline. So you can see us continuing to do deals even as we delever.

Sure. Sure. I guess when you get to 2028 and you look at the balance sheet position, wherever it may land and the integration is largely complete and given the scale of the business, how would you characterize the balance sheet capacity at that point versus pre-Amicus?

By the time we get to '28, yes, great question. So when we say by middle of next year and getting to this current deleverage target and pre-Amicus deal firepower, that's in the $4 billion to $5 billion range. So I think by the time we get to 2028, with the continued growth in the EBITDA profile, I think it would be another click up from there. So it could be approximately $6 billion.

Sure. Sure. Got you. So it seems that integration progressing well, got a good handle around the cost side and then you put out targets for -- or guidance for POM-OPF and GALAFOLD over the long term. So maybe just to take investors on -- or give investors a bit of granularity around your confidence levels on achieving those GALAFOLD and POM-OPF targets. We've talked a bit about the patient identification I've talked about the geographic expansion. Just some of those elements to give us confidence on the $2.6 billion, I think is the total, yes.

Yes. Total is about $2.6 billion, you're right, by the mid-2030s. So $1.4 billion for GALAFOLD, $1.2 billion for POM-OPF. GALAFOLD represents the single largest absolute opportunity, $1.4 billion. There is -- primarily, we believe, geographic expansion is part of it, but the larger opportunity is increasing the diagnosis rate in Fabry's disease. There's a lot of patients who are not diagnosed, quite a few patients that are diagnosed but not treated. But this is where leveraging our capabilities that we built up over 25 years. We've done this time and time again. This is where these assets and these medicines are worth more in our hands than -- because we have these capabilities, further leveraged by the way, by, obviously, AI and advanced analytics allows you to do a better and better job of finding patients.

So that's primarily on the GALAFOLD side. I mean, that being said, about 40% of revenue for GALAFOLD and POM-OPF is in the United States. There's a lot of opportunity to further grow GALAFOLD in the United States. We think by the mid-2030s, we can more than double the number of patients in the United States on GALAFOLD.

With POM-OPF, it's primarily more about switching. We think that the evidence and the real-world data coming through with regard to POM-OPF really shows the benefits that POM-OPF can show as efficacy wanes with the other treatments for Pompe disease. So that's primarily a switch market. That's longer and slower, and that's also why the peak is a little lower than GALAFOLD.

So we think that these are both realistic long-term objectives that we're aiming for. There are actually scenarios where we can do better than $1.4 billion, $1.2 billion if we can significantly -- if we can start to impact, for example, the top -- very top of the funnel. But we're going to hold that and keep people updated as we go forward about our efforts there. There's nobody better than BioMarin to be able to do that because of our genetics capability, but we don't want to get ahead of ourselves. $1.4 billion, $1.2 billion is, I think, good estimates right now for the peak sales potential.

Great. Maybe just moving on to the competitive dynamic in VOXZOGO. So you reported really strong growth in Q2 and you upgraded guidance, which I think surprised many for the full year, which must say that you've got a good deal of confidence around the evolving competitive dynamic and the launch of competitive products. So just to gauge your confidence around that and what you expect over the long term. And I'll leave it there, and I've got more, but yes.

Yes, I'm sure you do. I'm sure you do. Yes, I mean we're really pleased. I've already mentioned it. We're really pleased with the growth rate that we're seeing with VOXZOGO. As you know, the majority of patient starts that we've already been realizing has been the 0 to 2 population. And this is where we have an indication advantage and a data advantage, which will remain BioMarin's exclusive indication for the next several years. So we're seeing a lot of patient starts there.

And with regard to switching, that switching dialogue is very much the way that I thought it would go with caregivers and physicians. This is really a segment of the patient population where the caregiver is interested in convenience. But we're still seeing just tremendous growth, 20% growth in the quarter with VOXZOGO.

And now, of course, and I'm sure you're going to touch on this. And now we, of course, have this settlement with Ascendis with a 20% royalty rate in the United States and 18% in Europe, Brazil and South Korea. This means that we're benefiting from TransCon, from their results in potentially adding new patients, patients that perhaps wouldn't have come on VOXZOGO will have that revenue opportunity. And then, of course, we have the pending indication approval with hypochondroplasia, which is not factoring in, obviously, into our '26 outlook. But hopefully, at the beginning of next year, we'll have that additional growth lever for VOXZOGO going forward.

So yes, it's exciting to see. It's all but one of our blockbuster potential products that we -- this guidance will mean that we hit $1 billion this year for VOXZOGO. So it will be BioMarin's first blockbuster product.

Sure. And on the hypochondroplasia opportunity, just sort of your commercial prep and your commercial readiness. So if you did see an adverse impact on the achondroplasia portion of the business, if you did see it, just your ability to offset that through the uptake in hypochondroplasia and your thoughts around that?

Well, we think the growth in the achondroplasia market, we're seeing the 0 to 2 growth and our ability to retain patients plus the hypochondroplasia and the growth opportunity there means that VOXZOGO is set to continue to grow through these competitive launches, which is an exciting picture. I mean we're in 55 countries with VOXZOGO. It takes a while for a competitor to be able to match that. Obviously, 5 years head start, additional head start when it comes to the infant population. So the growth continues, and we're excited about that profile.

Sure. And I guess roughly 3/4 of revenue comes from outside the U.S. for VOXZOGO. So do you think differently about the competitive dynamic and how that might unfold in Europe? And do you think it's more challenging for a new entrant in terms of market access in rest of world markets?

I mean market access in the rest of the world, I'm not telling anybody here, any news they don't know, is much more complicated. It's different, but it's more complicated with long lead times in the rest of the world and really require tremendous amounts of local expertise. In an 80-country footprint, as I said, we're in 55 countries with VOXZOGO. That level of local market access expertise, those are BioMarin personnel in the majority of those markets. And we believe that gives us a real competitive advantage. So there's -- I think there's a time lag but there's also an outcome difference that I think BioMarin will have an advantage there.

Sure. Switching gears over to the Enzyme franchise. So PALYNZIQ grew, I think, 27% to $135 million with the adolescent label approved in the U.S. How large is the 12- to 17-year-old opportunity?

Yes. I mean we've talked about the patient potential being about 10% additional with the adolescent indication. We are really pleased with how that launched. I was actually visiting treatment sites, PALYNZIQ clinics last -- or PKU clinics last week, and they're having a lot of success with the adolescent population.

It's exactly what we thought it would be. These are very motivated parents with kids that are thinking about the transition to college and into adult life. This is a great opportunity for them to have a very efficacious treatment and to be able to go to the college cafeteria and be in line for a hamburger and not to have medical nutrition. That's the potential you can have with PALYNZIQ, which is very, very differentiated. So very happy with the adolescent launch, and you can see that in the growth rate of PALYNZIQ.

Sure. Just on the VIMIZIM number, the underlying market trend there and where you think that product can ultimately go?

Yes. I think -- we think that VIMIZIM has the potential to also exceed $1 billion in revenue. This is what we think the potential of this product is. You look at it quarter-by-quarter and ordering patterns can mean, especially with our ex-U.S. footprint, you have a lot of government purchases. So it can be lumpy quarter-to-quarter.

I would say that we're very happy with the growth rate we're seeing with VIMIZIM. If you look on an annual basis, 2025 annual growth was 7% for VIMIZIM. And historically, it's been clicking along at around that rate. So it's growing extremely well, and we see no reason why that's going to slow down.

I would just add, we encourage everyone to look at our full year performance and full year guidance as the best performance indicator for the company because of those quarter-to-quarter, mostly international order timing dynamics.

Got you. A couple of pipeline questions. So BMN 333 produced more than 13-fold higher free CNP exposure than another long-acting agent. But why should that translate into better efficacy? And what growth velocity do you think is needed to establish it as best-in-class?

Yes. So we believe that higher free CNP levels will translate to higher efficacy. Clearly, we need to do the experiment, and that is what we're aiming to do. What we showed in the Phase I with healthy volunteers is we showed, as you mentioned, that we can achieve high free CNP levels, 13x the level of the currently approved long-acting CNP.

So now the experiment needs to be done, and that's what we're doing in the Phase II, Phase III operationally seamless study. We'll find out in the middle of the year where that translates to clinical efficacy to both higher levels of annualized growth velocity, together, most importantly, with other health benefits, and we'll be aiming to study that in the Phase III.

Why do we believe that's the case? Well, we think that our preclinical experiments have shown that high free CNP translates to higher growth. We think you can also see it in the real world with people with naturally high levels of free CNP are much taller. So we think there's a good reason to believe that the experiment needs to be done. And there's a great opportunity here. Whilst cross-trial comparisons are problematic, I think everybody would pretty much say that so far, nobody has shown better efficacy than VOXZOGO.

And so that opportunity now remains, and we're going head-to-head against our own drug. And I like that. I like that BioMarin is pushing the envelope and challenging ourselves to do more for these patients.

Another kind of pipeline question, but on the ALE1 acquisition, just the strategic rationale and the clinical opportunity, how do you see both of those?

I mean I'm really excited about this asset. So ALE1 is for hypophosphatasia or HPP. It's already a large validated market. You've got STRENSIQ, which I think last year sold $1.7 billion with AstraZeneca saying that this market size potential is $3 billion to $5 billion.

And this is a really differentiated molecule, and it's much more than a first-in-class oral treatment. Right now, HPP is very much focused. The treatment is very much focused on the bone manifestations of the disease. By having an oral therapy that reduces pyrophosphate at its source, we potentially can have a systemic effect, dealing with more of the things like muscle pain and fatigue, which is associated with the disease, particularly in the adult population. So pediatric onset but diagnosed in adulthood. There's a tremendous opportunity.

So this is a lot more exciting than an oral therapy competing against both subcutaneous and intravenous therapies. This could potentially be transformative. And we have also the opportunity here. It's about 6,000 patients diagnosed in the U.S., only about 10% to 30% of them actually treated. We think this, an oral treatment with this sort of profile, we should be able to not only increase that treatment rate, but then have the opportunity to significantly increase the diagnosis rate as well, which is exactly what we do in other disease areas.

Given the rise in China innovation, does that influence your BD or R&D strategy at all?

Yes. It's a topic in the leadership team and the Board. We have not yet seen China be particularly present when it comes to rare disease. As you know, the main focus hitherto has been oncology, I&I and cardiometabolism. But we're starting to see that the Chinese health care system focus more and more on rare diseases from both the reimbursement and from a diagnostic capability. Obviously, the numbers of patients and their ability to diagnose at scale is really intriguing as well as the source of innovation in the market.

So we're paying more of a closer attention on the BD side. We also think it's an exciting market for us to meet the needs of patients. And in the future, also from an R&D standpoint, although hitherto, we haven't done that much from an R&D standpoint there.

Wonderful. Thank you. Well, we're right at time. Is there anything that I didn't ask that I should have?

I don't think so. I think that was...

Yes, I think we covered...

I think we covered it all.

Well, thank you for your time, gentlemen. That was great.

Thank you, Sean.

All right. Thanks a lot.

Thanks, everyone.

All right, everyone. Well, welcome to day 2 of Citi's Back to School Biopharma Conference. I'm Eric Joseph, senior biotech analyst with the firm. And this session is with BioMarin, and I'm happy to be joined by Chief R&D Officer, Greg Friberg; and Chief Commercial Officer, Cristin Hubbard. Thank you both for joining us here.

Maybe just before we kind of dig into questions, it would be good to kind of have some high-level remarks from you both and just what some of the key priorities are at the company looking over the next 6, 12 months?

Great. Thank you, and thank you so much for having us, Eric. So just to take a step back, BioMarin, we're a leading global rare disease company and we're really focused in and around genetically defined conditions. And what we have now is 9 commercial therapies across how we're organized, which is in 2 business units, and that includes skeletal conditions and metabolic conditions.

Now we're a highly profitable company. We have strong revenue growth. And really, we're increasing cash flow, which is fueled in large part by the patient demand that we are creating across the 80-country footprint that we work in. Now we recently in our Q2 call announced that we've got 4 products that are tracking to blockbuster status, which we're excited about. And VOXZOGO is in the lead.

So at our full year 2026 guide, we had said that VOXZOGO, the range would be $1 billion to $1.05 billion. So that will be our first blockbuster product this year. And what also happened this year that we talked quite a bit about in the Q2 call was the closing of the Amicus acquisition. So what that did for us was it brought in 2 high-growth commercial products that is Galafold for Fabry and Pombiliti and Opfolda, which we call PomOp for Pompe disease.

And what we shared in the call was that our peak potential for Galafold is at $1.4 billion in the mid-2030s. And for Pombiliti and Opfolda, that's $1.2 billion potential in the mid-to-late 2030s. So as a company, we really do -- after this acquisition, we really do expect substantial non-GAAP EPS accretion from these assets in 2027 and we really are generating significant cash flow from it that we can then reinvest in innovation.

So with that, I'll hand it over to you, Greg.

Thank you, Cristin. Everyone can hear me okay. Thank you for the invite. It's fantastic to be able to talk a bit about BioMarin's research and development. We are in the process of building out our pipeline, but there are a couple of highlights I want to share for you. One is actually published just yesterday, so hot off the press, our hypochondroplasia data. So this is taking the CNP analog VOXZOGO and applying it to a related but distinct disease, hypochondroplasia. Those results actually exceeded our expectations, both from a growth standpoint as well as some of the secondary endpoints. We're very proud of that data. It's actually been submitted to the FDA, and we'll be able to update folks soon once that filing is accepted and we have a PDUFA date.

If you think back more towards the pipeline, we've had two new additions to the pipeline, one that came along with the Amicus acquisition, molecule that was referred to as DMX200 from Dimerix. We have the U.S. rights. We call it BMN820. This is for focal segmental glomerulosclerosis or FSGS. It's a CCR2 oral inhibitor, and that is a Phase III program running in that renal indication, which will have Phase III data looking at 2-year proteinuria out in 2028.

So thrilled to be able to add that in the U.S. rights to that molecule. Another hot off the press update for you. We closed just last week, acquisition of a post Phase I product from Alesta Therapeutics. This is ALE1. This is a molecule that's trying to address hypophosphatasia, but rather than being an enzyme replacement, this is more of a substrate reduction therapy. Again, the promise there is that not only might you have an oral convenient therapy, but there may be an opportunity to reach some of the tissues that the bone targeting biologics are unable to reach just because of their PK and their distribution. That includes muscle and joint and so forth.

I'll just wrap up by saying that we've got internal innovation as well that's continuing to percolate through our pipeline. Probably the star of the show is BMN333 which is our next-generation CNP analog, more long-acting weekly administration. And our goal there, I think we'll talk about it a little bit more, is going to be to actually deliver a greater pharmacodynamic effect than what Voxzogo can achieve.

And we have a variety of proof points again that tell us that we're headed in the right direction, and we have a molecule that can answer this question definitively. That's in Phase II right now. We're enrolling and it will have data available next year before we launch a seamless Phase III thereafter.

Okay. Well, great. Lots to dig in there. I think it might bring us all the way back to the start with VOXZOGO and the commercial franchise in achondroplasia today. I guess one of the things that's come across in the -- for a couple of quarter updates now is just the growth that you're seeing within the underage 2 cohort of the market, right? Can you just talk about sort of how much headroom that segment -- how much headroom for further penetration you're seeing in the under 2-year-old population and how much of a growth driver this could be going forward? And then perhaps even just stepping back, as we think about the franchise as a whole within achondroplasia, what some of the key growth opportunities are looking forward?

Yes. Thank you for the question. So specifically to Voxzogo, we did report in our earnings call strong growth. So revenue at 14% year-over-year and importantly, patient demand at 20% year-over-year, and that's our global numbers. And what we had said is that, in particular, that growth and especially in the U.S. is being driven by exactly what you just referenced, Eric, and that is that 0 to 2 population.

It is such an important population for this therapy, most importantly, because if you look at medical consensus guidelines, it really does suggest that you treat right at the time of diagnosis because that is where that child can then benefit the most in the long run. And so we're really excited that we have the exclusive label there, and we anticipate being the only product approved in the 0 to 2 population for the next couple of years. And so that's an area that we really do see exciting growth coming out of. Not to mention some of the other growth drivers are that we're continuing to expand and accelerate in certain countries globally outside the U.S.

So as a reminder, 75% of our revenues come from outside the U.S. And there, we have growth happening in countries where we're already well established, and this is where you see the highest growth coming from that 0 to 2 population because it's an incident population that you're catching at birth. In other countries, we're either newly launching or still expanding into those countries. And so you see growth across all age groups. So it really does come down to a kind of country-by-country look at where that growth is coming from.

But in total, we are commercialized in 55 markets in our 80-country footprint, and that is an area that we'll continue to grow in. So very exciting for achondroplasia. And I certainly want to mention the fact that what we also announced since the quarter closed was the settlement that we reached with Ascendis in terms of getting royalties on net sales of YUVIWEL, which was the first competitor to launch in this space.

So we have a 20% royalty on U.S. net sales and an 18% royalty in the EU, Brazil and South Korea. And what excites us most about this is that this does just kind of clear an overhang for us. This is something that enables us to capture value right away, which our ITC proceedings would not have done. We would have been in further litigation in both the U.S. courts as well as the jurisdictions where IP is.

But I think most importantly, for us, we think that this is a really important moment for both patients as well as BioMarin to kind of clear this overhang and be able to move forward. So that's looking at achondroplasia. But another big and exciting growth driver for VOXZOGO is in hypochondroplasia, and I know you'll speak more to this. But we're anticipating a launch should the regulatory bodies approve in the coming year. So we have the team certainly gearing up around that. And then as we look further out, we are looking to, as Greg had mentioned, really bring forward the hopefully best-in-class long-acting CNP. So the durability of that franchise, you can see over time growing.

Let's hold off on hypochondroplasia for a second, just kind of stick with achondroplasia. So two things. One, just picking up on the competitive dynamic a little bit with YUVIWEL now, right? Appreciating that the settlement has allowed you to capture some preserve, I guess, value, right, or capture some upside, I guess, up the front versus ongoing litigation. I guess that said, from a share standpoint, what do you anticipate in terms of switching away to YUVIWEL from the existing franchise? And then yes, I'll leave the question there and follow up on a different point in a second.

So what we shared so far has been that we've seen 90% retention on VOXZOGO out through July. So mind you that YUVIWEL launched in February, we've still seen 10% have now switched in the U.S., which is where they've launched. 10% have switched over to YUVIWEL. We've retained 90% on VOXZOGO. And primarily, what we hear from families around why they stayed is multifold. One is that they're seeing the benefit of the product. And that for them is really important when they know that the safety is there, the efficacy is there, and they're seeing their child benefit from it. In addition to that, many have created a daily routine that they're comfortable with, and that's working for them.

And then we've also heard that they've really appreciated the wraparound services that we have put in place with our clinical coordinator team who are there to help them with injection education, et cetera, that has been beneficial. So that is in large part what we've heard. What that story turns out to be, we are monitoring very closely. We will continue to provide color on as we see more, but we're quite happy with seeing that 90% have stayed. And I think it also does show that this is not achondroplasia, in particular in the U.S., is not an easy market just to come into and just kind of overturn or somehow capture all the market share. It is an area that these are patients that are being treated by multiple specialties. They're dispersed in the communities. They don't necessarily see their treating physician frequently and some are still reticent to treat at all. And so I think that we're seeing -- we've seen that certainly, but I think we're also seeing our competitors see the same.

Got it. Okay. And then can you touch on any of commercial implications possibly from a full approval of VOXZOGO next year? Could full approval meaningfully influence demand, access or pricing of the product?

Maybe if I can take that first from the regulatory standpoint. I think the full approval provides 3 changes for the way that I think the world will view the label. Two of them tend to be rather tactical. One has to do with, again, the way that materials are reviewed by the FDA, and it streamlines them and makes them easier. Second would be on the regulatory level, when there is a full approval for an indication, that does create a headwind for new accelerated approvals in the exact same case. Though to be fair, the FDA uses their discretion. And if they feel, again, it's in the best interest of patients, that tends not to be blocking for follow-on.

The third is it gives us an opportunity to have our full data set into the label. And that is really where we see the most opportunity. Yes, there will be some physicians who I think value the idea that this is full approved. It's not on an exploratory endpoint or not on an accelerated endpoint. But more importantly, it's the details of what goes in that label. So the kind of things that are being reviewed by the FDA now are the upwards of 10 years of safety data that we have. There's 1,200 patient years of clinical trial data. That's a tremendous amount of evidence.

And so in addition to the safety that affords, and again, the opportunity to tell that story, we will be telling, of course, the height story, and that's not just annualized growth velocity, but there's an opportunity to present something that often is called final adult height, which is a bit of a misnomer. It's a defined time point with 5, 6 years of growth, for example.

Similarly, we'll be able to put forward our proportionality data, looking -- we'll look at body composition. There'll be an opportunity to have them review our foramen magnum data as well. We've got a variety of data sets, including quality of life that will be in front of them. Again, it will be up to their discretion in our back and forth on what makes into the label. But that will allow us not just to have medical dialogue, but the opportunity also to have our sales reps also work with the physicians and share that totality of evidence.

And what I would say is that it's not necessarily and we don't expect a change in how the medicine is necessarily used because our label really already covers children with achondroplasia that have open growth plates. But what I do expect is that it creates more confidence because of all the data that you've just described, Greg, I think that it really does create more of that confidence in the product given the amount of patient years we have, the safety, the efficacy that we're seeing, et cetera. And just as a reminder, it would be the first product that would be fully approved for the treatment of achondroplasia, which is also exciting.

That's great. Well, let's shift to hypochondroplasia, right? You made note of it. We have seen the publication just out yesterday. Maybe just from a market sizing standpoint, it would be good to have you frame the opportunity in hypochondroplasia, maybe perhaps relative to achondroplasia, not only in terms of prevalence, but also rate of diagnosis and really treatment seeking interest in patients.

And these are precisely the things that we're working on now. So I'll start off with just the prevalence. We anticipate or expect that the prevalence is roughly that of achondroplasia. And what we've shared in terms of the total addressable patient population in achondroplasia, we've shared that the global number is estimated, we estimated around 20,000. However, we've said in hypochondroplasia, we see the total addressable patient population at 14,000. And the reason for that big delta is actually the diagnosis rate, not that the prevalence is necessarily different, but the diagnosis rate is dramatically different.

The estimations now in terms of diagnosis are somewhere around 30%. We intend to move the needle on diagnosis, and that's the work that we're doing now. And Greg, I can certainly have you speak to that. So there's the work that we have to do on diagnosis, but also what you alluded to there was around also the treatment patterns and the urgency to treat. One of the most important things that we are working on now and we'll continue to do is to raise awareness around the condition itself so that treaters and families alike understand the comorbidities that come alongside hypochondroplasia and importantly, why the importance of treatment really is there. And so that's work that we're currently doing now. Is there anything you want to elaborate on that for that, Greg?

No. A lot of -- I mean, what we would call market shaping that's gone on. That includes, again, this idea of education. But also we've been side-by-side with physicians a consensus guideline for definition of the disease and how to define it is out now. And similarly, we've been working with pathologists even on nitty-gritty factors like trying to reclassify so-called variants of uncertain significance.

Again, we know that there's a variety of mutations in the FGFR3 protein that cause hypochondroplasia. This is slightly different than what you see in achondroplasia where one mutation dominates. Here, it's a big long tail of different mutations. So clearly, making sure that, that bin is accurate, those mutations, they fit into, again, this diagnosis, that's an important factor. And of course, when we start looking at efficacy, we want to make sure we see activity across all of those subsets as well. And in the publication, we have that data. It looks great.

And so really quickly, just while we say the pacing of this will be in large part how fast we can drive the diagnosis rates up as well as the urgency to treat, the benefit that we have here is that we're not starting from scratch. We've built a commercialization capability in and around skeletal conditions, achondroplasia. These are the same treaters, thought leaders, et cetera. And this really, I think, does kind of provide a benefit for us as we come out and launch this product.

I was just going to add, we also have a story to tell that's not just about height any longer. This is in the publication, but we actually type 1 error controlled were able to show that when you treated with Voxzogo versus placebo during that first year of double-blind placebo control that there was a highly statistically significant difference in arm span as well. And you may say, well, yes, arms, how is that different than the legs and the height? Well, it's absolutely important in the way that these children interact with their environment, think about combing their hair, reaching up onto a shelf, driving, these sorts of things.

And so from that standpoint, we think both the payers and the patients are going to see this data set and like we were quite pleased to see that there's -- presuming it gets approved, a safe and effective therapy for patients.

On the issue of potential approval, is full approval on the table here? And if not, do you have clarity -- regulatory clarity of what would be needed to support full approval excuse me, hypochondroplasia?

Yes. It's an excellent question. Of course, we've been talking about the full approval package for achondroplasia. And clearly, there are precedents where that could set up a follow-on indication if it's closely enough related for a full approval to be considered. Ultimately, that will be at the discretion of the regulators, but I just want to reassure you, we're working very closely with them. We have 2 files that are in the FDA right now, other regions as well. And so from that standpoint, looking forward to being able to close the book again on that full approval for achon and again, see what comes with hypochon. So more to come. And I think as we get more clarity from our interactions with the FDA, we'll be able to share more details on earnings calls.

Before we leave this space with skeletal dysplasia, maybe we could touch on BMN-333, where you've guided to an update from the Phase II study portion of the pivotal trial you're currently running. Maybe just you could help us sort of stage setting there, the endpoints that you're most interested in interrogating in that Phase II study portion? And what would you hope to see that would satisfy differentiation versus VOXZOGO?

Yes. And what we know about BMN-333, number one, it was engineered to have a longer half-life. So it's got about a 100-hour half-life roughly. And it's a construct that again releases the free CNP into the bloodstream. Think of it like a depot in that sense. So it's more of a continuous administration. That's very different than, of course, VOXZOGO that's got less than an hour half-life, more of a sawtooth pattern for PK.

Now with that continuous exposure, we ask two questions. Can we see more PK coverage safely as compared to, say, YUVIWEL? And can we see more PD at least in the bloodstream? And the short answer is yes. We published a Phase I protocol at the end of this year, where we saw up to 13-fold increases in AUC for free CNP as compared to what YUVIWEL was able to produce. Similarly, that was accompanied by conservatively a two to fivefold increase in cyclic GMP in the plasma. Again, it's not the growth plate. But again, it shows that there's more biology at least to be tapped into, at least in the bloodstream. So one step closer.

The next step, of course, is we need to move out of healthy volunteers, and we need to move into patients. We're running a study in treatment-naive achondroplasia patients. So you need to again go to the countries where those patients exist. We're in 7 countries around the globe right now. That's increasing. We're in the steep part of the enrollment curve. More to come in that regard. But that study is a classic dose-ranging study. It's looking at 3 different doses of BMN333 call it, high, medium and low. And we will be looking at an internal control of Voxzogo there as well. Our goal is to pick a dose as compared to Voxzogo that will give a high confidence in a Phase III to have a superior growth profile.

So what are we going to look at in that Phase II to determine that? Well, two things. One is we will be measuring annualized growth velocity. We will cut the data when every patient has at least 6 months of follow-up. So again, it will be more than 6 months in some patients. There'll be a Bayesian approach applied. There's an internal control of 10 patients on Voxzogo. That will be a quick spot check. We have hundreds and hundreds of patients of Voxzogo. data that we can put into a model if we need to as well.

But the goal there is, again, not only looking at the dose response, but also we'll have the ability to look at exposure response, which across 3 dose levels of 333 is going to give us hopefully, a good spread of exposure there. And with that, we would pick a dose to move forward to Phase III. We'll, of course, look at safety data as well. But the Phase III, as it's currently designed, is a superiority study. There's no placebo. So patients either receive Voxzogo or 333. And we've powered it to have 90% power to detect a 50% improvement in attributable AGV. That's not the minimum detectable number, and you can back calculate the that, but it's 60 versus 60 in each arm. And again, the dose signal would come out of the Phase II. That Phase II data will be available to us, and we would be planning to publish that. That is going to be something that we will announce sometime in 2027.

Okay. Great. All right. Let's shift gears a little bit to the pipeline. I want to pick up on the Alesta ALE1 acquisition. You acquisition closed recently, right? Just last week, right? Just by MOA, just to be clear here, this is an ENPP1 inhibitor, if I have that correct.

It's a small molecule ENPP1 inhibitor. So in these individuals, they have high pyrophosphate. That's their problem. That's a direct inhibitor of bone mineralization and fantastic work that's been done for the field with Strensiq and the follow-on agents that are basically replacing the deficient enzyme, which is tissue nonspecific alkaline phosphatase. And at the bone, it's taking that high pyrophosphate and converting it through to its end products.

A lot of great work has been done there. This is a slightly different approach. I guess, similar to Gaucher's, this is upstream. It's trying to deplete the substrate, try to deplete this pyrophosphate by inhibiting the enzyme that creates inorganic pyrophosphate, and that's ENPP1. A lot of good preclinical data. There's some sort of gene load mouse crosses that suggest that about a 50% reduction in ENPP1 enzyme activity can restore bone mineralization in HPP models, in rodent models. What we've seen with this small molecule inhibitor of ENPP1 is we've seen healthy volunteer data and a limited amount of patient data, again, looking at the PK profile, the PD profile and the safety and again, seeing that the molecule is meeting the requirements that we would want to see to take it forward into patients.

So now again, we are acquiring this molecule. It's finishing up its Phase I portion. This is a study that's running outside the U.S. So of course, we're going to finish chronic tox and get it filed in the U.S. But the promise here is that you don't just have a more convenient Strensiq. The promise of the molecule is that it actually will also be able to reach those compartments that aren't bone related.

So particularly, the HPP patients fall into a couple of different bins, a couple of different buckets on when the phenotype presents itself. And particularly those where it presents later in life through the adults with HPP, many of their complaints are not the classic bone-related pathology. Instead it's things like fatigue, malaise, muscle pain. A small molecule without the bone targeting biologic aspect has the promise to be able to target those compartments as well.

So that's where we see the opportunity here. It's an established commercial space. There are established regulatory endpoints, some great work that's been done by the alkaline phosphatase molecules really to work on these patient populations, understand the endpoints. We're hoping just like they are to learn from that and again, bring patients something of value. Anything you want to add, Cristin?

Just in relation to the ongoing study, yes, just any sort of loose guidance you might offer in terms of when we would expect an initial readout and sort of the scope of that readout, understanding that it's both -- let me have this right. Is it both in healthy volunteers and in patients?

There are HPP patients in. And since the data is a week old, we're still working through, again exactly how the Phase I to Phase II transition is going to play out. We, of course, need to engage with regulators. The short answer, though, is we plan to publish this data next year. There will be a public disclosure of both the healthy volunteer and some amount of patient data. And what you can expect is not only PK profile, but also PD enzyme inhibition.

Again, as I mentioned, the preclinical models suggest something between 30% and 50% reduction in ENPP1 activity could have dramatic influences on pyrophosphate. Again, it's been shown quite nicely by the alkaline phosphatase molecules that all of the benefits that they achieve in these older patients. We're not talking about infants, but these children through the adults really tracked with decreases in pyrophosphate. So we think this is a fairly derisked approach. And again, we'll be presenting that data more broadly next year.

And just in thinking about the spectrum of disease where you hope -- that you hope to address, particularly the sort of the older adult onset that you spoke to earlier. I guess we have a lot of development and regulatory precedent in the juvenile side. I imagine a little bit less on the older. Maybe you can just sort of speak to the development outlook or what development plans could look like in that segment and what you would ultimately hope to demonstrate clinically?

I think what the field has learned, and it's been some great work is that these are distinct populations. You can talk about when the onset of it, is it a juvenile onset adult, an adult onset adult, a teen, a pre, post bone growth plate closure. All of this is important. But you have to target not only the dosing, but also the endpoint measurements to the right population. So clustering them together is probably not the right answer.

So moving forward, again, we envision teasing these populations out. And then again, the beauty of the timing of this is that we can look at those individual populations and continue to do endpoint development, particularly with the adults. Once the growth plates are closed, you can't look at the Rickets scores and so forth. You don't have that window into bone formation. So the more blunt endpoints like 6-minute walk test, some of these functional endpoints have been notoriously fickle in order to see the effect of your drug.

There are newer technologies that are measuring motion. There are subsets sit to rise. There are a variety of different measures that we would intend to explore in our Phase II program so that by the time we reach Phase III, again, we would have solved not only the patient population question, but what's the right endpoint and what's that effect size? How do we power that study?

Excellent. Maybe again, sticking moving further down the pipeline or elsewhere in the pipeline, I should say, I want to pick up on the Dimerix compound, BMN820 in FSGS. I guess that study is now fully enrolled and you talked about sort of a readout in 2028. That being said, right, and I guess it's on 2-year eGFR that you're looking at. I don't know 2-year proteinuria...

It's a big movement in the field. And some great sparsentan has done some great work opening this up, but the FDA now accepts 2-year proteinuria as a full approval endpoint.

Okay. Right. Okay. And you -- yes, because the question that is lingering in my mind is whether there's an opportunity for accelerated approval based on 1-year endpoints that are being leveraged in like disease or in the kidney disease category. Thoughts around sort of the flexibility that you -- any optionality, I guess, in the context of this trial where you might look to either look at data early and file on an accelerated time line?

So our current belief is that the 2-year reduction in proteinuria is the endpoint, and it's fairly solid. Now that being said, we have some knowledge of, again, how the study is performing already. The study remains blinded. There was a fairly small Phase II data set that this Phase III study was built upon. That being said, we know that the study has, number one, passed through a futility analysis. And number two, we know that it also -- from the standpoint of sample size that it's adequately powered to measure a meaningful decrease in proteinuria.

So there was a formal sample size reassessment done, again, on blinded data, and the study is appropriately sized. It overenrolled a little bit, I think, which is great. That was by demand. Patients were interested in being on the study. And again, the promise here is that an oral therapy, it targets CCR2. So the idea here is it's not necessarily a valvular targeting agent. It's targeting this macrophage-induced inflammatory response that, again, leads to the destruction of some of the kidney podocytes.

And the hope here is that by having a molecule that would have a meaningful reduction in proteinuria and not have the baggage of things like a black box warning, not having the baggage again of having to restrict to certain levels of proteinuria to non-nephrotic syndrome patients that, that would be of great interest to the community.

Being a different mechanism of action than the pure vascular side as well, the idea of combining these agents becomes important. This study is designed to add on to ARB therapy as a baseline. So it's not displacing like sparsentan did a prior ARB inhibitor. It's an ARB inhibitor plus/minus the DMX, the BMN820 compound. And from that standpoint, again, you have to make sure you look at it through that lens. But that meaningful decrease in proteinuria is something we know the study is well sized for. And again, a lot of promise with regard to this mechanism of action that it will offer patients something important.

Excellent. Excellent. I'm going to end on a thematic question here. And our colleagues in tech were also running a conference this week. And so perhaps I'm asking this question on their behalf. But obviously, we're often thinking about how AI, AI-enabled tools impact our businesses, all of our businesses. How is BioMarin making use of AI tools today? And how are you measuring their impact?

Yes. And the tools can be quite powerful. If you put them in the hands of the right people, you feed them the right data in the right format and then you do something with it. And so I would say there's 2 places in R&D that we've really leaned into. One is reading and writing, right? I mean we have a very document-heavy work. So the idea of cutting out the white space between times, for example, when we lock a database and we file a program, it is about using AI tools to create some of those documents, the filings, but also inserting that into the workflows in the right way so people can get these work products out as fast as possible.

We had a great example of the success recently with hypochondroplasia, 79 days between database lock and the submission to the FDA. That does put us in -- we think at least the McKinsey numbers would put that in kind of the top quartile. But the whole field is moving fast. That's great for patients. Otherwise, this is busy time, so to speak. So you can imagine having that kind of approach all along a drug's life cycle and whether it's filing of an IND or again, filing for a new clinical trial, all of these factors can add up and reduce cycle time.

I would say that the second major area that we're using AI has to do with patient finding. And in that regard, using some of these algorithms to look at very complex data sets. They might include genetic data, so looking for hotspots around the globe. They may include social listening. And again, the activities that are going on where we know that patients who are quite educated are seeking out information. They're just not finding their way to a physician. And then, of course, the opportunity to do good old-fashioned looking at claims databases and so forth. That does allow us to find patients not only in the commercial sector, but also for our clinical trials.

And we have some great examples where we even found a patient who was an I mean in utero patient. It was a mom looking up for hypochondroplasia on the Internet. And again, she was reported to one of our clinical trials. So they work. It's very helpful. I would say that the area that I would love to see us lean into more, and we're dipping our toe here is giving these tools to the scientists and allowing them, again, when it comes to molecular design, organic chemistry and amino acids are another form of a language, right? So the large language models do a good job creating some of these reagents. That will hopefully cut down the time and the number of molecules that we have to test as we go through our own funnels to bring these things into the clinic.

So we have the luxury at BioMarin of -- we have some resources. Again, with all the work we've been doing, we have about $1 billion of free cash flow a year. That means that we don't always have to be on the bleeding edge of these technologies, and we're finding that there's a very vibrant third-party sector. They battled it out for the winners. But for writing things like clinical study reports, we're able to actually test a couple of them and see which of these tools is the one that works best for us.

And we're finding that in addition to some of our work with Veeva and so forth, getting our data lined up, I do think that there's a major opportunity here to do more with less. And as an R&D guy, I've got a budget, and I need to get as much activity into it and get as much to patients as I can. And that's really the name of the game right now. Technology is part of it, but it is enabling the people who have the creativity to do the work.

Great. Well, that's a good note to leave it on. Thanks so much, Greg and Cristin for your time today. We really appreciate it.

Thank you.

Okay. Hi. Good morning, everyone. Welcome to day 2 of our Cantor Healthcare Conference. My name is Olivia Brayer. I'm one of the senior biotech analysts here at Cantor. And really excited about this morning's fireside chat with the BioMarin team. We have Cristin Hubbard, who is Chief Commercial Officer; and Greg Friberg, who is Chief R&D Officer.

Thank you both so much for being here and making the trip to New York.

Thank you for having us.

Thank you.

So it's been a really busy year for BioMarin. A lot has changed. You've done some deals. You've added some new assets. Maybe just talk about the state of the company today, how it's evolved over time? And what, kind of, the vision is for BioMarin going forward from here?

So I'll kick us off. For those of you following us, we're BioMarin. We're a leading rare disease biotechnology company. And we operate specifically in genetically defined conditions. We have 9 commercial products that are across -- that are spread across our 2 business units, so skeletal conditions and metabolic conditions.

Now very recently, we announced the acquisition of Amicus. And with Amicus, that gave us 2 high-growth commercial products. One is Galafold in Fabry disease, which we just announced peak revenue estimates at $1.4 billion in the mid-2030s. And the second being Pombiliti and Opfolda, which we call PomUp, in Pompe disease, which we've also announced expectations of $1.2 billion at peak in the mid- to late 2030s. So really exciting acquisition, a huge strategic fit for us to really strengthen and diversify our portfolio.

Now at the quarter, we announced very strong results, 20% growth year-over-year. And really, what we're excited about is the fact that we've got 4 products in our portfolio now that have the potential to be above $1 billion, and our first of which will be VOXZOGO, which in our 2026 full year guidance, we are saying that we will be at $1 billion to $1.05 billion is the range that we've given for the full year.

Now our focus as a company is really about driving top line growth, about expanding our margins and importantly, about generating cash flow because with that, we can then continue to invest in our pipeline. We've recently announced another acquisition for a pipeline asset, ALE1 that, Greg, I'll give it over to you to talk a little bit about our portfolio.

Yes. From the portfolio standpoint, a lot of news, again, fast moving at BioMarin. We just revealed our data in hypochondroplasia, which again, was published yesterday and presented in Europe at the ESPE meeting. Very excited. That result would be -- provide us with another first-in-disease indication. This is for VOXZOGO in beyond achondroplasia and hypochondroplasia, data really outperformed what we were expecting. We're thrilled about that opportunity.

And similarly, we've been rebuilding our pipeline as well with a variety of different assets. Along with the Amicus acquisition came a molecule that we call BMN 820 or DMX-200. This is for focal segmental glomerulosclerosis. That's a study that will have a Phase III card turning over in 2028. Similarly, we have 2 other pipeline assets now. The recently acquired and closed last week ALE01 (sic) [ ALE1 ] from Alesta Therapeutics for hypophosphatasia as well as, of course, we've got our in-house created molecule BMN 333 is a next-generation asset for CNP, again, looking for superiority over VOXZOGO. Both of those will have data to be revealed next year.

Yes. A lot to take in. Well, maybe we'll start with the Amicus deal. I think there's been a lot of investor interest in that Amicus deal. I know you all have given some recent updates in your second quarter earnings call just around some of those assets as growth drivers. Can you talk about how transformational that deal is for the company? And then, Cristin, maybe to put it in context, right, like, when you think about your future cash flow opportunity, your future earnings power, what do those products actually do for you?

Yes. So as we've already talked a little bit about, driving top line growth is an important component of our strategy and these assets help us to do so. It's really exciting to think about what we can bend the curve on in terms of the treatment of Fabry disease as well as Pompe disease with both of these. But as you've mentioned, Olivia, there's the financial components here. And we really do see this as a huge accelerator.

So what we talked about at the quarter were the fact that we are going to recognize about $220 million in synergies that will come in 2028. This gives us substantial EPS accretion in 2027. And this is an area that, again, we're really looking to be able to use the cash flows that will come from this so that we can continue to allocate a lot of capital into growing our pipeline, investing in innovation and so on. So we think that this has been a real accelerant on many fronts.

Okay. Helpful context. And then you did just have a big update on VOXZOGO, especially from an IP legal perspective with the Ascendis settlement. Can you maybe just talk about how you're thinking about VOXZOGO as a future growth driver? And then maybe just give us a little bit of context around that settlement, what it does for you? Does it change your strategy at all around how you think about the way you're commercializing VOXZOGO just given the economics that you do get from another asset now?

Yes. So VOXZOGO, I think it has -- we can talk about it a little bit in horizons in the different disease areas, right? We have achondroplasia, which I'll get to, but also hypochondroplasia in the future. And then longer term, and maybe you'll speak to this, Greg, looking out at BMN 333, which is our long-acting CNP that we look to develop the best-in-class CNP, which I know you'll get to.

But going back to, kind of, the near-term growth and achondroplasia in particular, as you've said and as you've alluded to, Olivia, we did just reach a settlement with Ascendis. We think that this is very important, both for BioMarin, but also importantly for the patients. This settlement allows us to get 20% royalty on net sales in the U.S. and 18% royalty on net sales in the EU, South Korea and Brazil. And so really, what this does is this enables us to capture value now it's retroactive to any commercial sales.

But also importantly, I think it enables us to clear a little bit of the overhang on VOXZOGO and really share in not only a percent for any patients that might switch off of VOXZOGO, but also importantly, for any market growth that might be -- that might start as a result of Yuviwel now being on the market, we'll now get to share in that and not just compete for it. So that at least helps us to clear that overhang.

But importantly, thinking about VOXZOGO as a growth driver. We are confident in the growth going into next year with VOXZOGO, and that is in part based on how we're growing in achondroplasia. And that is largely where we're seeing the 0 to 2 population, which is what we have a label in and anticipate having an exclusive label there being the only company labeled there for the next couple of years. This is where we're seeing the most growth. And it has -- medical consensus guidelines tell us that it is very important to treat these patients at the time of diagnosis, which in achondroplasia happens very, very young in infancy. And so to treat right then is most important, and that's where VOXZOGO is indicated and where we're growing most.

We also have VOXZOGO marketed in 55 countries around the world, and that number is growing as well. Our international expansion is continuing. We're seeing continued revenue and patient demand growth in these countries. I should say that 75% of our revenues are actually ex U.S. So these are really important territories for us where we're continuing to grow. And that expansion, both in countries where we already are, but still newly launching countries is continuing to help us grow.

So as we build on that momentum, we also have potentially hypochondroplasia coming in next year, starting in the U.S., which we're very excited to go in. And then as I mentioned, longer term going into 333. So along -- I think along -- many horizons for the VOXZOGO and skeletal...

Yes. And you did all just raise guidance for VOXZOGO to the higher end of your guidance range. What gave you the confidence to do that? And what are you actually seeing play out in the real-world market now that there is another asset for achondroplasia patients?

Yes. So we did. As you said, we've raised the guidance for the full year to $1 billion to $1.05 billion is the range. And really, what this was based on is the strong growth that we saw in the first half. And then looking out, and that includes what we're seeing in terms of now there being a competitor that was launched in February. In the U.S. market. And what we shared at the quarter was that so far, we've seen 90% retention on VOXZOGO treatment in achondroplasia. And what we hear from patients and families alike is really that these are patients where they're seeing the efficacy, they're seeing the benefit of the treatment and importantly, have made a daily routine for themselves that is working for that family.

So all of the things that helped us to raise the guidance was the fact that we had the momentum going in the first half. We have an understanding of what that switch rate is looking like. And we had announced that there were 2 big market access renegotiations that were on the horizon this year for VOXZOGO. One we have cleared with a good outcome and the other is in -- is still in the works. And so with those things combined, that gave us the confidence and behind our raise.

Yes. And you've brought up hypochondroplasia a few times. I know you just had data that came out this week. Can you maybe just -- maybe, Greg, at a high level, talk about the highlights from that data set. You've commented that maybe they were even better than your expectations. So maybe what is it about that data set that is driving that sentiment at BioMarin?

I think there's 2 factors. We actually just published the data that's in NEJM Evidence, if any of you are interested in looking into it. Two factors in particular that popped off the page. One was that as a marker for pharmacodynamic activity, we look at AGV, we look at annualized growth velocity. And we saw more of a delta, more of an attributable AGV than we had seen in other conditions like achondroplasia. We saw 2.33 centimeters of AGV. Interestingly, that was a result that was consistent across a variety of subsets, whether it was by mutation type, again, in comparison to achondroplasia, lots of different FGFR3 mutations in hypochon. So seeing consistent results across different AGVs, different genders, different mutations was great data.

But the second factor I want to highlight is this wasn't just about linear growth. In that testing cascade, we had preserved alpha. We had type 1 error control. And we were able to show that in that year of randomization, again, you only get a year in these studies where you truly have double-blind placebo controlled and everybody goes on therapy after a year. In that year, we were able to show a highly statistically significant improvement in arm span as well.

Why is that important? Well, as you can imagine, it's a big contributor of quality of life. Think about being able to brush your hair, think about being able to reach off of a shelf or even drive when you're an adult. These sort of factors actually are driven by arm span more than simple linear height alone. And so having those with a robust data package and, of course, a safety profile that was consistent with, if not maybe a little better than what we saw in achondroplasia, these are results that we know our physicians are excited about. At the conference yesterday, I think there was a lot of excitement about. And we're looking forward again to getting this to patients.

Hypochondroplasia is slightly different than achondroplasia also in terms of its diagnosis. The patients are not born with the same deficit in their height. So they're not as readily diagnosed in utero, for example. A lot of the work that we're doing is trying to advance the field, get diagnosis at a younger age, spread the word that, again, this isn't just a mild form of achondroplasia. This is a stature deficit that has health and wellness consequences as well.

So we've submitted our file to the FDA. We'll look forward to updating when we have additional information. It's our second file with the FDA. We have the full approval for achondroplasia being reviewed with a PDUFA date in February as well. So hypochondroplasia does represent a pretty big opportunity for us.

And I guess all I'd say to just looking at the potential commercial opportunity there, you could imagine the teams are certainly gearing up and getting ready for a potential launch coming soon, really focused in and around what Greg has talked about as it relates to diagnosis, but also important disease awareness so that, that urgency to treat is there. What we have shared is that while the genetic prevalence is estimated to be that of achondroplasia, the big -- there's a gap in diagnosis as we've discussed. So we've said that we think the global total addressable patient population is around 14,000. And yes, as I said, we're getting ready for what we hope to be a very successful launch.

So as you think about the opportunity set that you do have with hypochondroplasia, 14,000 addressable market, I mean, how big do you think this could actually be in terms of a commercial opportunity set for you? And from a diagnosis rate and penetration rate, I mean, what kind of go into some of your assumptions when you think about the ultimate growth curve that you do have with hypochondroplasia?

Yes. So we haven't shared estimates yet on what the total opportunity will be, and that will come as we near getting ready to go to market. But what I will say is that what really helps us out in this regard is that the treaters, a lot of the, kind of, the surrounding community is very similar to that of achondroplasia. And we now have extensive experience in this regard, both from a, kind of, physician relationship component, but also importantly, from a market access component in the different countries in which we operate across our 55 countries. So that really helps us to accelerate, which we're not building from scratch like we had to in achondroplasia, having been the first therapy in that space.

So that is the helper. The part that will -- what paces us, I guess, is really around the diagnosis rate and that urgency to treat. That is why we have had our medical teams very compliantly working on really trying to drive that in advance of the launch so that we can accelerate that as much as possible.

I'll just add that we know that there's a pent-up desire to have a therapy here. We hear it from the patients, and there's a new advocacy group as well. They're self-assembling. But we also saw in our pivotal study where we just reviewed the data, we recruited multiple quarters faster than we had originally anticipated. And we're seeing a similar finding in the infant study as well, where there are patients out there and there's a desire to have a treatment.

And it's interesting because we've seen this time and time again that when there's a treatment is when you really start to see the energy and, kind of, the dialogue happening, the kind of the self-organizing, if you will, because now there's an option on the horizon. And so I think that, that will also inflect.

Yes. So you bring up a few interesting points, right? You obviously have achondroplasia as a great analog, but you also have the achondroplasia market has been built out, right, from a reimbursement perspective, from a go-to-market strategy perspective. So as you think about hopefully being the first to market, that could be a great positive, right? But it also means that you can sometimes have to build out the market and find the patients yourself.

So how do you think about -- or maybe how should we be thinking about that adoption curve? Is it something similar to what we saw with achondroplasia? Could there be maybe a faster go-to-market or maybe not go-to-market strategy, but actually getting this to patients in a number of different countries? Like what are some of those pushes and pulls?

Yes. And we'll share more about this as we get closer to launch. But I think really thinking about it that the big -- what will accelerate is what I just talked about. The fact that we've built this infrastructure, we know where to go. We know the physicians. We know what the access landscape can look like. But what will slow us down is this diagnosis rate and the urgency to treat. So I think that between those 2 things, they start to balance each other out, quite frankly. But the hope is that we can continue to get out ahead of that education, that awareness, et cetera. We are putting a lot toward that and that, that can help to accelerate.

Two quick breadcrumbs just for you to follow the trail. We're doing all the work to try to make sure that, again, the community has the tools they need some international consensus guidelines were just published about a month ago for hypochondroplasia, some great work by an independent group of physicians on what the diagnosis takes, cranial circumference, tibial length and ultrasounds and so forth.

And a second factor that we've been working on is reclassification of certain FGFR3 mutations from what we typically call the dreaded VUS, a variant of uncertain significance, into pathologic criteria. And again, we feel a duty and an obligation, but also an opportunity that we can help the field move along. And so we've been able to take the data that we have and allow for some of that reclassification. These are the kind of activities, again, that started years ago, and we're going to continue those as we go into the launch phase.

And Cristin, you mentioned earlier that you do expect VOXZOGO to grow in 2027, especially with the opportunity set that you have with hypochondroplasia coming online. Can you talk about the geographic split that you see across that market? I don't know if there are numbers that you're able to put, right? You have that 14,000 addressable patient population. But how do you think about the ex-U.S. opportunity, the European opportunity, the U.S. opportunity as you think about that rollout and that TAM?

So we haven't shared geographic -- we haven't prospectively shared geographic splits for hypochondroplasia, except to say that for achondroplasia, right, we're 75% ex U.S., 25% in the U.S. But trust that we will follow in every country that we possibly can and do our best in every country. And so it remains to be seen what that split will be.

Okay. Fair enough. And you do have a next-generation CNP that's in development. I know that's in a Phase II/III. Can you just talk about what the ultimate goal is with BMN 333?

So BMN 333 was designed to be, again, to build upon our learnings from VOXZOGO. VOXZOGO has got a very short half-life under an hour. It's administered daily. So again, think of a PK profile that's more like a sawtooth where you have daily quick administrations, but quick declinations from a PK standpoint. We engineered this using albumin binding lipid technology and a hydrolyzable linker to have more of a continuous exposure of CNP.

The hypothesis here, both from preclinical models as well as genetics and some human available PK/PD data that's out there to be able to continue to push that growth response curve beyond what has been achieved by drugs that are available today. What was dose-limiting for VOXZOGO with that very high Cmax that came down quickly was that there are blood pressure abnormalities that when you go up too high in a Cmax can drive dose-limiting effects. By having a more continuous exposure, you can avoid those Cmaxes and have more of an AUC approach where the area under the curve drives the growth.

What we saw in our Phase I study was that BMN 333 was able to have up to 13-fold the AUC for the free CNP. That's the drug that's released from the total construct as compared to the other marketed long-acting CNP product out there. Along with that, we also saw that there were increases in a plasma biomarker called cyclic GMP. Now this is systemic. It's not at the growth plate, but seeing two to fivefold increases over what would be expected from the dose of the other agent gave us confidence again that there's more biology to be had there.

When you put all of that together, we feel that we've designed the right study to test this question, whether more CNP exposure will lead to more growth. And we're running a Phase II dose-ranging study right now that will ask that question. It's measuring that versus VOXZOGO. And the goal here is to have a superior product.

And so we have a Phase III designed, presuming that, that study reads out the way that we're anticipating. We'll select the winner dose and put that against VOXZOGO, looking for an effect size that's about a 50% improvement in attributable AGV with a 90% power. So I have a lot of confidence in the molecule. It's the right molecule to test this hypothesis. This is, again, a molecule we've been working on for quite a while. It was made in-house, and we're looking forward to seeing that data in 2027.

Yes. And Greg, can you just talk about the decision to run this as a superiority study versus VOXZOGO? And you mentioned the 50% treatment effect size. How did you come up with 50%?

Yes. So a couple of factors go in here. Of course, we're very proud of the work we've done with VOXZOGO, and it's being reviewed for full approval right now at the FDA with the PDUFA date on Rare Disease Day, February 28 of next year.

So in a world where there's not only multiple marketed products, but one that's fully approved, we want to move the bar. We want to develop a molecule that we think, again, moves the field. It's not just an aesthetic convenience, but one that actually offers something more value. Now we measure that with AGV. That being said, all the markers of health and wellness that we know have tracked historically with AGV are things that we're going to continue not only to measure with 333, but also create the evidence package to remind the world that more growth will translate into faster and better outcomes with health and wellness. So that's more work to do.

With regard to the AGV increase, we picked a number that from a practicality standpoint, was something that we felt was achievable. That was a combination of not only the PK/PD that's available in the public space for other long-acting agents, but also our preclinical work. Ultimately, we landed at this 50%. We think that that's a meaningful improvement. That is not the minimum detectable difference. You can do the math and back calculate that. But this 2.25 centimeters is our target. It's what the study is powered to detect. And it's a combination of the preclinical and the clinical data that's available there.

Okay. Great. And that's assuming about a 1.5 centimeter change for the...

VOXZOGO. Yes. And all of the agents that are out there, if you actually normalize for age and baseline AGV, they have about that range. So we're looking for a 50% improvement in that attributable growth.

Okay. Makes sense. What can you tell us at this point about how that study is progressing just in terms of enrollment? And when can we hope to start getting updates from that Phase II portion?

This is one of our highest priorities this year. Speed to enroll is, again, one of the rate-limiting steps to being able to get the data on the back end. So we are in 7 countries around the globe right now. These are studies that are enrolling CNP-naive patients, treatment-naive patients with achondroplasia. So the mix of countries, of course, requires us to go to countries where either reimbursement or penetrance of the molecules that are commercially available aren't as profound.

So we're actively enrolling. We need to enroll 40 patients, 4-0, in our Phase II portion of the study, and we're on the steep part of the enrollment curve right now. What we would anticipate is that in future earnings calls, we would be giving you updates on that recruitment timing, and we'll then be able to zero in a bit more on the quarters by which we would have data that would ultimately read out from the Phase II.

Okay. Great. And then maybe I'll ask you both longer term, how do you think about VOXZOGO and then ultimately BMN 333 coexisting and maybe even being complementary?

Yes. And I'll just -- from the data standpoint, if we have the opportunity to -- with proof and evidence that we have a superior product, we would want that product to be the one that we would get to as many patients as possible.

Yes. That's -- I'd share that sentiment.

Okay. Great. Well, maybe we'll talk a little bit more about your Amicus products, PomUp and Galafold. You did just decide to raise long-term peak sales guidance for both versus what you all had previously communicated. So Cristin, maybe just talk about the decision to do that. Why now? What gave you confidence in those peak sales numbers?

Yes. So it's a great question. And what we did since the time that we were -- that we signed the deal was really look market by market to understand where we think the real opportunities are. What we shared is the peak numbers, $1.4 billion for Galafold, $1.2 billion for PomUp, but the CAGR going out into that. So 10% CAGR for Galafold over 20%, around 20% CAGR for PomUp. And what gave the confidence is really in the drivers of how we intend to do that. So first and foremost, we'll have geographic expansion of both of these products into our country footprint, so additional 10 for Galafold and an additional greater than 20 for PomUp. But also importantly, what underlies that growth is really how we intend to get after it.

And for Galafold in Fabry, we really believe that the driver here is in diagnosis. We want to do the best that we can to use our commercialization capabilities that we've built over decades really in driving diagnosis and then creating that urgency to treat once these patients are diagnosed. And we think that there's a lot of opportunity there, not only from family cascade screening and genetic testing that we do today, but also a lot of really important AI advances in the platform that we're working on to help to find these patients. Patient data tokenization is helping with that, really buying different types of data sets where we can look at some of this data and get insights to find where these patients are at. That's going to be the biggest driver for Galafold.

On the PomUp side, this is really about having these patients have the confidence in switching to Pombiliti and Opfolda as a treatment for them. Now what we found is that really the -- helping patients to understand what it looks like when they are not improving on their current therapy or they might even be clinically waning and not waiting for the doctor to do a technical assessment for that. But helping the doctor understand, hey, I don't get up my stairs the same. I'm not having my daily activities happen the same. We want to encourage that conversation so that they understand that, that is the time to think about switching to a new therapy.

In addition to building real-world evidence that helps provide that confidence that when you do switch to PomUp that, that is, in fact, a benefit to those patients. So I don't know if you want to speak to that, Greg.

No, I would just add that, again, this is a case where data often comes from real-world evidence when we're showing again what the opportunities for this next-gen product is when there's just a high prevalence of treatment with the first generation. I would just add that there are some registries that are currently enrolling around the world where in other health care systems with the tender process, there's often an entire population that will switch. We have a couple of examples of those. We're following them very closely. And they do provide opportunities to show whether it's Lumizyme and Nexviazyme moving to PomUp or vice versa, what the results of those would be from a clinical standpoint. We want to generate the right evidence so that the patients feel pulled to their next opportunity, not just the disappointment that one therapy might be not meeting their needs.

So the confidence comes from zeroing in on those strategies and then looking market by market at how we can do that.

Yes. And there's been a lot of interest just in the level of accretion that you all could see from a deal like this and these 2 assets. So I mean, how much of that accretion actually comes from the revenue opportunity set and the upside and the growth from a top line perspective versus some of the cost synergies that you were mentioning earlier?

I think it's both.

Yes. So it is indeed both. So again, substantial non-GAAP EPS accretion in 2027 and the realization of $220 million in synergies in 2028, which will largely come from G&A is the biggest driver of that. But when you ask about kind of what's driving that, I'd say the bigger driver is the revenue growth of the 2, but all of these things combined really help us with.

Okay. Great. And maybe the last question I'll ask is for you, Greg. You guys have spent a lot of time rebuilding and broadening your pipeline. So are you happy with the pipeline that you have today? Are there still any gaps that you see or that you'd like to fill?

Yes. And you don't sit in my chair if you're entirely pleased with the scenario. We want to continue our journey here. We have spent the last few years shifting our pipeline focus. We have a future that we know exactly what we want to be and where we want to go. We have our 2 business units. We have some areas additionally that are adjacent to those that we're thinking about. Internally, we've pivoted away from gene therapies, well understood, looking at more classic off-the-shelf pharmaceuticals. We have a couple of, I think, important molecules that we've added even in the last couple of months, the DMX-200 that we call BMN 820 for focal segmental glomerulosclerosis. We have the U.S. rights to that acquired through Amicus. We've also added in the skeletal space. We have added ALE01 (sic) [ ALE1 ] from Alesta, small molecule for hypophosphatasia, again, with the opportunity to not only be a substrate reduction therapy, but one that biodistributes to the muscle and potentially the joints where some of the more bone-targeting agents might not have their best efficacy.

These are the kind of molecules that both externally we want to create and internally from an organic standpoint, we have a focus, again, on reimagining the molecules that we bring forward. And I think what you're going to see in future years is that our pipeline evolution is going to be roughly a 50-50 mix of those, organic versus inorganic. We're in a fortunate position from a balance sheet standpoint, where we have the ability to go out and bring in those molecules that we think in our hands, we could not only use our development machinery, our patient finding machinery, but ultimately, our commercialization machinery to bring forward.

So to answer your question directly, we've made a lot of good progress, and we are going to keep going. We have the luxury of keeping going. And I think we have the know-how how to get these molecules and move them through the system.

Great. Well, Cris and Greg, thank you very much. Great discussion.

Thank you for having us, Olivia. Thank you.

Great. Thank you so much for joining us for this afternoon session. My name is Mohit Bansal. I'm one of the biotech and pharma analysts here at Wells Fargo. And I'm joined by Team BioMarin with us today. So we have Greg Friberg with us, the Head of R&D at BioMarin, and then Cristin Hubbard, she's the Head of Commercial at BioMarin. Thank you very much for joining us today.

Thanks for inviting us.

Awesome. So maybe let's just start with big picture. There has been a lot of development at BioMarin since you both joined. So what makes you excited about all the accomplishments in the last 1 year or so? And tell us about the investment story at this point?

I'll start. Okay. Well, we are really excited at BioMarin. As you've mentioned, we've had a lot of updates over the last year, and I'd say the last couple of years. And I know you'll get into some of the R&D updates. But some of the things that we're really excited about is that when we look at our established business units, so we have 2 of them, one which we used to call enzyme therapies, but since the acquisition of Amicus, we're now calling it metabolic conditions. And we have a lot of exciting activity there.

And this was historically a durable franchise, if you think about it, right? We had 5 products that we considered, in that, 4 of which were first in disease. And these were products that we've seen 9% CAGR over the last 3 years, going up to $2.1 billion at full year last year. And this was things that aren't coming from new launches, right? These are -- we have Naglazyme launched in 2005, hit $500 million last year. We have Vimizim launched in 2014, $800 million last year. We have a really durable franchise there.

But then we have the addition of Amicus, just as we closed this last April, really exciting growth story that I know that we'll likely get into, but we were able to talk a little bit more about the opportunity in our Q2 call. And this is where we're talking about the potential. These are 2 commercial fast-growing products that we have real potential to expand on, growing to possibly $1.4 billion for Galafold in Fabry and $1.2 billion at peak in the mid-2030s, late 2030s for POMBILITI and OPFOLDA in Pompe.

So really exciting growth areas for us, not to mention what we have going in skeletal conditions, which I'll touch on quickly. We did just recently announce just to start it off, a settlement with Ascendis, which I think helps to clear some of the competitive overhang, which I'm sure we'll get into. But this is also an exciting area for growth for us in terms of VOXZOGO.

We had 14% revenue growth at the quarter, 20% patient growth in Q2 year-over-year, but also growing sequentially. And just a really exciting time where we're seeing great growth coming out of the younger population for VOXZOGO, but also importantly, we're seeing global expansion of this brand. So very exciting times. And then we've added some things to our pipeline that I know you'll get into, Greg. So I'll hand it over to you.

Yes. No, hot off the press is, of course, this morning, we were able to show the world the totality of our hypochondroplasia data. Really excited about that. Again, the opportunity for really a first-in-disease therapy for VOXZOGO as an extension. The results exceeded our expectations. And again, not only on the efficacy side, but the safety came out quite nice. And again, that is currently -- has been submitted to the FDA for review.

Similarly, we're looking across our portfolio and really trying to restock our pipeline. That involves both internal as well as external innovation sources, we most recently closed the deal with Alesta Therapeutics for an HPP oral therapy. I'm happy to get into it if we have additional questions. And then, of course, looking forward to our next-generation CNP product in BMN 333, which will turn over a card looking for superiority versus VOXZOGO in achondroplasia next year.

I'll just kind of wrap it up by saying along with the Amicus acquisition, we also acquired the U.S. rights to a molecule called DMX-200 that we call BMN 820. This is for FSGS, focal segmental glomerulosclerosis. And again, that is an ongoing Phase III study that will read out in the 2028-time frame. So our pipeline is looking different than it did even a year ago when I was sitting here, and we're looking forward to continuing to build it, both with internal as well as external innovation sources.

So you guys have been very, very busy between Amicus and all those deals you have done. So let's just start with the base business first, right? For years, this base business was growing at like mid-single digit to low single digit. What is the secret sauce for this like 9% growth in the last 3 years or so? Is this like extra effort on sales because this market is very sensitive to sales and marketing effort and finding patients effort as well? So talk a little bit about that.

Yes. So what we've really been focused on with regard to our metabolic conditions business is a platform, a commercialization platform, I would say, that we've built over the last couple of decades at BioMarin. And what we focus most on is what we call kind of the 3 pillars that we focus on. It's find, find patients where they are, start patients on therapy and then work to make sure that they stay on therapy and they adhere to therapy.

A lot of what I would say the secret sauce has been really in that find category. These are conditions for which there was no previous prior treatment. So it wasn't like you had people that knew to necessarily seek treatment. But what we've done is we put a lot of energy and resources into making sure that we are finding patients. This comes in the form of genetic screening. It comes in the form of family cascade screening.

So once you identify a member in the family, how can we ensure that other patients in that -- or sorry, other members of that family get tested? But we're now introducing new areas of using technology, AI technology, investing more in different forms of data, both structured and unstructured, in addition to just making sure that we're investing in digital campaigns to find patients, educate on these conditions and then hopefully get them to a point where they can be treated.

Lastly, I'd say in terms of the starting, we have a country footprint that is 80 countries wide. These are not necessarily easy countries to find reimbursement and really navigate the reimbursement landscape there in. So that's what we've also been focused on is really understanding in each of these respective markets, how can we ensure that we have the right commercial, medical, but importantly, market access capabilities so that we can get patients on therapy and keep them there.

Got it. Very helpful. And then that's a nice segue into like that's exactly what you talked about when you acquired Amicus that like -- so you could use that infrastructure for both Galafold and Pompe. Amicus has done a tremendous job in selling that product by themselves as well. So help us understand which geographies they were not in and where you can actually add value to that franchise here.

Yes. And to your point, Mohit, I think Amicus did an incredible job at kicking us off in both Fabry as well as Pompe. What I would say is that we have gone by country by country and understanding in our 80-country footprint where we think we could provide the most value. In some cases, for both Fabry and Pompe, this is going to be to accelerate in some of the countries they already were in. So when we acquired Amicus, Galafold was already in 40 countries, PomOpf was in 15 countries.

We looked at this country by country and found that we very much think that we could successfully expand into 10 more countries for Galafold and another 20-plus countries for PomOpf, just given where it is in its life cycle. And like I said, we wanted to make sure we understood the landscape there, what is the competitive dynamic in each of these countries and how can we build on this.

We've also found that even in countries where they were already marketed, we believe that there are areas that we could add additional resources to that could help us to accelerate in those specific countries. So again, we've done a country-by-country buildup, and that was what then informed those peak year revenue numbers that we provided.

Got it. Completely understand. And that's the reason why you raised the guidance...

That's right.

Peak revenue, everything. So on that -- the question is there's this recent shortage for Sanofi's drug related to manufacturing issues. Are you seeing any early signs of any switches to PomOpf?

Yes. What I can say at this point, and we'll update as soon as we have more information and are able, we are definitely hearing about the shortages primarily in the EU. We've heard that from the community, physicians alike. And so what we're doing is we're working very closely with the community as well as the regulatory bodies to see where we might be able to provide, but until we have more information.

Understood. So I want to talk about VOXZOGO and then we'll get into BMN 333 with that segue a little bit. So VOXZOGO has grown really well. And now you have settled with Ascendis as well. So can you talk a little bit about like the thought process behind the settlement, first of all?

And then the competitive overhang is still there. So what dynamics switch versus non-switches you have seen so far in the U.S.? And do you think there's a bolus there that could stabilize over time? So how should we think about that?

Yes. So with regard to the -- first, the first part of the question, which was the Ascendis settlement, we just announced this very recently. And this is something where we will get retroactive royalties applied to any commercial sales, net sales for Ascendis, and that's 20% in the U.S. and 18% in the EU, Brazil and South Korea. We are really excited to do this because we think that it does help to clear the overhang, quite frankly.

It also enabled us to actually capture value immediately because we were in the midst of our ITC litigation in the U.S. that doesn't actually provide rewards. They cannot rule on rewards. And so we would have had to go through U.S. district courts and then litigations in multiple jurisdictions in other countries. So we felt like this was a very good thing to just clear that overhang. Most importantly, it helps the community.

We know that it's good for patients to have options. And if and where Ascendis is able to drive any additional growth in territories that we were not able to, we could also share in that value capture. So excited about that. But with regard to our commercial strategy and how it affects what we're doing on the day-to-day, it doesn't affect anything we are doing commercially. We will still continue to grow and to compete just the way that we've always been.

And really where we see the biggest drivers for VOXZOGO are in what I talked about, the 0 to 2 population. So this is about getting patients as early as possible, treating them when we know that this provides the most benefit to their overall health. And we will have exclusively -- we believe we'll have the label in those 0 to 2 population exclusively for the next couple of years. So an area that we certainly intend to drive growth.

In addition to the broad swath of countries that we are continuing to commercialize in, we've built a network in 55 countries where we're commercially available. This is not necessarily easy to catch up to. This has taken time, and we anticipate that it would take any competitor's time to do that as well. With specific regard to your question about Ascendis and how we're doing with the competition, we were able to report in the quarter that we have retained 90% of our patients to date on therapy.

We believe in large part, these are families that have seen the benefits of VOXZOGO and have gotten used to the daily routine that they have, and we anticipate continuing to do what we can to keep these patients on therapy. It remains to be seen whether or not this is a bolus, if this is a steady state in terms of the competition, and we'll look to provide color in future calls.

Got it. Makes sense. But then -- so the guidance you have given, you assume some amount of competition for the year?

Yes. So what you're referring to is the guidance that we updated on the quarter call. So we raised the midpoint for global VOXZOGO sales to be at $1 billion at the midpoint. And really, this did take into consideration the switching rate that we were seeing. It takes into consideration the growth that we're seeing globally, not only in the U.S., but also in addition to that globally.

And importantly, we had talked a little bit about there were 2 major market access renegotiations that are underway. One, we've -- has come through favorable to us and the other is still underway. So all of this was taken into consideration as we looked at the updated guidance. And I do want to say we did not update the guidance, nor do we think that there'll be a big impact in this year due to the settlement itself.

Got it. Completely makes sense. And then, I mean, you did touch upon the international markets. I mean, they are the bigger portion of the business here. What are the puts and takes in those markets? Like are they similar to U.S. market? Are they different versus U.S. market? And there's a time element there. You have to negotiate country by country; it takes time to get there. So how defendable do you think this -- your position is in international markets versus U.S. market?

Yes. So our global business outside of the U.S. is 75%, currently 75% of our revenue contribution on VOXZOGO. And we believe that this is a defendable state, if you will. And like I mentioned earlier, it certainly takes time to understand local market dynamics, how to expand on those dynamics and really how to build those relationships. And so what we've seen is that it really does depend on country.

In some cases, you find more centralized single-payer countries, which you can really get out the gates quickly on, you can treat the broad population quickly, and we've seen that in some countries. In others, it's a little more of a build. So it does depend on country by country. But what I would say is that I think that some of those countries or many of those countries are going to take longer for any competition to really entrench into.

Got it. Completely makes sense. So from defense to offense actually. So BMN 333 is offense. So talk a little bit about like -- I mean, the dose selection was very interesting. So you -- in the PK study, you had like the 500 microgram per kilogram dose actually produced significantly high increase in free CNP level. I think almost 14x the...

Yes, 13x...

Yes, something like that, right, of the other longer-acting CNP. So how should we think about the greater cCNP translating into AGV improvement here? And then the reason for selecting the 350-microgram dose versus the 500-microgram dose.

Yes, so it's pretty typical in single-dose studies to test 1 dose higher than you're going to go in your multi-dose study. And that has to do with the fact that it's a 100-hour half-life molecule. So there's some accumulation. So that's really the only reason that, again, that there was a higher dose in the single-dose study.

The 3 doses that we picked, 150 micrograms, 250 micrograms, and 350 micrograms per kilogram, all represent molecule or represent levels that met our criteria of what we were looking for. We were looking for a sustained 3x AUC exposure to free CNP. And that gets roughly 3x, 5x and 7x. Interestingly as well, and this was in our poster from the Phase I study, all of those also provide increases in plasma cyclic GMP levels. Again, that's systemic.

But again, a nice biomarker that we're getting closer to the physiologic activity and showing that there is more biology to be had there. Beyond that, what we've looked at, of course, is the exposure response as well as the dose response data from the available therapy, from the YUVIWEL data.

And again, we're convinced that there is additional growth to be had there. There are a variety of ways to measure the sigmoid curves that are there. But again, there is a good belief that not only do we have a lot more free CNP that we're going to be able to deliver, but that we believe that there is no plateau that's been clearly established if you look at the mathematics behind those curves.

Got it. Completely makes sense. And then how much room there is for this mechanism to improve the AGV here because there is a natural barrier, right? I mean, these kids grow at about 6-plus centimeters per year, normal healthy kids versus these kids are more like 4 centimeters -- 3.5 centimeters to 4 centimeters...

Yes. Our investigators always kindly remind me that during growth spurts, teenagers can be 10 centimeters, 12 centimeters, even 15 centimeters a year. So physiologically, there's growth to be had. With the achondroplasia and to a lesser extent, but still true with hypochondroplasia, part of the challenge also is fighting that growth deficit that they're either born with or because of the lack of the growth spurt is there.

The question of whether there is a plateau and when it will be reached is an unanswered question. What we think we have with BMN 333 is the right molecule to answer that question. Again, from an AUC standpoint, the cyclic GMP and again, the behavior of the molecule, we think that the weekly administration of 333 is going to be able to answer that question.

So in Phase II, we are measuring 3 different dose levels. We have a control arm of VOXZOGO as well. Of course, we've got the world's largest supply of data for VOXZOGO also that we can use when it comes to looking at the Bayesian model. But our goal there is to have that result, which we would have next year and be able to again inform what a Phase III study for superiority versus VOXZOGO would look like.

This is a 6-month trial or 1-year trial. This is a 6-month trial.

So predicted AGV coming from at least 6 months of data for all patients on the study. We are going to use the totality of data once we've completed, but it will be at least 6 months on every individual patient, and we'll be projecting towards what the AGV, so the 1-year data would be.

Got it. Completely makes sense. So can you help us set expectations around that? Like what exactly you want to see, like this could look like a superior drug because like there will be investment going in for that. So just trying to understand that.

Well, so the most direct answer I can give you is to talk about the design for the Phase III study. With 60 in each arm, there's a 90% power, detect a 50% improvement. So that would be just doing the math out from about 1.5 centimeters delta of AGV up to about 2.25 centimeters.

Now that's not the minimum detectable difference, but that, again, is the powering of the study. And certainly, we believe that, that would be a meaningful increase. We talk a lot about AGV, but we've learned a tremendous amount from VOXZOGO on all the measures of health and wellness that actually track along with AGV.

Part of our goal with 333 is going to be to leverage that data, not only to measure in the study during the randomized portions but also put together the evidence package that more linear growth will translate into more measures of health and wellness as well. More to come there. But again, that is the ultimate goal here, not just children that are taller, but children that are healthier and straighter.

Got it. So just scenarios here. In case it is less robust than what you are thinking in Phase II, what are the aspects of Phase III design that could still be altered to improve the probability of success?

Well, I think if we look at the 6-month minimum cumulative data and the results are not as clear to us, we could always run the study out to 12 months and look at the data as well. But we're not planning for that. Again, we're planning for a weekly administration for a superiority endpoint. Of course, if that hypothesis didn't play true, we could evaluate other opportunities, but that's not what we're planned for.

Got it. And then like there's also data for growth hormones plus CNP. I mean, like if you talk to 10 doctors who get 10 different responses on that, by the way, right? So some believe in something that it does help, some things it doesn't help. Now like let's just say if the benefit lasts for 2 years, which is a big if, at this point, would you think differently about BMN 333? Would you change anything about the clinical trial design here?

Yes. A couple of thoughts off the top of my head. Growth hormone is not approved for achondroplasia in almost every jurisdiction around the world for a reason. That is that it can uncork a year or 2 of growth, but that has not historically resulted in an improvement in final adult height. And that has the specter of whether or not, again, the growth plates are closing earlier.

So uncorking more growth at the expense of the amount of time that the growth plates remain open. So that is an unanswered question. I think that with regard to the data that's out there, combining with CNP, the jury is still out. It's too premature. Again, we're seeing salami slices of every 6 months, whether it's increasing or decreasing, we can argue that.

What we believe 333 offers is the world -- it would offer the world one drug that would offer the superior growth. We think that, that will be valued. And even if growth hormone is there, combining with the best CNP product is what we believe the world is going to value most. So we think there's a place for BMN 333. And again, sticking with the plan at this point, it's premature to think about adding growth hormone into that paradigm.

Got it. Completely makes sense. So rounding out this topic, so how are you thinking about the oral that is coming to the market in this space? How do you think about that as a competitor?

So from a science standpoint, again, I think the 1-year data, again, which was published, speaks for itself. That is a very different scenario, though, than looking at 10 years of safety data. Again, we put in our full approval package, not only for what we call final adult height, but again, all of those measures of health and wellness over time. So it is a bit premature to compare one to the other.

I do think that with the small molecule tyrosine kinase inhibitors, we're always interested in seeing the long-term safety profile as well. This was a drug that, again, had a life before it was given at these doses. It's got a label. It's got an animal tox package. It's got warnings and precautions.

Those are things that, again, I would want to see additional follow-up data before we would try to compare them head-to-head. That being said, again, it's good for patients. The fact that there are multiple therapies out there, this is something that we're prepared for. And again, what we have with CNP is an undeniable safety and efficacy profile that patients can depend on.

And the only thing I'd add to that, just kind of looking at the marketplace, I think to your point, one of the things that we see as most valuable to these families is the safety profile, especially because you're treating young kids. So that will obviously be something that everybody is looking to. But I also think that if we even look at the kind of the entry so far of another competitor, I think it does show that this is not necessarily an easy kind of marketplace, if you will, thinking about the U.S. just to come into overnight.

It's certainly these are patients that are not seen very often. They're dispersed among specialties and you still have some reticence to treat in some cases. So I think that this also will be an evolving landscape that it will be interesting if more entrants come into is what happens over time.

If I could just add one other comment, which is we're talking about achondroplasia. I think when we think about hypochondroplasia, we're very proud of the data published online this morning in NEJM Evidence. This may be a different biology that we're dealing with. The mutation in FGFR3 that causes achondroplasia is, for the most part, it's a single mutation.

There's a large basket of mutations that are involved in hypochondroplasia. And again, preclinical data that's published have suggested that the IC50s for those mutations might be variable for a small molecule inhibitor. Our published data for hypochondroplasia showed that across the different mutations, we have the same effective range. And so again, the CNP story in hypochondroplasia might be slightly different than it is in achondroplasia.

Got it. Very, very helpful. Sorry, I did not get a chance to look at NEJM paper this morning. Thank you very much. Appreciate it. So A bunch of other pipeline questions as well here. So BMN 351, the DMD asset, I think we'll see data for the higher dose, 12 milligram per kilogram dose later this year. Talk a little bit about what do you need to see to move forward. And then how should we think about the...

The name of the game in Duchenne muscular dystrophy now is the benefit-risk profile. And so at the end of the year, we're going to have additional data from a higher dose level. That's the 12 milligrams per kilogram. But most importantly, when you think about benefit-risk, yes, it's benefit with regard to dystrophin levels, but the field is also interested in, I think, the pull-through of the more functional measurements.

That's normalization of CK, that's looking at mobility measures, whether that's with stride velocity 95C, whether it's with the North Star Assessment, all of those go into the totality of the package, and we will have additional follow-up on those endpoints, both from the 9 milligram per kilogram as well as we'll have the 12 milligram per kilogram.

And of course, on the safety side, we're going to see, again, that chronic safety profile and weigh that. Ultimately, it will be the benefit risk profile that will allow us to make a decision about whether or not, again, moving forward with 351 makes sense.

Got it. Very, very helpful. Last couple of questions on the pipeline side. So HPP assets, right? So obviously, there is STRENSIQ out there. The question here is that this is an oral. So how do you think about the differentiation? Is it because it's an oral, it could go early in the disease spectrum? Or do you think it could replace the injection?

Yes. And our goal is not to develop a molecule that's a more convenient version of what's already available. The oral therapy actually targets upstream of where -- this is a disease where pyrophosphate increases, and that's a direct inhibitor of bone mineralization. So by inhibiting the upstream enzyme, the goal here is to have almost a substrate reduction therapy, similar to, say, Gaucher's where enzyme replacement and upstream have been successful.

Our goal is to have this upstream decrease. Again, that will afford the ability to provide an oral therapy. But more importantly, as a small molecule, it also allows us to administer a drug that could potentially reach compartments but a bone targeting biologic would not be able to address as robustly.

That being areas like the muscle, where when you think about patients with HPP, particularly the older patients, the older phenotypes, it tends to be muscle pain, fatigue, more of these malaise-type symptoms that become of interest. And so great work has been done again by the alkaline phosphatase replacement therapies. We would hope to build upon that, both for children as well as adolescents and adults. Anything else that you want to add?

No, just to add that -- and it is a commercially validated market, if you will, given the -- how STRENSIQ has done since launch. And I think that this is an area that we know -- we believe there's about 9,000 patients alone that are estimated in the U.S. and only 10% to 30% of them are currently on treatment. So we think that there's a real opportunity to bring something different to market that could be commercially successful as well.

So the Phase I data that's currently still enrolling, both in healthy volunteers as well as patients, we'll plan to share that next year. So that will be a moment where, again, we can reveal some of the data that we've seen already.

Got it. Very helpful. Speaking of data reveal, so obviously, Phase III for FSGS is fully enrolled now. I think readout is in '28. But can you talk a little bit about your thoughts around this particular asset? It doesn't get talked about a lot. You got it via Amicus. I mean, FSGS like Travere, I mean, they are selling quite nicely in that market. So how do you see your assets there? Does it need to be differentiated? It's a different mechanism. So like can you talk a little bit about that, your thought process there?

So what we're calling BMN 820, formerly known as DMX-200, again, being developed by a company called Dimerix. We're partnered with them and have the U.S. rights for the molecule. This is being studied as a CCR2 inhibitor. Again, it works slightly differently than prior generations of CCR2 inhibitors. This blocks the dimerization with the angiotensin pathway. And so in that regard, gives an opportunity to target the disease at a very different place than the pure vascular targeting agents.

Unlike say sparsentan, this is a study that's a slightly different design. It takes patients on angiotensin receptor blocking therapies and it layers on either 820 or placebo. Some great work that's been done in the field, both by investigators as well as some of the other products really to move the FDA's position and now 2-year reduction in proteinuria is a legitimate validated endpoint for full approval.

And so that's what this study is built to measure. It's a study that's fully enrolled, as you mentioned. It's, of course, made its way through a futility analysis at this point. We believe that the study is appropriately powered. The promise of the molecule is that this different pathway, targeting macrophage-driven inflammation will offer not only a different mechanism of action, but a potentially differentiated one.

We're looking for meaningful reductions in proteinuria. Of course, we'll measure eGFR as well. And again, the promise is that there wouldn't be the liabilities of, for example, a black box warning or again, limitations based on nephrotic syndrome. Again, the hope would be that this would have a broader targeted group of patients, and we're looking forward to, again, seeing that data in 2028.

Got it. Very helpful. My last question for both of you. Fast forward 1 year, Wells Fargo 2027 Healthcare Conference. I hope you both are here. I hope I'm here. What would make you look back at the year and say it was a great year for us?

Do you want to start?

I'll start. We are in the midst of a restocking of our pipeline, and we're going to continue that process. So that will mean additional organic as well as inorganic growth opportunities, whether it's clinical stage or preclinical.

Again, we have the ALE1 molecule we've talked about, did a smaller deal with a company called n-Lorem recently. We want to keep going, both from a BD standpoint as well as our organic development. And I'm hoping that a year from now, we'll have more to talk about on the pipeline side.

I think on my end, really focused on execution and making sure that we don't miss a beat. When I think about the skeletal condition side, I want to be talking about an incredibly successful launch in hypochondroplasia. That will be just an amazing thing to do and then talk about what the global expansion plans for that are.

For metabolic conditions, I want to see continued strong growth and the continued real growth trajectory for the Amicus product showing that we can not only integrate a company but also grow it at the same. So we'll have a lot of exciting things to talk about, I think.

On that high note, thank you very much for joining us today and all the best.

Thank you so much.

Thanks for having us, Mohit.

All right. Good morning, everyone. Thank you so much for joining us. My name is Whitney Ijem. I'm one of the biotech analysts here at Canaccord. And it's my pleasure to introduce BioMarin Pharmaceutical this morning. And on behalf of BioMarin, we have Brian Mueller, CFO. Thank you for being here.

So just to start off high level for anybody who's not familiar, for anybody who that might be, I don't know, BioMarin is a household name. But for anybody who is not familiar, can you briefly introduce the story, like who is BioMarin currently? And where are you trying to go over the next 5, 10 years?

Yes. Thanks, Whitney, for having us. Really glad to be here. Thanks, everyone, joining in person and those online. Yes. So I do think there are some folks that may not be familiar with BioMarin. So I thought I'd give a little bit of maybe the past, present and future, and then we can get into more details in the business.

So BioMarin Pharmaceutical is one of the largest rare disease-focused companies. The company has been operating for a bit over 25 years. And it's interesting back when we started our journey, there were only a handful of rare disease companies. There was BioMarin, there was Genzyme, Shire, TKT. However, those other companies are now part of larger pharmaceutical companies because they were acquired over the years. And while now there's hundreds of other rare disease companies, BioMarin spent the last couple of decades plus growing and scaling while retaining that rare disease focus.

We've got 6 first-in-disease medicines, 9 approved therapies overall. We've got higher-than-average success rates in the biopharmaceutical sector, and that's largely because of our focus, not just rare disease, but genetically defined conditions. So we ensure when we embark on research programs that we understand the underlying genetic causation of the condition. And then we design a precision medicine aimed directly at that genetic cause. That comes with a number of competitive advantages in biopharma.

First of all, rare disease patient populations are often smaller, which means smaller studies, which can be run in shorter amounts of time. There are certain regulatory incentives like orphan drug protection and other accelerators in the regulatory pathways and a lot of community support. So rare disease patient advocacy is very strong. So we partner with regulators, the patient communities, and that's been a significant part of our success.

But now we've grown and scaled the business into close to an expected $4 billion of revenue this year. We've built global world-class biopharmaceutical capabilities. We have in-house manufacturing, end-to-end research and development and commercial capabilities. We operate in over 80 countries worldwide. So again, rare disease at scale and one of the leaders.

Shifting into the present. We just reported our Q2 financial results last week. We had nearly $1 billion of revenue for the quarter, which was 20% growth year-over-year. We raised our guidance to $3.875 billion to $3.925 billion for total revenue. We also raised our non-GAAP earnings per share guidance from $4.90 to $5.10.

Another significant announcement last week was in closing the acquisition of Amicus Therapeutics. During the quarter, we shared our plans for the Amicus business. Amicus is a rare disease-focused company based here on the East Coast. They had 2 commercial assets, Galafold for Fabry disease and Pombiliti and Opfolda for Pompe disease. These are both high-growth assets and very complementary to BioMarin's business. We announced the acquisition back in December and closed it during Q2.

Part of the strategic rationale for this transaction was taking these 2 high-growth medicines in a small company into the BioMarin infrastructure and global platform where they should actually be more valuable. And what we shared last week was our aspirations for the Amicus business. We shared our view on peak revenues for Galafold, which is $1.4 billion and for Pombiliti and Opfolda, $1.2 billion, both in the mid- to late 2030s, respectively. We shared that -- we shared our view on synergies. We believe that we can synergize approximately 50% of the legacy Amicus operating cost base.

Again, 2 companies together, BioMarin at scale. We have the platform. So when it comes to infrastructure, most of the synergies are coming from general and administrative expense and other business support. That's where the bulk of this 50% synergies comes from. Very importantly, we preserved and left intact. And if anything, we're investing in the Amicus sales and marketing, all of those customer-facing capabilities. Again, these products are in their high-growth phase. So it was important that we preserve that growth and invest in it. So we weren't aggressive with any synergies within sales and marketing.

So with that revenue growth profile of the Amicus business and with some of those cost synergies, what that results in is a substantially accretive business over time and significantly increased cash flows. We shared that we accelerated our deleveraging target. BioMarin took on leverage debt for the first time to do this acquisition. And at the time of the acquisition, we shared a leverage ratio target of less than 2.5x within 2 years of closing the transaction, which was again just back in April. After doing our work on both that revenue growth and the synergies, we accelerated that deleveraging target by roughly a year, and we think we can be at that less than 2.5x by the middle of next year.

And the last thing on the accretion is, again, the combination of the revenue with those cost synergies over time, over the next few years, say, by 2030, we think the Amicus business can operate at a 60% operating margin, also contributing to what is already a healthy BioMarin operating margin. So that's some of the present.

And in the future, our strategy is to realize the growth potential of the business, lots of commercial execution to do, both on our base legacy business and in successfully growing and completing the Amicus integration. I should have mentioned in the sort of past to present, we also transformed the company over the last couple of years, significant changes in our focus, in our operating model. We substantially improved our profitability and cash flow. It was great timing that we did that because now when we layer on the Amicus business, it's on top of this reengineered transformed BioMarin operating model. And so we're expecting to generate significant growth in revenue, earnings per share, but most importantly, cash flow because cash flow is the vehicle to be able to reinvest in the business.

Our top capital allocation priority is to continue to invest in future growth and thereby shareholder value. We talk about sometimes this virtuous cycle where we're growing and reinvesting in the right assets, both our internal innovation and inorganic business development external innovation, continuing to grow and reinvesting. So again, this virtuous cycle with a flywheel effect, that's the strategy.

Yes. Excellent. Okay. Very, very helpful and a lot to dig in there. I think we'll stick with Amicus and start there. So as you mentioned, delevering 1 year sooner than originally thought. You touched on it, but can you give a little bit more color around what is driving that? Is it really upside on the revenue front? Is it more synergies? Or are there other levers that are kind of different as you got in there versus...

Yes, of course. Thanks, Whitney. Great question. Yes, it's multiple levers. So I might start with where I kind of finished the opening remarks with that transformed BioMarin-based business. We've gotten to a level where we're generating not just significant levels of operating cash flow, free cash flow, but that EBITDA base for leveraged debt. So even without the Amicus business, we've got a healthy growing solid base of cash earnings, if you will, and growing into next year.

On the leverage target itself, I'll share that with BioMarin as a first-time debt issuer, it was very important that we go on the record at the announcement of the transaction with a sound financial policy. That was at less than 2.5x within 2 years. I will share that there was some room in that. If you were to model out our EBITDA, and the debt we raised was about $3.6 billion. We also have a $600 million convertible note on the books, but that actually matures next May. So that helps deleverage a bit in itself. So it was a healthy situation to begin with is my point.

And then to your question, once we layer on the Amicus business, because we are growing revenues, we think there's more of an opportunity than, again, Amicus stand-alone, we can get more into what those levers are as well. But then with the cost synergies, the combined EBITDA profile over the next 12 months really got us comfortable that we can accelerate that deleveraging target.

Okay. Really, really interesting. And then going back to the revenue guidance for Galafold and Pom-Op, I'm just going to use the short version, Pom-Op.

Sure. I might as well.

Yes, exactly. $1.4 billion for Galafold and $1.2 billion for Pom-Op. I think that was ahead of consensus and kind of how we had all been thinking about it. So can you talk us through what's driving that as well? And maybe as you're doing that, probably part of the answer is around retaining the existing sales force and the relationships and just kind of help us understand how all that works together.

Yes, of course. Yes, maybe picking up where you left off. So really important to retain, preserve and grow the capabilities because both of these medicines are still in their high-growth phase. The capability that applies to both Galafold and Pom-Op is the BioMarin global scale and capabilities. There's a couple of elements of that. First is global reach. I mentioned a few moments ago that BioMarin commercializes its product in 80 markets globally. Amicus had previously commercialized Galafold in about 40 markets and Pom-Op in about 15 markets. So that global expansion is a huge opportunity for us.

To be clear, we're not expecting to take both products into all 80 markets. Some of those are small and unique to just a couple of assets in our portfolio. But nonetheless, the pure geographic expansion is one lever. Second is just some of those global capabilities. It's not uncommon for earlier-stage commercial companies as they're growing when they do expand internationally to use a partnership distributor model. BioMarin does use distributors, but in most of our countries, we've got BioMarin capabilities on the ground. This is both marketing and traditional commercial, market access, medical, regulatory. When you get out to several of these international markets, those are very complex. They take time. But BioMarin, again, has been doing it for over 20 years. So that should also be not just an accelerant, but an improved capabilities.

And then a couple of nuances on the medicines themselves. For Galafold and Fabry, it's believed that Fabry is still significantly underdiagnosed. And this has been one of the areas where BioMarin has built outstanding capabilities over the years, which is improving diagnosis. When I mentioned in my opening remarks that 6 of our medicines were first in disease, that's not just novel science and bringing a therapy to these disease areas that had no therapy available before. On the actual commercialization front, we actually had to build those markets. There's often not a treatment home or again, advocacy may be dispersed. So building these markets is what BioMarin has done.

Fabry, Galafold was not the first to market, so that you can say that the Fabry market was already built, but this underdiagnosis, we believe, is a big opportunity. We're going to be working on things like AI-enabled patient identification, newborn screening globally and in the U.S., that's done at the state level in the U.S. And then familial genetic line screening because Fabry is genetic and can be -- manifest itself in different levels of severity and different levels of symptoms. It's been seen already that if you do genetic family cascade screening, one patient can lead to many. So that -- those type of efforts, again, this is the type of infrastructure that we've built over the years.

And for Pombiliti and Opfolda and Pompe disease, it's a little bit of a different strategy. That's more of a switching strategy. Again, there are other products on the market for Pompe, traditional enzyme therapies. However, it's been seen that the efficacy for some of the existing therapies can wane. And there's an emerging body of real-world evidence for improved outcomes with Pombiliti and Opfolda. So getting that messaging out there through the medical community, driving these switches is -- plus the geographic expansion is the strategy for Pom-Op.

Okay. So while the commercial team is executing on all that, that's going well and harvesting those synergies, can you talk to us about BD and where you're going next? I think again, when the deal was initially announced and your -- the delevering time line was a little bit longer, the goal, you kind of said, well, we're going to say -- we're still interested in BD, but it will be smaller kind of pipeline. Does the delevering time line change impact that at all? Or kind of what's the mandate for the BD team now?

Yes. Thanks, Whitney. Great question. Yes, I'd say a couple of keynotes on the business development strategy and as it relates to the deleveraging strategies, as you noted. So first of all, the Amicus transaction was unique for us. Again, very large, close to $5 billion of total purchase price, commercial stage assets, a company already at somewhat of a reasonable scale as they had several hundred million in revenue. And again, we're a global company themselves. But because of that high strategic fit and the ability to transact, that was the right transaction to do last year.

In the end, again, because of the growth and the synergies and the improved profitability and cash flow profile for the company, it actually serves as an accelerant to our long-term BD strategy. The current focus is building out our pipeline at the moment on the BD. That's what the BD team is focused on. Even without considering the leverage profile, we believe we can and will continue to execute on early-stage clinical deals that can fill up that early-stage pipeline. And we'll always do early-stage collaborations. We announced just a couple of weeks ago a collaboration with the n-Lorem Foundation for RNU disease.

Again, not very material, and that's how BioMarin over time has had a lot of success and built our profile. It's this early-stage in-licensing where then you wrap around the BioMarin development capabilities and we make it a BioMarin asset over time. We will always do those. And then as we delever and have the opportunity to look at larger deals again, the priority will still be building out the pipeline. So then it could be mid- to late clinical stage assets, but still a bit early to comment on any specifics in terms of size or timing.

All right. Sounds good. So maybe to try on a different specific. In terms of like therapeutic vertical modality, are you looking broadly, presumably rare disease is the lens, but are there any other filters you place as you look outside?

Yes. Thanks. Great question. So yes, rare disease focus. And then further within there, genetically defined conditions. Again, we think this is very important. I mentioned it as being part of the foundations of the company and our past success. So the first priority within those parameters will be areas where we can leverage our in-house capabilities. I already mentioned in-house manufacturing. We also have a robust global external manufacturing network. We can manufacture and develop in multiple modalities, large complex biologics, oligonucleotides, even small molecules. So that -- and then also just research and development, regulatory, clinical operations, commercial capability. So making sure there's a strategic fit there so that we can get the leverage from our own infrastructure.

Further focus next would be within our therapeutic areas. So we've got 2 business units: metabolic conditions, which includes kind of the legacy BioMarin enzyme therapies and then Galafold and Pombiliti and Opfolda. And the second business unit is skeletal conditions, which today includes VOXZOGO for achondroplasia, on file for hypochondroplasia, BMN 333, the next-generation CNP, also in the skeletal conditions business unit. So you can think of assets that fit not just within rare and genetically defined conditions, but within those business units, lots of leverage. And we are open to expanding into other therapeutic areas as a third priority where we can still get some of that leverage from the base infrastructure that I mentioned.

Okay. I could keep asking you questions separately, but I will switch over to VOXZOGO. And again, at the quarter, you raised guidance for VOXZOGO to at least $1 billion. So what are the drivers of that raise? And I guess, what gives you confidence at this point to do that relatively early into a competitor launch?

Yes. Thanks. Great question as well. Strong first half performance is the start and confidence in the second half of the year. VOXZOGO revenues grew 14% in the first quarter, and we added 20% new patients globally for VOXZOGO. And then, again, confident in the outlook for the second half. So that really gave us the confidence to increase the revenue guidance, which is now a floor of $1 billion, BioMarin's first potential blockbuster therapy.

At the beginning of the year, we highlighted a handful of variables in the 2026 guide. One was a couple of international price renegotiations that were in process at the time. This is a normal part of the process. VOXZOGO has been on the market for 5 years in most countries. And outside of the U.S., there's often a process to either renegotiate or change over from a named patient sale model to a national formulary model that involves a negotiation. One of those was resolved with a good outcome. The other one had some initial setbacks but remains in process, but nonetheless was a net positive. So that was one of the variables that was partially solved for and in the guide does include the different potential outcomes for this year.

And then the other dynamic was patient switching as you mentioned, a competitor came to market earlier this year. So that remains another factor. And then just the variability of estimates at the beginning of the year and execution, and that's where I come back to how I started with that strong first half and confidence in the second half.

Okay. Got it. That sounds good. And then I guess you mentioned approved VOXZOGO, sticking with that, approved in achondroplasia, hypochondroplasia is up next. How should investors be thinking about the revenue trajectory post approval there? Is it going to be a bolus? Is it going to be a sharp inflection, more of a chug, stay chug?

Yes. Very excited. This is BioMarin's first opportunity for kind of a true label expansion into a new indication. So VOXZOGO was approved in 2021 for the treatment of achondroplasia, which is the most common form of dwarfism. Hypochondroplasia is a genetically similar condition as achondroplasia. It's the same pathway where the active ingredient in VOXZOGO, the CNP analog, which acts downstream from the FGFR gene, we believe has -- and data shows has the potential to be efficacious in hypochondroplasia as well.

We were pleasantly surprised that the Phase III study that we announced earlier this year, the data exceeded our own internal expectations. There's been an investigator-sponsored study going with VOXZOGO in hypochondroplasia. Dr. Dauber, his study, he released 3-year data, which again showed sustained efficacy for VOXZOGO. So with that Phase III data in hand, we filed -- we announced last week that we filed the supplemental NDA with the FDA in record time, again, AI-enabled. We benchmarked it and we're top quartile with the best companies out there in terms of Phase III data timing to filing.

Now the FDA still needs to review and accept the file. We'll share an update on our Q3 call on that, but we did want to share that the filing at least was submitted. So if accepted, that would mean a potential approval and launch next year. Achondroplasia, we estimate at 24,000 patients worldwide. Hypochondroplasia is a bit smaller. We estimated at 14,000, but still very substantial.

And as you touched on, the market preparation are the key efforts right now. Of course, we can't officially market until approval, but we can prepare the market on the medical side, building condition awareness, building the case for VOXZOGO as a mechanism. we should have as a tailwind, the trust and history with VOXZOGO in achondroplasia, which was very well received. There's thousands of patients that have had years of positive experience on VOXZOGO. So that's a good starting point for hypochondroplasia. Diagnosis is going to be one of the challenges. It's -- hypochondroplasia is more difficult to diagnose than achondroplasia. And that's why, again, these medical efforts will be important.

So that's the work that we're doing. I can't predict at this time a bolus or what the ramp might look like. We'll talk more about the market as we get closer. But I will say that different from other therapies where if we've had a rapid development pathway, get approved and then we're building the market as we launch, the advantage here is at least with VOXZOGO and achondroplasia, a lot of that market preparation have been done. So now it's hopefully a matter of just adding hypochondroplasia into that VOXZOGO ecosphere.

Okay. Perfect. We are out of time. I'm going to squeeze in one last question. I didn't get to ask about 133 (sic) [ 333 ] , which is the long-acting CNP or Palynziq, but I'm going to skip ahead to the FSGS program from Amicus. And can you just talk about the level of internal focus and enthusiasm there? And is there any potential to accelerate that by chance?

Yes. We're very excited about what was DMX-200 at Amicus is now BMN 820. This is a small molecule for FGFS (sic) [ FSGS ] kidney disorder. I'll share that when we originally did the Amicus transaction, when we did our valuation because that was a development asset and because there was so much value and we were focused on Galafold and Pombiliti and Opfolda, we did not assign a significant amount of value at the time of the deal to BMN 820. However, since digging in after completing the acquisition, we're very excited about it.

While there is another therapy on the market for this condition, it's a relatively narrow label. So BMN 820 is a novel approach and a potentially larger patient population. BioMarin has U.S. rights only. Dimerix is the developer. But we estimate that at about 30,000 patients in the U.S. So potentially broader label, slightly different mechanism of action. The other positive development is that the FDA has agreed to proteinuria as the primary endpoint, which is a positive. So we just need to let the study run now. It is a 2-year study. It was fully enrolled recently. Just a reminder, Dimerix is the developer. So BioMarin or Amicus actually doesn't do a lot of the operational R&D, but we'll be watching it closely.

Excellent. Thank you so much. Appreciate everything.

Good afternoon, and welcome, everyone, to the BioMarin Pharmaceuticals Second Quarter 2026 Conference Call. Today's conference is being recorded. [Operator Instructions]

At this time, I would like to turn the conference over to Traci McCarty, Head of Investor Relations.

Thank you, operator, and thank you all for joining us today. To remind you, this nonconfidential presentation contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc., including expectations regarding BioMarin's financial performance, commercial products and potential future products in different areas of therapeutic research and development. Results may differ materially depending on the progress of BioMarin's product programs, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market and developments by competitors, and those factors detailed in BioMarin's filings with the Securities and Exchange Commission, such as 10-Q, 10-K and 8-K reports.

In addition, we will use non-GAAP financial measures as defined in Regulation G during the call today. These non-GAAP measures should not be considered in isolation from, as substitutes for or superior to financial measures prepared in accordance with U.S. GAAP, and you can find the related reconciliations to U.S. GAAP in the earnings release and earnings presentation, both of which are available in the Investor Relations section of our website. Please note that our commentary on today's call will focus on non-GAAP financial measures unless otherwise indicated.

Moving to Slide 3 and introducing BioMarin's management team joining today's call, Alexander Hardy, Chief Executive Officer; Cristin Hubbard, Chief Commercial Officer; Greg Friberg, Chief R&D Officer; and Brian Mueller, Chief Financial Officer.

I will now turn the call over to Alexander to provide our quarterly highlights. Alexander?

Thank you, Traci, and thank you all for joining us today. Starting on Slide 5. BioMarin delivered a standout second quarter, combining strong growth to nearly $1 billion in revenue with the successful close and integration of Amicus while delivering on milestones that strengthen our leadership in genetic conditions. Our strong performance demonstrates both the value creation of our portfolio, and the continued execution of our commercial organization, executing at scale, integrating meaningfully accretive assets and continuing to innovate, enabling us to bring important medicines to people living with rare diseases as we enter an exciting new phase of growth.

Second quarter highlights start with 20% year-over-year total revenue growth accelerated by a more diversified portfolio and setting up an even stronger second half of 2026 to be fueled by full third and fourth quarter Galafold and Pombility and OPFOLDA contributions and sustained demand across our other products.

Turning to VOXZOGO, double-digit revenue growth in both the U.S. and international markets, led us to increase VOXZOGO full year guidance, putting it on a path to become BioMarin's first $1 billion product. In its first quarter with a U.S. competitor, -- the continued revenue growth demonstrates our ability to defend VOXZOGO leadership position. Building on this momentum, we are pleased to share that we have submitted our sNDA for the approval of VOXZOGO to treat hypochondroplasia based on strong pivotal data shared during the quarter. We will provide an update on the submission as part of our third quarter results.

Turning to Amicus. As anticipated, when we announced the acquisition, this deal demonstrates that BioMarin can leverage our scale and capabilities to rapidly integrate high-growth assets to maximize value creation. Today, we provide estimated peak revenue for Galafold of $1.4 billion and for Pombility and OPFOLDA of $1.2 billion. Together, these innovative therapies combined with significant cost synergies expected to reach approximately $220 million annual run rate in 2028, are anticipated to drive substantial EPS accretion and operating cash flow. Most importantly, we look forward to bringing Galafold and POMBILITI and OPFOLDA to more patients with Fabry and Pompe disease worldwide.

Briefly on our pipeline, which continues to build momentum. We recently added BMN 820, formerly DMX 200, an exciting new late-stage pipeline opportunity resulting from the Amicus acquisition that Greg will expand upon in a moment. I'm also impressed by the speed at which we submitted the sNDA for Voxogo for the treatment of hypochondroplasia. The speed of our submission reflects the benefits of our investments in AI capabilities and sets the new standard for how BioMarin will execute going forward. Together, these results tell a clear story BioMarin is executing at scale, raising guidance, outperforming on the Amicus integration with substantial combined peak revenue potential ahead and advancing pivotal pipeline data towards VOXZOGO next indication. As we enter the second half of 2026, BioMarin is stronger, more diversified and better positioned than ever to lead in rare disease and deliver for patients worldwide.

Now on Slide 6. The addition of Amicus transforms BioMarin's growth trajectory through the mid-2030s with a combined peak revenue potential of $2.6 billion from Galafold and Pombility and OPFOLDA and significant cost synergies layering in along the way we expect meaningful non-GAAP EPS accretion, standing operating margins and stronger operating cash flow, hiring our next phase of growth.

Moving now to Slide 7. And starting with Galafold, a growing product in a growing market. From a $522 million base in 2025, we project peak revenue of $1.4 billion by the mid-2030s, supported by 2 complementary growth drivers. First, we see significant opportunity to expand diagnosis and treatment. Leveraging BioMarin's proven diagnostic capabilities, our goal is to more than double the number of U.S. patients treated with Galafold. We plan to do this through scaling AI-enabled patient identification initiatives expanded genetic testing, newborn screening and family cascade screening, helping more amenable patients access treatment earlier.

Second, we see meaningful opportunity to expand market penetration globally. With Galafold already established in 40 countries, we intend to deepen penetration within existing markets while selectively expanding into new geographies, leveraging BioMarin's global commercial infrastructure to accelerate access and broaden reach. Together, these drivers are expected to support approximately 10% CAGR from 2027 to 2032.

Turning to Slide 8. POMBILITI and OPFOLDA is at an earlier stage in its commercial journey compared to Galafold. We estimate $1.2 billion in peak revenue by the mid to late 2030s, and growing at a greater than or equal to 20% CAGR from 2027 to 2032. We expect growth to be driven primarily by increased patient switching and global market expansion complemented by continued improvements in diagnosis and treatment leads. We believe switching will be supported by growing awareness amongst health care providers and patients of the expanded body of real-world evidence demonstrating the benefits of POMBILITI and OPFOLDA on disease outcomes. At the same time, we plan to leverage our diagnostic capabilities to identify and support treatment of additional eligible patients across our global footprint. These growth drivers are expected to be further strengthened by a planned expansion into more than 20 additional markets over time.

Turning to Slide 9. We are pleased with the significant cost synergies identified, which we expect to contribute to substantial EPS accretion beginning next year. We anticipate approximately $220 million of synergies to be fully realized in 2028, representing a roughly 50% reduction from Amicus' 2025 non-GAAP operating expenses of $432 million. These synergies are weighted towards G&A, which makes up more than 70% of the total, with the remainder coming primarily from R&D. As planned, we retained Amicus' commercialization team to ensure patient continuity and supplement our global capabilities. These synergies, combined with peak revenue aligned with the value creation we anticipated when we announced the deal last year and demonstrate our ability to successfully integrate large accretive assets that strengthen our growth profile.

Turning to Slide 10. By accelerating our financial profile with the addition of accretive assets that benefit from our proven global expertise, serving patients with genetic conditions. The Amicus acquisition sets the stage for our next phase of growth. With peak targets of $1.4 billion for Galafold and $1.2 billion for POMBILITI and OPFOLDA these revenues, combined with $220 million in anticipated annual cost synergies fully realized in 2028, support substantial expected non-GAAP diluted EPS accretion beginning in 2027 and a significant increase in operating cash flow.

Galafold and POMBILITI and OPFOLDA combined are expected to reach over 60% non-GAAP operating margin by 2030. At the same time, we believe our rapid integration and growth plans will enable us to deleverage approximately 1 year sooner than initially communicated. This quarter reinforces what sets BioMarin apart -- we are the leading rare disease company operating at scale with a proven integration capability to maximize the value of high-growth assets. We look forward to updating you on our progress, scaling Galafold and POMBILITI and OPFOLDA as we enter the next exciting phase of BioMarin's growth.

I will now turn the call over to Cristin for the commercial update. Cristin?

Thank you, Alexander. The second quarter demonstrated the strength and growing diversity of our commercial portfolio.

Now turning to Slide 12. Galafold and POMBILITI and OPFOLDA are off to a strong start as we move quickly to integrate following the April close. On a pro forma basis, second quarter revenue for Galafold grew approximately 10% year-over-year and POMBILITI and OPFOLDA grew over 65%. The will delivered broad-based patient growth across both established and newer markets. This was driven largely by increased diagnosis and patient identification including continued success with family cascade screening and expanding newborn screening programs alongside ongoing gains in reimbursed access.

For POMBILITI and OPFOLDA, we continue to add patients, both in the United States and in more recently launched geographies, supported by its differentiated clinical profile as we help more physicians better identify disease progression on prior therapies. Importantly, both brands maintained commercial momentum while we rapidly integrated, a testament to the focus of our combined team has Capon patients and execution. These are the levers Alexander described, and the results to date reinforce our confidence in the long-term opportunity for both medicines.

Turning to Slide 13 and the broader metabolic conditions business unit, formerly known as enzyme therapies. With the addition of the Amicus medicines, we have changed the name of the business into the metabolic conditions business unit to better capture the breadth of our portfolio. Total metabolic conditions revenue was $695 million, and grew 25% year-over-year, inclusive of Galafold and POMBILITI and OPFOLDA and the number of patients on therapy grew across every 1 of our marketed metabolic conditions brands, both year-over-year and sequentially. ZEC revenue grew 27% year-over-year on continued patient demand, while also benefiting from order timing in the U.S. during the quarter. We were pleased to have recently received European approval to broaden the PALYNZIQ label to adolescents ages 12 and older with PKU. In the U.S. we have had a strong start in the adolescent age group, and the team is energized to have the opportunity to serve this population more broadly.

And across the rest of the portfolio, revenue in any given quarter reflects the timing of large orders. In the second quarter, order timing was a headwind for Vimizim following a strong first quarter, while it was a slight tailwind for Naglazyme ahead of an expected lighter third quarter.

Because of these dynamic shifts between quarters, our full year metabolic conditions guidance remains the best indicator of expected underlying performance. Beneath that quarterly timing, the consistent signal is that patient demand continues to grow across our portfolio, both year-over-year and sequentially.

Now turning to Slide 14. VOXZOGO delivered 14% year-over-year revenue growth in Q2, driven by double-digit growth in the U.S. and OUS markets. The number of children treated with VOXZOGO grew more than 20% year-over-year globally, and approximately 3/4 of VOXZOGO revenue was generated outside of the U.S. Notably, even in the first quarter facing a U.S. competitor, the number of children in the U.S. treated with VOXZOGO increased year-over-year. We also saw continued traction in the under QA Group, which represented more than half of the new U.S. patient starts in the quarter reinforcing our position as the only approved treatment for children to and younger. As expected, we did see switching to the competitor products since it was approved in February of this year. Since the competitor's launch, approximately 90% of the U.S. children treated with VOXZOGO remained on therapy as of the end of July based on information available to us. That reflects the continued confidence physicians and families place in VOXZOGO evidence based.

Internationally, momentum remains strong across both established and newer markets, and we expect both patient additions and order timing to drive higher total VOXZOGO revenue in the second half of 2026 compared to the first half. We're confident in VOXZOGO durability built on a growing evidence base and the experience of the thousands of children treated to date and their caregivers. That durability is further reinforced by our exclusive ability to treat patients from birth worldwide. Our ambition is to remain the leader in skeletal conditions through competitor launches in the near term, supported by VOXZOGO anticipated launch for hypochondroplasia in 2027 and the potential of BMN 333 should data be supportive.

Stepping back, VOXZOGO was on track to become BioMarin's first $1 billion product. Galafold and POMBILITI and OPFOLDA are on the path to join it, each carrying peak revenue potential well above $1 billion and Vimizim is expected to also reach the $1 billion mark over time. Together, they are a clear sign that we can take innovative, genetically targeted medicines and expand their reach worldwide.

With that, I'll turn it over to Greg.

Thank you, Cristin, the second quarter was a productive period for our pipeline with meaningful progress across our portfolio.

Turning to Slide 16. You can see that we have had a lot of positive news over the last few months I am particularly pleased to highlight our very recent submission of the supplemental NDA for VOXZOGO for the treatment of hypochandroplasia. By implementing parallel work processing aided by technological advancements, we were able to shrink the time from database lock to filing down to just 79 days, easily within the top quartile for modern industry benchmarks. The full Phase III data will be presented at SP as a late-breaking oral presentation in September. As Cristin noted, we're also very pleased that adolescents in both the U.S. and Europe will now have access to Palynziq following the label expansion in both regions earlier this year.

Moving now to Slide 17 and BMN 820, formerly known as DMX 200, a late-stage addition to our pipeline resulting from the Amicus acquisition. BMN 820 is a first-in-class oral CCR2 inhibitor, which it accomplishes through blockade of receptor heterodimerization -- it is currently in Phase III development for focal segmental glomerulosclerosis or FSGS. This is an asset for which we hold exclusive U.S. commercialization rights and are partnered with dimeric who remains responsible for operationalizing the Phase III study. If the data are supportive, this could provide a new mechanism of action for the treatment of FSGS. FSGS is a progressive kidney disease that leads to proteinuria and declining kidney function over time. There are an estimated 30,000 addressable patients in the United States. Only 1 therapy is approved as of today, and its label is somewhat narrow excluding patients with nephrotic syndrome.

Durable stabilization of kidney function remains a significant unmet need. M20 targets an orthogonal mechanism to the vascular targeting agents with the potential to treat a broad FSGS population. It has shown a favorable safety and tolerability profile to date. The FDA has agreed that proteinuria is an appropriate endpoint for approval in our Phase III ACTION III trial, and we expect Phase III data in 2028. If the data are supportive, BMN 820 represents an attractive new pipeline asset with upside in a large area of unmet need.

With that, I will turn the call over to Brian. Brian?

Please refer to today's press release for detailed second quarter 2026 results, including reconciliations of GAAP to non-GAAP financial measures, which will also be available in our upcoming Form 10-Q.

Turning to Slide 19. We were pleased that second quarter revenue reached nearly $1 billion, representing 20% top line growth year-over-year. Second quarter non-GAAP operating margin was 36.4%, with non-GAAP diluted earnings per share of $1.20. Non-GAAP R&D and SG&A expenses each increased year-over-year reflecting the operating expenses of the acquired Amicus business, together with continued investment in our pipeline and commercial execution. On a GAAP basis, second quarter SG&A results also included approximately $84 million of transaction and integration-related charges associated with the acquisition. These charges are excluded from our non-GAAP results.

Below the operating income line, interest expense increased year-over-year due to the acquisition debt financing and interest income decreased as we liquidated investments to fund the acquisition. These items, along with the higher operating expenses contributed to the year-over-year decrease in non-GAAP diluted earnings per share. I want to spend a moment on our interest expense and interest income. to make sure your expectations are aligned with ours. Based on current interest rates, interest expense associated with the acquisition debt financing is estimated at approximately $200 million on an annualized basis or approximately $50 million per quarter. With the term loans and senior notes scheduled to mature after 2030.

Importantly, this interest expense is included in our non-GAAP results and therefore, reduces non-GAAP diluted earnings per share. In addition, due to lower cash and investment balances following the close of the acquisition, we expect interest income to decrease year-over-year in the near term.

Turning to Slide 20 and our updated full year 2026 guidance. On the strength of our first half performance and our expectations for the balance of the year, we are raising our full year total revenues, VOXZOGO revenue and non-GAAP diluted earnings per share guidance. As you can see, our guidance updates today reflect double-digit growth from the midpoint. -- our strong trajectory leading into the second half of 2026.

Briefly on phasing, we expect third quarter revenue to be slightly higher than the second quarter reflecting a full quarter of Amicus revenue contribution and continued patient growth across our brands. Similar to prior years, we expect the fourth quarter to be our strongest quarter of the year. with a significant step up versus Q3 and representing well over 50% of our second half revenue outlook primarily due to ordering dynamics in select markets. Our non-GAAP diluted earnings per share, the third quarter will reflect a full quarter of Amicus operating expenses, while benefits from cost synergies are expected to become more meaningful in the fourth quarter. Combined with the anticipated revenue phasing and realization of synergies, we expect third quarter non-GAAP earnings per share to be slightly higher than Q2 and fourth quarter non-GAAP earnings per share to be significantly higher representing the highest quarterly earnings per share of the year.

In summary, the second quarter reflected strong execution, disciplined investment and continued progress integrating Amicus. While some integration activities will continue into next year, the integration is well underway and on track with the majority of enabling decisions made in operating plans in place. We are impressed by and appreciative of the focus and efforts of both our BioMarin colleagues and all of our Amicus colleagues since the close of the acquisition. We are looking forward to the second half of this year, where we remain focused on delivering our updated 2026 outlook while building towards the longer-term revenue and earnings potential that Alexander outlined in his remarks.

Thank you for your attention. We will now open the call to your questions. Operator?

[Operator Instructions] We'll go to our first question from Chris Raymond at Raymond James.

I got 2 actually. First, on Amicus. You guys gave a lot of metrics here on synergies with this integration. Just looking at 2028, synergies that look really impressive was wondering if maybe you could maybe give a few way points as we get through 2027 and tell us the specific steps you're taking to get to these numbers? And maybe what's behind the delivery of the 2.5 leverage a year early. And then I have a VOXZOGO question.

Chris, it's Brian. I'll take that. Thanks. So yes, just to start, we know we communicated a lot of metrics today. We do believe that this Amicus integration framework demonstrates the comprehensive value creation from this acquisition. We quantified synergies at this approximately 50% level. That's going to drive significant accretion powered by the revenue growth as well. This not only validates our hypothesis at the time of the transaction but exceeded our expectations at the time. And I'd also like to emphasize that these decisions are made. We are now executing on an end-to-end integration plan to bring the Amicus business onto the BioMarin platform. And as I noted there in the prepared remarks, it took a lot of work on both sides, and it's going very well.

This accretion also translates to cash flow. As you noted, we pulled forward our leverage target by approximately 1 year. And altogether, we're not only delivering on the potential of this transaction but exceeding it. And specific to your question in terms of Waypoint, we shared that we expected the transaction to be modestly dilutive in calendar '26. I'll share that that's still the case, but it's honestly close to breakeven still expecting it to be accretive in the first calendar year. But I would point you to the substantial accretion that begins next year and then 2028 being the first full year because we are still integrating next year. 2028 will be the first full year where we're realizing all of the benefits from the synergies and integration.

And in terms of a way point, I might guide you to saying that next year, we're expecting half to slightly more than half of the synergies to be realized.

Great. And maybe on Fox Ogo, just hearing Cristin's commentary around 90% of VOXZOGO patients remaining on therapy. I think you mentioned post the UV well launch. Ascendas gave us some numbers today. I think they said 70 patients are enrolled to start therapy, and I think 2/3 of those are actually paid. Maybe just doing some math on the switchers -- and based on your commentary, can you maybe give us a sense of the dynamic in terms of your competition for new patients?

Thanks very much for your question, Chris. This is Alexander. Yes, I think this is really important to sort of unpack the numbers and make sure there's no misunderstandings here with the various data points communicated by both companies. I mean, clearly, the number was based on a total patient enrollment number. That includes naive patients, VOXZOGO discontinuations whenever those may have happened. And of course, switches from Box ago. And of course, the latter one, the switch rate is, of course, the 1 that's relevant for us. So according to our data, and we have good visibility, as you would expect, in the United States in terms of patient numbers and ongoing treatment. We've seen approximately 10% of patient switch. That translates to less than 100 patient switches in the approximately 6 months since they would have been approved. That translates, of course, to a very small impact on our almost $4 billion in revenue this year.

So taking all things into account, based on the strong growth that we are seeing and projecting with 20% of increase in patients globally on VOXZOGO in the quarter. We feel comfortable increasing VOXZOGO revenue guidance for the year for over $1 billion. I think zooming out as well, if I could comment, I think bigger picture, their update on the launch and the pace reflects how hard the U.S. market is in chondroplasia -- when you have geographically dispersed patients, you have low visit frequency, hair split between general pediatricians and specialists. And this all impacts the opportunity and the pace of switches and starts. And of course, as you know, new patient starts dominated by the 0 to 2 patient populations. The guidelines say, diagnose and treat as early as possible after birth. And as you know, that remain -- we remain the only product with the less than 2 indications, and we expect to remain so for a good amount of time.

So I hope that helps, gives you a little bit of perspective on the data and what we're seeing and what we're looking forward to in the remainder of the year.

We'll go next to Cory Kasimov at Evercore ISI.

I also want to ask something on the heels of the competitive update this morning. And I'm wondering how you think about the combination of weekly CNP analog plus growth hormone eventually slotting into the treatment algorithm? And is there anything that's stopping you from -- or physicians using VOXZOGO and/or BMN 333 in the future with growth hormone.

Thanks, Cory. This is Greg Freiberg, I think I'll tackle that one. Looking at that data, I think, first and foremost, we have to recognize that the COACH study is a small study. I think it's about 21 patients single arm split into 2 cohorts. So we have to be careful in over interpreting it, particularly when we slice the data at 6-month intervals. Now that being said, I think the question with the growth hormone combination today is the same as it has been from the start. We know growth hormone alone can cause increases in AGV, but they're temporary. And actually, they don't result in major increases in achondroplasia and increases in final adult height. So the question remains, what are we learning from the data set. With this data point, I would say just the eyeball test tells us that it looks like the effects of growth hormone, adding on to CNP appear to be waning. I don't know why that would be in the naive patients more than the add-on to people who are already on CNP, it's a small data set.

But the question then becomes, is this the beginning of a longer-term trend. It's an unanswerable question. I think the question that our endocrinologists care most about, which they're a sophisticated group. They've worked with growth hormone for a long time is, will this ultimately contribute to the health and wellness and by extension, the final adult hide of patients. The concern always is that growth hormone may close growth plates early. And that is not something that is in a short study of 18-month duration, something that you can really get a read on. So I think today, it's incremental data. We're certainly seeing that the growth spurts might be declining. You see the slopes increases. And that's as compared to the achieve -- I'm sorry, the APPROACH study, where you don't see that kind of a shift out of 2 years happy to see that they're following up on the 2-year data there as well.

And again, I think there are unanswered questions that time will tell. Of course, we're watching this very closely. We're going to follow the data. We're going to make evidence-based decisions and from a biologic standpoint, there is nothing unique about TransCon CNP when it comes to taking a CNP agent and combining it with growth hormone. It's too early to tell, and we're looking forward to seeing more data out in the order of 3 years plus.

We'll take our next question from Jeff Fye at JPMorgan.

I was curious if you could speak to whether those synergies associated with the Amicus deal will fall to the bottom line or whether you expect those to be reinvested in the business?

Jess, it's Brian. Thanks. Great question. We do expect those synergies to drop to the bottom line. However, to your point, there is also a reinvestment so part of the strategy is to accelerate the growth potential of Galafold and POMBILITI and OPFOLDA, which will require some incremental investment. I'll share with you that compared to the synergy numbers we shared today, it is a modest portion of that. But more importantly, and this is why we spoke to synergies on a gross basis. Any of that reinvestment fits within the existing structure of our P&L. It's part of normal metabolic conditions, sales and marketing going forward. So we don't consider it an offset to the synergies itself, which will live on -- and again, if you chose to calculate net synergies with the investments, it's very modest.

Our next question comes from Salveen Richter at Goldman Sachs.

This is Tom on for Salveen. Curious if you could provide more detail. You spoke to the mechanisms behind driving increased diagnosis and switching for POMBILITI and OPFOLDA and for Galafold. These efforts differ in -- or strategy differ in the U.S. versus ex U.S.? And a follow-up, what is your appetite for future BD and what stage or type if so?

Yes. I'll take that first part of the question, Tommy. Thank you so much. And I hope you could hear it in the prepared remarks, but I'll say it again, we are absolutely delighted about what we have both the opportunity and quite frankly, the responsibility to do for both Fabry and Pompe communities. And the more we've been able to dig into it since the close, we've really on earth, I think, are some meaningful levers that we can pull to drive the growth and therefore, target the peak revenues of $1.4 billion for Galafold and $1.2 billion for Pompe -- excuse me, for in the future.

Now looking specifically, and I know you asked the question kind of differentially across the U.S. and ex U.S. In large part, the overall lever the levers are very similar. While they may get executed at the country level slightly differently, the areas that we're going to really put our investment into are quite similar. And they fit very well within the BioMarin set of capabilities that we've built over the decades that we've been doing this. For Galafold, this really is going to be about diagnosis. We recognize that in the medical population or in the Fabry community at large, really is still a very limited diagnosis, especially for those with late onset and/or the female patients. So we plan to really target those communities trying to drive broader diagnosis and importantly, really starting to close the gap between kind of diagnosis and treatment so that we can show that kind of physicians that treating earlier and even in milder sets or mild dirt conditions is really important.

On the Palm op side, this really is about accelerating switches, and this is true again in both the U.S. as well as outside the U.S. And here, our focus is going to be on the waning or the clinically declining patients that are on a current therapy where we believe that we can really kind of continue to show what disease progression could look like and if patients aren't meeting those targets, how to ensure that they're advocating for treatment. So those are the areas we're really going to be focused. And I know that the next question. Greg, do you have something to add?

I would just add, Pammi, from the medical affairs standpoint, particularly for Fabry, where we know I would say generously maybe only 40% of the patients are actually diagnosed with the condition. Just to give you some granularity there. Electronic health record work to, again, shorten the time between diagnosis and again, symptom when the symptoms arrive, family cascade testing and reclassification of variance. These are things that we've done previously in other settings. There are also some great work that our former Amicus colleagues had begun, and we have the opportunity to scale that a bit larger. Just to give you a data point, there's over almost 50 different diagnostic activities and programs going on around the globe right now. And so it is a very local phenomenon. We think that we can put more firepower and technology behind some of those assets.

These are things that we can start right away in the countries where Galafold and Pam Op are already commercialized. But what's also really important to note is that we plan on geographically expanding these products. So in over 10 countries, relative to where we are today with Galafold and more than 20 countries for POMBILITI and OPFOLDA which will also help to drive that growth. Over to you, Alex.

Ramy. Yes. This is Alexander. I'll answer your BD question. So as you heard from Kristen and from Greg, the integration and acceleration of Galafold and POMBILITI and OPFOLDA strengthen our growth outlook for -- so with our now more diversified and growing commercial portfolio, our focus is now more shifting to expanding our clinical stage pipeline. Of course, we're going to continue doing research collaborations as we've always done. I think you just saw -- you would have seen the announcement recently of the collaboration with Loro -- but as we delever, you can expect us to do deals to expand out our clinical stage programs over the next 12 to 18 months.

We'll move to our next question from Phil Nadeau at TD Cowen.

Two from us. First, on the upcoming ITC case, we expect a decision by the end of August. I was curious to get your most recent thoughts on that case, in particular, any thoughts you have on the possibility of a settlement?

And then second, just a follow-up on the diagnosis points that you just made. I think 20 years ago, we heard from Genzyme that they thought they were going to penetrate more quickly the late onset and female patient population. So you've talked about what you can do, but why haven't those patients been diagnosed so far, it does seem like others have had efforts. Where are those efforts fallen short?

Thanks for your question, Phil. This is Alexander. I'll take the opportunity just to clarify some of the some of the time lines and the facts around the ITC case. But as you can probably expect, I'm not going to get into our legal strategy or speculate on the outcomes.

So on the 21st of this month, the 21st of August, the administered law judge will deliver their initial determination within weeks following that initial determination, the commission decides whether they're going to review that initial determination. The final decision is expected on the 21st of December of this year, that's either affirming or reversing all of portion that initial determination. And then either party has 60 days to lobby the President. It has a presidential review period which goes through February 21 of next year. But I would just highlight that if an exclusion order is determined in that decision by the commission then it's effective during that period.

So that's sort of what you can expect from a time line perspective, and we're awaiting that data to which is coming shortly. I'd also highlight that upon the completion of the ITC process, we would expect to enforce our patent in Federal District Court of course, monetary damages are available.

This is Greg Friberg. I'm going to tackle your second question on the diagnostic points, if that's all right. With regard to why there hasn't been more progress in the field, I think it's a pretty simple answer in that this is a very elusive disease -- it's 1 where patients can have a very heterogeneous presentation, something like 7 different organ systems that can be affected presenting in a variety of clinics and true with all rare diseases, it's this elusiveness of diagnosis, the 7 to 10 years to actually make their way to knowing what's causing their symptoms. And Fabry is really a case study in that. That's why we're trying to focus on where we think we can have the most impact. And again, we highlighted a couple of them. But obviously, this isn't just about educating community physicians to be on the lookout. -- Using technology, using electronic health records using testing and training approaches to try to identify flags earlier.

Again, it's not just about patient finding, it's about shortening that time to diagnosis. I would say that on top of that, 1 of the very fruitful endeavors that we've been involved with in other genetic conditions in family has can test. -- you find 1 person in the family who is affected by this, again, you do the boots on the ground work to find the other patients that could be affected. Finding them early is the name of the game with Fabry, but it's been elusive up till now. And I think it reflects the wiliness and unfortunately, the anterogeneity of this disease.

Next, we'll go to Ellie Merle at Barclays.

So I guess of those 10% of patients in the U.S. who switched from Voxelgo by the end of July, I guess what trends or characteristics are you noticing in those patients versus say patients that are more likely to stay on VOXZOGO? I guess, what degree of switching in the U.S. is baked into the guidance for this year.

And then a second part of a question on VOXZOGO, you mentioned that over 50% of U.S. new starts were in ages 2 and under. Maybe just how should we think about, I guess, the annual incidence of new stats under age 2 or maybe just the size of the U.S. incident market for that age group? And how you're thinking about this as a growth contributor going forward.

Yes. Thank you very much for the question. So on to the first question around the 10% that has switched. I mean, primarily what we're hearing is injection fatigue or wanting to try a weekly therapy. But what I think is more important is looking at the 90% who we retain. And what we're finding there is that really, it is about not only the surround sound services, we have around these patients and their families, namely with their clinical coordinators, how we're in there talking to the family and really building out that trusted relationship that is so important in this community, but also importantly, reminding them of the evidence base that we have, the safety, the efficacy and something that, quite frankly, no competitor can catch up to, that is something that we find is continue to be very compelling, and I expect that to be true in the future.

Now with regard to the incidence of the 0 to 2 population, we estimate that there's about 150 births in the U.S. a year for -- with infants with achondroplasia. And so our intention is to very much target treatment as early as possible. As you know, the consensus guidelines certainly state that this is the most efficacious and beneficial for them to be treated early. But also what we're finding is that by targeting new specialties such as maternal fetal medicine and really getting out early to help them understand possibly when in utero or even right at birth, the attributes of treating early, that's what we're out there doing, and we find that to be quite successful.

Thanks, Cristin, it's Brian. I'll take your guidance question. Absolutely. We appreciate the interest in switch assumptions, especially given the competitor update today and our competition metric as well. As noted in February, when we initially gave guidance, we do expect switching, and we share what we're observing today. Our guidance did include a switch assumption, but we're not going to quantify that at this time nor comment on expectations at this time.

Next, we'll move to Mohit Bansal at Wells Fargo.

So Cristin, regarding the 10% patients were switched, based on market as -- your market research, where do you think -- where do you expect this to settle in the U.S. market? And the related question is, how different or similar ex U.S. market in terms of your -- how intense you are versus how challenging it could be for the competitor to come in and take share from you?

And Mohit, if I could maybe, could you maybe the second question, just so I make sure I answered it. I didn't quite understand the question on the second one.

So the question is like how excess market is similar or different versus the U.S. market? In terms of setup and structure where it could be challenging or easy for a competitor to take share versus the U.S. market. So just trying to understand the structure of the U.S. versus excess market for the current aplasia there.

Very good. Okay. for the question. Now of course, to the first question as to when do we expect -- what we expect going forward, as Brian shared, we're not necessarily going to share our expectations because the truth of the matter is we need to continue to monitor this and closely watch if this levels out if this is a bullet or if this is a steady state, this is something that we need to very much monitor at this stage in time. I do think that what you would find most likely is that the segment is most apt to switch first and foremost, as I said, are those that either have injection fatigue are looking for the convenience of a product that has a very -- that VOXZOGO has a very similar efficacy profile to it. However, they might want a weekly shot.

So those are kind of what we're seeing out there, but I wouldn't be able to comment at this juncture in terms of how this is going to go in the future. Now looking at it relative to the ex U.S., I would say the biggest difference, and I know we've talked about this before in the U.S. as you have a much more segmented market, much more geographically dispersed. You have more specialties involved. And we see that certainly as I guess, a component in the competitive dynamics here. What we expect ex U.S. We don't -- we have not seen there's not been any approvals or any product in other countries at this point in time. But what we expect ex U.S. might -- well, I'm not going to speak to necessarily, but I don't think that the dynamics are going to be wholly different ex U.S., but that is something, again, that we will have to remain vigilant on and continue to see.

Moving next, we'll go to Akshay at Jefferies.

This is Phebe on for Akash. Another 1 on Voxogo. Can you talk about what market work you've done so far for hypochondroplasia and whether you expect any bolus at initial approval? And if you've already identified a certain number of hypochondroplasia patients.

Yes. Thank you very much for the question. I suppose, Greg and I might want to take this on together. I think in terms of the hypochondroplasia market, what we've said very clearly is that we expect a global total address missile patient population of around 14,000. But the work now is really getting in there in the countries and identifying those patients as early as possible so that by the time, assuming we're able to get a regulatory approval, -- by the time we get there, we can launch immediately and cover as many of those patients who are amenable to treatment as possible.

And so we've already talked a little bit about some of the global initiatives we've been working on to include to improve diagnosis -- we talked about some of the targeted genetic reclassification work we're doing as well as a lot of the physician and caregiver awareness that we're doing. Most recently, we've launched tactics that are really around having multiple kind of digital and media campaigns really primarily targeted in the U.S. and that's about shaping the marketplace. And what we want to do is make sure that we're including HCP directed disease education content as well as caregiver and patient awareness programming that really, again, is about making sure that we're getting as many patients diagnosed as possible and then importantly, shortening that path from the time that they are diagnosed to the time that they're willing to treat.

Over to you, Greg.

Yes. Thanks. And just to go back as well, we only turn the card over 2 months ago. We're really pleased by the data that we saw in Phase III. Again, the AGV exceeded our expectations hit statistical significance on the height variables as well as arm span, and we're looking forward to presenting the subsets and additional safety data and so forth at SP in September.

I would say with regard to patient finding, you can be rest assured that we are working hard to bring what we think could be a potentially safe and effective therapy to hypochondroplasia patients. We're doing testing work. Again, we have metrics looking at not only testing rates, but testing yield, We're certainly preparing again, to know what we think, again, the age of diagnosis is and so forth, and that's work that's ongoing right now. We see that age going downwards, which again, is a good sign the classic challenge here that these patients aren't making their way to the right specialist is something that we've intervened with at another time, I'd be happy to talk about other implementation science work we're doing, again, to try to prepare the field in a pre-approval appropriate way to, again, make sure that the science is following and that we'll be able to, again, reach the most number of patients as possible.

We'll go next to Paul Matteis at Stifel.

On BD, what's next in terms of the scope of the types of things that BioMarin looking at? And Alexander, when you take a step back now and look at the revenue base and the profitability profile you have, -- what's the optimal number of, I guess, like Phase I, II, III assets in a pipeline of BioMarin size?

Thanks so much for the question. So we're looking, obviously, at -- we see ourselves as the leader in the space of genetic conditions. We have strong business units. As you've heard now, we call it metabolic conditions, selections. So those are areas we're looking to supplement the many products we have in those spaces that the 9 products in our portfolio -- but we're also interested in genetic conditions where it's a good fit with our capability, our expertise in genetics, for example, our regulatory expertise, our manufacturing expertise for commercialization.

So we aren't getting specific at this point about what those additional therapy areas within the umbrella of genetic conditions, I think you probably have a sense of the sorts of types of diseases, which really leverage that capability. And I think when you look at the Amicus acquisition was, it dropped perfectly into that metabolic conditions business unit -- you can see it's really the capabilities that we have that we can leverage it allows us to really say that the peak sales potential of these products is greater than they were before. So we think there's a really great opportunity for us to do that with other programs. but bringing them in, in the clinical stages.

So expect more progress in the next 12 to 18 months. We're looking for a nice steady flow of products at all stages of development. We were excited, and I think it's worth just highlighting we're excited to announce.

This quarter. We actually put more of a focus on really digging on the DMX 200 asset, which we cool DMN 20. And we're really excited with that asset as we do it to have a Phase III asset in the regional space. So this hopefully gives you a sense of kind of what we're thinking about from a BD standpoint in a general perspective, but we're excited about the growth prospects and the opportunity for cash flow generation and the optionality this gives us to further strengthen our pipeline.

We'll take our next question from Sean Laaman at Morgan Stanley.

I guess if you look at the $2.6 billion in Palm up and Galafold guidance, the mid-2035 like how much of that is like market acceleration versus what BioMarin is adding to the pie? And since you've been able to get the business under your hood, what have you learned down that front that gives you good confidence that you might not have known before?

And then if I can slip 1 in on BMN 333, -- how would you characterize the rate of enrollment in that study? And when might we see the next signpost.

Yes. So thanks for the question, Sean, around kind of how much of the contribution there is related to perhaps what we can do differently. I'd say that when you look at the contribution in the build, and we really did do a bottoms-up, looking kind of country by country, about what we could do. So we weren't playing around with the prevalence numbers or changing anything about the disease characteristics per se.

This really was about when we put this on to the BioMarin platform, what could we do differently and how does that look country by country. So I would say the biggest kind of contributor, as you would expect on the Galafold side was opening up the diagnosis. Certainly, treatment rate plays a role there, but really the biggest contributor there was around opening up the diagnosis rates -- on the POMBILITI and OPFOLDA, that really was the biggest contributor was definitely around switches and how quickly we get rate to move on that. And so the question becomes, how are we able to do this? And so as I've mentioned, we looked at this country by country.

And really do feel confident about how we can click these into either existing countries where they're already opened up in those markets or importantly, have already set in motion what is going to be the regulatory as well as the reimbursement pathway moving into those specific countries. I'd say that, that is the -- that's the biggest thing. And again, this wasn't about changing prevalence numbers or tweaking with the funnel in that way. This really was about building on our own capabilities.

Yes. And thanks, Sean, for the interest in 333. We, of course, are incredibly excited. We have active enrollment going on in multiple time zones, multiple countries around the world. We're looking for naive patients. We're entering the steep part of the enrollment curve I don't expect that we'll give an update until we're completed enrollment in those 40 patients for the Phase II portion. But we want to just reiterate that again, our expectation is in 2027. We're going to answer this question. I know that there's been debate out there of whether or not, again, the free CNP will translate into more -- we have a strong conviction that it is an absolutely valid hypothesis, happy to drill into that with others in more detail.

Now is the time, building on the Phase I data that we saw when we know we can increase exposure of free CNP. We know that pulls into pharmacodynamics in the plasma cyclic GMP now is the question to look at growth, and that will be a question that we answer in the next calendar year.

We'll go next to Alex Hammond at Wolfe Research.

Just 2 from us. So first, on the guidance bump on Fox. Does that have left to do with about switching or more about growth? And is that growth more U.S. or OUS. And then on the nitrite as well, how does the ASPEN study operational seamless design give you levers to pull the time line forward from the Phase III perspective?

This is Brian. I appreciate the question on the FOX guidance raise. First and foremost, pleased with the performance in Q2 and our confidence in the outlook for the second half of the year to be able to raise the guidance and get VOXZOGO to the blockbuster status at the bottom end of the guidance. I'll note that you'll remember previously 1 of the variables that I pointed out at the beginning of the year when we guided was a couple of international price negotiations that were in process. I'll share that 1 of those closed successfully with a good outcome. And the other had some initial setbacks, but we are continuing with the process. But there was some upside there to some of the contingency that was in the range. So that was a bit behind it.

And then the rest of it was growth in performance. And I'll just say that it was both U.S. and global, adding new patients, growing revenue confidence in 2026.

Yes. And thank you for the question again on 333. The operationally seamless Phase II/III design really gets most of it -- or provides most of its benefit through recruitment acceleration and site start-up. Not every country can start at the same time. They have different requirements with regard to regulatory approvals and so forth. This allows us to under the umbrella of 1 protocol, work with the same IRBs, work with the same sites have a parking lot of patients identified.

And really, I think the most impressive benefits will come with the Phase III recruitment. The Phase II, again, is up and going, and we are off to the races.

And this concludes our Q&A session. I will now turn the conference back over to BioMarin's CEO, Alexander Hardy for closing remarks.

Thank you, operator, and thank you all for joining us today. We at standout quarter across the business, 20% top line growth, a rapid close and integration of Amicus, advancing pivotal data would VOXZOGO second indication hypochondroplasia. Strong demand for our innovative products and us to increase guidance today, including full year total revenues, VOXZOGO now at the low end of $1 billion on GAAP earnings per share. As we enter the second half of 2026, BioMarin is stronger, more diversified and positioned than ever to lead in rare disease, liver for patients worldwide. Thank you for your continued support. Look forward to speaking to you soon.

And this concludes today's conference call. Thank you for your participation. You may now disconnect.

Good afternoon, and welcome, everyone, to the BioMarin Pharmaceutical First Quarter 2026 Conference Call. Today's conference is being recorded. [Operator Instructions] At this time, I would like to turn the conference over to Traci McCarty, Head of Investor Relations. Please go ahead.

Thank you, operator. To remind you, this nonconfidential presentation contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc., including expectations regarding BioMarin's financial performance, commercial products and potential future products in different areas of therapeutic research and development. Results may differ materially depending on the progress of BioMarin's product programs, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market and developments by competitors, and those factors detailed in BioMarin's filings with the Securities and Exchange Commission, such as 10-Q, 10-K and 8-K reports.

In addition, we will use non-GAAP financial measures as defined in Regulation G during the call today. These non-GAAP measures should not be considered in isolation from, as substitutes for or superior to financial measures prepared in accordance with U.S. GAAP, and you can find the related reconciliations to U.S. GAAP in the earnings release and earnings presentation, both of which are now available in the Investor Relations section of our website. Please note that our commentary on today's call will focus on non-GAAP financial measures unless otherwise indicated.

Beginning on Slide 3 and introducing BioMarin's management team joining today's call are Alexander Hardy, Chief Executive Officer; Brian Mueller, Chief Financial Officer; Cristin Hubbard, Chief Commercial Officer; and Greg Friberg, Chief R&D Officer. I will now turn the call over to BioMarin's President and CEO, Alexander Hardy.

Thank you, Traci, and thank you all for joining us today. I am so pleased that we completed the Amicus acquisition last week, starting a new and exciting chapter for BioMarin with the addition of two innovative therapies, Galafold for Fabry disease and Pombiliti and Opfolda for Pompe disease. The acquisition accelerates our anticipated year-over-year 2026 revenue growth to 20% at the midpoint of today's updated guidance. The strengthening trajectory is just the beginning of BioMarin's enhanced longer-term financial outlook supported by our larger, more diversified commercial portfolio.

Since announcing our plans to acquire Amicus late last year, we have been preparing for rapid integration beginning on day 1 with the goal of increasing the peak potential of these newly added products. Following the recent close of the transaction, we initiated our targeted integration plan, focused on leveraging BioMarin's operating scale and capabilities to drive diagnosis and treatment rates for patients with Fabry disease and late onset Pompe disease. Next quarter, we plan to share this roadmap as well as more detail on BioMarin's growth acceleration with the addition of Galafold and Pombiliti and Opfolda to our commercial portfolio, and DMX200 for FSGS in Phase III to our late-stage pipeline.

Turning briefly to first quarter results and outlook for the remainder of this year and starting with enzyme therapies. I am pleased with the strong interest we are seeing from the PKU community following the recent PALYNZIQ adolescent label expansion in the United States. With Cristin will discuss in more detail. We expect enzyme therapies will deliver robust growth in 2026, further supported by the addition of Galafold and Pombiliti and Opfolda to the portfolio.

Moving to our skeletal conditions business unit. We saw strong patient demand for VOXZOGO with new patient starts increasing across all regions in the first quarter. In the U.S., the majority of new patient starts were from the under age 2 cohort. These results reflects our focused investments and increasing adoption of VOXZOGO, particularly among younger patients. Building on our leadership in achondroplasia, we are pleased to have submitted the sNDA and full approval of VOXZOGO. We expect to hear the timing of our review in the coming months. I want to congratulate our regulatory team for the outstanding work that went into this comprehensive submission package. We also look forward to pivotal results for VOXZOGO in hypochondroplasia and BMN 401 for ENPP1 deficiency both later in Q2.

In summary, we expect 2026 to be a momentous year for BioMarin. Our immediate focus remains on the seamless and rapid integration of Amicus to accelerate our growth trajectory this year and beyond, pursuing regulatory next steps following the 2 upcoming pivotal data readouts. The addition of Galafold and Pombiliti and Opfolda to BioMarin's portfolio of innovative medicines provides an opportunity to reach more patients around the world, creating significant value for all of our stakeholders in the near and longer term.

As we enter this next chapter, I would like to express my appreciation to the employees of both BioMarin and Amicus, whose dedication forms the foundation of our shared mission to serve patients. Thank you for your attention. And I will now turn the call over to Brian to provide additional financial updates. Brian?

Thank you, Alexander. Please refer to today's press release for detailed first quarter 2026 results, including reconciliations of GAAP to non-GAAP financial measures. All first quarter results will be available in our upcoming Form 10-Q, which we expect to file in the coming days.

Now moving to Slide 7. Total revenues in the first quarter were $766 million and increased year-over-year, supported by increased patient demand across both enzyme therapies and VOXZOGO. And as expected, those organic growth drivers were partly offset by order timing dynamics as well as lower revenue from Roctavian, KUVAN and royalties. Enzyme therapies revenue increased 6% year-over-year, led by growth in VIMIZIM, NAGLAZYME and BRINEURA. PALYNZIQ first quarter revenues were impacted by U.S. order timing which resulted in elevated stocking levels in the fourth quarter of 2025, as discussed last quarter. We expect the stocking dynamic to normalize and anticipate year-over-year revenue growth for PALYNZIQ in full year 2026 as growth in new patient starts in the under 18-year-old population gains momentum and patients continue to titrate to their maintenance dose.

VOXZOGO revenue was supported by new patient starts across all regions and in line with the expectations that we shared on our prior quarter earnings call. Looking ahead, due to anticipated order timing and consistent with 2025, we expect VOXZOGO revenue to be higher in the second half of 2026 compared to the first half. Cristin will provide more color on commercial dynamics in a moment.

Turning now to Slide 8. Cost of sales increased year-over-year in the first quarter primarily due to a $31 million charge associated with an unsuccessful process qualification campaign to extend NAGLAZYME manufacturing capability. Importantly, this did not impact commercial supply. While this event decreased margins and earnings per share in the first quarter, we expect this charge to be offset in full year 2026 non-GAAP diluted earnings per share guidance.

Q1 non-GAAP R&D expense increased year-over-year, primarily due to spend to support BMN 401, our Phase III clinical program acquired in the Inozyme transaction in the second half of 2025. Development activities for VOXZOGO for hypochondroplasia, BMN 333 for achondroplasia and BMN 351 for Duchenne muscular dystrophy also contributed to higher year-over-year R&D expense. Non-GAAP SG&A expense also increased, partially driven by investments to support commercial expansion across enzyme therapies and VOXZOGO and partially driven by pre-close costs associated with the Amicus acquisition.

First quarter non-GAAP diluted earnings per share was $0.76 and was significantly impacted by the drivers of increased operating expense that I just mentioned as well as the impact of Q1 revenue which we believe will be our lowest quarter of the year. The impact of the cost of sales charge and pre-close costs associated with the Amicus acquisition resulted in a $0.20 earnings per share impact to our non-GAAP earnings per share result.

Looking past those elements helped to measure BioMarin's underlying business performance as well as how this Q1 result fits into our full year earnings per share guidance, which remains unchanged for the historical BioMarin business before layering on the Amicus business.

Now moving to Slide 9 and our updated full year 2026 guidance, which now includes the Amicus financial outlook starting last week. We are raising enzyme therapies revenue guidance to a range of $2.725 billion to $2.775 billion for the full year 2026 inclusive of meaningful contributions from Galafold and Pombiliti and Opfolda, resulting in approximately 30% growth at the midpoint. Adding these high-growth products to our enzyme therapies portfolio increases our full year total revenue guidance to a range of $3.825 billion to $3.925 billion with the midpoint representing approximately 20% year-over-year growth in 2026. For VOXZOGO, we are maintaining our revenue guidance of $975 million to $1.025 billion, which continues to reflect high single-digit growth at the midpoint. On non-GAAP diluted earnings per share guidance, we are updating the guidance range to $4.85 to $5.05. As previously communicated, the acquisition of Amicus will be slightly dilutive for the full year 2026. We continue to expect the acquisition to be accretive to non-GAAP diluted earnings per share in the first 12 months after close and substantially accretive beginning in 2027. The Amicus P&L will be incorporated into BioMarin's financial results as of last week's closing of the transaction. In 2026, we expect to include the base Amicus operating expenses less initial cost synergies anticipated in 2026.

As Alexander touched on, now that the transaction is closed, we have engaged more deeply with the Amicus business, and plan to share our outlook on both commercial revenues and cost synergies on our next quarterly earnings call. To give some perspective on timing of the updated guidance, we expect order timing for the historical BioMarin products and 2 full quarters of Galafold and Pombiliti and Opfolda revenues in the second half of the year to drive significantly higher revenues as compared to the first half of 2026.

To provide context, we expect more than 55% of total 2026 revenues to be recognized in the second half of the year. And likewise, on the expected timing of our profitability, we expect Q2 non-GAAP diluted earnings per share to be just modestly higher than Q1, partially due to pre-close Amicus costs incurred in April, plus a higher amount of the 2026 Amicus dilution being weighted to the second quarter. Further, the revenue timing weighted to the second half of the year results in most of our expected profitability occurring in Q3 and Q4. These earnings timing dynamics drive approximately 2/3 of our 2026 earnings per share expected in the second half of the year.

Briefly on evolving geopolitical uncertainties. We are watching the situation in the Middle East very closely and note that today's guidance reflects an allowance for a modest amount of disruption in that region in 2026. Looking ahead, we look forward to sharing with you our expanded financial outlook, enhanced by the addition of Galafold and Pombiliti and Opfolda setting the stage for accelerated near and midterm growth. Thank you for your attention. I will now turn it over to Cristin for a commercial update. Cristin?

Thank you, Brian. We were encouraged by the commercial execution across our portfolio so far this year, with strong patient demand across enzyme therapies and VOXZOGO. We look forward to providing a more detailed commercial update on our plans to maximize the potential of both Galafold and Pombiliti and Opfolda next quarter. Our initial priorities therein are focused on driving diagnosis in Fabry and switch in Pompe. This will support increased penetration in countries where Galafold and Pombiliti and Opfolda are marketed, while we can currently work on geographic expansion plans for both products. We look forward to updating you on our Q2 call.

Now moving to Slide 11. I'll begin with an update on first quarter 2026 performance, starting with enzyme therapies. As Brian outlined, enzyme therapies delivered 6% year-over-year growth in Q1, led by VIMIZIM, NAGLAZYME and BRINEURA. Across the enzyme therapies portfolio, we continue to see strong patient demand and adherence.

Turning to PALYNZIQ. In the first quarter, we continued to expand the underlying patient base and physician engagement remains strong. Importantly, following the FDA approval of PALYNZIQ label expansion to those 12 years and older in February, we have successfully launched in this age group and are seeing encouraging early momentum. We have observed broad interest and engagement from caregivers and health care providers treating adolescents during this critical stage of their development. Since approval, we have observed meaningful enrollments and new patient starts and people under the age of 18. From a prescribing standpoint, adolescent uptake is being driven by both physicians with significant experience prescribing PALYNZIQ as well as by clinicians who are newer to the therapy. Recall that it can take a patient many months to titrate up to their maintenance dose of PALYNZIQ, so we would expect to see the results of positive early prescribing over the coming quarters. PALYNZIQ continues to standalone in its ability to enable people with PKU to reach physiologic Phe levels while reducing dietary restrictions regardless of severity. With the U.S. adolescent launch underway and European approval expected later this year, we are excited about the impact PALYNZIQ can have for additional families over time.

Turning now to VOXZOGO on Slide 12. As discussed, first quarter results reflected expected order timing dynamics following a strong Q4, particularly in international markets. Importantly, we have reserved strong growth in patient additions globally with the number of children being treated with VOXZOGO increasing by more than 20% year-over-year. With the competitor having recently entered the U.S. market, our focus has remained on executing our strategy, and we continue to see strong momentum. During the first quarter, VOXZOGO progress continued, supported by ongoing patient additions across all regions in ages, strong adherence and persistence globally and continued expansion of the prescriber base. Our teams are focused on driving new patient starts across all ages with an emphasis on children under 2 years of age, where international consensus guidelines for achondroplasia recommend early diagnosis and treatment with VOXZOGO as soon as possible.

In the United States, we are encouraged to see that our efforts educating and engaging with caregivers and HCPs, are having an impact in the under 2-year old age segment. In Q1, over half of new patient starts were from children under age 2, a greater proportion compared to last quarter. Additionally, we have seen an approximate 10% decrease in the average age of children initiating VOXZOGO treatment in the under-2 segment, narrowing the window between diagnosis and treatment states.

Internationally, building on our global expansion into 55 countries to date, our strategy remains focused on reaching more patients and regions that have further opportunity and treating infants in countries that already have high penetration rates. With our sNDA for full approval now submitted, we believe the depth and durability of VOXZOGO's clinical evidence can be further reinforced, strengthening its role in treatment decisions for infants and children with achondroplasia. At the same time, we're making progress in preparations for potential expansion of VOXZOGO into hypochondroplasia. As we get closer to the Phase III data and potential launch, our pre-commercialization activities continue to accelerate. Our initiatives in the U.S. are making a difference. More people are being diagnosed at a younger age, diagnosis rates are rising and more doctors are requesting diagnostic tests. We look forward to the Phase III top line results in the second quarter of 2026 and submitting to global health authorities in the second half of this year with potential approval in 2027. In summary, we are pleased with the strong patient demand observed across the portfolio with continued momentum in our core business units and a compelling set of near-term opportunities to accelerate growth. With that, I'll turn it over to Greg for an R&D update. Greg?

Thank you, Cristin. As expected, 2026 is shaping up to be an active year for R&D, and we're looking forward to delivering multiple meaningful milestones. Moving to Slide 14. We've built a comprehensive VOXZOGO evidence package that goes well beyond describing annualized growth velocity, highlighting long-term durability and clinically meaningful health outcomes for children with achondroplasia. Recently, at the Pediatric Endocrine Society Annual Meeting, we shared data from 3 ongoing long-term extension studies that illustrate the sustained benefits of VOXZOGO over time. Consistent and cumulative improvements in Z scores were observed across all age groups over the 6 to 8 years of follow-up as depicted on the left of Slide 14. On the right side, you again see consistent and cumulative gains in height and height Z scores with durable results out to 8 years of follow-up. In addition to anatomic measures of benefit, we also presented data demonstrating VOXZOGO's favorable impacts on quality of life measures. Importantly, these sustained efficacy findings are supported by a robust safety database now comprising more than 10,000 patient years of exposure, reinforcing VOXZOGO's well-established long-term safety profile. Taken together, this extensive body of evidence reinforces VOXZOGO's differentiated profile with no other achondroplasia therapy supported by this level of long-term data with regard to safety, efficacy and functional outcomes. Importantly, this data spans the full pediatric age population, and VOXZOGO remains the only therapy approved for use immediately from infancy. This allows for early treatment initiation and enables a long window to positively influence endochondral bone formation and all the potential downstream benefits to health outcomes. Together, these data formed a strong foundation for our full approval submission intended to fulfill our post-marketing requirement, which was submitted to the FDA in April and will afford us the opportunity to share direct evidence of VOXZOGO's long-term value with the community via peer-reviewed publications and presentations later this year.

Now moving to Slide 15. The remainder of 2026 includes several anticipated pipeline updates, including two particularly important pivotal data readouts expected in the second quarter. Starting with hypochondroplasia, we believe the health care provider community is looking forward to a targeted therapy that addresses this skeletal condition, and we are confident in the scientific rationale for VOXZOGO in this indication. That confidence is grounded in the strong proof of concept and durability demonstrated in Dr. Dauber's investigator-sponsored study and in the rapid enrollment we observed in our own Phase III pivotal trial. We look forward to sharing these Phase III top line results in the second quarter.

In parallel, enrollment is progressing very well in our Phase II study in children under the age of 3 highlighting early interest in VOXZOGO as a potential option from infancy in hypochondroplasia. We also expect Phase III top line data for BMN 401 in the second quarter of this year. As a reminder, ENPP1 deficiency is a rare, serious and progressive genetic condition affecting vascular, skeletal and soft tissue systems. BMN 401 has the potential to be the first disease targeted therapy for ENPP1 deficiency. The ENERGY III study in children aged 1 to 12 includes 2 co-primary end points. The first is change from baseline and plasma measures of inorganic pyrophosphate through week 52. The second is change in the RGIC or Rickets Global Impression of Change after 52 weeks of treatment, assessing improvement in skeletal health. Clinical experience with BMN 401 in older patients has shown that normalization of pyrophosphate is accompanied by improvements in bone mineral biomarkers, functional performance and patient and physician reported outcomes. In addition to these pivotal readouts, I also like to highlight progress with BMN 333, our long-acting CNP therapy. We are pleased to share that enrollment is underway in our global registrational-enabling Phase II/III study. We are rapidly progressing this program with the goal of establishing BMM 333 as a potential next-generation standard of care for achondroplasia and potentially for other skeletal conditions.

Before closing, I'd also like to touch on BMN 351 for the muscular dystrophy at the Muscular Dystrophy Association Congress in March, we presented initial data demonstrating dose-dependent increases in dystrophin at week 25 in both the 6 and 9-milligram per kilogram dose cohorts. These findings were accompanied by notable decreases in creatine kinase, a biomarker of muscle injury and the prevention of functional decline as measured by the North Star Assessment and the 6-minute walk test when compared to historically matched controls. So far, we are encouraged by both the dystrophin expression levels and the functional improvements observed in our development program. Enrollment in the 12-milligram per kilogram cohort is ongoing and we look forward to providing an additional update by year-end as this program continues to advance.

Finally, we would like to thank the patients, families and caregivers whose commitment continues to make this progress possible. Thank you for your attention today. We will now open the call to your questions. Operator?

[Operator Instructions] We'll go first to Sean Laaman at Morgan Stanley.

This is Mike on for Sean. I just wanted to touch on two things. First, looking at the recent data at the Pediatric Endocrine Society, can you help to contextualize the benefits you saw in bone mineral content in hypochondroplasia? And how does that maybe inform or influence your expectations heading into the top line?

Yes. Thanks for the question, Mike. This is Greg Friberg. Yes, in addition to measuring growth velocity across both achondroplasia historically and hypochondroplasia, of course, we're measuring a variety of factors of health and well-being, including bone biology and bone health. The dexa scans that were presented and that cumulative data suggests, again, that that in addition to growing bone length and stimulating endochondral bone formation, that, yes, that bone is healthy and a strength that we would like to see. And again, reiterates what we've seen in the other FGFR3-related mutation condition of achondroplasia as well. Going into the card flip for the Phase III study, we're certainly excited to see that data. The event is going to occur before the midway point of this year. So we mentioned that it's in the second quarter. We're eager to see those results. And again, I think it highlights that the data at PES highlights the fact that hypochondroplasia, while a unique and individual indication as compared to achondroplasia, the related biology suggests again that the hypothesis is a strong one. We've seen in Dr. Dauber's data from National Children's, again, we've seen the kind of growth that certainly would meet the criteria for a statistically significant improvement that our study is developed to measure. And with regard to that safety profile, we're not anticipating any unexpected events there as well. So fingers crossed, and we'll be updating you all when that data is available.

That's really helpful. And then just maybe circling back on to the intro comments. Regarding the integration Amicus, you alluded maybe there's like a road map for future growth acceleration. We were just wondering if you could help to comment. I mean, specifically for Pombiliti and Opfolda, what leverage do you see for driving increased switch rates in that market?

Yes. This is Cristin Hubbard here. And just having closed last week, I can say we are really, really excited about the commercial potential of both of these products, both in high-growth products to add to our portfolio. As we've mentioned before, but I'll expand a little bit, for Galafold specifically, we really do think that the biggest growth lever is in and around diagnosis. We know that a large proportion of the amenable patient population remains undiagnosed, and driving diagnosis is exactly where Amicus has really started to build momentum, but we feel that using BioMarin's capability in this regard, we can really continue to drive that forward. On the Pombiliti and Opfolda side, that's more about a switching opportunity. And we really do think that there's going to be a sizable opportunity here to build over the next few years as patients on their existing therapies begin to progress. So we're really working on initiatives that, again, Amicus has started, and that is around kind of starting new therapy, looking at patients that have identified their own progression and understanding what progression looks like. That's an area that we're really focused on, not to mention the continued generation of evidence to show the benefits of a switch. So again, these are areas that we feel confident in our capability at BioMarin and are very excited about the future trajectory. So we'll share more on that on our Q2 call.

We'll move to our next question from Salveen Richter at Goldman Sachs.

This is Tommie on for Salveen. Just a quick one on VOXZOGO. Wondering if you've seen any early signals of different behavior from competitor entry, whether it be switching or in new patient adds.

Yes. Thank you for the question. This is Cristin again. And as you heard in our prepared comments, our demand in the first quarter really does remain strong. Our enrollments in fact, exceeded. In Q1, our enrollments exceeded that in the average of second half last year, and that trend continued into April. So as we see it now, we're really excited. As you know, we're very much focused on the 0 to 2 population based on the consensus guidelines, and we're seeing real momentum there. Not only were our new patient starts weighted and more than half of them being in that 0 to 2 population in the first quarter. But we're also seeing a reduction in the time we have from diagnosis to treatment in that population. That is -- that's reduced by 10% already. So we know that, that real focus therein working. In addition, we're focused on the patients that are already on treatment and making sure that the -- those patients for whom they're doing well on treatment, we want to make sure that they understand the totality of the evidence that exists for VOXZOGO and continue to have a positive experience in terms of the benefit. So we're very pleased. Good how Q1 went and look forward to continuing on that trajectory. .

We'll go next to Paul Matteis at Stifel.

Great. Just kind of previewing your update next quarter as it relates to Amicus integration. I was wondering if you could set the stage for us and just what you might be providing as it relates to the duration of the revenue outlook? Would you talk about peak sales at all? Or update those us or anything else? And then secondarily, anything you can do on setting the stage on our expectations related to accretion, cost synergies, and again, the duration of the profitability outlook as well?

Paul, thanks. Appreciate the question. And yes, we wanted to highlight today having just closed the transaction a week ago, brief update on the integration to date, which a weekend is going well, and you saw the update of our revenue guidance today, adding our expected range of the 8 months of Amicus revenues, resulting in a $500 million midpoint and the updated guidance, which is 20% year-over-year. We also wanted to set the stage for the Q2 update. The transaction announcement, we discussed how the strategic fit between these two businesses was very strong. And that because of the both global and commercial and medical capabilities of BioMarin built over time in our existing portfolio, that these two medicines should truly have more potential within BioMarin. That was a key rationale underlying the transaction, and we've been making plans up to this point of closing. And now that we've closed, we're just digging in and engaging more deeply with the Amicus business. And that's why we're going to wait until Q2 to give this additional update, but it will include a number of details and metrics about the long-term potential, including our views on peak revenue. Just a reminder, based on our due diligence at the time of announcement of the transaction, we reiterated what Amicus had shared with respect to peak revenue potential of roughly $1 billion each for Galafold and Pombiliti and Opfolda. But as we developed that long-term business plans and strategies to expand both of these medicines, we think that has some potential to be higher. So that's what we'll share. We'll be -- it will be important for us to share some of the key metrics and tactics in terms of how we expect to achieve that long-term potential. So stay tuned, and we'll look forward to sharing more in Q2. And by the way, that will include some of the other financial elements as well, such as synergies, long-term profitability, accretion, et cetera. I will share that for today. We are reaffirming our previous expectation that while, as you saw in the EPS guide today, the Amicus acquisition is slightly dilutive to calendar '26, but accretive for the first 12 months following closing and then substantially accretive for beginning full year '27. So we look forward to sharing more, but we're off to a strong start.

We'll move next to Ellie Merle at Barclays.

This is Jasmine on for Ellie. So just for VOXZOGO for hypochondroplasia, what's the latest on what you're thinking will be good data and what you're looking to see on AGV? And also, how are you thinking about the contribution to VOXZOGO revenues from hypochondroplasia next year? So what do you think the cadence of uptake will be in this population? And can you talk a little bit about your commercial preparations.

Thanks, Jason. This is Greg Friberg. Maybe I'll take the first part and then hand it off to my colleague. With regard to the VOX HCH, we're turning over, of course, -- we'll be looking at the data in the second quarter of this year, absolutely looking forward to that. And of course, the success is a statistically significant improvement in growth as compared to the control arm. And in this world, of course, we're measuring a variety of other measures. We're looking, of course, at other anthropometric measures as well as, of course, the safety profile. And really any statistically positive improvement in growth, we think that that's a win for these patients.

I'll just add that we've seen pretty dramatic I think, accelerations of recruitment, both for the older children as well as I mentioned in the prepared remarks, the infants on our hypochondroplasia study, really suggesting that this is a market that's hungry for a disease targeted therapy. Again, the biology is significantly similar to that of achondroplasia with regard to the mutation that drives this condition. And so from that standpoint -- and of course, built upon the data that Dr. Dauber has seen, we're quite excited to see what those end results will be. I think there was a question also about the marketplace, and I'm going to hand that one off to Cristin.

And so overall, our goal, of course, is to continue the growth of VOXZOGO into the midterm and hypochondroplasia provides an important component of that. Really where we're focused today on our prelaunch activities is in and around diagnosis. We have shared before that the total addressable patient population globally is at 14,000, and that assumes that we can continue to drive diagnosis and awareness of this condition. So our goal at this point in time prior to launch really is around increasing the number of hypochondroplasia patients that have been identified that we're getting physicians to understand the genetic testing and make sure that they're orders for that. And really, the idea being that patients get diagnosed at a much earlie. So our goal today is to improve upon that and make sure that we have identified patients at the time of a potential launch.

And Jason, if I could just add one other factor from the medical affairs standpoint. -- we're obviously actively working in the community even prior to seeing our data to really try to accelerate the number of patients that are diagnosed with this condition. There's probably 3 prongs to that. Of course, getting patients to be able to be referred sooner, to be evaluated, of course, more testing as well as we're doing work on the genetics side to reclassify so-called VUSs variance of uncertain significance. And so in that world, we're anticipating again that there will be patients available and ready for this therapy should become available. .

To throw out a few components, if I could, quickly. On the success we've had already, when looking at the diagnosis program that we're running to date and these kind of nonpromotional prelaunch activities, we're already seeing a 90% increase in the number of hypochondroplasia patients that we've identified as well as a 70% reduction in the age. So those are precisely the types of numbers that we're driving for and want to continue throughout our launch period.

We'll move to our next question from Cory Kasimov at Evercore.

This is Adi on for Cory. I had a question on the guidance increase. The $500 million from midpoint increase in guidance. Can you frame that the contribution from Galafold, Pom-Op, is that conservative relative to the $600 million revenue that generated in fiscal year 2025? And what are the key assumptions for adding these two assets into the guidance?

Ed, this is Brian. Thanks a lot for the question. I appreciate the opportunity to provide a bit more color on this important element of today's update. So yes, I'll frame it up for you. First of all, the $500 million represents a midpoint of a range that fits within the range of our existing enzyme therapies guide for '26, but I'll speak to the midpoint. From a timing standpoint, just a reminder that with the transaction closing last week, that $500 million midpoint represents mostly the 8 months remaining from May to December for this year. I will share in terms of your question around conservatism. I would say it's neither conservative nor aggressive. We think it's realistic. I'll share that we've analyzed the unreported period of Amicus product revenue from January through April. And when we looked at that versus consensus, January through April performance, while not reported was ahead of consensus. So both Galafold and Pom-Op together are off to a strong start in 2026. So with that being said, again, it's -- this is -- the transaction closed just a week ago. We'll come back next quarter with additional color, including the long-term potential I'll also share that since you commented on the $600 million reported for 2025, the range that's underlying today's update from an Amicus organic year-over-year growth rate standpoint, ranges from the high teens to the low 20s. So we think it's a really healthy growth. And we're excited that these assets are now part of our portfolio. And again, you see this 30% increase year-over-year as a result of layering this on to the BioMarin enzyme therapies and total revenue, 20% at the midpoint. So we're feeling good about it, and we'll share more going forward.

We'll go next to Jessica Fye at JPMorgan.

This is Jose on for Jess. How should we think about the adoption of hypochondroplasia relative to achondroplasia? What do you see as similarities and differences between these markets? And second, can you help us bridge the disconnect between the 20% year-over-year patient growth in 1Q versus a 3% revenue growth. Is it entirely explained by larger orders in the fourth quarter last year?

Yes. So I'll address the first part of the question in terms of how we see it in terms of uptake going in. I think we can consider it being similar to that of achondroplasia. But I think as I've mentioned kind of earlier, what is most important to us is ensuring that the amount of disease awareness, the urgency to treat and the diagnosis are really what we're focused on because we believe this is what accelerates that adoption curve. So our intention has been to drive as much of that so that we have patients identified at the time of our potential launch in the beginning of 2027. But importantly, that we continue on with that momentum because that ultimately is going to be what drives the shape of the adoption curve.

And Cristin, from a medical standpoint, if I could just comment. Hypochondroplasia, children are not born with the same growth gross deficit that the achondroplasia patients may be born with. And as a result, they often are diagnosed a bit later. They're referred and diagnosed. So that data point that we referred to earlier, which was one of our goals to try to shrink that number in terms of age of diagnosis is something that we see as a real positive sign that the work that we're doing to get these children in the hands of the right physicians who, again, can know what to do for them. That seems like a real early success, and we're looking forward to continuing to help shape that community and make these these therapies should they become available actually in the hands of the physicians who treat the patients.

Cristin, I'll take that revenue timing or fluctuation question. I appreciate you pointing that out because it is important to emphasize that the disconnect between that underlying patient demand growth in reported revenues is entirely order timing. There's a couple of different layers to that. One -- both of which we discussed last quarter, by the way. One was large international orders that were processed in Q4 that just didn't recur in Q1. Then the second was something that was somewhat unique to our business when looking back over the years, which was a modest amount of U.S. stocking impact from Q4 to Q1. This affected both PALYNZIQ and VOXZOGO. It wasn't significant, just about an extra week of inventory, but it was enough to show up as a variance in the quarter-over-quarter revenue. So this is why we wanted to emphasize the underlying patient demand growth. There's no significant price drivers in there, by the way, it is entirely order timing dynamics.

We'll move next to Phil Nadeau at TD Cowen.

Two from us. First, could you give an update on the ITC hearing and in particular, we're curious to get your thoughts on the ITC pretrial brief that was recently posted online. That's first. And then second, in the press release, there's a a note that there's going to be some data from BMN 333's Phase II/III trial in 2027. Could you provide a little bit more details around what data will be released at that time? .

Thanks very much, Phil. It's Alexander. I'll take the first part of your question and then hand it over to Greg for the second part. So with regard to the ITC, I mean, overall, we believe that assuming an exclusion order enforcing our IP is the most expeditious way to protect our IP in the United States. As you mentioned, we recently completed the ITC evidentiary hearing and post-hearing briefs are now being submitted to the presiding Chief Administrative Law Judge. So what happens next is we expect to receive a decision on whether product infringes our patent on or about August 21. At that point, if the full commission decides to review the decision and the final decision is expected on or about December 21. So this is a little bit of where we are and what can we expect going forward. I will also add that on completion of the ITC process, we would expect to also enforce a patent in the Federal District Court, where, of course, monetary damages are available. And I'll now hand it over to Greg.

For the question, Phil, about BMN 333. And as a reminder for those on the call, this is our long-acting CNP analog, again, designed to release continuous potentially higher AUC exposures of CNP when administered on a weekly basis. Again, as a reminder, in our Phase I, we saw over 10x increases in the AUC levels that we were able to achieve safely in the healthy volunteers. And we've recently initiated our Phase II/III study in children with achondroplasia. This is a multiregional clinical trial. It's currently open in a variety of countries around the world. We're enrolling as we speak. And our goal is to run the Phase II portion, where 1 of 3 doses of BMN 333 will be administered to the children, and there will be one arm that has VOXZOGO as well. There's no placebo on this study. What we will ultimately report out in 2027 is that we will be able to measure the annualized growth velocity at the 6-month time point, and we'll be using that data along with other measures, measures, other measures of safety and well-being to make a decision based on the analysis of which dose we should bring forward into a Phase III to run head-to-head against VOXZOGO. Again, looking for a superiority profile when it comes to AGV with the presumption that more AGV will drive more in the measurements of health and wellness that we're all familiar with.

We'll go next to Chris Raymond at Raymond James.

Yes. Just a question on the pivotal trial for BMN 333. I know this has come up before, but I guess I want to just ask maybe in a more pointed way and the decision to go with a superiority trial versus noninferiority. I think I've heard what you guys have said around 333 providing 2 to 3x free CNP and that, that should translate into higher efficacy. But maybe just strategically, if a non-inferiority trial could show that data, why take the risk and run a superiority study?

Yes. Thanks for the question. This is Greg Friberg, our goal with BMN 333 is to evolve this space. not just make a more convenient version of VOXZOGO. I'll just highlight that, that 3x target was at least 3x. We're actually testing a 3x to 5x and greater than 7x AUC exposure. And so from that standpoint, we believe strongly that BMN 333 is the right reagent to test this hypothesis. I'll also add that from a non-inferiority standpoint, it's a natural question to ask, wouldn't this be easier? From a pure mathematical standpoint, it's actually much harder and the study would be upwards of 10x the size in order to show non-inferiority versus even a drug like VOXZOGO. And so from that standpoint, there's a practicality of designing the study but I do want to reassure you that we will have an opportunity to look at the data after our Phase II portion. And if there need to be adjustments that the model gives us an update that tells us we should be reevaluating those would be potential opportunities. That being said, we are very clear with what we want out of this molecule. We want a superior CNP product that can be the cornerstone for future therapies for achondroplasia.

And I would just add absolutely, as Greg said, this is -- we think the opportunity in the need here is really around superiority. In terms of efficacy, AGV and all the benefits beyond linear growth, but also by this design of a study, we actually have an active control with VOXZOGO. So the size of the study is smaller than it would have been if it was in non-inferiority design, as Greg has already covered. But we also think the proposition to both caregivers and physicians means that this should be a study that's very attractive to potential patients to sign up to be included and therefore, speed of recruitment, which is extremely important. So we think that superiority profile we're aiming for from an efficacy standpoint, together with rapid trial recruitment and milestones being achieved is really a compelling proposition.

Yes. Placebo-controlled studies, when there are active safe and effective therapies are no longer really possible to run. It's not the right thing to do either.

We'll take our next question from Mohit Bansal at Wells Fargo.

This is Chen for Mohit Bansal. So we -- I just want to double-click on the BMN a little bit. I think you guys discussed that BMN targeting improvement in achondroplasia. But just wondering with a competitor that is also advancing their weekly CNP analog together with the growth hormone and potentially reporting a higher -- just how should we think about BioMarin's view of this evolving treatment landscape and the role that 333 could potentially play it over time.

Thanks for the question. This is Greg Friberg, again. And it is true. I think the data in combination with growth hormone, of which we've seen about 12 months of data, does show in the early studies that there is potentially additional growth to be had by adding in a second agent. But I want to caution you that it is early days for the combination. Growth hormone has been around for quite a while. And in achondroplasia, it's only approved in one market that I'm aware of that's Japan. And the reason for that is that growth that can be stimulated with growth hormone ultimately has not historically resulted in increases in final adult height. It's growth that gets uncorked but at the expense of potentially closing the growth plates earlier. And that remains an open question. I think we do need to see data at 2, 3 years or more, not only to see the safety, of course, growth hormone, while it has a manageable safety profile, does have its own set of challenges that need to be monitored by a physician. But we need to see whether or not those gains are long-standing. I want to reassure you that this is something that we're watching very closely. And if there are opportunities and levers that can help CNP do its job better, so to speak, we will evaluate those at the right time and place. We don't feel that, that is the correct time right now, and we're certainly interested in seeing additional data before the paradigm shifts. And this is consistent with what we've heard from many of our stakeholders as well.

We'll move to our next question from Joe Schwartz at Leerink Partners.

I was wondering if we could get some more perspective on your guidance raise for the enzyme therapies business. We see it increase by $500 million, and we estimate that Amicus generated around $450 million in revenue for Galafold and Pam-Op in the comparable 8 months last year. And that implies low double-digit growth around 11%, I think. But I heard you reference high double-digit percent growth, Brian. So I'm just wondering if you can help us reconcile that difference?

Thanks, Joe. Appreciate the question and your math there. I'd probably attribute the reconciliation difference that you're trying to get at with two elements. One, by doing a pro rata 8 months of 2025, there's certain -- there's some in variables there and a lack of precision that we couldn't do a strict apples-to-apples comparison. And then secondly, on a full year basis, again, I pointed to that strong performance for the first 4 months of the year for both Galafold and Pombiliti and Opfolda. So again, not reported. This is internal management data. We're not disclosing it because it didn't go through the usual external reporting process like a regular quarter does. But we thought it was important to add color to that full year. So I'd say it's more important and this goes to our own business as well when we think about some of these quarterly timing dynamics. I think it's most important to compare the full year annual cycle year-over-year, and that's where when we piece together the range that's implied today over that full year $634 million that Amicus reported for '25, we have a range of high teens to low 20s. I'd encourage you to anchor that rather than trying to calculate them intra-quarter map.

We'll move next to Jason Gerberry at Bank of America.

Alex, just to follow up on the ITC question. I'm trying to just get my head around, do you have any knowledge of the Ascendis' ability to do manufacturing workaround? And just help us think through scenarios if you get a positive ruling like, could a decision be stayed pending any sort of appeals? And then just a follow-up, just on Pom-OP, I believe you've inherited the asset basically launched into 15 country markets, and I think the goal is to get it into 80 country markets. So how should we think about the phasing of that now that you've got the asset either 2026 or 2027?

Thanks very much for the question. Unfortunately, I'm not going to hear any details of the of the ITC the potential scenarios around it. So I hope you can understand that we don't want to get into too many specifics, especially whilst the case is very much pending. So I'll hand it over now to Cristin for the second part.

Yes. Thank you very much for the question Pom-Op. And you're absolutely correct in that there -- currently, we are reimbursed in 15 countries. And what we've been doing before the transaction was closed, we've been doing deep dive into discovery sessions really looking at the business in each market for both Galafold and Pam-Op, really understanding what the dynamics are therein, but then importantly, looking at, as you've mentioned, our 80-country footprint and saying, where would the potential and the opportunity be. We're identifying opportunities for both Galafold as well as Pom-Op, given that Pom-Op is much earlier in its launch trajectory, you can imagine that there will be a larger number of countries to look at therein. But it's important to note that we're not necessarily going to put it into our entire 80-country footprint but importantly, look at where we believe the potential opportunities are and then have a cadence to that, that we'll share more of in the Q2 call.

And that concludes the Q&A session. I will now turn the conference back over to BioMarin's CEO, Alexander Hardy for closing remarks.

Thank you, operator, and thank you all for joining us today. This quarter, as you can tell, marks a really important inflection point for BioMarin. With the recent close of the Amicus acquisition, expanding our commercial reach, strengthening our 2026 revenue growth outlook to 20% and enhancing our ability to serve more patients globally. We're encouraged by the robust patient demand observed across our portfolio. In enzyme therapies, we anticipate that the momentum from the PALYNZIQ launch in adolescence will continue to build. With VOXZOGO, the consistent rise in new patient initiations, more than 20% year-over-year in Q1, especially among younger children, demonstrates confidence in its long-term safety and efficacy and highlights the importance of starting treatment as early as possible.

With the integration of Amicus now well underway, several near-term catalysts ahead, pipeline readouts. We are focused on translating this momentum into accelerated growth, broader patient impact, meaningful value creation. We appreciate your continued support and look forward to updating you next quarter. Thank you.

And this concludes today's conference call. Thank you for your participation. You may now disconnect.

Good afternoon, everyone. I'm Ellie Merle, one of the biotech analysts here at Barclays. Very excited to have BioMarin here with us. Certainly, a very important year for you with commercial launches and clinical readouts. Excited to have Brian, CFO; Cristin, Chief Commercial Officer. Thank you both so much for joining us.

To kick it off with an overview question before we kind of go into some of the specifics. Just can you give us a brief overview of the key highlights of BioMarin's progress over 2025 and what we can look forward to in 2026?

Yes. Thanks, Ellie. Appreciate it. Thanks for having us. Thanks to those of you joining in person. Really pleased to be talking to you today at this point in the year as we transition out of what was a very successful 2025 for the company and a very exciting 2026.

Starting with how we finished 2025, BioMarin grew total revenue at 13% for the full year, and that included 26% revenue growth for VOXZOGO and 9% growth from our Enzyme Therapies business unit. On the profitability side, we've been on a profitability improvement journey over the last couple of years. We've had several quarters in a row where we're growing earnings per share at a rate greater than revenue, and that includes full year 2025, where -- after adjusting for some of the special items that did hit earnings in 2025, we were more than 2x leveraged on the bottom line.

And the other big momentum build coming out of '25 is the announcement of the Amicus acquisition, and this kind of sets up perhaps what we're excited about in 2026. So the Amicus acquisition we announced in December. We expect to close it in the second quarter, subject to all the customary closing conditions for an acquisition like that. And that adds 2 high growth or subject to closing, will add 2 high-growth approved rare disease assets to our existing portfolio of more than $3 billion of revenue from 8 rare disease products.

Beyond that, within the existing base business, we're expecting to grow revenue within both of our business units at the high single digits, Enzyme Therapies and Skeletal Conditions, both growing at 7%, 8%. We do have a small growth rate headwind on total revenue because some of our royalty and other revenue is decreasing, and that's about a 3% headwind. But the most critical parts of our growth are the business units, and we're excited about that.

We're also advancing our pipeline and have a number of pipeline catalysts in 2026. First is the Phase III readout for hypochondroplasia for VOXZOGO. VOXZOGO is currently approved in achondroplasia. Hypochondroplasia is a similar condition and we have proof-of-concept data from an investigator-sponsored study and the Phase III study will be reading out in the first half of this year.

Another Phase III readout is BMN 401. This was the asset that we acquired with Inozyme last year, which was our first acquisition of 2025. This is an enzyme replacement therapy for ENPP1 deficiency. And again, data in the first half of the year.

We also have clinical stage assets progressing. BMN 351, we shared some data early in the year. This is a second-generation exon skipper for Duchenne muscular dystrophy. At -- we're testing 3 dose levels. And at the middle dose, we shared that we achieved 5% dystrophin expression, which at 25 weeks, which is about halfway through to what it should take to get to steady-state dystrophin expression at 52 weeks or more. That 5% shows us that we could be on track to reach our target of 10% dystrophin expression, which while there are approved products, there's still an unmet need. And while it's a competitive space, this does have the opportunity to be best in disease. So we'll be looking forward later this year to sharing the results from the highest dose, the 12-milligram dose.

And then the other clinical program that's advancing internally is BMN 333. This is BioMarin's long-acting CNP, possibly a weekly injection, but what's noteworthy about BMN 333 is that we're designing the product and its target product profile is more than just convenience. We're designing the Phase II/III study to actually be superior in efficacy to both our own drug, VOXZOGO. It's a head-to-head program with VOXZOGO, but also potentially superior efficacy-wise to the competition.

So we appreciate that VOXZOGO is facing competition, including a recently approved competitor. But frankly, we're excited to compete. We're confident in VOXZOGO's profile. We have established ourselves in the achondroplasia community and with patients and physicians. We believe that switching will be complicated. We'll continue to have the infant label for ages 0 to 2, where it's most important to start treatment of achondroplasia with VOXZOGO as early as possible, that's published in international treatment guidelines.

And then just a reminder, since I started talking about the VOXZOGO competition that we are talking about just 25% of VOXZOGO revenues being in the U.S. that's subject to the competition, which is approximately 7% of our total revenue. So we've got this base business that's growing, including VOXZOGO in 2026. The midpoint of our guidance is $1 billion. So through competition, VOXZOGO potentially reaching blockbuster status and still growing healthily in its fifth year after launch. So that's -- we're excited about all that.

Yes. There's certainly a lot of investor focus for what, as you rightly say, is 7% of your revenue. But yes, maybe let's start there talking about VOXZOGO sort of you outlined 2026 guidance for VOXZOGO revenues. Maybe if you could sort of outline some of the assumptions behind that, both from a U.S. and ex U.S. perspective in terms of what's baked in, in the guidance.

Yes, of course. So VOXZOGO guidance is $975 million to $1.025 billion for 2026. The two most noteworthy swing factors in that range beyond the fact that it's earlier in the year, and it's an estimate at this point in the year, we need to execute and there's natural variability. That's why we estimate a range. But the two largest swing factors are, first, some international market access negotiations that we're in the process of concluding this year. On the low end of the range, that could involve a price discount. But if that's the case, in some markets, including those that we're negotiating in, that's just a short-term headwind because what we could be doing is taking a short-term price discount to actually open up access to more patients over time. So a short-term headwind because of price, but long-term tailwind because you're accessing more patients over time. And on that one, on the high end of the range, it would just assume that the pricing gets negotiated more in our favor.

And then the second swing factor is the competitive impact. So on the lower end, that assumes that there will be more VOXZOGO patients switching potentially earlier and at the high end, less switching later. But you can -- again, back to the 25% of revenue and the 7% of total revenue, you can see that our assumptions even around different levels of share loss to competition, it still fits within that $50 million band. So these are not largely material swing factors on what is a $3.3 billion, $3.4 billion portfolio.

Also important to note is the anticipation of closing the Amicus acquisition. I talked about how this brings 2 commercial assets into the portfolio. We will, of course, update our guidance at some point, assuming we close after the close. But if you look at the 2025 revenues for those Amicus products, it's over $600 million. So -- and these are high-growth assets. So as we bring in the Amicus assets, VOXZOGO becomes an even smaller portion of our total revenue.

Certainly, probably quite high margins on the Amicus products as well.

Galafold has a slightly higher margin. It's a small molecule. The Pombiliti + Opfolda product is slightly lower. It's a combination product. It does include a biologic -- but we're familiar with some of the cost of goods sold initiatives, second versions of the manufacturing process that Amicus has been working on. So we'll look forward after closing to looking at those opportunities.

I have more questions on that. So first, I just want to talk about VOXZOGO. So what's interesting is there's all this focus on competition, right? But we've talked about how 75% of your sales are ex U.S., which probably will be a lot stickier than the U.S. But then you also have hypochondroplasia, which assuming that the Phase III reads out positively in the first half of this year, which I personally think is a readout that people should be talking about more. But just from a commercial perspective and modeling, like how do we think about -- like this could be launching this time next year. So how do we think about the revenue contribution from hypochondroplasia and the cadence that we could see of that?

Yes. And we will -- we are very much looking forward to the data readout in the first half of this year. And we are, of course, gearing up on our go-to-market plans, and we'll share more about that as the data comes out. But what I think is important to note is that hypochondroplasia, while we believe that it's genetically prevalent as the same as achondroplasia, so we say that there's a total addressable patient population of 24,000 with achondroplasia. The big difference with hypochondroplasia is the diagnosis rate. It's much lower. Estimates are that it's diagnosed at about 30% of patients being diagnosed. So what we've said is that we think that the total addressable patient population is in and around 14,000 for hypochondroplasia. And again, the big reason for that is the lowering of the diagnosis rate.

So where our teams are really focused now and will continue to be after launch, after assuming we get a launch is in and around the disease awareness as well as how can we shorten that diagnosis pathway. Right now, kids are getting diagnosed around 5 to 6 years old. We want to see that happen earlier and importantly, make that journey to get that confirmation of diagnosis quicker for them so that they can get on the appropriate treatment. And should we be approved, VOXZOGO would be the only treatment for hypochondroplasia.

And feel free to not answer this question. But based on your commercial work and seeing how many patients are diagnosed today and getting a sense of awareness because presumably, these patients see that achondroplasia patients get VOXZOGO, how are you thinking about whether there could be an initial maybe bolus of patients next year? And from a revenue contribution, how we should think about that?

Yes. I think that in the centers where you have KOLs or they've been involved in our clinical trials, for instance, that's where you're going to see those that already know who those patients are, and we could expect quicker adoption in those particular centers. But the truth is these patients are spread out. They're being seen by pediatricians. They might be in endocrinology offices. So that's where you get a little bit of a slowing relative to that bolus. So I think it kind of normalizes into what I would argue would be a normal launch curve, but recognizing that the total addressable patient population will be lower because of that diagnosis rate.

Makes sense. And of course, longer term, I know you're running sort of the CANOPY Phase II trials in ISS, Noonan, Turner and SHOX. How are you thinking about the opportunity set there?

Yes. So to remind you, so we are -- as you said, we have the CANOPY trials that includes hypochondroplasia, but in these other conditions, including ISS, Noonan, Turner and SHOX. This is an area where we have said that the bolus that -- that total patient population size across those four is 385,000. But what we had said is that we would only expect to get a very, very small fraction of those patients and those that are the most severe. So I want to remind you, these are Phase II trials. We're currently enrolling them and are very much looking forward to seeing how the data turn out next year.

Yes, exciting readout. Going back to the Amicus conversation, how should we think about any -- like you already have a global rare disease sales force of commercial operation. How much more spend do you need to support these revenues? And basically, I'm asking kind of how much of the top line just goes directly down to the bottom line?

Yes. Thanks. Great question, Ellie. Maybe I'll start and Cristin can talk about how we genuinely believe that these two medicines in our hands have the potential to reach more patients because of our global capabilities and reach. But to your point on OpEx, first of all, we need to get through subject -- get through the closing period and actually engage with Amicus and get to work on the integration. But based on what we know about their business, first of all, there's a significant amount of capabilities that they've been able to leverage and be successful with through the growth of these assets. I mean, speaking of switching, they're in the switch market themselves on both of these assets, and they've been very successful in switching patients to Galafold and Pombiliti and Opfolda. And so we plan to preserve and grow those capabilities and continue to use those to drive the sustained growth in these Amicus medicines.

We also think there'll be a level of investment required. We'll get some leverage from the global BioMarin commercial infrastructure, but as Cristin will touch on, if we get into improving diagnosis or expanding the global reach, some of that will take some direct investment. So there's a level of investment in OpEx, but we also believe that the complementary nature of the business model means that there's going to be operational and -- operational expense synergies as well. So -- but that's work to do after the closing, and we'll talk more about it when we -- after close.

Okay. Got it.

Do you want to touch on the expansion?

Yes. Just on the expansion or acceleration, I should say. I mean what we want to do is make sure that we, first of all, do no harm and continue the trajectory that those medicines are on today, but then we're thinking about how do we inflect that curve. And the ways in which we think we can do that is to accelerate and deepen penetration in the countries in which they already are. So Galafold is currently in 40 countries. Pom-Op is in 15. We have a country footprint of nearly 80. And so we're looking today at where can we drive deeper penetration in the countries that they already are and importantly, to expand into our country footprint. So teams are currently looking at which markets would we want to go into first and looking at the cadence following that.

Yes, that makes sense, certainly. A lot of synergies there. So we look forward to the updated guidance because I believe I think it's much more accretive than people are appreciating. So I'll leave it there.

I appreciate the support.

Maybe just turning back to sort of the commercial dynamics. I guess, following PALYNZIQ's recent label expansion, how should we think about the impact of the near term on revenue in 2026 and over the longer term?

So we're really excited about the expansion, the adolescent expansion that we just received in PALYNZIQ. It's really exciting for these patients. So this is in 12- to 17-year-olds because what we know to be true about the adult population is that this really brings down the Phe levels to within normal range and allows you to have a normal diet. You can only imagine how that must feel for an adolescent who wants to be included with their friends, wants to eat like their friends and wants to make sure that their condition is under control.

So if we look at the adult population, just to give you relative commercial sizing, we have about 7,000 patients that are eligible for PALYNZIQ and that are not yet lost to follow-up, meaning that they're being seen in clinics. More patients as adolescents are actually in clinic, and that is in large part because their parents are having to manage this and ensure that they're staying both in clinic and adherent to therapy. So we think that there are about 1,500 patients in the U.S. who would be eligible for PALYNZIQ. And so we're really excited to bring this opportunity to them and ensure that not only can we lower Phe levels once they get up to their maintenance dose, but importantly, lead a normal life and set them off in the right direction into adulthood.

And maybe just on the revenue side. So PALYNZIQ continues to grow strong even before this label expansion grew at over 20% the last 2 years. And so -- and the medicine was approved in 2017. So that's just a good indicator of its gradual and continued uptake. And for the reasons Cristin noted, while this opens up a new segment of the population, because of that parental oversight and the benefit for adolescents in their lifestyle, we actually think we'll get deeper penetration within that segment, which we are excited about as an opportunity. But since you mentioned revenue, it is important to note that PALYNZIQ has a very gradual and steady dosing induction and titration phase where patients could be at a very low dose of the medicine for several months, up to 6 to 9 months or more until they get to the steady-state efficacy dose. And those smaller doses mean less revenue. So even if we're adding adolescent patients this year, you may not see it in revenue until next year. But again, chronic therapy for life, just like most of our other products. So once they're on drug, it's a steady revenue contributor.

And yes, we've certainly heard the feedback from physicians that once patients have finished the titration that the adherence is very high. Earlier today, we had PTC here who is launching SEPHIENCE. Curious kind of what you're seeing on your end in terms of any impact to PALYNZIQ?

Yes. So in terms of direct impact to PALYNZIQ, we are not seeing an impact in terms of patients switching from PALYNZIQ over, especially those patients that you would see at their maintenance dose, they've reached their efficacy and they're really content on therapy. What I think is really interesting, though, about having another option out there for patients is what we've heard PTC saying is that they're seeing some of those lost to follow-up patients that are now coming back into the system and being treated with their drug. And what that only does is that actually starts to enhance the patient population if you're bringing in that 60% of lost to follow-up patients, if you're bringing them back in the clinic, the hope would be that whatever therapy they're on is efficacious. If that one is not, they might then choose another therapy, which could be PALYNZIQ. So we see it as a real opportunity.

Makes sense. Heading into the Phase III data for ENPP1 this year, what are your expectations for data? And then also, how should we think about the commercial opportunity?

So we're looking forward to that reading out here in the first half, so very soon. This, of course, will be looking at normalizing pyrophosphate levels as well as having a functional endpoint, which is a radiographic endpoint. So we'll be looking to see improvement in both of those in the pediatric population. This is another one of those areas that ENPP1 deficiency, there are no current treatments for it. And so again, something that is in the sweet spot of BioMarin being that it would be the first and only therapy for the treatment of ENPP1 deficiency. We estimate the total addressable patient population to be anywhere from about 2,000 to 2,500 patients globally. Now this is something where the publications, it's unclear what the actual prevalence is. But as we've seen on our MPS products that when you have a medicine, you start to see more, the diagnosis rates increase and you start to see more of these patients coming. So for now, we think it's about 2,000, 2,500, but that number could grow over time with an efficacious therapy.

Absolutely. Brian, heading into 1Q, I know that your business is particularly subject to some seasonality with ex U.S. orders. But can you remind us just for modeling purposes, how we should think about any specific setups into 1Q?

Yes. Thanks. I appreciate you bringing that up, Ellie. It's important to reemphasize for those tracking. So if you look back over the years, we've historically seen kind of a ramp over the course of the year, specifically in Q4 and then a step down in Q1. Hard to call it true seasonality. As you know, from quarter-to-quarter, it's often these -- the variable timing of some of the large international orders that can cause some volatility quarter-to-quarter. That tends to just increase at the end of the year. It could be, for example, most of our customers outside of the U.S. are these single national health care system payers. And so it could be them consuming their budgets for the year, stocking for the next year. So we've definitely observed that.

And yes, so this year coming out of Q4 '25 into Q1 '26, I'd say it was just a bit exacerbated on the international order front. We also saw something that we haven't have observed as acutely before, which was a bit of U.S. inventory stocking. It's not much. We're talking about going from an average of 2 weeks of inventory on hand to 3 weeks. We don't have big pharma stocking and buy-ins, but that small amount on our larger products is enough to make a difference.

So overall, we expect revenue to look from a trend standpoint in '26 at the quarters similar to '25. For VOXZOGO specifically, we expect -- and for total revenues, but VOXZOGO as well, we expect Q1 to be a low point and for VOXZOGO on par with last year. Again, it's just these timing dynamics. Two last things. We do point to full year guidance and performance is the best measure for this exact reason, some of this quarterly volatility. And what's also important is that every quarter for each of our marketed and growing commercial products, we're steadily adding patients, which at the end of the day is true demand. We don't have material price volatility. That means you need to tease through revenue growth in terms of whether it's price or demand through patient additions. So when we see that nice steady growth of new patient additions across the portfolio across the last several quarters, and then you look at some of the, at times, noisy order patterns, we get comfortable that it is just timing.

Okay. But that's a helpful reminder in terms of 1Q. Lastly, I mean, I think the Amicus deal is a great deal from an M&A perspective. What is your further appetite and capacity to do further business development?

Yes. Thanks. Very important because it remains a key part of our strategy. What's most important is, of course, getting through the Amicus closing, paying very close attention to the integration and making sure that we're successful in protecting and growing their business. We did share -- we are levering up for the Amicus acquisition, and we shared a deleveraging strategy. Because of the complementary nature of the two businesses, because Amicus reached operating profitability on their own, the deal is actually operationally accretive early. We're taking on a significant interest expense load with the new debt. Part of that is why we do expect the deal to be dilutive this year, but accretive in the first calendar 12 months after the acquisition and substantially accretive beginning next year.

That leads to a rapid deleveraging strategy. So we said that our target deleveraging is less than 2.5x within 2 years after the acquisition. That was really important to go on record. We were a first-time debt issuer in the leveraged debt markets. But I'll share if you do the math, which it sounds like you've done, you can see that the two companies' combined EBITDA actually has us on a path to delever even faster than that, which means we are able to replenish firepower at a greater level and earlier.

So while the priority will be integrating Amicus and commencing on this deleveraging strategy, we will continue to look for opportunities on the BD side. And different from the Amicus transaction, we'll now be focused on pipeline clinical stage transactions. So we're excited about our internal pipeline, but recognize that building long-term shareholder value is most closely correlated with building long-term expected revenue growth. And so bringing on derisked clinical stage assets that have a clear view for investors to revenue growth is where we'll be focused.

Yes, absolutely. Great. Well, Brian, Cristin, thank you so much for the time today and sharing your insights.

Thank you, Ellie.

Thanks so much, Ellie. Appreciate it. Thanks, everyone.

Welcome to this fireside chat with BioMarin. It's my pleasure to host. I'm Joe Schwartz from the biopharma equity research team at Leerink Partners, and I'm pleased to be joined by Brian Mueller, Chief Financial Officer; and Cristin Hubbard, Chief Commercial Officer.

Thanks for joining us. Thanks for having us, Joe. Good morning.

Excited to be here.

So before we get into individual products, Brian, can you frame what's driving BioMarin's next phase of growth, particularly the mix of near-term commercial execution, upcoming pipeline milestones and portfolio expansion?

Yes, of course. Thank you, Joe. We're really excited about 2026 at BioMarin. We're coming off a strong performance year in 2025. We grew total revenues 13% in 2025. Within our business units, we grew our skeletal conditions business unit, which includes Voxzogo revenue at 26% last year and enzyme therapies at 9%.

Looking ahead to this year and beyond, I think the way to frame it up, Joe, is there's three pillars to our corporate strategy: growth, innovation and value commitment. On the growth side, we're continuing to plan for strong growth from both of our business units. The midpoint of our guidance is high single digits for both skeletal conditions and enzyme therapies. We are also very excited and look forward to the assumed closing of the Amicus acquisition in Q2, which is going to bring two high-growth products into our commercial portfolio with an outstanding strategic fit in rare genetic conditions.

On the innovation side, we're very excited to have a number of programs advancing. Just recently, we announced the approval of Palynziq in adolescents. I'm sure we'll get to it, and Cristin can elaborate on the opportunity there. We're expecting two Phase III data readouts this year, one in Voxzogo being examined in hypochondroplasia. This would be the second indication after the current approved indication of achondroplasia. And then BMN401 for ENPP1 deficiency.

This asset came to us through the Inozyme acquisition last year. And then we're also advancing our additional clinical stage pipeline assets, BMN 351 for Duchenne muscular dystrophy, BMN333, which is BioMarin's long-acting CNP for achondroplasia, as well as our early-stage research programs. And then on the value commitment side, we transformed the company over the last couple of years with a significant focus on efficient cost allocations and disciplined expense management while growing the top line. This has led to leveraged growth.

If you look through some of the special items in our 2025 P&L, we're growing earnings per share at the midpoint of our guidance at approximately 3x revenue. also looking to our third year of operating margin expansion and cash flow growth. So we're making great progress across all three pillars of the strategy, and we think creating a lot of value for shareholders.

Great. We appreciate that overview. So let's talk about Voxzogo. And I'm wondering since you're having such strong new patient starts and patients under age 2 now, how do you think about stickiness and whether -- I'm wondering if whether you have any strategies to forestall switching once new options become available and we have patients in multiple age segments? And how do you think about those dynamics?

Yes. And this is something that we've been doing a lot of thinking about, obviously. And first and foremost, I'd be the first to say that more options are great for patients. It certainly gives them the ability to choose what is right for them. And what we hear a lot of, Joe, is we're going out there and really understanding what today's market and the future market can look like is that at the end of the day, the decision makers for a switch are going to be the parents, the caregivers.

Physicians tell us very often that they are there to provide any factual truths to lay out the options that are there. But at the end of the day, it's going to come down to that caregiver and that family and the decision that they choose to make for their child. So what we see in much of our market research in addition to the conversations that we're having is that for patients -- for the patients for whom there is efficacy that is being seen that that's going to be a high burden to switch. They've gotten used to their daily injections. They've gotten used to whatever the routine is.

And so that we're seeing on average, about 2/3 of KOLs, physicians and caregiver research telling us that the chances of switch if the patient is doing well on therapy are low and not as compelling. So I think that really, at the end of the day, what it comes down to is efficacy matters, safety matters has over 10,000 patient years of that data to hold behind it, and then convenience comes third.

And that's really helpful. And as you look at the achondroplasia market, do you have a sense of how many patients are attracted to a value proposition, primarily based on growth and how many decision-makers view growth as a surrogate for other health benefits and how many individuals are just not interested in treating this condition?

Yes. And while I wouldn't say we have rigid numbers in terms of the buckets of specifically that, I will say that this landscape has evolved, and you would expect it to. Voxzogo was the first treatment ever available for achondroplasia hormone. And we're seeing this landscape evolve.

As more data is being generated, as more publications are being made, we're certainly seeing there be more focus on the benefits beyond height. So AGV was, of course, what we had agreed to with the regulators, and that was the most visible sign of the product working. But at the end of the day, what is most compelling to families, to physicians, to those who treat achondroplasia is the broader health story, and that is precisely where we're building that body of evidence, and we're really moving the needle on that front.

Great. And can you talk a little bit more about that? What kind of efficacy on proportionality, if that's the right way to think about this, that there might be read-through from that? Obviously, BioMarin has the most experience of anyone in this space. So it would be great to hear some more about the strategy to communicate those benefits.

Yes. We've continued to publish, for instance, at SB in 2025. We've continued to publish our body of evidence and we are seeing areas such as for and magnum benefits. We are seeing symptomatic spinal stenosis benefits.

We're certainly seeing proportionality where we have statistically significant data to show that proportionality is improved by treatment, including things like leg deformities, so tibial bowing, like any of the kind of various things that could affect their gait and their mobility at the end of the day, in addition to overall quality of health data, quality of life data, where you see also the kind of the more just overall life improvements and how they feel on the day-to-day. We're seeing all of these things benefit in our longer-term data, and we are continuing to publish on those and really share that story with physicians and families alike.

And just to add, this is an area where BioMarin will always be in the lead. We started our Voxzogo development program more than 15 years ago and we've got patients who have been on the therapy for 10 years now. The drug was approved in 2021. One, it was a conditional approval.

One of the post-marketing commitments to file for full approval was this long-term data set where we followed a number of patients through final adult height. We now have that data, and we'll be filing it this year. And we'll see if that turns into something on a label amendment. But at a minimum, we're always -- and this is the level of publishing that Cristin mentioned, we're generating the longest and most robust data set.

Right. Okay. That makes sense. And then BMN 333 showed much more free CNP than Voxzogo. So I'd love to, as you embarked on a Phase II/III trial, discuss the strategy there to generate height as well as other health benefits. How much of a proportionality benefit or anything else do you think it would take to encourage patients to switch from Voxzogo or maybe one of the newer options to BMN 333.

Yes. Thanks, Joe. So our strategy with BMN 333, which I touched on is BioMarin's program for a long-acting CNP. However, it's really important to note that BMN 333 is not designed as just a convenience strategy. It's designed to be superior to Voxzogo and the competition based on the data we've seen.

And to your question, we think that the Phase II/III seamless design study that we're enrolling will have the ability and the power to detect both the annualized growth velocity target as well as benefits beyond height. It's 120 patients designed to statistically detect a superiority to Voxzogo at the 90% level.

Okay. And switching gears to hypochondroplasia, the next potential opportunity for Voxzogo. How do your early indicators of market demand in hypochondroplasia compared to where you were at a similar stage of launch in achondroplasia?

So I'll start here. So we're really excited about being able to turn over the card and see the hypochondroplasia data coming up here soon in the first half of 2026. And the reason for that is that we have high confidence in the science. We saw really strong signals in Dr. Dauber's sponsored trial and therefore, are very much hoping to see that continue in our Phase III trial.

Now importantly, when you asked the question about kind of what's the excitement around this, how do you see this playing out? I think the biggest and best proxy that we have to date in terms of the excitement around this indication is how quickly our Phase III trial enrolled. It went well beyond our expectations in terms of speed of enrollment, which oftentimes is a very good proxy for the excitement level.

Now the work that we're doing today and the work that we think is very, very important for hypochondroplasia is in and around education and the diagnosis of this condition. While we believe the prevalence to be very similar to that of achondroplasia, we know that we have -- that we look at much lesser in terms of the -- or the TA, the total addressable patient population. And the reason for that is because it's not diagnosed at the rate that achondroplasia is.

So we're doing a lot of our work today focused on disease awareness in addition to really figuring out how we can enhance the diagnosis journey and also shorten it because many of these patients are on average diagnosed around the age of 5 or 6. And similar to achondroplasia, we want to ensure that we're really getting patients treated as early as possible. So that diagnosis journey is very important.

And we hear that there's a wide or a fairly wide spectrum of severity in hypochondroplasia. And at the one end, the most severe end, some patients might already be on Voxzogo, but then we hear that there's some under the pope.

That they start to ask these questions in and around what might be happening, should we get a genetic test, et cetera. So that is specifically why we are so focused on ensuring that people understand some of those early signs of the condition and importantly, what that pathway to getting diagnosed can and should be.

There are a significant proportion of these patients who would be eligible for treatment with Voxzogo, should those data turn out to be positive and importantly, in the way that we design the trial, a very significant proportion. But the bigger challenge is going to be ensuring that they are diagnosed early and that they are seen as eligible.

Okay. Great. And just one more question. Given we're almost halfway through the first half of the year, when is the hypochondroplasia Phase III data expected?

We have a few months left for the...

First half. Understood.

So stay tuned, Joe.

Great. We will, for sure. Okay. Great. Well, congratulations on the recent Amicus acquisition. It seems like a perfect fit for BioMarin. I guess to start, you've highlighted that Galafold is currently available in around 40 countries and BioMarin operates in around 80. So I'm wondering beyond simple geographic expansion, how much of the projected accretion in '27 relies on just deeper country penetration versus other dynamics?

Yes. So we are really excited about being able to say more as soon as we close, and we'll give far more detail at that point in time. But I think it's important to address your question specifically, we really do believe that there's the opportunity for both country expansion, given that, as you said, Joe, they're currently in 40 countries, and we have a larger country footprint of 80. But we also know there's opportunity for a deeper penetration in the markets in which Galafold already exists.

And we say that because we know one of the biggest opportunities for Galafold and Fabry is really in and around diagnosis. And given that that's such a sweet spot for BioMarin to really be able to drive diagnosis of disease and then get those patients on therapy and have them stay adherent to said therapy, there's a big opportunity for both expansion into new countries and deeper penetration in the ones they're already in. And we're looking at those teams working diligently on and precisely what those plans will look like right now.

Gret. Yes. Thanks, Cristin. I'll just jump in, Joe, since you touched on accretion. I'll share that through these levers, again, subject to closing of the transaction, as we get deeper into the integration, we believe that there's opportunity to unlock even more value from Galafold and PomOp when we built our model to support the deal, of course, that's something that we have to have high confidence in to be able to make a share price bid and be confident in the value of the acquisition.

What I mean by that is higher confidence usually means some base level of measured conservatism as well. So through these expansion opportunities, we think that we're actually going to be able to unlock more value over time.

And Mike, in our comments at closing around accretion, which was, should we close the transaction in the second quarter of this year because we'll be incurring significant interest expense and just integrating the company, which comes with some cost, we think the transaction could be slightly dilutive in calendar '26, but accretive for its first 12 months and substantial accretion starting next year. And that's, again, based on that deal model. We'll say more upon closing, should, assuming we close.

Okay. Understood. Look forward to that. So Amicus on their own did a great job with Galafold and penetrated the amenable Fabry patients well. And it seemed like they were starting to get good traction with PomOp. And I'm just curious, at a high level, what kinds of operational does BioMarin bring to the table to take things to the next level for those kinds of products?

So I think very similar to what we just discussed with Galafold. I think that with PomOp, there's an even big opportunity. They're currently reimbursed in 15 countries and going back to the fact that we have a much larger country footprint, that's going to be an exciting opportunity out the gates.

But I think what's really important, specifically for PomOp is the continual publication of real-world evidence that demonstrates the value of PomOp relative to those patients who have come off another enzyme therapy and Amicus has done a great job at starting to generate and publish those data, and that is something that we will very much look to continue so that you can generate a faster switch for those patients who are progressing in their disease.

It seems like there's a nice opportunity for PomOp. It's just getting started. And that takes me to my next question. Manufacturing has been a skill set that we associate with BioMarin doing in a really high-quality manner, and PomOp is a challenging product to manufacture. What is your plan on that front? I think they currently manufactured in China. They had talked about doing second source manufacturing has BioMarin settled on the strategy for manufacturing that product.

Thanks, Joe. I'll take that one. Yes, that question unfortunately falls into the category of we need to closed the transaction to be able to say more. During this period of time, it's really important that the two companies continue to operate as two independent entities. And there's some integration planning that we can do ahead of closing, but that level of deep integration with respect to manufacturing strategy is something they'll -- we'll have to wait to talk about.

But the premise of your question is the right one which is that BioMarin is world-class manufacturing entity and we've got a great track record across our portfolio, both the commercial portfolio and the research and development portfolio of manufacturing globally and look forward to bringing that skill set to the Amicus asset.

Yes. Okay. That makes sense. Okay. So moving on, I guess we're looking forward to seeing the next data cut for BMN 351. And we have MDA going on now as we speak. Can you give us an update on what the next data cut will be for the first dose cohort and when we'll see data from the second dose cohort and what you hope to see there?

Yes. Thanks. So there's 3 doses, 6, 9 and 12 milligrams. So far, we've announced data from the 9-milligram dose at 26 weeks where we observed a mean dystrophin expression of 5%, so the key next data point will be watching the higher dose in the 12-milligram reach its next couple of milestones. But beyond dystrophin expression, we're also going to be looking at clinical benefits, which is really important in this community. We're doing both the North Star Ambulatory assessment, as well as forced vital capacity. So hopefully seeing a correlation between that dystrophin expression and the clinical benefits will be something else we're looking for.

And remind us of the threshold for you deciding to advance this program.

We're aiming for 10% dystrophin expression. But again, I would point to the clinical benefits that we're observing, and we'll look at the totality of the data to decide how to move forward.

Okay. Great. And let's touch on the Inozyme programs, given you have pivotal Phase III ENERGY-3 data expected also in the first half. Can you talk a little bit about what you hope to see on that front?

Yes. So we're, again, another program that we're very excited about and feeling very much that it fits right in the BioMarin sweet spot in rare disease, and that is really in being in a rare condition in ENPP1 deficiency where there is not otherwise a treatment.

So we're very excited to see the pediatric data here coming up soon. And what we've estimated, and you can imagine the data are quite a wide range. But we believe that the total addressable patient population to be in and around 2,000 to 2,500 patients worldwide. And so our job, again, will really be to ensure that we can find those patients, get them diagnosed and get them on treatment as quickly as possible.

Now as I said, this is just an estimate. As we found on the Naglazyme story back in the day was that you can estimate something. But then when there's a treatment available, it's amazing how much you learn about the condition and how many more patients and physicians are coming out to be -- are getting diagnosis because importantly, there is actually an option, which raises awareness. So we saw that quite a bit with the Naglazyme story. I don't know if you want to elucidate on that.

I will. Thanks, Cristin. It's -- this is a profound data point. I think, first of all, doing incidence, calculations in ultrarare disease as difficult as it is. But it is often the absence of a therapy that leaves these patients identified and once the therapy exists, with the improvement in diagnosis and disease awareness, you can really start to bring those patients in. You can look back at our 10-Ks on this. Naglazyme was approved approximately 20 years ago. And we used to cite global prevalence of the disease as 1,100 patients in existence. Here we are now 20 years later, we probably have almost 150% of that number actually on commercial there. So it's -- and again, this is what BioMarin does.

Still growing. Okay. Great. Well, maybe a couple of commercial -- more commercial questions to round out the discussion. I can't resist, but go back to Voxzogo. So can you discuss what underpins your assumption that Voxzogo revenues in the second half of this year are expected to be greater than the first half. Is that entirely due to OUS orders? I know there might be several moving parts because we might have the emergence of some competition. But can you just give us some insight into your crystal ball on that front?

Yes. Thanks, Joe. I'll take that one. So that timing, we shared on our Q4 '25 call that first of all, we'd see a similar lower first quarter as we did last year in 2025. And that for the full year, Voxzogo revenues would be weighted to both the back half generally and then even more specifically Q4. This is entirely order timing and largely international order timing.

75% roughly of Voxzogo's revenue is -- comes from outside the U.S. And most of those international customers are single national payer health care systems. So whether it be the way that their cash flows and budgeting works or their procurement model, we've observed this trend before where the purchasing patterns, again, across dozens of these countries just happens to be weighted to the second half of the year.

What's really important to note and we point to this across all of our portfolio when we experience some of the -- some of this quarter-to-quarter volatility on revenue is that we've continually to steadily add patients quarter after quarter -- we expect that to be the case here in 2026. And so it really is just the timing that drives that dynamic.

Okay. Great. Well, that's helpful. Thank you so much for the update today. We look forward to following more progress at BioMarin.

Thank you, Joe.

I appreciate your time. Thank you.

Good morning, and welcome once again to TD Cowen's 46th Annual Healthcare Conference. I'm Phil Nadeau, one of the biotech analysts here at Cowen, and it's my pleasure to do a fireside chat with BioMarin Pharmaceutical. We have with us today, Alexander Hardy, the President and CEO; and Brian Mueller, the Executive Vice President and CFO. Guys, maybe I'll kick it to you to begin. Could you give a brief state of the company overview, biggest strengths, biggest challenges? And what does BioMarin need to achieve to outperform over the next year or 2?

Excellent. Well, thanks very much. Thanks, everybody, for joining us. So I've been CEO of BioMarin for the last 2 years and started off with a kind of a strategic refresh, what's the strategy of the company. It was very clear to me that BD should play a significant role in the future of BioMarin, hadn't played much of a role beyond early BD up to that point because we've got some really clear competitive advantages of being a rare disease company operating at scale. So it's really cool to have done 2 M&A last year, buying Inozyme and then obviously, the acquisition of Amicus, which is on track to close in the second quarter of this year.

So we've got that together with the enzyme therapy business is going to drop right into those -- both of those acquisitions will drop right into our enzyme therapy business, which is already operating at scale in 80 countries around the world. And then our skeletal conditions business anchored by Voxzogo, but now with 333 coming. So we've got these pillars of multiple pillars of growth, multiple paths of growth, good clarity of continued top line growth, leverage to the bottom line over the next several -- over the -- yes, through the next decade.

And so that's really cool to see that all in place. It's obviously not reflected in the share price, but we're confident that the things we're doing are creating tremendous shareholder value. In terms of the challenges, obviously, entering now a period of competitive intensity. We've been preparing hard for this over the last 2 years. We've been taking advantage of every additional delay in terms of the launch time lines for our competitors, whether it's for the overall approval or for the infant population, which is a very important part of skeletal conditions, the incident population. We've used our time well, and we're now ready to compete. But this is this period. There's no doubt about that.

And I'm sure that's going to be part of what you're going to be talking to us about, Phil. I think also in '26, and maybe Brian, you can absolutely expand upon this is, obviously, we've made the strategic decision around Roctavian. So we don't have, albeit the unpredictable sales of that in 2026. And obviously, Kuvan generic continued generic erosion. So some of our nonbusiness unit nonstrategic income is -- provides a headwind, and that's obviously part of our guide for this year.

Yes. Maybe just what Alexander is referring to is our 2026 revenue guidance. It includes effectively a 3% headwind to our growth because of the decrease in some of this other revenue. There's the removal of our expectations for Roctavian revenue. There's continued decreasing Kuvan revenue. Kuvan has been generic in the U.S. for more than 5 years now. And then lower royalty revenues. We had a partnership agreement related to an out-license years ago, and it's now run through its period where BioMarin receives royalties. So that's a substantial number of more than 100,000 -- more than $100 million. When you adjust for that headwind, both of our business units are expected to grow at the midpoints of high single digits. enzyme therapies at 7% growth at the midpoint and skeletal conditions through competition, as Alexander mentioned, at 8% at the midpoint.

Maybe while we're on guidance, what are the key risks to the guidance? What could cause performance to fall short in 2026? And then similarly, what could drive outperformance? If you were to beat the guidance, why would that be?

Yes. Thanks. It's a great question, Phil. So I mentioned just in terms of framing of the guidance, there's first that other revenue kind of downward adjustment headwind. But within the guidance itself, when we guide, we try to be measured. We have a plan. We monitor all of the material swing factors within our guidance, and then that's how we develop a range. So on enzyme therapies, I think there's a couple of underlying drivers. One, by the way, is just execution. It's early March and a long way to go in this year, and it's more than a $2 billion business now. So there's just some level of estimation.

And as you know, Phil, there's an element of our business, which is order timing. A lot of our customers and payers are single national health care system payers, and they can tend to order variably over the course of the year. So depending on how those orders stack up in a particular quarter or do not, we get some order timing. So I think that's a risk especially with the events over the last couple of weeks, we continue to monitor for geopolitical risk instability, global economic risk, again, take some of that in control.

But obviously, as events unfold, we're watching that closely. So that's enzyme therapies. In skeletal conditions, there's probably beyond the comments that I made, which apply to both enzyme therapies and skeletal conditions. The 2 key variables, I think, within the guidance for skeletal conditions are the ultimate impact of this competition. The competitor was approved by the FDA on Friday. We're ready to compete. We think we will compete. We believe that any switching of our Voxzogo patients will take time and be difficult. But to the extent there are more or earlier switches, we try to account for that. It's in the lower end of our guidance. And to the extent we do better, that would be the higher end of the guidance.

To be clear, in all points in our Voxzogo revenue guide, we do assume competition. So to the last part of your question, how can we overperform? I think it's going to be continuing to grow in the under 2 population where we are the only approved therapy, continue to expand our outside of the U.S. revenues. Only 25% of Voxzogo's revenues are in the U.S. So while this competition narrative gets a lot of attention, it's actually a small part of our business. in that 75% outside of the U.S. revenue, we are both penetrating existing markets more deeply, and some of these are large markets, and we're still expanding into new markets, launching into new countries. So to the extent we do better there, that would be an outperformance.

And the guidance also assumes a 40% operating margin this year, which is an increase year-over-year, excluding the impact of Amicus. Is that achievable? How are you increasing operating margin during 2026?

Yes. Thanks. We believe it's absolutely achievable subject to the Amicus slight dilution. We've been on this mission over the last 2 years. As Alexander mentioned in his opening remarks, -- the strategic review completed in 2024, not only refreshed and refined the overall corporate strategy, but our financial growth strategy. So we identified that $0.5 billion cost transformation program. That is complete. We're still realizing part of it this year, but it's been implemented.

We've constrained overall operating expense growth at the right levels to where we can balance investing in the business, but also cost control. If you look at our performance over the last couple of years, we've got consistent leverage growth where profitability is growing at a 2, 2.5, sometimes 3x rate of revenue growth, which is pretty healthy. We've gotten the revenue growth, I think, very clear and in line. You see that over the last year and in this year's guidance. So that revenue growth, cost under control, that gives us that margin and really healthy growth in EPS as well.

There's some debate as to what Amicus is going to do to your numbers this year. You referenced on the earnings call that there's kind of a wide range of estimates out there. We have put Amicus into our model for the second half of the year, and we have 2026 total revenue of $3.7 billion and non-GAAP EPS of [ $4.80 ], so modestly dilutive in 2026. I know you're going to update your guidance later, but just generally, does that sound reasonable?

Yes. Thanks, Phil. So yes, so we will give an updated view on 2026. All the numbers that I mentioned were excluding Amicus. And we expect to close in the second quarter. And with the sizable business that Amicus would bring subject to closing, whether it's earlier in Q2 or towards the end of Q2 could be a swing factor. But I like the way you framed it, kind of simplified it and just took second half of the year for discussion purposes here today. And this isn't guidance, but that's not unreasonable, the [ $3.7 billion ].

In earnings per share, again, we'll wait until we update the guidance to quantify that. We did share that we expect the Amicus acquisition to be slightly dilutive in calendar '26, but accretive for the first 12 months and then substantial accretion beginning next year in '27. So that's a dynamic that will be clear. We did announce as part of the Q4 earnings that there is $0.25 of loss per share related to pre-closing costs on the Amicus acquisition. We raised our debt. We're starting to incur some interest expense. There's some other transaction fees that we incurred before closing. So that's some of that headwind. but we'll talk more about.

And if I could just jump in here, little bit. I mean, this is focused very much on the short term, the '26. But the benefits of the Amicus acquisition, again, we plan to really elucidate more on this post close. As I already said in my first comments, we believe very strong hypothesis that these assets are worth more in our hands, these medicines. We'll be able to reach more patients in more geographies around the world. And therefore, during the announcement, we said we feel comfortable with their estimates for the deal of $1 billion peak for each of the assets. We believe that we'll be able to do better.

And so we'll explain what we expect and how we're going to do that. I mean the very simple math, and it's a lot more than this, is that they were in 50 countries, we're in 80 countries. It's very simplistic because we're much deeper in many of those countries. These are where the prevalent population is outside the United States and outside Europe. This is what we've built over 30 years at BioMarin. And then there's obviously the earnings leverage on top. So both of these 2 are going to be -- you're not going to see much of it in the short term. But over the next 5 to 10 years, this is going to be very, very significant and very exciting is what we believe, and we're going to share more about that.

I'm sure you're not going to comment on what I'm about to say, but when we put Amicus into our model in the late part of this decade, we had about $3 of EPS accretion. So EPS went from $7 to $10. So massive accretion. Like I said, I don't think you're going...

If I'm not commenting on '26 EPS with the transaction, I'm definitely not coming.

Before we dive into the programs in a bit more detail, just in terms of business development, Alexander, as you mentioned, you did Inozyme and Amicus last year. Where are you in your business development strategy today? Do you have more capacity to do additional deals? Or do you think for now, you're relatively full?

We're -- the BD team, again, we believe that business development is a very important part of our strategy going forward. So the BD team is right back at work. Our primary focus is further strengthening our pipeline. Obviously, we need to delever from the Amicus acquisition to do anything very significant. But given the economics that we've just been touching upon, we expect to be able to delever very rapidly. So in the meantime, you can expect us to continue to do sort of early pipeline deals, very traditional biotech business development. But in the course of time, we're really convicted that, again, BioMarin in its position as leading at-scale biotech company focused on rare diseases, there's a significant value creation opportunity for us. So watch for us to be -- continue to be active.

Turning to Voxzogo, perhaps the biggest investor debate. Brian, began to discuss the competition and the impact on the franchise. Could you go into a bit more detail, how do you consider Voxzogo's competitive position today? What is the approval of TransCon mean in the short term? And then longer term, how is the competitive environment going to play out?

Yes. Well, I'm excited about this moment. We've been preparing it for this for the last couple of years. We've been taking advantage of the delays to further prepare. We've been quite quiet about the specific competitive strategies, the very obvious one, which is the ex U.S. footprint, that's been very, very clear. We're obviously going to continue to grow significantly in the 75% of our revenue, which is outside the United States. We're still expanding, as Brian already said, in large underpenetrated countries, and we're also launching in new countries. So that is one aspect of why we're going to continue to grow through competition, we believe. But we also have the 0 to 2 indication, which we will be the only one that has that for several years.

Not surprisingly, the TransCon CNP label was for 2 and above. So we are the only drug approved for 0 to 2 population. That in achondroplasia, that is where the guidelines say you should diagnose and initiate is as early as possible. And the majority of our patient starts are in that 0 to 2 population. So essentially, our competition is coming in with a drug that looks short term, similar efficacy, similar safety with a convenience advantage. The dynamics of a switch market, which they face is a very complicated one. What's most important to caregivers and to physicians is long-term durability and safety.

We have lots of evidence for Voxzogo for that. It's a complicated decision to switch. which is between the physician and the caregiver. And we think that this is going to be a dynamic that will play out over time. This will not be a rapid switching market because again, 90% of patients on Voxzogo are adherent. They manage the injections. They're part of the family's daily routine. Patients do very well on Voxzogo. And this convenience aspect is well down the list of what's most important to both caregivers and physicians. And all of our market research reinforces that the switching dynamic will be a complicated one and a long conversation between caregivers and physicians and a lot of different dynamics.

There's a big burden on the physician's office and on the caregiver to go through that whole switch dynamic. to going through the payer coverage to the training. It's a burden on the physician practice. This is not going to be something our research shows that the physician is going to drive. Again, it's going to be a dialogue. Some patients will switch, and we have taken a conservative approach in our guidance with regard to that. And now we're ready to compete and looking forward to this playing out. I think part of our knowledge from this is our relationship built over 5 years. We have a 5-year head start. We have, for example, again, this is the sort of detail that I was not going to share until the point of approval. We have an outstanding clinical coordinator team.

These are nurses -- these are BioMarin employees who train the family on the injection process and then stay in continued contact with the child and the family as the child grows up. So as investors, what you should be thinking about here is that we have a relationship and eyes on every single patient in the United States with achondroplasia. We have a very strong relationship and a really good understanding of what's most important to those patients and a relationship. And again, we've been preparing for this, and we're ready to compete.

Can you remind us of the status of the case in front of the ITC?

Yes. This is about to be heard. So they went through the Markman hearings with regard to what the basis of the court case would be. That happened just recently. And now it's in April that the judge will start hearing the case expecting a preliminary decision in the August time frame.

Competition isn't the only thing going on with Voxzogo this year. You do have the hypochondroplasia trial reading out. Can you remind us of the design of that study? And what are BioMarin's expectations for the results?

Yes. So hypochondroplasia, we're very excited about that study. I mean it's -- as a rare disease company, anytime you potentially bringing a first-in-disease treatment, this is what we're really about. This will be our seventh first-in-disease treatment. So a cause for celebration and pride. And the treatment community is really looking forward to this. Again, there's no targeted treatment option right now for these patients. With regard to the study design, we designed it and powered it based on a 1.5 centimeter annualized growth velocity, which is the same as we saw in achondroplasia.

In the -- what is called the [ Dauber data ], we call it the Dauber data, Andrew Dauber from National Children's Hospital. He did the proof-of-concept study. He saw a 1.8 centimeter annualized growth velocity in hypochondroplasia. So we powered at 1.5. We think there's good reason to believe that we can actually achieve, and there's good scientific reasons with this, actually, based on the differences between achondroplasia and hypochondroplasia that actually do suggest that you're probably going to get better growth velocity.

So we're quietly confident. We want to see that card turnover. We see excitement from the treatment community. The work that we're doing right now in the prelaunch, pre-promotional phase is shortening the diagnostic journey. These unlike achondroplasia, these patients are diagnosed later in childhood. Obviously, just like achondroplasia, the later the start, the less the benefits in terms of long-term outcomes. So we want to start to really increase the diagnosis rate and shorten the pathway to a specialist, and that's the work we're doing right now whilst we wait for the Phase III results.

How large is the diagnosed patient population today? And how rapidly would a drug like Voxzogo be taken up by the community?

Yes. We talk about a total addressable global population of about 14,000 patients. So the genetic prevalence is very similar to achondroplasia, about 24,000, but we reduce it down because of that diagnosis rate isn't as high. And these patients are there. In many cases, they're sitting outside the skeletal dysplasia clinics because there's no approved treatment. So this is -- again, this is the story of rare diseases. Once there's an approved treatment option, we expect that many patients will be reaching out to a specialist, and that's the work that we need to do.

Maybe one more on this franchise. BMN 333, you released promising data last year. It's moving into a pivotal study. Can you discuss the design of the pivotal and what you think 333 could do for the franchise.

Yes. We're -- this is another reason why we're confident with regard to Voxzogo's profile, its durability of its profile, its benefits with the evidence that we've got of its benefits beyond height and the geographic footprint. These are the reasons why Voxzogo is going to continue to grow through this next several years. And then we have 333 coming. And this was the exciting thing for us to see with the data from BridgeBio that we didn't see a similar AGV result as the Phase II. The Phase III annualized growth velocity looks very similar to Voxzogo. So the lane is still open for superior efficacy.

And that is our goal with 333 is not only to offer the convenience benefit of weekly but also superior efficacy than the gold standard Voxzogo and better than anything else that's in clinical development. The PK data that you mentioned, we were very excited about this. I mean it's PK data, so it's in healthy human volunteers. But we were aiming our threshold to move ahead with 333 was to achieve 2 to 3x the level of free CNP that our other -- the other long-acting CNP had shown, 2 to 3x in that PK study, the highest dose cohort, we had 3 dose cohorts that exceeded that 2 to 3x. And the highest dose actually had a 13x the level of free CNP. We believe, and we have reasons to do this, reasons to believe this, that there's a strong predictive that high free CNP sustained over a period of time will translate to higher efficacy.

We now need to show that in patients with achondroplasia, and that is the work that we're going to do in this Phase II, Phase III operationally seamless design study. So we're taking the 3 cohorts that exceeded that 2 to 3x into that Phase II. We'll then choose the best dose to take the single dose into that Phase III study, and it will be head-to-head versus Voxzogo. We have said that we're aiming for 2.25 centimeters of annualized growth velocity. So this is approximately 50% better than Voxzogo. That is the floor. The target product profile, as you can imagine, is not the same as that, but that's how the study is powered.

During the first half of this year, you will get pivotal data from BMN 401, which you acquired through Inozyme. Can you remind us of the design of that study and what BioMarin's expectations are for the data?

Yes. So I mean, this is -- it's exciting. Again, this will be another -- this is another first -- so this year, 2 Phase III readouts, potential first-in-disease treatment. So this is definitely worth highlighting that there are no treatment options for ENPP1 right now. So this first Phase III is in a pediatric population. The design of the study is a co-primary endpoint of phosphate levels together with Radiographic endpoint, a functional endpoint, which is a radiographic scan. And this is what we'll see reading out, and we're expecting that readout in the first half of this year.

How does BioMarin size the market and the market opportunity?

Yes. We've been -- again, this is always challenging to do when you've got a first-in-disease treatment. There's no treatment options. We end up -- in most cases, it ends up being more patients, but we want to be on the conservative side. We're saying around 2,000 to 2,500 patient potential for this. Important to note that around 70% of the patient potential is in the adult population.

So based on these results in this pediatric population, we will then design the Phase III in the adult population. So this would then be potentially an indication would be approved in the early 2030s and then part of that continued sustained revenue growth that we plan for BioMarin. So there's a lot more to come, a lot more indications to come with the NPP1. We're not just in the interest of time, we won't get into ABBC6, but there are other indications and other interesting possibilities with that.

Palynziq's label was expanded this weekend. What impact will that have on revenue growth?

Yes. We're excited. I mean, even before this adolescent indication, Palynziq last year grew by 22% -- so in our very successful high single-digit growing enzyme therapies, this is an asset that probably gets -- doesn't get the attention that it really deserves. And this will then add on top of that growth potential. Why is the adolescent population so important?

Well, whilst numerically, it represents about a 10% increase in the total addressable population, that significantly understates its potential. We, with Palynziq, have been seeking to treat the adult population. And in PKU, this is the hardest population to reach and to get on treatment. As many of these patients are lost to follow-up, not under the care of a specialist, whereas in the adolescent population, they're still under the care of a specialist. They're under the roof of their parents who may or may not have some degree of control over an adolescent.

And they're motivated by the fact that they're going through a stage in life where they're about to go off to work, independents, college, et cetera. And so everybody is really motivated to try and get their Phe levels under control and to them to have the possibility of a life which is less limited by PKU. And here, I'm alluding to a very important aspect of an unrestricted diet. So I think you've got a really worthy treatment goal. You've got a drug which clearly works and you've got conditions which I think, again, specialists, adult, I think we're going to see a higher penetration in this population, and it will be a significant contributor to Palynziq's growth.

Great. With that, I think we're out of time. Thanks for making the trip to Boston for the conference.

Thank you for standing by. My name is Kate, and I will be your conference operator today. At this time, I would like to welcome everyone to the BioMarin Pharmaceutical Fourth Quarter and Full Year 2025 Conference Call. [Operator Instructions]

I would now like to turn the call over to Traci McCarty, Head of Investor Relations. Please go ahead.

Thank you, operator. And starting on Slide 2. To remind you, this nonconfidential presentation contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc., including expectations regarding BioMarin's financial performance, commercial products and potential future products in different areas of therapeutic research and development. Results may differ materially depending on the progress of BioMarin's product programs, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market and developments by competitors and those factors detailed in BioMarin's filings with the Securities and Exchange Commission, such as 10-Q, 10-K and 8-K reports.

In addition, we will use non-GAAP financial measures as defined in Regulation G during the call today. These non-GAAP measures should not be considered in isolation from, as substitutes for or superior to financial measures prepared in accordance with U.S. GAAP, and you can find the related reconciliations to U.S. GAAP in the earnings release and earnings presentation, both of which are now available in the Investor Relations section of our website. Please note that our commentary on today's call will focus on non-GAAP financial measures unless otherwise indicated.

Moving to Slide 3 and introducing BioMarin's management team joining today's call, Alexander Hardy, Chief Executive Officer; Brian Mueller, Chief Financial Officer; Cristin Hubbard, Chief Commercial Officer; and Greg Friberg, Chief R&D Officer.

I will now turn the call over to BioMarin's CEO, Alexander Hardy.

Thank you, Traci. And moving now to Slide 5. Thank you all for joining us today to discuss BioMarin's fourth quarter and full year 2025 results as well as our outlook for 2026, which will be an exciting year. We are particularly proud to have accomplished our strategic goals for 2025, while achieving outstanding growth. In 2025, total revenues grew by 13% to a record $3.22 billion for the year and operational excellence led to strong profitability and increasing cash flow. This result was fueled by a 9% increase in enzyme therapies revenue and a remarkable 26% rise in Voxzogo revenues. Importantly, enzyme therapies revenue has grown at a 9% CAGR over the last 5 years, demonstrating the durability and reach of this $2 billion-plus franchise across our 80-country footprint. With Voxzogo, now in its fifth year on the global market, we're very pleased with the consistent strong growth already achieved and have deep conviction in our ability to continue expanding should another product be approved.

BioMarin's 2025 performance and 2026 outlook highlight both our deep global capabilities and the vital importance of our targeted therapies to patients we serve. Building on the strong foundation in 2026, we will expand our therapeutic and commercial reach with the addition of assets from two significant acquisitions announced last year. The first, Inozyme, strengthened our enzyme therapies portfolio with the addition of BMN 401 for ENPP1 deficiency. This is a condition for which there is no approved targeted therapy. So we're really pleased about the possibility of launching what could be our sixth first-in-disease enzyme therapy should pivotal data be supportive. We look forward to sharing that update in the coming months and to filing submissions soon thereafter. Our second acquisition, Amicus, potentially adds both Galafold for the treatment of Fabry disease, and pombility and folder for Pompe disease to our commercial portfolio and is expected to close next quarter. This transaction presents a particularly compelling opportunity that further build on Amicus' success by leveraging our scale and global capabilities to serve even greater numbers of patients. In addition to the expansion of BioMarin's portfolio from acquisitions, we're particularly excited to build upon at Voxzogo's leadership in achondroplasia with a potential addition for treatment of hypochondroplasia. Because CNP is the master regulator of bone growth, and supported by the 1-year results from the investigator-sponsored study, we are excited to see and share the upcoming pivotal results with Voxzogo for the treatment of hypochondroplasia in the coming months. We look forward to the possibility of adding hypochondroplasia to our global skeletal conditions treatment offerings by early next year.

On top of Voxzogo indication expansion, based on the very encouraging PK data recently shared, we're preparing to begin enrollment in our Phase II/III study of BMN 333. We believe this next-generation, long-acting CNP therapy has the potential to set a new standard of care and to demonstrate superiority compared to any candidates under development for achondroplasia. Those are just a few of the anticipated pipeline highlights expected this year so you can understand our enthusiasm for what's ahead in the coming months.

Turning to innovation. During the period where we are delevering the financing associated with the announced acquisition of Amicus, we will remain actively engaged in business development activities targeting pipeline assets. This is an important component of a larger pipeline expansion plan, a plan that both accelerates our financial performance and further diversifies our portfolio to drive durable long-term growth.

In closing, we are pleased that the transformational work implemented over the last 24 months has already delivered significant results and positions us for even more revenue growth, profitability and pipeline expansion. Prior to any contributions from the Amicus assets, this year, we anticipate BioMarin's enzyme therapies will deliver high single-digit growth and Voxzogo will continue along its trajectory towards blockbuster status. Following the completion of the transaction, we anticipate that integrating Galafold and Pombiliti and Opfolda will enable both medicines to reach more people around the world living with Fabry and Pompe, significantly enhancing our 2026 outlook and enabling accelerated revenue growth through the 2030s.

With that, I will turn the call over to Brian provide additional financial updates. Brian?

Thank you, Alexander. Please refer to today's press release for detailed fourth quarter 2025 results, including reconciliations of GAAP to non-GAAP financial measures. All 2025 results will be available in our upcoming Form 10-K, which we expect to file in the coming days. Starting on Slide 7. Our fourth quarter results reflect strong global demand, with total revenues of $875 million, representing 17% year-over-year growth. This strong performance was broad-based across our portfolio with Voxzogo delivering 31% year-over-year growth and enzyme therapies achieving 13% year-over-year growth in the fourth quarter. Palynziq revenue increased 25% in Q4, marking its fourth consecutive quarter of 20% or higher year-over-year revenue growth. For the full year, Voxzogo revenue increased 26% over 2024, totaling $927 million and underscoring the strong global expansion since its launch over four years ago. For the full year 2025, approximately 73% or nearly $680 million of the $927 million of total Voxzogo revenue was generated outside of the United States, reflecting BioMarin's differentiated global reach and infrastructure, deep rare disease expertise and ability to execute at scale.

Full year 2025 enzyme therapy revenue increased 9% year-over-year, led by 22% growth for Palynziq and 7% growth for Vimizim underscoring the durability and strong demand for these established brands. As expected, Q4 revenue benefited from the timing of large orders in both Voxzogo and enzyme therapies. In Q4, we recognized revenue from an approximately $30 million contracted government order for Voxzogo, the magnitude of which we do not expect to repeat in Q1 2026. Additionally, in Q4, we saw stocking levels increase in the U.S. and select global markets for Voxzogo, Palynziq and Vimizim.

Now moving to Slide 8. As an update on our plan to divest Roctavian, we recently made the strategic decision to withdraw it from the market. As a result, during the fourth quarter, we recorded approximately $240 million in special items on a GAAP basis. Approximately half of that amount relates to an inventory write-off that does not get adjusted out of non-GAAP income. BioMarin reported $3.15 of full year 2025 non-GAAP diluted earnings per share. And looking past the 2025 IPR&D and Roctavian charges, included in non-GAAP income, our underlying business earnings per share grew by approximately 34%. This performance contributed to $828 million in full year 2025 operating cash flow, a 45% increase versus full year 2024, further demonstrating the strength of our operating model and providing meaningful capital to reinvest in innovation.

We are pleased to see the operational transformation implemented over the last 24 months drive this level of profitability. Together with our revenue growth plans, BioMarin is positioned to sustainably grow profitability and cash flow while still investing in the business. As we prepare to close the Amicus acquisition, we were pleased to secure approximately $3.7 billion of debt financing consistent with the strategy that we shared upon announcement of the transaction. Confidence in the strength of BioMarin's business and financial outlook supported a positive credit ratings outcome and helps drive demand for all components of the capital raise, which enabled favorable pricing across the capital structure.

Now moving to Slide 9. Looking ahead to 2026, we are providing initial guidance that reflects BioMarin's growth expectations, excluding any post-close contributions from the announced acquisition of Amicus. Please note that currently available BioMarin consensus estimates include a combination of revenue estimates, some that include Galafold and Pombiliti and Opfolda revenues and some that do not. We plan to provide updated guidance on the combined business following the close of the acquisition expected in the second quarter of 2026, and we request that you wait for those details prior to updating BioMarin's models with the post-close Amicus contributions.

Turning to 2026 guidance items. We expect enzyme therapies revenue of between $2.225 billion to $2.275 billion, and Voxzogo revenue of $975 million to $1.025 billion. We expect continued high patient demand across both the enzyme therapies and Voxzogo in 2026, resulting in high single-digit growth rates of both business units at the midpoint. Outside of enzyme therapies in Voxzogo, we are expecting significantly lower royalty KUVAN and Roctavian revenue in 2026, which affects year-over-year comparisons of total revenue. We estimate those revenues to be between $100 million and $125 million in 2026, representing a 3% headwind to total revenue growth when compared to 2025.

Taken together, we anticipate 2026 total revenues in the range of $3.325 billion to $3.425 billion Again, this excludes any contributions from the Amicus products. And while we will wait for the acquisition to close to provide more details on 2026 revenues for the combined business, we are expecting a meaningful uplift to our 2026 total revenue growth rate once the transaction closes. We anticipate 2026 non-GAAP diluted earnings per share in the range of $4.95 to $5.15. Please note that our guidance reflects approximately $0.25 per share of preclose integration preparation costs and interest expense related to the Amicus transaction.

On non-GAAP operating margin, our underlying organic operating margin expectation without the Amicus transaction is approximately 40% for 2026, consistent with our previously communicated target. In the announcement of the Amicus transaction, we shared that we expect the Amicus acquisition to be modestly dilutive in 2026, which we expect to be a slight headwind to operating margin that could drive it slightly below 40% for the year. Aside from the impact of the Amicus transaction, we recognize that over the last two years, BioMarin has been able to solidify its revenue growth potential and transform its cost structure to realize the potential of a strong operating margin profile well into the future.

I will also comment briefly on quarterly dynamics in 2026. Coming off our strongest revenue quarter on record, we expect similar trends in 2026 as those observed in 2025. For example, we expect the first quarter of this year to be the lowest total revenue quarter of 2026, with both total revenues and Voxzogo revenue expected to be on par with Q1 2025. Q1 non-GAAP diluted earnings per share will have the additional impact of the vast majority of the pre-close Amicus cost just described, resulting in it being our lowest anticipated EPS quarter for 2026. For both Voxzogo and enzyme therapies, we anticipate large international order timing to contribute to higher revenue in the second half of 2026 compared to the first half and weighted to Q4, similar to the 2025 dynamic.

Our underlying business has consistently produced profitability growth that has outpaced top line growth, and today's guidance reflects our commitment to continue to grow the business operational efficiency and prioritized reinvestment and innovation.

Thank you for your attention, and I will now turn it over to Cristin for a commercial update. Cristin?

Thank you, Brian. I'll open by highlighting the outstanding work of our teams around the world. Their focus and deep expertise have been instrumental in driving another year of impressive commercial performance. Now moving to Slide 11, starting with enzyme therapies. In 2025, enzyme therapies delivered year-over-year revenue growth across every product in the portfolio, leading to 9% growth, driven by new patient starts across all products and consistently strong therapy-adherence rate. With 22% year-over-year revenue growth, Palynziq, again, outperformed expectations. As the only approved enzyme replacement therapy for PKU, Palynziq stands alone in its ability to enable people with PKU to reach physiologic fee levels while reducing dietary restrictions regardless of severity.

The performance further highlights our leadership in the PKU market having established invaluable partnerships with our stakeholders during almost 20 years treating people living with PKU. In 2026, Palynziq is expected to remain the primary growth driver in today's enzyme therapies portfolio, supported by the anticipated adolescent-label expansion with the U.S. PDUFA target action date of February 28 and an anticipated European approval later this year. Excitement is building among the treating physicians and families around the value proposition that Palynziq represents to the adolescent PKU community. This label expansion will enable young people with PKU to start treatment while living at home, supported by caregivers and under the guidance of their health care providers.

Adolescence is a pivotal time where dietary therapy typically starts to become unsustainable for those living with PKU, which can result in rising blood fee levels. The opportunity for adolescents to use Palynziq may provide dramatic fee lowering, the ability to eat more like their peers for social inclusion and ultimately, a better setup for them to enjoy an independent successful life.

Now turning to Slide 12. Voxzogo continued to be a standout growth driver, delivering 26% year-over-year growth in 2025. It's particularly gratifying to know that well over 5,000 children with achondroplasia worldwide were being treated with Voxzogo at the end of 2025. Now going forward, with Voxzogo its fifth year of commercialization, our growth strategy is focused on a multipronged approach. First and foremost, we are driving new starts globally across all ages with a particular emphasis in children under a few years of age, an age group where we do not expect another approved product for the next several years.

Next, in highly penetrated countries, which have become incident markets, our priority is to continue to find and start treatment-eligible infants going forward. In addition, we see meaningful opportunity to more deeply penetrate larger countries where we already have established commercial presence and large growth potential remains. And finally, we are expanding uptake in fast-growing newly launched markets where significant pools of eligible patients exist and streamlined care pathways are enabling access.

To provide more context on the results that these strategies are producing, I'll share a couple of recent examples illustrating BioMarin's deep global capabilities, commercial scale and more than 20-year track record serving patients around the world. In a recently launched country in the Asia Pacific region, Voxzogo reached approximately 40% penetration within seven months of launch. This success stemmed from early non-promotional prelaunch activities and strong relationship building with clinicians.

We ensure that there was a focus on patient identification beforehand and strong support for each patient's experience throughout the journey. In another example, in a midsized European country, Voxzogo achieved approximately 70% penetration within 12 months of launch. This was driven by early non-promotional engagement with clinicians and patient advocacy groups to build strong relationships with local stakeholders and drive momentum and awareness of Voxzogo. We tailor our approach to meet the needs of the patients and the respective country's ecosystem. We will build on these successes to drive deeper penetration in existing markets and to prepare for new country launches in 2026. These strategies are crucial to our growth outlook with Voxzogo since roughly 75% of total revenues are generated from countries outside of the United States.

In the United States, we are driving increased penetration across all age groups, supported by investments in data, digital and field force. We're seeing particularly strong momentum in the under 2-year age group, reflecting international guidelines for achondroplasia, recommending early diagnosis and treatment with Voxzogo as soon as possible and long-term data supporting its safety and efficacy from infancy. Approximately half of the new starts in the fourth quarter were children under age 2. Since we believe Voxzogo will be the only approved therapy in this age segment for the next several years, driving new patient starts in children under 2 is a key pillar of our growth strategy. With the potential full approval of Voxzogo on the horizon, we believe families and caregivers will have even greater confidence in Voxzogo's established safety and efficacy profile when considering treatment for their infants and children with achondroplasia.

In conclusion, I'm incredibly proud of what our teams have accomplished and energized by the opportunities ahead. I will now hand it over to Greg for an R&D update.

Thank you, Cristin. We have a very busy year ahead for R&D with multiple meaningful milestones. Moving to Slide 14. As Cristin mentioned, we are preparing to submit the full approval package for Voxzogo and achondroplasia. This submission will allow us to present a comprehensive story around final adult height as well as a broader health and wellness outcome data set. We have collected over 10,000 patient years of safety data, including data for some children who have been on Voxzogo treat for more than 10 years underscoring the value of Voxzogo across all age groups, including meaningful impacts on quality of life and anatomic outcomes. In addition to linear growth, Voxzogo's broad evidence package demonstrates the treatment's impact on key complications associated with achondroplasia, including foramen magnum stenosis and symptomatic spinal stenosis as well as improvements in body proportionality, arm span and leg deformities like genua varum and tibial bowing. These extensive data also show clear functional benefits with improvements in measures of mobility, gate and quality of life. Together, these findings support our plans to submit the full approval package to the FDA and to continue sharing additional data through peer-reviewed publications and scientific forums later this year.

Now moving to Slide 15. BMN 333 is our long-acting CNP therapy for achondroplasia. We previously shared our plan to initiate a combined Phase II/III study in the first half of this year. Today, we're pleased to share more details on the Phase III study design and powering assumptions. The Phase III portion of the study will enroll 60 patients into each arm and will have 90% power to detect a 50% increase in annualized growth velocity versus Voxzogo. This translates into a growth increase of 2.25 centimeters per year over placebo, an effect size that would represent a clear best-in-disease effect. This represents a floor, not a ceiling. We also anticipate that this would translate into greater benefits and other measures of health and wellness for achondroplasia, including portionality, and health-related quality of life. Our goal is to establish BMN 333 as the new standard of care for achondroplasia and potentially for other skeletal conditions.

Now turning to Slide 16. We have several additional exciting highlights expected across the pipeline in 2026. To note a few, we anticipate Phase III data readouts for Voxzogo in hypochondroplasia and for BMN 401 in ENPP1 deficiency, both serving as key steps towards potential approvals as the first genetically targeted therapies for each of their indications. We are approaching the U.S. sBLA action date for Palynziq for the treatment of adolescents with PKU. Given the unique clinical benefits of Palynziq, we believe families with teenagers seeking treatment will be particularly interested in a therapy that can deliver potent fee reduction as well as the potential to enjoy an unrestricted diet. Our PDUFA action date is February 28, and and we look forward to sharing that outcome when it becomes available.

Finally, BMN 351 for Duchenne muscular dystrophy demonstrated 5% mean absolute dystrophin expression at week 25 and in the 9-milligram per kilogram cohort, a level that translates to a predicted 10% absolute level at steady state. We are currently enrolling in a 12-milligram per kilogram cohort and plan to share those results in the second half of the year. Full results for the 6- and the 9-milligram per kilogram cohort will be presented in an oral presentation at the Muscular Dystrophy Association meeting in March.

In summary, 2026 will be an important year of many data readouts clinical advancements and regulatory activities across our R&D portfolio. We'd like to thank all of the patients, families and caregivers whose dedication and support enabled the advancement of these programs.

Thank you for your attention today. We will now open the call to your questions. Operator?

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[Operator Instructions] Your first question comes from the line of Mohit Bansal with Wells Fargo.

Congrats on all the progress. Just -- one point just -- and the dynamic in the achondroplasia market now that we have data for the oral medicine also out there, so how do you see this market evolving with the availability of weekly as well as oral at some point? And then the last part of the question is basically, if you do deliver 2.25 centimeters or above growth velocity, above or -- and/or placebo with BMN 333. Do you think injections could be the first-line therapy there before oral dose?

Thank you, Mohit. This is Greg Friberg. I think I'll take the first half of your question, and then I'll hand it off to Cristin. With regard to the recently released data for the FGFR3 inhibitor, our take there, of course, was that this was generally comparable to other CNP class effects at 1 year. Of course, this is 1-year data. We'll need to see both durability as well as safety data over time. And the read through, of course, in terms of how we believe Voxzogo can deliver value here is that Voxzogo not just having one year of data has a tremendous amount of supporting evidence behind it. We talk about the 10,000 patient years of safety. We also, of course, have a deep a wealth of information with regard to evidence beyond height, whether it's foramen magnum, physical function, tibial bowing, quality of life, all of this data, again, creates a real confidence that, that data is something that patients can rely on. With regard to 333 and the effect size, we've dated again what the powering assumptions would be, and we do believe that the 2.25 centimeters of growth not only are differentiating on a clinical level, but we have some preliminary market research that suggests as well that, that would be important. It's important not to get too caught up in the growth being the outcome that we care most about because the growth is a surrogate for the health and wellness of these patients. Again, going back to Voxzogo, we do believe that, that that increase in growth would, in all likelihood, again, lead to a best-in-disease profile to patients, payers and physicians with value. So with regard to the market dynamics, I'm going to hand it off to Cristin.

Yes. Thank you so much, Greg, and thank you so much, Mohit. I do think -- and as we've said before, I think having more options is certainly important for patients. So we're going to see how that continues to play out. But I think Greg has done a nice job articulating what we've seen in the recent data releases. But what I do think is really important is to understand kind of where Voxzogo plays in this dynamic and in this landscape. First and foremost, it's really important and the data continue to show as do the international guidelines that treating early is the most important thing you can do for patients. And that is something that we really have been able to generate, not only does our label allow us to do that, but importantly, the evidence that we continue to generate supports this that treating early will provide the longest-term benefit, and we have that in 1,000 patient years across all these groups actually in the pediatric space. So I think that's a really important component. The other piece is going to be the switching dynamic or patients that are doing really well going to switch over to another therapy. And what we see and what we hear in our market research and what we have in our field interactions is actually a fair amount of reticence, the large majority of what we're hearing in the marketplace and in our market research is that for patients that are doing well on Voxzogo. There's not going to be a huge incentive to switch right away, especially because the long-term data for safety and efficacy hasn't yet played out for the other products, and that's really important. We've learned that HCPs and KOLs alike are not going to be the drivers of switch, they will provide the data that is out there, but they are going to be the ones that they will be the patients and the caregivers who are actually driving the switch. So this is where that long-term safety and efficacy data really comes through, and I think that, that is going to play out as we see this dynamic continue.

Your next question comes from the line of Chris Raymond with Raymond James.

I'm hearing you guys on the switcher dynamic and the comment that if patients are doing well, there will be a limited motivation to switch, but we were kind of surprised to learn one of your competitors is anticipating about half of their patients in their early achondroplasia trials will be Voxzogo experienced. And I think their commentary is that there actually is a decent amount of parents and patients out there that are interested in switching to something. Just talk about what you're seeing more broadly. Is there a demographic or some attribute other than just performance that might drive this decision or desire to switch? And then if I can maybe ask a question on I'm kind of struck by this drug is mentioned in your commentary, but just looking at the dystrophin data, it looks pretty differentiated, if not superior to what's out there, maybe just talk a little bit about your plan to communicate this. I know there's data, the full data is going to be at the MDA conference next month, but just talk about your plan to communicate the way points on that drug, please?

Thanks so much, Chris, and this is Greg Friberg, again. Let me take your second question first. I would agree with you. The data is quite encouraging from BMN 351. The 5% absolute dystrophin measure, again, which -- if you look at our PKPD model predicts roughly 10% at steady state, that is an unprecedented number the exon 51 skip amenable patients. Now what we also know from the program is that data monitoring committee has allowed us, again, to go to a higher dose level and complete the study. So we see quite a bit of value to continuing the experiment for a variety of reasons. Number one, of course, the 12-milligram per kilogram level, we'll see whether we can see something superior to that number, knowing that within all these patients, there's some degree of variability. Number two, we'll obviously get to see more chronic safety data as well. And this is something, again, that in this field, of course, where benefit burden is key is something that we absolutely want to continue to follow. And finally, we'll get our first look at some functional data as well as we treat these patients for longer and look at, for example, the Stride Velocity 95C data. We expect that this next tranche of data will have it before the end of the year. And in the meantime, we will be presenting our complete 6- and 9-milligram per kilogram data at the Duchenne Muscular Dystrophy Association meeting in March, just a couple of weeks away. So we're sitting tight. And again, encouraged by what we've seen. We want to see more data there. for this weekly IV administered antisense oligonucleotide. With regard to Voxzogo, your question is a nuanced one. It's one of whether or not, again, patients, physicians, their caretakers, whether they can have the confidence in the data package for the medicine that they're given in many cases, to very, very young infants. And of course, with Voxzogo, we have a wealth of data. We're looking forward to present that in our full evidence package that we'll be presenting for full approval to the FDA in the coming months. And I think I've gone through some of the package there, that goes through, again, some of those data points. With that, though, from the commercial perspective, I want to Cristin, a chance to share her perspective.

Yes. Thanks for the question, Chris. And I'd be happy to kind of both dig in on the switching dynamic but also important on the market dynamic in the different geographies in which we operate. Again, going back to that notion of why switch, what we hear disproportionately is that above all else, efficacy and safety are the highest priority. Convenience is the third. So the fact that we have both kind of long-term safety and efficacy data, but also importantly, durability. We are showing data now that shows that Voxzogo continues to work year-over-year data that we published going 7 years out, which really matters to these caregivers, these patients and importantly, the physicians. So I think that this is going to be in the near term, in particular, when there is more data in favorite Voxzogo, I think that, that's going to be part of the switch decisions. Now importantly, when I think about the markets, we've got very different categories or phenotypes, if you will, on markets. We've got some which are larger markets, which we have highly penetrated. And these have become ends in markets. So really where we intend to grow Voxzogo there is going to be really in newborns, where our label enables us to. Then moving over to some of the bigger growth opportunities, I think we have where Voxzogo can really play a meaningful role. That's going to be both in countries that we're already in that still have meaningful opportunity ahead of us. Now let me be clear, these are more complex markets. They take a little bit more time. But we think that the value proposition of Voxzogo is there, and we'll continue to grow there in also, as you heard me say in the prepared remarks, we have some exciting markets where they are fast growing, there's access pathways, and we're growing quickly in those. And so between all of this, when you look at kind of 75% of our revenues being weighted outside the U.S. I think there's an important value story and important story for Voxzogo and all.

Your next question comes from the line of Phil Nadeau of TD Cowen.

The question on Voxzogo brand hypochondaplasia. Can you help us frame the upcoming results? What magnitude of growth velocity increase do you think would be meaningful in hypochondroplasia patients. And can you talk about the dynamics of that market? Would you expect the as quick as in achondroplasia, or are there other factors which could make it less rapid?

Thanks, Phil. This is Greg again. I'm going to take it for stab, and again, I hand it to Cristin at that point. With regard to the study, again, we're very excited that we'll be turning the card over in the first half of this year. The study is designed to measure an effect size roughly equivalent to what Voxzogo delivers for achondroplasia. That being said, that's a fairly conservative assumption. We know that Dr. Dauber's data, for example, is showing slightly larger, more like a 1.8-centimeter growth of AGV in the hypochondroplasia patients. And it's our goal and intent also to follow through, as I mentioned previously, not just measuring AGV, but also looking at measures of health and wellness for these patients. So we believe we've designed the right study. Now it's a question of reaching the endpoint and turning it over, and we're very excited to see the data. Cristin?

Yes. So I think once we see the data, the scientific rationale will have been proven. But I do think that the enrollment rate of the trial in and of itself shows the excitement level that could be here for hypochondroplasia, assuming that all plays out well. And I think that this is yet another example, though, of our leadership in skeletal conditions where we're out there defining area where nothing exists now. And so when I think about what the biggest opportunity is, and we've said it before, it's really in and around diagnosis. This is an underdiagnosed condition, and it doesn't quite have the infrastructure that is needed to ensure that, that can happen rapidly for these patients. So we're out there now doing a prelaunch non-promotional work. We're educating on signs and symptoms requiring further evaluation and genetic testing for hypochondroplasia. We're really talking a lot about the burden of the condition to really enhance that sense of urgency to treat. And we're working actually on establishing and disseminating guidelines for when to refer and test for these patients so that we can shorten that journey to diagnosis. So all in all, we really are working at ensuring that diagnosis which I think will be the biggest problem statement for hypochondroplasia that we can get out there and tackle that early. To remind you, the total TAP side that we understand it to be today is we expect that the prevalence is in and around that of achondroplasia. But because of these diagnosis rates being so much lower, we said that the TAP is around 14,000 patients. I hope that helps you to understand. We're really excited about this and think there's a lot of work there and help to grow space.

And that targeted patient profile includes what we studied in the clinical trial, which is those patients that are more negatively effective in terms of standard deviations for growth deficit.

Your next question comes from the line of Akash Tewari with Jefferies.

This is Siyue Wang on for Akash. One on Bokova again, just following on the infigratinib data, where does this fall in your scenario analysis for your 2027 revenue outlook? And additionally, can you talk about the importance of the full approval for Voxzogo with the final adult height, and how you expect that to impact patient preference?

This is Brian. I'll take the first part of the question on '27 and any impact from infigratinib data. We don't have new updates on '27 at this time. I will say in response to your question, that the assumptions we made in competition impacted scenarios when we did update our views on that range, this is in line, we assumed two competitors and comparable data to Voxzogo.

And this is Greg Friberg. Just commenting on the full approval. This is a real chance for us to work with regulators to present our totality of the data set. We know that we have confidence in the 7, 8, 9, 10 years of SDI and efficacy data that we have in achondroplasia. We will have the opportunity to also put in front of them those measures of health and wellness. I mentioned the foramen magnum data, the physical function, tibial bowing to see again whether or not it meets criteria for label inclusion. It's an important moment, having full approval, build on that confidence, there are some other technical, I think, benefits that come along with full approval. But most importantly, again, we see this as our opportunity to put forward what we see as a leading evidence package for achondroplasia.

Your next question comes from the line of Salveen Richter with Goldman Sachs.

This is Tommie on for Salveen. We just wanted to drill a little bit more into the factors assumed in your Voxzogo guidance, especially as it relates to new starts and potential switching in the context of upcoming competition. And also for 333, kind of your confidence in establishing as the preferred option for new patients from switching given that the long-acting competitor will have a bit of a head start here.

Tommy, it's Brian. I'll start with the first part of your question. Thank you. In terms of the Voxzogo guidance for '26, first of all, just to note, we're really pleased to have grown the product 26% in '25. Its fourth year on the market. And with respect to the range, the $975 million to $1.025 billion really just reflects a handful of scenarios. On the lower end of that range, you can assume a stronger competitive impact from the first competitor potentially coming to market in '27. I'll also share that we're being guarded on a couple of routine market access renegotiations in '26. These are normal course of business. Again, the product is fifth year on the market. Those will resolve this year, but we're being measured on those. And then at the high end of the range, it would just assume a lesser impact from those couple of swing factors in the guidance. Cristin, anything I say on patient additions, and where they're coming from.

Well, I mean, we're continuing to generate patient demand. And really, our priorities remain the same. Now our execution at a country level may look different depending on what choices are available inside country. But at the end of the day, our priorities remain the same. And these profile we've seen so far are very much in line with with what we anticipated. And importantly, where we tend to continue growing patient demand is what I've said, it's in that 0 to 2 population and ensuring that we're really protecting switching.

Yes, [indiscernible], this is Greg. With regard to the 333 question, the ultimate issue here is whether or not convenience is the lever that we're focused on or whether or not patients, physicians, regulators can have confidence in the data package we put forward. We believe that we've designed the appropriate study to show that 333 can have a superior growth profile over all the available agents. And in that regard, really have an opportunity to differentiate itself as the most active agent in the field, not just for AG, but also the pull-through of health and wellness as well. The study is certainly powered to detect the size difference that we mentioned there. But the question I think behind your question was whether that those powering assumptions were aggressive or conservative. And I would argue that they're somewhat conservative. Our animal model data as well as our PK/PD model, or dose response model suggests that any one of the doses that we're putting into Phase II could potentially deliver the profile we're looking for.

Your next question comes from the line of Ellie Merle with Barclays.

Just your latest expected timing for the data readouts from the Phase II CANOPY basket study for Voxzogo, and second, just to ask a bit more on the Voxzogo guidance. Could you comment specifically on what the guidance reflects or how you're thinking about U.S. growth versus ex U.S. growth over the course of the year? And then if you could just elaborate on that last comment that you're being guarded on a few routine market access conversation and sort of the implications for that for Voxzogo.

And this is Greg. Maybe I'll knock down the CANOPY question first, if that's okay. We're anticipating that we're on track for data in the 2027 time frame, as we've stated previously. No updates in that regard. And that refers to IFS, and the Noonan's and Turner SHOX program. Our CANOPY study, of course, also includes hypochondroplasia, which we're excited to turn the card over in the first half of this year.

Thanks, Ellie, this is Brian. I'll start with the first part of your guidance follow-up. We're not delineating further individual growth dynamics in the U.S. and ex U.S., again, we've discussed before about growing in all markets. By the way, even with competition coming to market, Voxzogo's 50 on the market, we are satisfied with to be able to confidently guide to a high single-digit growth rate in '26 and at the midpoint, having the product reach blockbuster status, I'll remind you that the -- we're expecting to have the infant market in the U.S. even if competition comes to market, so that will remain 100% of Voxzogo and Cristin's already touched on the level of opportunities ex U.S. So we'll keep you updated from quarter-to-quarter on the growth dynamics, but not breaking it out further at this time.

Hi, Ellie, this is Alexander. I'm just going to come back to your question about the reimbursement processes that Brian mentioned to just give a little bit more color on those. They're in a number of markets, when you get into 5 years on the market and the product is very well established and has broad usage. You tend to go under formal reimbursement processes. And this represents actually an opportunity for us to broaden the access in those countries. Up to that point, they may well have been under a name patient single patient access type approach. So you go into a negotiation and you offset potentially a reduction in price, but with the opportunity to significantly expand the population. Obviously, in the first year that it happens, and there's two of these countries where it's going to be happening in you obviously have a price reset on your entire population. But then in front of you, you have the potential to reach many more patients. So it's a very exciting actual opportunity for Voxzogo in those markets and overall.

Your next question comes from the line of Cory Kasimov with Evercore ISI.

This is Adi on for Cory. I had a question on BMN 333. Based on the preclinical data and initial first -- should we expect the safety profile to largely mirror Voxzogo, or are there any meaningful differences emerging that could differentiate the profile one way or the other?

Thank you for the question, Adi. Our preclinical models, and in this case, the Cynomolgus Monkey models, in particular, have not demonstrated any additional safety concerns for 333 over Voxzogo as a free drug. The reality actually is that the profile for free CNP allows us to go up to much higher exposures when given in the form of 333 as compared to the daily administration of Voxzogo. And again, that's opened this therapeutic window that has allowed us to go to 3, 5, 7x and higher AUC exposures. And again, we're quite hopeful that recapitulate what we've seen in efficacy animal models that we're going to have a bet in disease profile.

Your next question comes from the line of Paul Matteis with Stifel.

I'm not sure how limited you are, and how you can speak about Amicus and things going forward, but I thought I'd give it a brief try. Just -- as it relates to the integration of the business, Alexander, you, I guess, reorg BioMarin's commercial infrastructure with different business units, and this was kind of, I think, more in reaction to [ Valarox ] a number of years ago. But how do you think about Amicus fitting into that going forward? And how much do you think you can leverage a lot of the reps you have, the units you have existing relationships versus kind of building out a whole new way of selling some of these products?

Thanks very much for the question, Paul. Yes, I mean these two products, our intention is post closure, these are going to drop right into our enzyme therapy business unit. I mean they just fit perfectly. The entire go-to-market model is exactly the same as our current portfolio. So the opportunities and the opportunities for us to drive synergies on the top line as well as synergies in terms of the way that we operate are tremendous. We're looking forward to sharing more post lows. We're on track right now for a second quarter close. And then we'll share more about our specific plans and our expectations for what these really exciting products that Amicus has done such a good job bringing to market what the pro forma looks like when you add those into BioMarin. So more to come, Paul.

Okay. And if I could just ask one quick follow-up. But Brian, I think you said earlier in the call, please don't update your models just yet for the deal. I think a number of models have been updated. Are you seeing anything in the way people are modeling this, that is missing the point that you want to make sure you guys can articulate your vision first, or I guess I'm not -- by any means asking you to give kind of guidance or context here, but from our end, it seems like as Alexander lists, it isn't all that -- it's fairly straightforward. So where are you coming from on that point?

Yes. Thanks a lot, Paul. I appreciate the opportunity to clarify that. the comment was based on entirely just the mixed bag of some analysts having post-close Amicus revenues clouded in their bone remodels and some not. Thanks for the opportunity to clarify that had nothing to do with the direction of what we see and those that are including it.

Your next question comes from the line of Joe Schwartz with Leerink Partners.

So one of the levers you highlighted for longer-term growth when you announced the Amicus acquisition was some initiatives to identify patients who might have Fabry and Pompe that wasn't diagnosed yet. I think Amicus had some pilot programs to do this. And in a few centers -- and I was just wondering if BioMarin had the opportunity to see the results of the pilot programs and if they are along the lines of what you expect to roll out. Can you just talk a little bit about your initiatives there?

For the question, Joe, it's Cristin. So you are indeed exactly what you just said that there are -- they've been running pilots. There's different models. And just to reiterate that we are in the process now of really digging between sign and close really understanding what's going on, what makes sense, given what we already have in our company versus going on over there. And at the end of the day, we are running as two independent businesses at this point in time. And so they're continuing their work on any of the pilots that they have ongoing. I think the real opportunities that we're excited about for both Galafold and Pom Op as Alexander has already spoken to is certainly how it fits to -- it fits within our business unit model here on enzyme therapies. But also importantly, the really big opportunity there is to increase the diagnosis rates both Galafold as well as Pom Op. But then when you're talking about Pom Op, really driving that switch. So important areas that we'll continue to work on, but we're in the process now of really diving in and understanding what's exactly going on.

Your next question comes from the line of Olivia Brayer with Cantor.

I have a few follow-ups on Voxzogo. First is just maybe can you talk about level of confidence in actually hitting the numbers that you laid out this year? Just in light of a weaker first quarter due to those ordering patterns that you highlighted, Brian. Anything more you can tell us on those ordering patterns, and why they might be so heavily weighted to the fourth quarter this year. I'm just trying to understand how having a new entrant on the market could impact some of those patterns and just cadence of quarterly Voxzogo revenue this year? And then a quick follow-up on hypochondroplasia. When do you think we could realistically see that launch and uptake in those patients? And any comments at this point just around how quickly you could start to see added sales from hypochondroplasia patients especially as you think about navigating some of the competitive headwinds in the achondroplasia market next year.

Thanks, Olivia, this is Brian. I'll start with a little more color on the quarter. I appreciate the question. Yes, so a few brief things there. First of all, we've always experienced these kind of bolus orders and the potential volatility of quarterly revenue. And by the way, we've typically seen step-down from Q4 to Q1. We do -- I think we -- especially after this year, we definitely observed some Q4 buying globally. It isn't always inventory levels. It could be, in some cases, of single national payers kind of just making their way through their budgets. There's a number of factors. But we've seen this in Q4, it was -- seen this before for Q4 was exacerbated here in '25. Another item I'd share is, and this is to your point about the competition, I mean two things. One, when we map our revenue to global Voxzogo patient additions. It is amazing how clear of a straight line, the study patient additions have been quarter-after-quarter over the last several years, frankly. But yes, when you look at revenue, it bounces around a bit because of these -- because of the order timing. In fact, while Q4 had a bolus effect, there's actually some markets where it was kind of a catch-up because revenue was flagging patient additions, so that's number one. And number two is I think we're going to continue to observe that this year. I'll share and this should also help you all estimate the proportions of revenue for Voxzogo, we expected the quarters will be similar to last year. So I already said that Q1 is on par with Q1, but we also expect a lot of it to be back-loaded to Q4, and any confidence, any assumptions around the competition are fully baked to?

And with regard to your second question, so as you've heard us say, we'll be presenting or sharing the top line data in the first half of this year for hypochondroplasia, and then our submissions will happen in the second half of this year. So what that means is, hopefully, approvals coming 2027, and we would expect to see immediate revenue impact at that point in time. And we'll share as we see the data, we'll share more on our go-to-market plans as we move further along in the process.

Your next question comes from the line of Jason Gerberry with Bank of America.

Just on the Phase III powering in the 2.25 centimeter per year. Is that a threshold effect when you're doing your Phase IIs ranging, if you're learning that perhaps that may be too ambitious of a target, would you just kind of adjust your statistical analysis plan. Is it -- I think in your earlier comments, not to get too hung up, I think, on that 2.25 number. So if it looks like you're on a trajectory for, say, 2 or 2.15, is it still worth moving forward in the Phase III with BMN 333. So I just wanted to clarify if that's the title of effect in a go no-go threshold in the dose-ranging work?

Yes. Thanks for the question, Jason. And that 2.25 really comes from the sample size that we've laid out, that's 60 versus 60. There's some standard deviation, some alpha numbers behind that as well. But we wanted to share with you again what our ambition was, what we thought not only statistically significant, but clinically meaningful. We will have a chance to look at our Phase II data. It's not a straightforward black-or-white situation. We're doing actually a basin approach where we'll be looking at the totality of the data. And setting a certain threshold for confidence to move forward. Rather than get into the details there, I will just answer your question directly and say we would have the opportunity to potentially modify the protocol thereafter. But those numbers and announcing them again, I think they stated appropriately our ambition of what we think a meaningful and clinically relevant improvement over what is already a well-established, safe and effective therapy in Voxzogo would look like.

This concludes the Q&A portion of the call. I will turn it back to the CEO, Alexander Hardy, for closing remarks.

Thank you, operator, and thank you all for joining us today. We're particularly proud to have accomplished our strategic goals for 2025 while achieving an outstanding growth. In 2026, we will build on this momentum and expand our therapeutic and commercial reach with the addition of high-growth assets from two significant acquisitions announced last year. We also look forward to sharing a number of key regulatory milestones, data readouts and label expansions throughout the year, setting us up to deliver even more growth, profitability and pipeline expansion. We're energized by what lies ahead this year and intend to deliver again on an ambitious set of priorities, demonstrating our dedication to innovation and sustained growth in ways that we will believe patients, we will believe we'll benefit patients, employees and shareholders. Thank you for your continued support, and we will speak to you soon.

Ladies and gentlemen, that concludes today's call. You can now disconnect. Thank you, and have a great day.

Great. Good morning, everyone. Welcome. My name is Jess Fye, and we're continuing the 44th Annual JPMorgan Healthcare Conference today with BioMarin. First, you're going to hear a presentation from the management team, and then we're going to go into some Q&A. [Operator Instructions] Before we get started, I have to read this. It says, please note that JPMorgan has a role on the potential transaction involving Amicus and is subject to restrictions. As a result, I will not be discussing the transaction during the session nor taking questions from the audience on that topic during Q&A. So with that out of the way, let me pass it over to BioMarin's CEO, Alexander Hardy for the presentation.

Thank you very much, Jess, and thank you all for joining us this morning, 2 years in the role as CEO of BioMarin. We've been busy as a team working on transforming BioMarin and setting the path for another era of significant growth and really excited to update you on our progress and our plans today. I'm going to be talking about BioMarin's future plans. And so please take note of the forward-looking statement.

Okay. So BioMarin is a leader in genetically defined conditions with an extraordinary track record of innovation. We have 6 first-in-disease treatments, many best-in-disease treatments. And this is all driven by the capabilities we've built over almost 25 years of our history, capabilities such as our geographic footprint in 80 countries, our track record for a global regulatory and approval standpoint are really impressive R&D capabilities and our in-house manufacturing that has driven not only tremendous progress for patients with these conditions, but has also delivered an extraordinary and strengthening financial outlook, of growth on the top line and increasingly growth on the bottom line.

And this is only further strengthened by the changes we've made over the last several years and most recently, the Amicus transaction. But very importantly, what is our focus at BioMarin, but all the employees every day think about is our purpose. To be the biotech leader that translates the promise of genetic advances and discovery to really make a profound difference on the patients that are depending on us. This is what motivates us every day. By doing this really well, we actually also create an enormous amount of value for our other stakeholders.

So what have we been doing over the last 24 months, we've been very, very busy. These are the pillars that we outlined at our Investor Day in September of '24. And I'll briefly summarize our progress on each. First, with regard to innovation that we prioritized our pipeline to focus on the things which -- in our pipeline, which we believe have the most transformative potential for patients. That focus is great to see in the next 12 months, we're going to see a lot of different readouts. And Gregory Friberg, our Head of R&D, will be up next to tell you a little bit about our significant progress. And we have some important updates to share today with you all.

It's great to see the fruits of that focus acceleration of key assets like 333 and 351. And that ability now that we have with regard to BD to supplement our internal innovation with external innovation. Our second pillar growth, we've really been able to significantly drive our growth rates. Today, we'll be announcing our preliminary '25 revenue and if you look at our CAGR over the last 2 years, we've achieved a 15% CAGR during that period. This has been driven by our Enzyme Therapies business unit. We've refocused into business units and our Enzyme Therapies with additional focus. We've really achieved very significant growth, growing at approximately a high single-digit growth rate.

And then our skeletal conditions and our drug VOXZOGO is now in 55 countries. We have the standard of care in achondroplasia, and we're looking forward to pivotal data in hypochondroplasia this year with a potential launch if approved in 2027 of hypochondroplasia. Just as a reminder, this is the first of 5 additional indications we're going to be seeking with VOXZOGO. So we're really only at the beginning of the impressive growth potential of this asset.

And then our third pillar, value commitment. As a team, we've been really optimizing BioMarin's ability to operate at scale, cost transformation, where we identified $0.5 billion of cost to take out of our ongoing and forward-looking business operations, this allowed us to dramatically increase profitability and also, therefore, improve our cash flow, generating a really compelling balance sheet. And we talked to you all about our capital allocation strategy. Very, very proud of the team at BioMarin for putting that to work and completing 2 M&A deals in 2025, doing what we said we were going to do, do value-creating deals for all of our important stakeholders.

When I take a step back and look at this progress over 24 months, I am incredibly proud of the team at BioMarin. Many of the leadership team is sitting here in the front row, we have delivered on an executed in terms of our financial performance, all at the same time, while transforming fundamentally BioMarin and setting us up for a really, really exciting future. That is really impressive. I really can't think of companies that have managed to do those two things at the same time, and it's a tremendous credit to the employees of BioMarin, so that is the past and the present.

Let's talk about the future. What are our priorities for 2026? And this -- I will start to bring in some of the new news today. It's very, very exciting. So our first priority is to accelerate revenue. We've already had an impressive level of revenue growth over the last several years. We're aiming to build upon that with VOXZOGO in achondroplasia. And then as I already mentioned, the growth in hypochondroplasia, which is ahead of us. Our Enzyme Therapies are performing extremely well. We have the potential addition of an important indication expansion for PALYNZIQ in adolescents. And then, of course, the Amicus integration, which you can expect, I would be talking about, it's going to come in the next few slides. It's going to be a really important addition to our growth rates out into the future years.

But secondly, this is the lifeblood of biotech is innovation. We've really got an exciting year from a catalyst standpoint ahead of us. We have 2 Phase III data readouts this year. We also have announcing today a filing for full approval for VOXZOGO in achondroplasia. So we have completed the post-marketing requirements for that drug, and we're going to be seeking full approval. Greg will share more details. There's a lot more additional that we're aiming to do with that regulatory update. We also have 2 label expansions expected in the next 12 months and we have 2 data readouts, which are really important in terms of our pipeline molecules for 333 and 351.

And Greg. Again, Greg will share more details in a moment. And then finally, our priority -- the third priority for us is strengthening our pipeline. We're very excited about our innovation engine at BioMarin, but we're supplementing that with external innovation. This BD capability that has secured us 2 important M&As in 2025. Whilst our current or short-term focus is deleveraging following the financing of the Amicus acquisition. Our focus from a BD standpoint will be earlier-stage pipeline deals to supplement our growth outlook in the longer run.

So a very, very exciting 2026 ahead of us. So let's talk a little bit about the Amicus transaction. I'm going to be quite brief here. We announced this obviously on December 19, equity value of $4.8 billion. Why is this really exciting? I mean, this is an incredibly compelling transaction for BioMarin. And we believe for patients with Fabry and Pompe disease around the world because it's first and foremost, this is an exceptional strategic fit. These 2 drugs just drop perfectly into our enzyme therapy business is a perfect match with what BioMarin does really, really well and our track record of success in enzyme therapies built over 20 years.

So exceptional strategic fit. The second compelling proposition from this acquisition is this is further accelerates and diversifies our revenue growth. We've got a compelling revenue growth picture of BioMarin alone. Adding Amicus further strengthens that growth outlook and diversify our revenue base. So following this acquisition, we'll have 4 major growth drivers within our portfolio. This is pretty compelling and quite differentiated versus the rest of the sector. And because of very much the similarities in mission and purpose between Amicus and BioMarin. We are able to realize significant financial benefits from this transaction.

And we're confident of our ability to begin to be accretive within 12 months post closure of the deal and to be substantially accretive beginning in 2027. So all in all, an exceptional fit bringing exceptional value to all of our stakeholders. But let's talk about the 2 key products that are part of the acquisition of Amicus. The first is Galafold. Galafold in Fabry disease. This is the only oral therapy in Fabry disease. The proposition that we have here is to build upon Amicus' tremendous success. Galafold has been a very successful launch. Amicus is an extraordinary company that's done a great job, but under our -- in our hands and with our capabilities, we believe we'll be able to reach more patients around the world. The simple point is that at the moment, Galafold is available in around 40 countries around the world. And we'll be aiming to bring it into our 80 country footprint over a period of time.

But this is more than just about numbers of countries. It's also about depth in countries. We have BioMarin operations in many of the 80 countries BioMarin employees, not only distributors. So we have a depth of capability, which really we will put to work to really maximize the impact of Galafold and reach those patients. There's also a tremendous opportunity to increase the diagnosis and treatment rate of Galafold. Fabry disease is a prevalent population of about 100,000 patients globally. There's only about 18,000 of those patients that are actually diagnosed right now with Fabry disease, 12,000 of those are treated.

So you can see here that we have an opportunity to increase the treatment rate and the diagnosis rate, increase the switch rate and increase the naive patient initiation rate with Galafold. Again, building upon what Amicus has done, we believe we can do even more. With regard to Pombiliti and Opfolda or Pom Op, in Pompe disease, there's also a significant opportunity here. There is also the opportunity for us to maximize the impact of our global footprint.

Pom Op is available and reimbursed in 15 countries around the world. So you can probably very quickly see that there's a growth potential there with, again, the breadth and the depth. But with Pom Op, we're also very, very exciting about the really impressive data, real-world data that Amicus has been producing. This is really very important. This is really compelling in driving the switch where that is on label, driving the switch to Pom Op. And then in addition, there are tremendous opportunities for label expansions with the potential to increase the age population, for late-onset Pompe disease, but also to expand this drug into Infantile-onset Pompe disease.

Bottom line is you can see here significant additional growth opportunities ahead for Pom Op as well as Galafold. But in terms of growth drivers, it's important not to look past VOXZOGO, a really impressive growth rate over the last several years as we also expand this out into our geographic footprint. Now today, we're announcing the 2025 preliminary revenue of $920 million for VOXZOGO translated on a quarter-to-quarter basis, fourth quarter of this year, that would effectively mean a growth rate of 27% year-over-year. So you can see VOXZOGO is growing extremely well and very strongly.

And this is even before we expand out into those additional indications. And then, of course, you've got the geographic growth opportunity as well. We're in approximately 55 countries out of our 80 country footprint. So there's also the opportunity to bring VOXZOGO to more patients around the world. In terms of our Enzyme Therapies business, we've -- as already mentioned, we've been achieving high single-digit growth rates up to this point. But we're really at an exciting point because ahead of us are really some exciting growth opportunities.

We have BMN 401, which we acquired as part of the Inozyme acquisition with pivotal data reading out this year and potentially first indication next year. And then, of course, on top of that, we've got the Amicus drugs Galafold and Pom Op contributing to our growth rates in the future. Now I'm sure this is probably going to be a question. You're not going to hear from us today what we project that future growth rate is going to be. But you can imagine that we're confident we can do a lot better than we were saying of a high single-digit growth rate.

Let us integrate, complete the transaction, close the deal, integrate Amicus and we will then provide you additional color on a really exciting growth rate and potential for our Enzyme Therapy business unit going forward. So my last slide before I hand over to Greg. This is the overall outlook for BioMarin, and it's a really compelling outlook. Today, for 2025, we're also announcing our estimated preliminary revenue number of $3.2 billion for 2025. When we look ahead to this year, of course, with the closure of Amicus projected in the second quarter, we'll be adding on top of our growth rate this year, we hope, Pom Op and Galafold. And again, we'll -- when we provide additional outlook following closure, will provide the guidance as to what that looks like.

But what I'm particularly excited about is when you layer all of this on top of each other, you layer on top the 401, the momentum we've already got with VOXZOGO in the Enzyme Therapy business. And on top of it, Pom Op and Galafold from the Amicus acquisition. And then pipeline assets like 351 and 333, we think we're well on the way of achieving our ambition of targeting sustained double-digit CAGR from now into the 2030s and this is enormously exciting.

So with that, I'm very pleased to hand over now to Greg, our Head of R&D, to provide some clinical updates.

Thank you Alexander, it is an absolute privilege to be able to represent the countless individuals who work in the R&D group at BioMarin and have prepared much of this data for us. As Alexander highlighted, we've got a busy 2026 when it comes to events from R&D, 3 major data readouts, including the newly announced filing for full approval for VOXZOGO this year, adolescent expansions, six new Phase II indications where we're doing indication evaluations in a variety of skeletal conditions.

And then, of course, 2 pipeline agents, BMN 351 and 333, which will have some data that we're going to share with you today. First of all, with BMN 351, this is our antisense oligonucleotide for Duchenne muscular dystrophy. We have turned over the cards for the first 2 cohorts and we have seen encouraging dystrophin responses. The study is continuing as planned. And with the 12-milligram per kilogram cohort initiated as we've noted, we're hoping to have that data and be able to present a more totality of information before the end of the year. So what did we exactly see? What you see on the left is actually a depiction of the actual data. These are mean absolute dystrophin numbers from patients on the study. They were treated at 9 and 6 milligrams per kilogram and you see a clear dose-dependent dystrophin response in the data that we've seen.

The findings were consistent across multiple assays. That's Western blot as well as mass spec. Mass spec is what's shown here, it's the better assay to look at quantification. And just as a reminder, we look at these numbers without the double correction for histologic adjustment for muscle content. So that 5% number certainly was a number that gave us what we thought were encouraging results that this study demands continuation.

We know that the tissue half-life for this chemistry is longer than what's seen for the so-called morpholinos, so we expect that these numbers, as you see in gray, depicted on the left, will continue to rise over the course of the next 6 months. Now what will we see by the end of this year? What we're going to see is, of course, dystrophin expression at the next dose level, the 12 milligrams per kilogram. But we're also going to see long-term safety data, both for that 12-milligram per kilogram cohort, but also the 6 and the 9. Those patients are all remaining on treatment.

And of course, for daily -- weekly administered chronic therapy that benefit burden argument is something that we want to flesh out more -- with more granularity. Finally, we'll also get a first glimpse at functional data. The intermediate endpoints, looking at dystrophin expression, I think we're all familiar with that this is a good start, but ultimately functional measures, including Stride Velocity 95C, that's the kind of data that I think will be really transformative for this community. You can expect to see these full results for the 6 and the 9-milligram per kilogram cohort in an oral presentation at the Muscular Dystrophy Association meeting in March.

Moving to BMN 333. We have mentioned that the early results supported the initiation of the Phase II/III study in achondroplasia, as a quick reminder, we had wanted to develop and engineer a long-acting product that would allow us to reach multiple fold increases in free CNP AUC as compared to another long-acting CNP agent. Our target was to see a 3x increase. And what you see today is the data that we're newly releasing that actually, not only did we beat that 3x margin in 3 consecutive cohorts, Cohort 4, 5 and 6, but the highest was -- increased that AUC by over 13-fold. So clearly, what you have there. These aren't necessarily going to be the doses we bring into Phase II, but it gives us a range to work with.

A very clear range where it's not just a small amount of increase, but a dramatically improved exposure to free CNP that we believe we will be able to offer patients with achondroplasia. So the next stop is to initiate the Phase II/III study -- that study is going to initiate shortly in the first half of this year. We're actively working currently. It will be a combined Phase II/III study. We're in the first stage, 1 of 3 doses, high, medium and low. Of BMN 333 will be benchmarked straight up against VOXZOGO.

Once we have a winner from that arm, we anticipate moving rapidly into Phase III and doing a head-to-head against VOXZOGO looking for superiority. AGV, of course, is the primary endpoint here. That's growth-related -- though that's not what patients, again, are most interested in. We've learned a lot from VOXZOGO. We're going to come back to this in a moment, but we will be measuring a variety of factors in this study, including, of course, proportionality, anatomical changes and importantly, mobility changes as well.

So more to come there, and we anticipate that this could be potentially on the market as soon as 2030. And we're, of course, trying to accelerate that with every lever that we have at our disposal. Quickly, just wrapping up. BMN 401, first-in-disease, ENPP1 deficiency, card turning over in the 1- to 12-year olds midyear. And of course, we're working on other age groups as well, looking forward to that data and building upon the legacy that Inozyme is nicely prepared.

As Alexander noted, hypochondroplasia also, we talk a lot about achondroplasia, but whether we look at Dr. Dauber's Phase II data or again, our own experience, we're quite hopeful that this is going to be an active, safe and effective therapy that is VOXZOGO for hypochondroplasia as well. We recruited the study very quickly, and we'll be turning the cards over for that Phase III study in the first half of this year. That's just the beginning of the journey. We're also working to prepare the community, make sure that they understand the disease and again, the genetics behind it and so forth. So more to come there.

I'll just wrap up in terms of the regulatory updates on Rare Disease Day February 28 is our FDA PDUFA action date for the adolescent expansion in PALYNZIQ. The results were quite effective similar to what we've seen in adults, both in terms of decreasing phenylalanine levels, but also the opportunity to increase native intact food that these adolescents could consume. This is important, of course, because before these individuals go off, into adulthood, having this window from 12 to 17 years with the support of their community and their family is really important to be able to get them to a point where this would be a therapy that they could benefit from maximally. So more to come there.

I'll just wrap up by highlighting that it will be a catalyst-rich year for R&D. We've talked about the Phase III cards turning over. We've talked about age expansion. We've talked about pipeline data being revealed, but I do want to highlight and end on this VOXZOGO submission for full approval. So this is something that in the first half of this year that we will be filing with the FDA. We've engaged with regulators about structure and format.

And it will be our opportunity not just to talk about final adult height, not just to talk about length, but really about the health and wellness of patients. We have a comprehensive and consistent wealth of data -- there's over 10,000 patient years of safety data. And of course, patients as old as having been on the therapy for as many as 10 years. We want to be able to show the data that really supports the value of this molecule across all age groups including some of those factors we noted previously, when we talked about certainly quality of life, but also anatomical changes.

In particular, we have some FRAME and MAGNUM data that we're very excited to share later this year. This data won't just be for regulators. It will also be for public presentation, and we expect a rich set of presentations that we'll be able to show this year to show the value of currently the only available and approved therapy for achondroplasia, that being VOXZOGO.

So with that, I want to hand it back to Alexander.

Thanks very much, Greg. It's really exciting to see all the catalysts that you and your team are going to be realizing this year. It's going to be a tremendously exciting seeing the difference we can make for patients across so many important genetically defined conditions. Just by way of closure, first off, we provided some preliminary financial data today. In the appendix to the presentation, you will see a summary of that. So you have that information in writing. In addition, information about EPS and Roctavian. So please refer to the appendix for that.

But in closing, I hope you can see the progress we've made the refresh strategy, the execution against that. And now we're in a period of realization of the enormous potential that BioMarin has as a leader in genetically defined conditions.

The potential to achieve sustained double-digit CAGR growth rates on the top line, a period of tremendous R&D excitement and catalysts. And we're going to aim to do supplement that with external innovation from our really impressive BD capability. And as a team, we're going to continue to execute, deliver significant profitability and cash growth.

And with that, I'd love to hand it back to Jess for questions on anything apparently except Amicus.

And as a reminder, for any questions in the room, just raise your hand or you can always submit them on the portal. Maybe just starting with VOXZOGO, what are the specific drivers that factor into how you're thinking about VOXZOGO's growth in achondroplasia kind of from here?

Yes. Thanks very much, I mean, VOXZOGO is still in a phase of growth in achondroplasia. We're in 55 countries. We're still expanding the number of countries with important launch countries happening within our global footprint of 80 countries. In addition, we have opportunities to further penetrate in currently developed markets where we already have a presence. We have an advantage of the 0 to 2 indication, the infant indication. This is extremely important. The guidelines now the international global guidelines for the treatment of achondroplasia talk about the importance of diagnosing and treating patients as early as possible. So often, the diagnosis is actually made before birth, the treatment decision in many cases is made before birth.

And increasingly, now the treatment is initiated within weeks or months of birth. And the advantage of our indication, which we will sustain for, we believe, for several years, whilst other potential competitors have to generate that data and seek approval is very, very important. So there's lots of room for additional growth and this is even before, obviously, we talk about the 5 subsequent indications we're developing VOXZOGO for.

So you mentioned at the beginning having, I think, hit whatever amount of data is you need to bring to the FDA to seek full approval for VOXZOGO? Can you just elaborate on kind of what that is that you've collected and when that filing could go in?

Yes, I'm going to ask Greg to elucidate further on that. But I would say this is very, very important. Beyond the regulatory milestone, the treatment of achondroplasia efficacy and safety are critically important. And when we talk about efficacy, it's actually sustained durable efficacy. So to be in this position where we're able to provide full final adult height is extremely important, not only from a regulatory standpoint, but we believe in terms of the treatment decision of physicians and caregivers in the treatment of achondroplasia. Greg, over to you.

Yes. From the standpoint, the drug has been on the market for nearly 5 years now. So we have a lot of data. The 10,000 patient years of safety data, of course, every year, we update the FDA. But this particular time is our opportunity to also look at different efficacy endpoints. I can refer you to the post-marketing commitments that are public in terms of some of the data that were required there. Clearly, final adult height, which is a bit of a misnomer. It's really 5 years' worth of treatment and how much height folks who reached a certain age group have achieved.

But also, it's an opportunity for us to look at data, whether it's body morphometry, looking at anatomic changes, that's both in the spine as well as tibial bowing. We've presented some of this data, though we've also uncovered some new findings, some new presentations that we're looking forward to later this year. In particular, this isn't just an update, for example, the older children. It will include all of the ages, including the infants. And in particular, we're hopeful that the data with regard to the FRAME and MAGNUM is something that will -- at least when we present it will be of interest to the community.

So these are, I would say, a comprehensive and a consistent set of data that really show what that value argument is for VOXZOGO. It's one thing to be an investigational therapy and to have that promise. It's another thing to have the data. I think that physicians and patients care about that and certainly, the payers care that. And we're looking forward to being able to present this wealth of data as the year continues.

What does patient retention look like thus far with VOXZOGO? And what do you think it will look like once there are additional players in the market?

The adherence rates on VOXZOGO currently extremely high. I mean obviously, across 55 countries, there are different data sources, but we've talked hitherto of adherence rates of approximately 90%, which really speaks to really how important a therapy this is, but also how caregivers, the family builds the daily injection into their routine. Looking ahead to when and if these currently investigational therapies if and when they're approved. It's great. There will be further treatment options available for caregivers and HCPs, but there is going to be a decision to be made. And it's going to be a shared decision in many cases between the caregiver and the HCP. I've already talked and I think it's very, very important.

We will sustain for several years, it's likely that infant indication, the 0 to 2 population. So we will be the only option for several years for the patients that most commonly now initiated in these first months and a couple of years of life. But for patients who are already on therapy, that switch decision will be a conversation between the HCP and the caregiver. And as is very similar to many of these pediatric rare diseases, the factors are safety, efficacy and convenience. You've already heard from Greg, the wealth of data, the long-term data and the benefits beyond height from an efficacy standpoint. That's going to be part of that conversation. The established safety profile, we have 10,000 patient years' worth of safety. It's very, very clear and very understood. And a very positive safety reputation.

And then they'll consider potentially convenient, but that will be a third factor in any decision. I think we fully expect and it's built into our plans. There will be some patients that will switch to more convenient formulations, but those other factors of safety and efficacy will remain paramount. And as a company, we continue to focus on generating that really compelling evidence, which is important as well as advancing BMN 333, you saw the data here that the PK data, you see now why we're so excited about this molecule and the potential for this to actually be in advance from an efficacy standpoint.

With those higher free levels of sustained CNP. So we think that, that will be a real game changer and an opportunity for us to further advance the treatment of achondroplasia in the longer run.

And can you recap the status of your various strategies to delay competition for VOXZOGO and just talk about how BioMarin plans to kind of defend its market position in the event these other products you gain approval?

Yes. Yes. We feel very strongly about the work that we did for many, many years to really identify the role of CNP in the treatment of achondroplasia, so we are going to vigorously defend our intellectual property. This is an important year in 2026 with regard to that. We have petitioned the FDA with regard to the Orphan Drug Exclusivity associated with achondroplasia requesting that the FDA delay the approval of any, I should say, of the currently -- the product currently under review until the expiry of our Orphan Drug Exclusivity, which is remaining 3 years left, but in addition, we have other intellectual property litigation ongoing. This year, you can expect the decision from the International Trade Commission in the United States as well as other litigation activities in the U.S. and in Europe potentially.

So maybe kind of stepping back, the company has undergone significant changes, right? You've implemented a lot of change over the past just 2 years. How and maybe when do you envision those changes translating into a valuation more aligned with your growth outlook?

I think that's happening as we speak. I mean I think we've -- it's been a work in progress of big, big changes that we've made. I think we very quickly made significant improvements in our profitability and in the growth rates on the top line for our Enzyme Therapies and the VOXZOGO business unit. But now I think the most important thing with regard to valuations is sustained long-term revenue growth. And I think with the strength of our business units, supplemented now by these wonderful products that developed by Amicus Pom Op and Galafold. In our hands, the possibility for them to reach even more patients. They're growing assets with very, very high significant potentials. We believe that in our hands, we believe that ramp and that peak is going to be higher. When you add that in and the combination, we think that's really compelling. And we think that investors are now starting to really -- they've seen the changes, and I think we believe you can really see the results projected now into the future.

And maybe with the last kind of minute here. You started out the presentation talking about BioMarin's unique attributes capabilities that are differentiated. So what would it take for another company to build that?

Yes. I mean it's taken BioMarin, and it's a huge credit to the organization and leadership over the years has taken BioMarin over 20 years to build those capabilities. It does take time. It takes a -- it also is about relationships and reputation in many of the markets we operate. This is not something that you can do overnight. So I think it will take time, and it will take focus from any potential competitor or anybody looking to build a presence in these genetically defined conditions.

Great. Perfectly out of time, so we'll stop there. Thank you.

Thank you very much.

Thank you.

Thank you for standing by. My name is Jayel, and I will be your conference operator today. At this time, I would like to welcome everyone to the BioMarin business update. [Operator Instructions] I would now like to turn the conference over to Traci McCarthy, Head of Investor Relations. You may begin. Perhaps, your line is on mute, Traci.

Thank you, Jayel, and good morning, everyone. Thank you for joining us to discuss BioMarin's acquisition of Amicus Therapeutics, expanding BioMarin's position as a leader in rare diseases and creating value for shareholders from day 1. Please find our press release and PowerPoint on the Investor Relations section of the website.

Moving to Slide 2, our forward-looking statements. This call is being recorded, and a press release and slide presentation are now available. I would like to direct you to our safe harbor statement, which in summary says that we will be making forward-looking statements through the course of our discussion today, and actual results may differ materially.

Moving to the agenda on Slide 3. Joining the call today from BioMarin is our CEO, Alexander Hardie; and CFO, Brian Mueller. Joining us for the Q&A portion of the call are Kristin Hubbard, BioMarin's Chief Commercial Officer; and Greg Freiberg, BioMarin's Chief R&D Officer. With that, I will turn the call over to you, Alexander.

Thank you, Traci, and thank you for joining our call on what is an important day for BioMarin and our colleagues at Amicus Therapeutics. Like BioMarin, Amicus seeks to deliver innovative therapies to people living with rare diseases, specifically Galafold for the treatment of Fabry disease and Pombiliti and Opfolda or Pompe, treatment of late-onset Pompe disease. I am tremendously excited about this deal for 3 main reasons.

First, BioMarin and Amicus are an exceptional strategic fit. BioMarin is operating at scale with a broad global commercial footprint, a proven ability to find patients living with genetically defined rare diseases and industry-leading manufacturing capabilities. Galafold and Pompe will add therapies to our commercial portfolio that have already transformed care for thousands of patients around the world. And this combination will enable us to reach more patients, consistent with the missions of both companies.

Second, this deal will accelerate BioMarin's revenue growth immediately upon close, adding 2 high-growth products with numerous global expansion opportunities. Galafold and Pompe each have the potential to reach $1 billion in peak sales. With the announcement today of the Galafold IP settlement, this growth is projected to continue through much of the 2030s. Third, the transaction will increase our already strong financial outlook.

The combined company will generate additional cash flow, enabling us to delever rapidly and continue to invest in both internally developed and externally sourced innovation. We expect this deal will be accretive to non-GAAP diluted EPS in the first 12 months after close and substantially accretive beginning in 2027. Brian will provide more financial deals in a moment. As we have shared with many of you over the last few quarters, any sizable transaction would need to have a compelling rationale for all of BioMarin stakeholders, patients, employees and shareholders.

With this exceptional strategic fit, the immediate acceleration of revenue growth and the strengthening of our long-term financial outlook, the value of this deal is clear. With that, I will now turn the call to Brian to review transaction terms and financial highlights. Brian?

Thank you, Alexander. Turning to Slide 5. We are pleased with the terms of this transaction, and I will take this opportunity to walk you through the financial highlights of this agreement. Under the terms of the definitive agreement, BioMarin will acquire all of the shares of Amicus Therapeutics in an all-cash transaction at $14.50 per share, valued at $4.8 billion.

As Alexander shared, we believe the addition of Galafold and [ Pompe ] revenues to our existing portfolio represents an attractive opportunity to strengthen our financial outlook and add value from day 1. This transaction will be financed through a combination of cash on hand and approximately $3.7 billion of nonconvertible debt financing. We expect to close the transaction in the second quarter of 2026, subject to regulatory clearances, approval by the stockholders of Amicus and other customary closing conditions.

The addition of Amicus products will immediately accelerate total BioMarin revenue upon close. As we integrate Amicus into BioMarin, our priority will be to maintain and build upon the company's capabilities and resources to support the ongoing growth of Galafold and Pompe. We also believe that there are benefits that can be realized through the synergies given the complementary nature of the 2 businesses and BioMarin's scale of operations.

We expect this combination to increase our profitability and cash flows, which provides the opportunity to delever quickly with a target of being under 2.5x gross leverage within 2 years from the transaction close.

Turning to Slide 6. One of the most compelling aspects of this deal is the ability to benefit from BioMarin's operating scale to accelerate the growth of Galafold and Pompe. On top of our growing 2025 full year total revenues seen on the left, we believe Galafold and Pompe will be significantly additive to BioMarin's top line growth through much of the 2030s.

On the right side, the addition of Galafold and Pompe will contribute substantially to revenues and further diversify BioMarin's commercial portfolio. We believe this is a clear and compelling opportunity that creates significant value, benefiting from the combined capabilities of BioMarin and Amicus. I will hand it back to Alexander for Slide 7. Alexander?

Thanks, Brian. I'm extremely excited by the strategic fit of Galafold and Pompe as part of BioMarin's Enzyme Therapies business unit and the opportunity that we have to increase market share, these differentiated products in growing markets. We believe the estimated prevalence for both Fabry and Pompe is higher than the current number of diagnosed patients, whether treated or untreated.

We will draw upon our years of experience finding patients and driving treatment rates, building on the success of Amicus to date. Moving now to Slide #8. Galafold, the only approved oral therapy for Fabry disease is currently available in more than 40 countries. We believe we have the opportunity to deepen the reach of Galafold in those existing markets as well as reach patients in new geographies across our 80-country footprint by driving diagnosis and treatment rates for both naive and switch patients.

Part of BioMarin, Galafold has the potential to reach many more patients around the world. Moving now to Slide #9. As you have seen in our press release this morning, Amicus has entered into settlement agreements with [ Aurobindo ] and Lupin, concluding the ongoing litigation related to Galafold IP. These settlements will not allow either manufacturer to enter the U.S. market before 2037, in line with the previously announced Teva settlement.

Based on our review of Amicus' intellectual property during diligence, we are highly confident in the growth of Galafold through much of the 2030s now that these IP challenges have been resolved.

Moving now to Slide #10. Similar to Fabry, we believe that Pompe disease is significantly underdiagnosed. Unlike existing single component enzyme replacement therapies, Pompe combines an ERT with an orally administered enzyme stabilizer. We are also encouraged by the real-world data that Amicus has generated, showing that more than 50% of patients switching to Pompe experienced clinically meaningful improvements in functional outcomes.

We believe this growing body of evidence differentiating Pompe from the 2 alternative enzyme replacement therapies is gaining momentum and will drive new patient starts. We have been really impressed with the work that Amicus has done with the launch of this innovative therapy, which was approved in 2023. Because Pompe is still early in its launch, we have a unique opportunity at this stage to accelerate growth by taking full advantage of BioMarin's scale and capabilities.

Moving now to Slide #11 and the conclusion of our prepared remarks. This is the second significant public company acquisition this year for BioMarin, positioning us for an exceptional 2026 and well into the future. The 2 deals together strengthen our financial outlook with potential for accelerated revenue growth now and in the future and an increasing cash flows from the combined organization immediately after close.

BioMarin has been dedicated for almost 30 years to transforming care for people living with genetically defined rare conditions. As I've gotten to know the team at Amicus, I see the same dedication to patients and shared mission-driven culture. I'd like to acknowledge the incredible work that the team at Amicus has done over the years to reach patients living with Fabry and Pompe.

I am confident in our ability to build on their success and to deliver on BioMarin's pipeline catalysts from our clinical portfolio. Today's announcement adds significant value for shareholders, employees and most importantly, patients around the world. I look forward to sharing more as we continue to make progress. Thank you for joining us today. Kristen and Greg will join us for the Q&A portion of the call. Operator?

[Operator Instructions]

Your first question comes from the line of Paul Matteis of Stifel.

This is Julian on for Paul. Very interesting acquisition, obviously. It's clearly on the larger size, I think, with respect to what people were maybe expecting. Can you just talk about the timing of this and why now is the right time to transact and just sort of assumptions and thinking about how this opportunity can bridge the revenue gap when thinking about competition from your existing product portfolio right now? Congrats on the deal.

Thanks very much, Julian, and thanks for the question. I mean I've talked about typical deal size. And I've also said that any larger deal would have to be clearly value creating. And this deal is clearly value creating. I mean it's an exceptional strategic fit. These products will fit very, very nicely into our enzyme therapy business unit. It will draw off the capabilities. We'll be able to leverage our incredible 80-country global commercial footprint.

Secondly, it's going to be additive to our revenue growth. And finally, it's very compelling from a financial outlook standpoint in terms of additional EPS growth, cash flow, et cetera. So this is really an exceptional fit, an exceptional opportunity for BioMarin. We're doing this, as we said, with regard to BD because we have a compelling set of capabilities, and we have the abilities to do deals and create value for our shareholders. This fits perfectly into that. At the same time, we're very confident of our ability to compete with Voxzogo in achondroplasia. But we can do many things at the same time, and we can create extraordinary value, we believe, for all of our stakeholders by doing deals such as this one.

Your next question comes from the line of Phil Nadeau of TD Cowen.

Let us add our congratulations strategically. This does seem like a hand-in-glove fit. We want to drill down on revenue growth for the franchises here and ask you kind of a 2-part question on that. First, just overall, what type of revenue growth do you think the franchises -- the Amicus franchises can achieve over the next 4 or 5 years?

And then second, in your prepared remarks, you suggested that the number of patients with Pompe and Fabry is greater than the number of patients on therapy. Curious to understand why that would be. Obviously, Fabrazyme and Myozyme have been on the market for nearly 20 years. So how can BioMarin help increase the penetration of therapies into these what seem to be rather mature markets?

Phil, this is Brian. I'll start with the revenue growth question. Thank you. So first, let's start with the 2 products that we're acquiring with Amicus and Galafold and Pompe. These are 2 on-market products. So despite the transaction size, this is a transaction that does not carry clinical risk and brings a base of revenue to BioMarin on day 1. We also know that both products are growing at a faster rate than the already healthily growing BioMarin-based portfolio. And therefore, we do believe that the addition of these products will be additive to our growth rate over the next few years.

Thanks, Brian. And maybe I'll build on the second part of your question, Phil, kind of talking a little bit more specifically about where we see the opportunity, both in Fabry and Pompe with these 2 assets. So our ambition overall, as you've heard from Alexander, is to really leverage our capabilities to build on the extraordinary momentum that Amicus has already built.

And when we think about Fabry with Galafold, this is an area where Amicus has done a brilliant job at really carving out a leadership position for those amenable patients or those patients with amenable mutations. And what we know about Fabry is that it is a dramatically underdiagnosed condition. So it's estimated today that there's 18,000 patients that have been diagnosed, but there are 6,000 that aren't treated. That right there is a really big opportunity for us to think about where Galafold could play.

In addition to that, we know that the prevalence is estimated to be much higher. And so we intend to build on BioMarin's capabilities of driving diagnosis and treatment rates to expand upon the Galafold growth story. Now moving over to Pompe and thinking about Pombiliti and Opfolda. This is an asset that's much earlier in its launch trajectory, and we really do believe that we have a unique opportunity again to leverage our scale to accelerate the growth of these assets.

Now this is something that given that they're only reimbursed in 15 countries today, we believe that we can deepen penetration in the countries they're in, but also importantly, expand across our large nearly 80 country footprint over time, of course, that will take some time to do. But that's a huge expansion opportunity, we think.

Not to mention, driving switch in this space -- we know that this is a progressive disease and driving switch in this space is really important, which I think is building on the real-world evidence that they've been generating and thinking about the benefit that they're seeing as people move from enzyme replacement therapy over to Pompe, they've seen some really compelling real-world evidence that I think will help to drive that switch. So we do see tremendous opportunity here, and our ambition is to grow share in growing markets.

Your next question comes from the line of Chris Raymond of Raymond James.

Congrats from us on the deal as well. So just 2 questions. I guess, Alexander, you guys have guided at length to having firepower of $4 billion to $5 billion. I guess, can you just clarify, does this sort of max out your capacity in this area, just doing this one deal? And then I have a leverage ratio question. I see that you guys, Brian, you're guiding to delever to less than 2.5 in 2 years. What are you projecting that number to be just after close?

Brian, do you want to cover the second question first?

Sure. Yes. Thanks. Appreciate the questions. And Yes. So we're taking on $3.7 billion of nondilutive debt as part of the transaction. As noted in the press release, we do have a bridge loan secured here at announcing of the transaction, and we will begin executing on the financing here in short order. Also mentioned the target gross leverage ratio of 2.5x by the end of '27 or within 2 years after close. To your question, at closing, on a pro forma basis, the gross leverage will be about between 3.0 to 3.5x.

And with regard to your first question, as you can tell, this is very compelling from a cash flow generation standpoint. We believe that with the cash flow that we'll be able to generate from our existing business together with Amicus and the value we'll create from the 2 assets, we think we're going to be able to rebuild our firepower within 12 to 24 months after the deal closes.

In the meantime, we have a level of strategic reserves. We have a revolving credit line, and we intend to do additional smaller deals to further build our R&D pipeline during the meantime. But taking a step back, we do believe, and I think these 2 deals that we've done this year show that BioMarin can do really compelling deals, leveraging our capabilities, adding value for our stakeholders. And we very much intend to use this cash flow generation to continue to do deals, which add value.

Your next question comes from the line of Sean Laaman of Morgan Stanley.

Alexander and team, congratulations on the transaction. I have 2 questions. Just the first one, using all debt essentially to do the transaction, what that might say about the enduring cash flow generating nature of your existing business sort of pre-acquisition and your view there? And the second one is just your feel for what OpEx synergies could be observed.

John, this is Brian. Thanks a lot for the question. So of note on this transaction, again, given the scale that Amicus has achieved on a stand-alone basis, approximately $600 million of revenue over the last 12 months. And they've been on their own successful profitability journey.

They reported non-GAAP income in 2024 and have said they're on track for GAAP net income in the second half of this year. So importantly, the combined business actually generates operating profits and operating cash flow on day 1. We do believe the transaction will be slightly dilutive in calendar 2026 and then starting to be accretive in full year '27, substantially accretive beginning at the end of that year.

And that's largely due to the interest cost that we're taking on with the debt associated with the transaction. But back to the cash flows, we do believe that this will be very quickly additive to BioMarin's cash flows. And while we will incur integration costs, we don't anticipate an impact on that BioMarin-based business cash flow. And then in terms of synergies, our priority is going to be to merge the 2 companies to maintain and build the great capabilities that Amicus has built over the years so that we together can continue to grow Galafold and Pompe.

We do expect that there will be synergies available. Again, as I mentioned in the prepared remarks, these are 2 very complementary synergistic orphan disease businesses. And again, while the priority will be maintaining operations and growing these products, we will commence integration and there will be synergies available to us over time that together with the scale of the combined companies will actually increase the net fully integrated profits and cash flows over time.

Your next question comes from the line of Corey Kasimov of JPMorgan.

Congrats to both teams on this deal. So I guess I'm curious, just the outlook here, commercially speaking, based -- first, based on Brian's comment that these Amicus assets are growing faster than BioMarin's base enzyme therapy portfolio. Do you expect to raise your long-term CAGR expectations for this side of the business? And how do you think about the competitive landscape in Fabry and Pompe?

Corey, it's Brian again. Thanks for the question. Yes. So just to start, the purpose of today's call is to announce the transaction. We're very excited to be adding these 2 approved high-growth products to our portfolio. Companies will continue to operate, of course, on a stand-alone basis until we close the transaction.

As I mentioned, we do believe that the combined business will grow at a higher rate through the rest of this decade and beyond. We do believe that the products will be meaningful contributors to revenues in '27, both absolute dollar and growth rate. However, we're not offering additional guidance at this time for 2027 or beyond. What is important to note is that we continue to grow revenue from BioMarin's base business, and these products both add to the growth and very importantly, diversify BioMarin's overall portfolio.

This is Craig Frabert. I'll take a stab at the competition question. Certainly, Galafold is an orthogonal mechanism to the other approaches that are out there. It's oral, it's targeted, it's highly active. And in a disease like Fabry where sadly, patients can respond, but that response can wane over time, having additional arrows in the quiver, so to speak, is really important for physicians and patients.

And we see Galafold for the amenable mutations is playing a really important part there. When you think about the landscape for Fabry beyond that, again, we see that Galafold is going to play a really important role for some time to come. There are substrate reduction therapies that are being looked at, though, again, unproven.

And from that standpoint, we see the opportunity to have a unique mechanism within our portfolio, building on the great work that Amicus has done to be a tremendous opportunity. On the Pompe side, it's another situation, another lysosomal storage disorder where first-generation enzyme replacement therapies did transform this disease. A real breakthrough in that sense, though newer therapies really have focused on this ability to drive more drug into the muscle and most importantly, of course, into the lysosome of the cells in the muscle.

So Pompe actually has been engineered to do that in a couple of different ways. One is through the so-called M6P. It's been selected to really get into the lysosome and do its job better. And then, of course, adding the stabilizing agent not only increases PK, you can actually see in the label, they show the PK very nicely and exposures when the stabilizer is added. But in preclinical studies, again, the suggestion is that, that goes even further.

This double whammy really is a next-generation approach to enzyme replacement therapies. And in that regard, while there are other options out there, again, we think the real-world evidence with Pompe and other preclinical data sets that Amicus has nicely been generating really show its value in this space, and that will only continue.

Of course, there are label expansions going on as well into the -- younger Pompe, for example, is only approved in adults right now, but there's -- certainly, I believe it's 12 to 17 is on the way shortly. So from that standpoint, hopefully, that answers your question, but we're really thrilled about the biology behind these molecules and their opportunity to help patients in fields where options are going to be important. These patients live a long time with these diseases and preventing end organ damage is absolutely the goal of therapies like this.

Your next question comes from the line of Joe Schwartz of Leerink Partners.

Congratulations to everyone on a very interesting deal. A lot of my questions have been answered. So maybe I'll ask about BioMarin's view on DMX200 in FSGS. Given you're acquiring Amicus shortly before another company has their PDUFA in FSGS. I'm wondering if you can give us your view of the clinical prospects and regulatory path forward for DMX200? And to what extent is BioMarin prepared to capitalize on that opportunity given nephrology would be a new commercial area for the company?

Yes. Thanks for the question. So for those who aren't entirely familiar, focal segmental [ glomerulosclerosis ] is the disease we're talking about. It's a rare and fatal kidney disease, probably about 40,000 patients in the U.S. are living with this at any given time. It's a therapy that while there's multiple different mechanisms of action being studied, there's really no approved therapies despite the fact that significant opportunity in terms of number of patients that are out there.

With regard to DMX200, so it's a potentially first-in-class small molecule. It's an oral agent given twice a week. CCR2 is the target. It's really a promising approach to inhibit the inflammatory cells that really drive recruitment of monocyte-driven diseases like FSGS. And in that regard, the early experience with the molecule, the Phase II data look quite promising.

I believe it was 86% of patients had reductions in proteinuria in that albeit early and smaller study. In the Phase III study, studying this new mechanism of action is ongoing right now. A recent announcement by [ Dimerics ] was that they completed enrollment, which is fantastic to see. And we're going to be closely watching this, assessing the opportunity and evaluating next steps.

What we do believe is, again, this is a condition that could benefit from, again, multiple orthogonal different mechanisms of action. We will, of course, be watching the competitor space closely. That being said, again, we're hopeful that there's a great opportunity here with DMX200 as well.

Your next question comes from the line of Olivia Brayer of Cantor Fitzgerald.

Congrats as well on the deal. Can I ask how you guys are thinking about peak sales potential for either of these new products? And I mean, how would you rank the 2 as you think about them driving long-term growth for the company? And then on the Pompe program, how are you guys thinking about competitive dynamics here in that space, just given the traction that Sanofi has been seeing in these patients?

Yes. Thanks for the question, Olivia. This is Brian. I'll start with just speaking to the revenue potential and then hand it over to Kristen for more color on the second part of your question. So we believe that each of the Amicus products has the opportunity to reach $1 billion each in peak sales. We aim to add the unique BioMarin capabilities and large global presence to potentially even build upon that outlook. This will take time. Again, we expect substantial growth through the remainder of this decade. We don't expect to achieve peak revenues until into the 2030s, but we're confident in the opportunity.

And on the competitive side on Pompe, thanks for the question, Olivia. Really, this is an area where, as I mentioned earlier, this is in the earlier phases of launch for Pompe. But importantly, what we're seeing is that there is a lot of momentum that Amicus has been building with regard to switch from enzyme replacement therapies.

And this is in large part based on the experience that they're having out there in the field that they've been demonstrating very encouraging real-world data that during the prepared remarks, had mentioned that more than 50% of patients switching from an enzyme replacement therapy to Pompe in Phase III experienced a clinically meaningful improvement in functional outcomes.

And these type of data, which we'll continue to generate are really important in understanding for a progressive disease, why it is important to have other options, as Greg had mentioned, and Pompe is a very powerful option for these patients. So we expect that we'll continue to see growth well into -- much into the 2030s, and we're really excited to build on that momentum.

Your next question comes from the line of Alex Hammond of Wolfe Research.

I guess what's the integration road map here, especially regarding commercialization, manufacturing, the global footprint expansion? And I guess as a follow-up as well, will this deal affect prioritization or funding for BioMarin 333 and 351? And then on 351, if I may, should we still expect results by year-end?

Maybe I'll take the first -- the last question first, if that's okay. For 351, we ask you to sit tight. And I will just comment that we view BMN 333 as well as BMN 351 as priorities independent of what we're discussing today.

With regard to the integration plans, I mean, obviously, as you well know, until the deal closes, BioMarin and Amicus are going to continue to operate as separate independent companies. We have, though, started integration planning. And when the deal is closed, then we'll obviously start the integration process. has already been covered in some of the prepared remarks and questions, we are operating at scale. We are in a very large global footprint.

We think there's -- there are synergies from the combination, but it's way too early to be specific around that. On the -- particularly on the commercial side, again, these are growing products at very important parts of their ramp. We aim to continue that ramp and then build upon it. So we'll be very, very focused on really building upon the really excellent success that Amicus has had commercially in many geographies. And that will be a very important part of our integration. We will absolutely not distract from the efforts from a sales and marketing perspective and growth perspective.

Your next question comes from the line of Jason Gerberry of Bank of America.

Just 2 follow-ups, just more specifically, I guess, on Pompe, your $1 billion-ish outlook in terms of peak potential here. For P&O, I'm just kind of curious, that implies maybe about 2,500 patients out of the 5,000 to 10,000 late onset prevalence. So I'm just wondering, does that assume that you drive an even greater level of switch versus the Sanofi product? I'm just kind of curious the general directional assumption there. And then just a follow-up on Alex's question. Just on the manufacturing, I believe that WuXi in China was the manufacturer, but they were in the process of moving that to Ireland. Would that just generally be the assumption? Or would you plan to move manufacturing into the U.S.?

So in terms of the first question, really our ambition, I mean, as we've said before, this is really in a very important part of the launch phase of this program, generating high-growth numbers 2024 going into 2025, as you've likely seen from Amicus -- and we intend to build on that. This is a very exciting time in a launch. And our intention here is to really build on what they've already -- on what Amicus has already done, but importantly, continue to leverage the scale, the operating scale, the commercial footprint that we have at BioMarin to expand this product as quickly as we are able to. Do we expect to generate more switch moving forward? We absolutely do. That is the intention here. And importantly, that is going to be driven in large part by the continued experience with Pompe out there in the field, but also importantly, with the continued data generation that demonstrates that this is a really important option for patients as they progress.

And thank you. With regard to the manufacturing question. I mean, obviously, this is part of what we need to do in terms of the integration planning period. We're going to evaluate the long-term manufacturing strategy for these important products. We do have a really compelling manufacturing capability at BioMarin with plants in both Ireland and the United States and an ability to manufacture enzyme therapies reliably and at high quality. So we think this is a very, very interesting part of how we can add value to all stakeholders. But again, our first priority is continuity, and we will be working to understand the current state of contract manufacturing organizations and our priority will be continuity of supply.

Your next question comes from the line of Mohit Bansal of Wells Fargo.

On the deal as well. Just trying to double-click on enzyme replacement therapy and the longer tail here. So I mean enzyme replacement therapies tend to have longer tail. I mean we have learned that from Sanofi enzyme as well as you guys as well. If you think about oral Galafold, the 2037, do you think there is a future beyond 2037 as well given that it's an oral? Or is the other drug which probably has a longer tail than IP here?

Thanks, Mohit. Thanks very much for the question. I mean it's very, very important. Obviously, the IP settlements that Amicus negotiated that really provide really clarity through to 2037 with regard to Galafold. I do think at that point, it's a long, long way into the future, rare disease, these sorts of conditions. I don't think you'll expect to see the same level of generic erosion that you would see with oral therapies in other disease states. But again, that's a long, long way into the future.

And then I would just actually -- I mean, you can take a little bit from our own experience with Kuvan, where we've actually -- the erosion rates have not followed the traditional oral path. They're a good example, and I would encourage you to look at that as an analog. Should Mohit your modeling out to 2037, I'm very, very impressed. You could probably use that as a basis.

Your next question comes from the line of William Pickering of Bernstein.

On the deal. Could you speak in relative terms about the magnitude of upside you see from geographic expansion as opposed to execution in existing markets for Galafold and Pompe? And a second question would be how you see the full commercial organization fitting into BioMarin's existing EU structure.

Thank you for the question. So at this stage, we're not providing guidance. We're not going to quantify the numbers, but I'm happy to say that we really do see opportunity here in terms of the level of expansion and being able to really build upon where we are currently in our country footprint of nearly 80 countries.

Now Galafold is already in 40 or so countries. So you can imagine there that the uplift will not necessarily be the same given where it is in the maturity of its life cycle, but also importantly, the penetration it has already in some of the countries. But I will say the important value driver in Galafold isn't only the expansion, but it's also importantly our ability to continue to drive diagnosis rates as well as treatment rates. And we believe that there is opportunity there, both for naive patients as well as for some switch patients moving forward.

Now Pompe is in a different phase of its life cycle. And it's, as I mentioned earlier, only reimbursed in 15 countries. So we see great opportunity here to expand it. So not only deepen in the markets that it currently is, but importantly, expand it. And this is going to take us some years as we've learned with our own enzyme therapies. So I don't want to promise that that's going to happen overnight.

But you can imagine throughout the integration planning, we are doing some very deep dive into looking at what that launch timing will be across our global footprint. We see this as a brilliant fit within our Enzyme Therapies business unit. This is an area that we feel that we've been historically very successful at. And again, that's about finding those patients, starting them on treatment and then importantly, continuing to drive high adherence rates, which Amicus has already been very successful at, and we believe that we can do that as well as we move forward. So we're very excited, as you can hear in our voices about the integration. And I believe that there is a lot of expansion opportunity.

Thank you. That concludes our Q&A session. I will now turn the conference back over to BioMarin's CEO, Alexander Hardy, for closing remarks.

Thank you, operator, and thank you all for joining us this morning. We believe this transaction represents a compelling rationale for all of our stakeholders, patients, employees and shareholders. It creates significant strategic and financial value immediately upon close and well into the future. With the second significant public company acquisition this year for BioMarin, we have strengthened our financial outlook and position BioMarin for an exceptional 2026 and beyond. Thank you very much for joining us, and happy holidays.

This concludes today's conference call. You may now disconnect.

Day 2 of our London Healthcare Conference. Great to see everyone. Always really appreciative of the attendance. My name is Akash Tewari. I'm a pharma and biotech analyst here at Jefferies. I have the pleasure of hosting the BioMarin management team.

Alexander, why don't I hand it off to you for some intro remarks, and we'll get started.

Great. Excellent. Thank you very much. Can folks hear me okay? Good. So thanks very much for joining us. Thank you for your interest in BioMarin. So actually, at the beginning of next month will be my 2-year anniversary as CEO of BioMarin. I just wanted to -- this is always a period where hit a milestone like this of a degree of reflection. We've done a lot of things, made a lot of changes. I think we're in a period of execution now of those changes.

So what are the things we've done? We've reorganized the strategy around 3 pillars, around growth, driving growth from our existing portfolio, innovation, our pipeline, supplemented by business development and then value commitment, realizing greater returns, increasing profitability, cash flow -- free cash flow from improving our operations. We identified $0.5 billion of cost transformation. A lot of that we've dropped to the bottom line to improve that cash flow and strengthen the balance sheet. But we've also reinvested into the growth drivers into that pipeline.

We're now, as I said, into execution phase, growing that current portfolio. But we're entering now a really interesting -- it's great to have Greg here, the Head of R&D, 14 months into the role. We're now into a period of pipeline readouts. So what can you look forward to in that? We've got 351 for Duchenne's muscular dystrophy, where we're on the verge of -- by the end of this year, we'll be sharing the top line results of that program.

At the beginning of next year, we've got the readout of the Phase III data of hypochondroplasia, Voxzogo, which will be another growth opportunity, the fourth of 5 additional indications that we're pursuing for vosoritide or Voxzogo. We have the Phase III readout for the 401 program. This is the program that we acquired as part of the Inozyme acquisition. And in addition, we have the pending approval by the FDA with an FDA action date of February 28 of next year of Palynziq in adolescents, which is an exciting additional growth opportunity for Palynziq. Palynziq is already growing at about just over 20% this year. So this will be another additional growth leg for that.

So there's a lot to talk about. Akash, I'm looking forward to hearing your questions.

Thank you. And actually, I'm going to start -- we'll get to the guide, we'll get to the products. But I wanted to talk a bit about the unique BD environment we're seeing right now. I've had 2 companies where there was a public offer and then there was a topping bid, and it is annoying for me to deal with, but nonetheless, you don't see that typically. I think the question I have for your team is there is this kind of dynamic of people who have cash and you have about $2 billion in terms of flexibility. But then you might be competing against a mega cap company where they might have a limitless balance sheet seemingly in terms of getting an acquisition done. How does that concern apply to your team? Because your new Head of BD has come in, you guys have talked out external acquisitions. Do you feel like it has been more difficult for you to identify assets that you find compelling and pay a price that makes sense? Or actually, that's not the case.

Yes. I mean we have built a world-class BD function. We do think that BD is a real opportunity for future growth to supplement our internal innovation. The space we're playing in, I mean, let's be really clear, we're focused on genetically defined conditions. We've defined that. That is an absolute requirement for anything we look at from an external standpoint. And that is a segment that we see little -- relatively little competitive pressure in terms of other people hunting after the same assets. They require very specialist expertise. Just for the very nature, these end up being a little bit smaller opportunities or smaller opportunities that will move the needle for the big pharma players that are the actors in the play that you're watching and enjoying watching. So we don't see that same context with the companies and the assets that we are going to do right now.

Understood. And to me, you're kind of thinking about like peak sales and risk adjustment. I can't help but think, Alexander, you're thinking, give me a Palynziq, Voxzogo like opportunity that fits into this business unit approach, right, genetic disorder, skeletal muscles -- skeletal conditions and then enzyme replacement. It seems like that's the kind of sweet spot and then either pre-commercial or just launch. I mean, is that the right framework we should be thinking about in terms of external BD.

Yes, we've largely got it spot on, Akash. I mean we're -- BD is about, for us, supplementing the growth rates in the medium term. That's what we're focused on doing. We don't need to buy revenue. We don't have any large loss of exclusivity events. But we believe that actually assets are worth more in our hands than where they're sitting right now. There's lots of under-resourced genetically defined disease or rare disease companies. And why do I say that? Well, actually, the prevalent populations for these genetic conditions sits outside the United States and Europe. This is a footprint that we're in 80 countries. It's absolutely remarkable. We've built that up over 20 years and occupied it with our enzyme therapies and Voxzogo. That's where the patients are. And these companies don't have that sort of geographic presence.

I'll give you the example of achondroplasia, which is Voxzogo's first indication. 68% of patients are outside the United States, Europe, Australia, Canada and New Zealand, 68%. So you need that geographic footprint. We have that, others don't. And that is just one element of the capabilities. Our capability advantage is across research and our deep genetics capability, our development, our ability to design studies, regulatory endpoints for these sorts of conditions, manufacturing. Again, many of these small rare disease companies use contract manufacturing organizations. We have our own manufacturing capability across multiple modalities. So we can do that more efficiently and effective. And I've already mentioned the commercialization footprint. So I hope that this investor audience can see that there's a real value proposition. As we announce deals, you'll be able to understand the value proposition of how this is going to actually be really good for the growth prospects.

Maybe just a point on that because I remember last year, there was this question of would you do -- you have your long-term guide, would you do a deal that would impair that. And I think your answer was like, look, in general, we want to keep our long-term approach. We think that's really important. If there's an asset that we think is super compelling, we're going to have to go for it. But I think lost in that kind of nuances and especially in what you just said, it's about acquisitions that are earnings accretive, right? Talk to me about the importance of if you are in-licensing assets, how does that change the long-term financial profile of the company? And how coherent is that with your long-term guide as well?

Brian, do you want to.

Yes, sure. I can start. First, maybe thanks for the question, Akash. Just to start on the financial elements of our transformation itself, those are on track. There's largely 2. First is executing on revenue, which we've been doing the last several quarters. And then second was cost, where we've always had a sense of prioritization. It was important through this transformation to fully get costs under control, which we have. That comes with disciplined investments in the right places as well as operating efficiency, which we're executing. We're, as Alexander mentioned, 2/3 of the way through here now on $0.5 billion cost transformation.

And importantly, it's not just investments prioritization and efficiency. During this time, we've been able to make actually incremental strategic investments across all parts of the business, whether it be global sales and marketing, within the business units or to accelerate the pipeline assets. So this was not outright cost reductions, but strategic investments. So that's on track, targeting 40% non-GAAP operating margin next year. That would be more than doubling of our operating margin back in 2023, which was 19%. Excluding our in-process R&D development charge this year, our operating margin is 33% to 34% target. So that's a substantial improvement.

But to your question, when faced with the choice of shareholder value creation and those long-term profitability targets, we'll choose creating shareholder value. So that could adjust where we land long-term margins, but these targets are solidly ahead of many benchmarks within the peer group. So we think we can balance both achieving and sustaining profitability and reinvesting in the business. That's the goal.

Okay. Understood. Now maybe just kind of stepping back. And as a part of that kind of revised tweak guidance, I think there's a bit of confusion about Voxzogo's trajectory both into next year and 2027. And this -- I'm just kind of thinking out loud. Would you agree, if I were to say, I'm very confident, a, Voxzogo is going to grow in terms of just net patient adds year-over-year in a manner that's quite similar to 2025. And then number two, in 2027, there are scenarios that we can easily imagine that patient adds in achondroplasia -- sorry, hypochondroplasia more than offset any competition you face in achondroplasia. How crazy is that framework for you?

I would say that we believe that Voxzogo is going to continue to grow over the next several years. There's still a lot of growth opportunities in achondroplasia, both in the U.S. and in that global footprint. And then as you mentioned, in '27, if we're approved, we have the hypochondroplasia launch. So we think there's sources of growth and plenty of opportunity for the drug to continue to grow through this time frame.

With regard to the -- you didn't directly ask the question, but with regard to the '27 guidance, there's a lot happening, obviously. This is the big question is the competitive question around Voxzogo. There's a lot happening over the next several years. We thought it was useful. We had this '27 guidance rather than saying that's a point estimate, there's a whole range of scenarios. And we decided the most useful thing was to communicate a range. And that low case scenario is not a scenario that we believe is the most likely. But we said, okay, what if there are 2 competitors that take substantial share from Voxzogo. What does that mean? And obviously, also backing out things like ROCTAVIAN. That translates to a number which is really in line actually with your own perspective on '26. That's our low case. That's not what we believe is going to happen. We're confident back to the first part -- your question and the first part of my answer. We're confident that actually Voxzogo will grow over the next several years.

Understood. And actually, I'm just thinking about this, there seems to be kind of a -- what I find kind of amusing, maybe a little sad is you have other CEOs that are entering in the space, and they are convinced that there's going to be this kind of explosion for their programs. And it almost implies not only is Voxzogo's share just going to go to 0 in a way that I just don't think maybe makes logical sense, but there's also just that -- there's just patients out there that we're not seeing, right?

From my perspective, there seems to be kind of consistent patient adds we see in achondroplasia. And in a lot of your markets, you're going from kind of a prevalence to an incident type of framework. So you've done a good job talking about 70% of your patients are ex U.S. But if you were to tell me, like roughly speaking, how much of the markets you're going in an incident market where you have a 0 to 2 label versus a prevalence market where there's still kind of room to expand. Help us understand that.

Yes. So there are obviously different markets in different stages. We're still launching. We're now in 55 out of the 80 countries. Again, that's part of how we're still growing. So obviously, those sorts of markets where new patients come from all different age groups. But in more mature markets, this is very much an incident market. The majority of patients with achondroplasia in many countries are diagnosed actually, in some cases, before birth, but within days or weeks of birth. It's very evident, unfortunately, the disease presentation. And we will be -- we have the 0 to 2 indication and to be determined how long it will take the competitors to get that indication. But that -- in many markets, that is the incident population. So competitors will have to switch in the more penetrated markets. They will have to switch existing patients.

And as you know, and I think you're intimating with your question, switching patients that are doing well on a treatment as they are on Voxzogo. This safety profile is very well established. There's a lot of confidence amongst prescribers and caregivers around the profile of the product is not a straightforward proposition, I would say. And I think this is a topic that the implied valuation has got wrong. This is not a zero-sum game. Again, in our low case scenario, which is not the one that we believe is the most likely, we've taken that into account and it sits right on top of consensus that the reality is going to be somewhere in between. And yes, there will be some patients to switch, but there will be many that decide to continue because they've seen great results with Voxzogo.

So I'm going to dig into that, and I think it's quite important as we get into the Ascendis approval. And that decision is coming up soon. Look, again, I have a horse in this race, but I can't just help but think. It's hard for me -- like I look at the multidisciplinary review for Voxzogo. There are age-match analyses that were done. There are ways that the FDA cuts the data and some of those analyses end up reflecting what's in the label. And we're in this kind of, I think, surreal scenario where if it's 0.3 or it's 1.5 -- or 1.3 versus 1.5, there's a perceived meaningful difference in terms of impact to your franchise. Do you feel like there are scenarios where the Ascendis label could show efficacy that looks numerically worse than Voxzogo on an age-match basis? And then Greg, I'd love if you could comment on this in terms of switch. What is the label that you anticipate them getting given that they did run a different clinical trial?

Yes. It's always a little bit tricky, and I never like to speculate on what -- how the regulators are going to view data sets. But you're correct, they will be looking at individual patient level data, both with regard to efficacy, but also with regard to safety analysis and how preferred terms are bundled, for example.

Our experience would suggest that for accelerated approval, for example, the indication statement that we've received is probably the most likely regulatory outcome, though. Again, I don't want to speculate, again, where the regulators will end on that. Beyond that, again, what we have in Voxzogo is we have almost 10,000 patient years' worth of data at this point. That means, of course, not only are we talking about 1 year or 2 years of efficacy, but we can extrapolate that out to 7, 8, 9 years, we can talk about tibial bowing in a meaningful way, interpedicular distance for hopefully prediction and prevention of spinal stenosis. That's a data set that we want to continue to publish on. We want to own the information that we have. Voxzogo is a safe and effective drug. And all of that data is something that we think will be valuable, certainly to patients and physicians, absolutely to payers.

Okay. So just to hit on that, we got into this question of full approval for Voxzogo and final adult height and whenever -- when does that end up getting reached. Could you potentially make an argument to the FDA that we shouldn't just look at final adult height when you're thinking about that decision, but maybe more holistically, looking at some of these other kind of secondary biomarker-driven endpoints as a part of a full approval decision? And could you be having that discussion with regulators right now?

This is absolutely something that's on our mind. Final adult height is driven by a mathematical calculation and negotiation with regulators. Any time we engage with regulators, it's an opportunity to put in front of them the totality of our data, which we think, again, will help prescribers and patients make an informed decision. We have a wealth of data from that 10,000 patient years' worth of safety and including following up on many efficacy endpoints. So what you can be assured of is that those are going to be active discussions, and we're very much looking forward to having those discussions with regulators around the globe.

Okay. Understood. Maybe just lastly, there is a regulatory and IP discussion to be had here. You guys have seen my research. I'm personally a little skeptical that you had a citizens' petition that perhaps a citizens' petition would be able to block a competitor product from getting on to the market. And to us, we dealt with this with Jazz and Avadel, where you had a once-nightly and that still got approved. But I think one of the things that maybe doesn't get caught in that discussion was there are 2 separate decisions that get made by the FDA, right? There is a separate division that makes a decision on granting both exclusivity and designation. And then there's a separate part of the FDA that actually grants approval.

I think if we look back at the Avadel scenario, there was a delay in outright approval as you waited for the actual ODE decision. Is that an angle we should be thinking about here with the citizens position? It's not just as binary as launch or not, but maybe potentially a delay.

Again, just like Greg, I don't really want to speculate on what the FDA will or will not do. You are correct. It is a separate part of the FDA. And I think we're all professional -- we've always been professional FDA watchers, but trying to understand kind of how decisions are made at the FDA right now. What I would -- I would sort of reframe this that this is -- we feel convicted in the importance of the orphan drug exclusivity to incentivize companies like us. We've now had 6 first-in-disease treatments. We know how important orphan drug exclusivity has been for the business case for ourselves and for others to make progress. And we think we made a strong argument. We will only know, obviously, that outcome at the point of approval. We'll find that out at the same time as you do. But it's not the only arrow in our quiver. We also have ongoing litigation in front of the International Trade Commission with regard to the U.S. We've got traditional IP litigation as an option in the United States on a point of approval.

And in Europe, there is also the possibility of additional IP litigation around new patents, which are pending at the European patent office. So we've got -- I think primarily, the focus of this conversation has been competing in the market with very satisfied patients, additional indications driving additional growth, our global footprint, our indication 0 to 2. In addition, we have this myriad of ongoing litigation, which I think investors should keep one eye on.

Understood. Now maybe going into hypochondroplasia. Can you talk about the size of that population relative to achondroplasia because there are degrees of severity with hypochondroplasia. And then number two, the Dr. Dauber data so far, I mean, it looks just as good in hypochondroplasia as it does in achondroplasia. Can you give us directionally your powering assumptions for that trial and what you expect on average growth height velocity?

And then maybe lastly, what investors love to know, is there warehousing? Have you identified patients? Could this be a bolus launch? Because it's the same doctor. So how immediate is that commercial opportunity for you, let's say, if you get approval in 2027?

Okay. I think there's three questions there. I'll take the first and the third, and you take the second. Okay. So with regard to the first, in terms of the size of the population, we think the genetic prevalence, and we have quite a good level of expertise here, is approximately the same as achondroplasia. So achondroplasia is about 24,000 patients globally. However, to your point, these patients present later. And we think it's likely that it's going to be a more severe subset of these patients, which are really the addressable population. So we would encourage you to use a figure of 14,000 patients. That's what we use internally is the addressable market.

The work that we have underway right now is to really create awareness and understanding of the disease. People talk about this relative to achondroplasia. I think the important thing is to talking about this relative to patients without those genetic mutations. There's around 3 to 5x the level of health care utilization. These kids aren't just shorter, but they have a myriad of health issues.

With regard to your third question, there are clearly -- this is the same prescribing universe, pediatric endocrinologists as achondroplasia. They're very excited about the prospect of a first-in-disease treatment for hypochondroplasia. They do have patients that they have tried in some cases in the United States to get reimbursement for and have been unable to because there's no approved indication. There will also be, just like we're now seeing with achondroplasia, the older patients are under the care of pediatricians in the community. So the ability to reach and connect with those patients. This is a capability we have that we've developed over multiple drugs using it in achondroplasia, where you get a ping of a diagnosis in a claims data saying that there is a hypochondroplasia patient, a particular pediatric practice. And then we go into action and encourage that patient to be referred into the specialists to get treated -- they're already diagnosed, but to get treated.

And very quickly, the study is powered to look for an AGV delta similar to what's seen with achondroplasia, 1.5 centimeters per year. And that is conservative compared to the Dauber experience, which saw more like 1.8 centimeters. I'll also add that the most powerful predictor of AGV change is AGV that you walk into the study with. So if you're a slower grower, you have the chance to grow faster. And we have refined for patients who are minus 3 standard deviations or less. So hopefully, that will, again, make the powering conservative for what we're looking.

We're out of time. I'm going to sneak one more question, and I think it's quite important. Greg, can you just comment on how to do an apples-to-apples comparison with your DMD corrector data versus the Dyne and Avidity datasets? I think it's quite important.

I think it's important to look at other Exon 51 skippers. So that would be Dyne. Dyne has reported the 3.2%, again, not adjusted for muscle or fat content, but that 3.2%, they recently, I believe, commented that they believe over time that, that will go up to about 4% at their next level. We will be looking similarly at an earlier time point than steady state. Our goal is that we have a level that will predict 10% at steady state. It's a different dynamic. It's a different timing with the phosphorothioate chemistry. It takes almost a year or more to reach steady state. A level of between 3% and 5% at 6 months will predict a 10% level out at steady state.

Got it. Thank you so much. I appreciate it. Thanks, everyone, for joining us. Thank you.

Thank you.

Hello, and welcome to the BioMarin Pharmaceutical Third Quarter 2025 Conference Call. [Operator Instructions]

I would now like to turn the conference over to Traci McCarty. Please go ahead.

Thank you, operator. To remind you, this nonconfidential presentation contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc., including expectations regarding BioMarin's financial performance, commercial products and potential future products in different areas of therapeutic research and development. Results may differ materially depending on the progress of BioMarin's product programs, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market and developments by competitors and those factors detailed in BioMarin's filings with the Securities and Exchange Commission, such as 10-Q, 10-K and 8-K reports.

In addition, we will use non-GAAP financial metrics as defined in Regulation G during the call today. These non-GAAP measures should not be considered in isolation from, as substitutes for or superior to financial measures prepared in accordance with U.S. GAAP, and you can find the related reconciliations to U.S. GAAP in the earnings release and earnings presentation, both of which are available in the Investor Relations section of our website. Please note that our commentary on today's call will focus on non-GAAP financial measures unless otherwise indicated.

Beginning on Slide 3 and introducing BioMarin's management team joining today's call, Alexander Hardy, President and Chief Executive Officer; Brian Mueller, Chief Financial Officer; Cristin Hubbard, Chief Commercial Officer; and Greg Friberg, Chief R&D Officer.

I will now turn the call over to BioMarin's President and CEO, Alexander Hardy.

Thank you, Traci. Good afternoon, everyone, and thank you for joining us on today's call.

Turning on Slide 5. I am very pleased with the strong results across the business, leading us to raise full year total revenues guidance at the midpoint and reaffirm our VOXZOGO revenue outlook for 2025. In addition to top line performance, BioMarin has delivered expanding profitability and significant growth in operating cash flow, bringing our cash and investments part to approximately $2 billion at the end of the third quarter. We are focused on finishing the year strong, positioning ourselves to achieve record commercial results for the full year.

To date this year, we have delivered 11% increase in top line growth year-over-year. These strong results are driven by the performance of our global Enzyme Therapies and skeletal conditions business units as we deliver for patients around the world. We have built the Enzyme Therapies business unit into a $2 billion-plus franchise over the last 12 months with continued growth anticipated. In the skeletal conditions business unit, our first indication with our first product, VOXZOGO, the treatment of achondroplasia is expected to generate more than $900 million in revenues this year, leading us to reaffirm our full year 2025 VOXZOGO outlook and representing 25% growth at the midpoint of our guidance range. As the established standard of care in achondroplasia, VOXZOGO revenue has increased 24% and year-to-date compared to 2024.

Now in the fourth year of its global launch, VOXZOGO has represented a breakthrough therapy for families seeking treatment for their children with achondroplasia. Building on this innovation, we are excited to bring VOXZOGO's second indication forward for the treatment of children with hypochondroplasia. We have high confidence in the upcoming pivotal data readout fiber chondroplasia expected in the first half of next year, based on proof-of-concept data and more than 10,000 patient years of safety and efficacy data in achondroplasia.

Building on the rapid and successful global commercialization of VOXZOGO in achondroplasia, now available in 55 countries, we are well positioned to execute a strong global launch in hypochondroplasia, targeting 2027 should the data be supportive. Cristin and Greg will provide more details in a moment.

Turning now to our broader strategic objectives. Over the past 18 months, we have undertaken a series of initiatives designed to prepare BioMarin for future growth and expansion. As part of this effort, we have made difficult decisions including the discontinuation of multiple research programs that did not meet our criteria for advancement. Accordingly, today, we are announcing the decision to pursue options to divest Roctavian and remove it from our portfolio as we focus on the business units aligned with our strategic priorities. Roctavian is an innovative gene therapy that holds potential within the treatment landscape for severe hemophilia A. As a result, we are working to find an alternative that will allow for Roctavian to reach its full potential by ensuring access to those interested in gene therapy treatment. In the meantime, Roctavian will be commercially available in the United States, Italy and Germany. Throughout this process, we will support and monitor patients who've received Roctavian as their well-being is our top priority.

As we look to the future, we are pleased that our breakthrough medicines are in high demand and reaching thousands of patients around the world. Our financial performance so far this year reflects strategic investments in the Enzyme Therapies and skeletal conditions business units, both of which remain central to our growth strategy along with increased business development opportunities and our own advancing internal pipeline. Building on this momentum, we look forward to the many data readouts and potential new approvals ahead along with new business development opportunities as we focus on the next stage of BioMarin's growth.

With that, I will now turn it over to Brian.

Thank you, Alexander. Please refer to today's press release for a detailed third quarter 2025 results including reconciliations of GAAP to non-GAAP financial measures. All 2025 results will be available in our upcoming Form 10-Q, which we expect to file in the coming days.

Starting on Slide 7, strong global demand across our portfolio of innovative medicines drove a year-to-date total revenue increase of 11% compared to the same period in 2024. Revenues from VOXZOGO and Palynziq each increased by more than 20% on a year-to-date basis. As we shared last quarter, we anticipate VOXZOGO revenue in Q4 to reach its highest level of the year due to the timing of contracted orders as well as increasing numbers of patients on therapy, and we expect full year 2025 VOXZOGO revenue of between $900 million and $935 million.

We are pleased with 8% year-to-date growth of the Enzyme Therapies business unit led by Palynziq. Due to large orders for Naglazyme and Vimizim in the second quarter, we note that Enzyme Therapies revenue was lower in Q3 quarter-over-quarter. And compared to Q3 2024, Enzyme Therapy revenue in the quarter was relatively flat primarily due to a higher volume of Aldurazyme quarter last year. Given the strong top line performance so far this year and our expectations for the fourth quarter, we are raising the lower end of our full year 2025 total revenue guidance to $3.15 billion, with the midpoint of the range representing double-digit year-over-year growth.

Now moving to Slide 8. Q3 2025 results include a charge of $221 million for acquired in-process research and development, or IP R&D. On a pretax basis related to the Enzyme's Pharma acquisition completed on July 1 of this year. This acquisition-related expense represents an approximate impact of $1.10 on a per share basis. The IT R&D charges significantly increased both GAAP and non-GAAP R&D expenses in the third quarter. And along with higher SG&A investments, across our skeletal conditions and Enzyme Therapies business units resulted in lower year-over-year operating margin and diluted earnings per share both on a GAAP and a non-GAAP basis. However, looking past the IP R&D charge, BioMarin's underlying strong revenue performance and operational efficiencies drove increased year-to-date GAAP and non-GAAP diluted earnings per share. Further, we recognized lower tax expense during the third quarter due to the timing impact of the Enzyme IP R&D charge on our quarterly estimated tax rate as well as some tax benefits from the recently enacted tax law.

Taking these dynamics into account, alongside our expectations for strong revenue growth and continued operational execution in Q4 2025, we are updating full year 2025 non-GAAP operating margin guidance to between 26% and 27%, and non-GAAP diluted earnings per share guidance to between $3.50 and $3.60. BioMarin continues to generate robust operating cash flow, reaching $369 million in the third quarter, $728 million year-to-date attributing to the company's total cash and investments balance of approximately $2 billion at the end of Q3. We expect this momentum to continue, both solidifying the sustainability of our profitability and cash flow and building incremental capital to invest in future growth through business development.