Pharming Group N.V. - ADR Stock

Thank you, operator. Good morning and good afternoon, everyone, and welcome to our Q2 2026 earnings call. I'll be joined on this call today by Leverne Marsh, our Chief Commercial Officer; Anurag Relan, our Chief Medical Officer; and Kenneth Lynard, our Chief Financial Officer.

In this call, we will be making forward-looking statements that are based upon our current insights and plans. As you know, these may differ from future results.

As you saw in today's press release, while we lowered our full-year revenue guidance, we are encouraged by the resilience of RUCONEST with robust underlying demand indicators. Joenja continued to deliver strong growth, and we are approaching a number of significant near-term catalysts. Before I go into more detail on the quarter, let me take a step back and put these developments into the context of the ongoing transformation of Pharming.

We are evolving Pharming into a more diversified rare disease company with an increasingly attractive long-term growth profile. This is supported by three key pillars, RUCONEST, which provides a durable source of cash flow; Joenja, a high-growth asset still early in its life cycle with significant commercial opportunities ahead; and a high-value pipeline with two potential billion-dollar opportunities.

Each of these pipeline programs has the potential to materially increase our scale and are important steps forward in our ambition to make Pharming a leading global rare disease company. We've made important progress across the business during the second quarter despite a 3% year-over-year decline in total revenue. RUCONEST revenue declined to $72.3 million compared with $80.4 million in the second quarter of last year. However, we are encouraged by the underlying performance indicators, which demonstrate the resilience of RUCONEST in an evolving on-demand HAE market.

One year after the launch of the first oral on-demand HAE treatment, the RUCONEST active patient base remained at 93% of the level a year ago. We are also seeing strong new patient enrollments, which have returned to levels close to those of a year ago, and we expect this to support momentum over the coming months as these patients initiate treatment.

We also continue to see new prescribers using RUCONEST, which underscores RUCONEST's differentiated value proposition for high-burden patients. Leverne will provide further detail on RUCONEST's performance later in the call. Turning to Joenja. We delivered another quarter of strong growth, with revenue increasing 40% to $17.9 million. We remain focused on expanding the opportunity for Joenja in APDS through both label and geographic expansion, and we are pleased to see commercial momentum accelerating in Europe.

Beyond APDS, we see a potentially significant opportunity for leniolisib in broader primary immunodeficiencies, including CVID. This indication represents an addressable patient population up to 40 times larger than APDS. Anurag will provide more detail on the mechanistic rationale underpinning our excitement in these additional indications.

With greater visibility into the current HAE market dynamics, which is much clearer a full year after the launch of the first oral on-demand treatment, we have decided to lower our full-year revenue guidance by $30 million. Nevertheless, based on the underlying trends we are seeing, we expect RUCONEST revenue to stabilize and return to growth during the second half of 2026. Importantly, our increasingly disciplined operating model has enabled us to maintain positive cash flow from operations.

We have also reduced our full-year operating expense guidance by $15 million, to a range of $315 million to $320 million. As we position Pharming for an important second half of 2026, our priorities are clear. First, we will continue to reinforce RUCONEST's differentiated value proposition for high-disease-burden patients and build on the solid underlying performance indicators that we have seen in the second quarter.

Second, we will continue to drive the growth of the Joenja franchise, supported by the potential pediatric label expansion in the U.S. and further geographic expansion into new markets, including Japan. And importantly, we expect to advance our pipeline at pace, with the readout in Q4 of the two Phase II studies for leniolisib in much broader CVID patient populations.

Success in this indication could expand the annual sales potential of Joenja to more than $1 billion and establish Joenja as a blockbuster franchise. With that, I will turn the call over to Leverne to discuss our progress on the commercial front.

Thank you, Fabrice. Good morning and good afternoon, everyone. Let me begin with RUCONEST. This quarter, RUCONEST revenue was $72.3 million, down 10% year-over-year, but up sequentially by 24%. The year-over-year decline reflected continued competitive dynamics in the U.S., completion of our planned withdrawal from international markets, and temporary inventory normalization.

I am pleased to report that nearly one year after the launch of a new oral on-demand treatment, the active RUCONEST patient base remains highly resilient at approximately 93% of the prior-year level. While some patients are evaluating new treatment options, the vast majority have continued on RUCONEST, as the drug remains especially important for patients who have more frequent attacks or severe attacks who need reliable on-demand treatment.

Also notable, we've not seen a reduction in RUCONEST utilization among patients receiving newer prophylactic treatments. This reinforces that preventive and on-demand therapies play complementary roles in managing HAE. We're also encouraged by the upticks in new demand. During the quarter, we recorded 84 new patient enrollments, up substantially from approximately 50 in the first quarter and close to the high level we received during 2025, quarter 2.

We also added 17 new prescribers, suggesting continued physician confidence even following the addition of a new competitor. Importantly, we see underlying U.S. demand improving. The resilient patient base, improvement in new enrollments, and continued addition of prescribers support our belief that revenue will stabilize and RUCONEST is expected to return to growth during the second half of the year.

Next slide, these patient retention and demand dynamics reflect the distinct role that RUCONEST continues to play in high-burden HAE patients. HAE is challenging to treat as it affects patients differently and no single treatment meets every patient's needs. Convenience matters, but for patients with more frequent attacks, with more severe attacks, reliability, rapid onset, and confidence in their treatment are critical, particularly when attacks occur in high-risk locations or other therapies have not provided adequate control.

RUCONEST is well-suited to meet these needs. By replacing deficient or dysfunctional C1 esterase inhibitor, it helps restore control of the pathways that drive HAE attacks while providing the efficacy and reliability of a self-administered IV treatment. This differentiated clinical profile explains why physicians could continue to prescribe RUCONEST, including for new patients with more severe disease. And, separately, RUCONEST's highly specialized manufacturing process limits the potential for direct biosimilar competition, supporting its durable commercial position well into the future.

Next slide, please. The data shown here bring that differentiated profile into focus. In clinical studies, 97% of acute attacks required only one dose of RUCONEST, and RUCONEST stopped 93% of attacks for at least three days. Importantly, RUCONEST also demonstrated a median time to complete attack resolution of approximately four and a half hours, a key point of differentiation versus competition.

Taken together, HAE patients with a high disease burden, this combination of efficacy, reliability, and rapid and complete attack resolution provides the confidence to both patients and physicians in choosing RUCONEST as their on-demand treatment. And these data reinforce our belief that RUCONEST will remain an important on-demand therapy for high-burden HAE patients and a durable part of Pharming's commercial portfolio.

Next slide, please. Turning now to Joenja. We delivered another strong quarter and continue to build momentum across the U.S. and international markets. Global revenue increased 40% year-over-year to $17.9 million, while the U.S. revenue grew 31% to $15.4 million and international revenue increased 150% to $2.5 million, reflecting growing uptake and high adherence. In the U.S., new patient starts continue to drive sales growth. By the end of the quarter, 132 patients were on paid therapy, up 16% year-over-year, and 5 patients sequentially over quarter 1.

We are also continuing to expand the diagnosed APDS population. During the quarter, the number of identified U.S. patients increased by 16 to 298, including 60 patients between the ages of 4 and 11, which is a key catalyst for future growth in APDS. As we identify more patients, we see meaningful room for continued growth in patients on therapy, both in the U.S. and internationally.

Next slide, please. Looking ahead, we see several opportunities to continue expanding Joenja. In the U.S., sources of growth in APDS include continued patient identification, increased genetic testing, and continued efforts to reclassify VUSs. Pediatric expansion is the next important growth opportunity. We are awaiting our October 24 PDUFA date for approval of the higher 40 and 50 milligram doses. And I am pleased to report the filing of the sNDA for the lower 20 and 30 milligram doses will be submitted to the FDA today.

We are also expanding internationally. Our first European launch is now underway in Germany, and we are preparing to launch in Japan in the third quarter. Together with continued growth in the U.K. and other markets, these launches significantly increase the number of patients we are positioned to reach. Finally, our phase II studies in genetic PIDs and CVID with immune dysregulation are evaluating substantially larger patient populations for Joenja beyond APDS.

Together, these opportunities provide multiple sequential drivers of growth for Joenja, supporting our ambition to build a broader immunology franchise and positioning Joenja for potential blockbuster status. With that, I will now turn over to Anurag.

Thank you, Leverne. I'll start by reviewing the science supporting leniolisib's potential beyond APDS and the scientific foundation supporting our two phase II programs. Let's begin by reviewing the relevant biology, where PI3K delta is a central immune signaling molecule. Specifically, it regulates lymphocyte activation, proliferation, differentiation, trafficking, and survival via the AKT, mTOR, and FOXO pathways. Consequently, imbalance in the pathway drives immune dysregulation, which can be clinically manifest as lymphoproliferation, autoimmunity, and inflammatory end-organ disease, specifically in the lung, liver, and the GI tract.

This mechanistic understanding forms the scientific rationale for Joenja or leniolisib in APDS and our development programs in more prevalent PIDs. Before turning to these broader patient populations currently under investigation, it's worth reviewing the clinical foundation we've already established in APDS with PI3K delta inhibition using leniolisib.

Leniolisib has demonstrated consistent and durable reductions in lymph node and spleen volume, showing sustained benefits with up to seven years of therapy in an open-label extension follow-up relevant to other PIDs. The safety profile is also well-established. Joenja has truly delivered life-changing benefits for patients, including fewer infections and hospitalizations, and a substantial reduction in treatment burden. What we have achieved in APDS gives us confidence in the potential for leniolisib to deliver the same meaningful benefits via PI3K delta inhibition to many more primary immune deficiency patients with immune dysregulation.

Other genetically defined PIDs, as well as CVID with immune dysregulation, have a similar underlying PI3K delta-driven biology. Because of this PI3K delta involvement, these patients share many of the same clinical manifestations I just mentioned: lymphoproliferation, autoimmunity, GI disease, and lung disease.

In addition to the mechanistic basis and our APDS experience, as we presented at the CIS conference in May, we have seen encouraging results in a small cohort of CVID patients who were treated in an expanded access program. In this clinician-reported experience, the breadth and consistency of improvement across cytopenias, lymphoproliferation, and end-organ disease provides a compelling early signal.

Our two phase II studies are designed to determine whether the same targeted approach can benefit a broader patient population and significantly expand the addressable market. Both phase II studies are now fully enrolled, with top-line results expected in the fourth quarter. The CVID study includes 20 patients and is being conducted across multiple centers. The second study is a 12-patient basket study at the NIH involving genetically defined PIDs associated with immune dysregulation. These studies are designed to answer two fundamental questions.

Can leniolisib produce clinically meaningful improvements across the key manifestations of immune dysregulation, and which dose regimen provides the appropriate balance of clinical activity, safety, and pathway modulation to support further development?

To answer these questions, we are evaluating lymph node and spleen size, blood cell counts, liver and lung involvement, as well as patient and clinician-reported outcomes and key biomarkers. With the endpoints in these two studies strategically very similar to those in our APDS clinical program. Improvement across these measures would establish proof of concept and guide the next stage of development, including a registrational trial endpoint in these substantially larger patient populations. Given that the PI3K delta pathway is seen as a shared driver of immune dysregulation, we currently anticipate conducting a single registrational phase III trial in the broader CVID indication, incorporating patient populations from both studies. With that, I'll turn it over now to Kenneth to review our financial results.

Thank you, Anurag. I will now cover our Q2 and H1 2026 results, along with our updated full year outlook. Q2 revenue was $90.2 million, down 3% year-on-year. RUCONEST declined, as you heard earlier, by 10% versus Q2 of last year, and Joenja increased 40% year-on-year. Our reported operating profit was positive in the quarter, despite lower revenues and incremental investments of nearly $9 million compared with the same quarter last year. Adjusted operating profit was also positive and declined by $5 million year-on-year, primarily impacted by the decrease in revenues and the higher R&D investments.

It is important to note that the adjusted Q2 2025 figure excludes $2.1 million of non-recurring Abliva acquisition-related costs, and the adjusted Q2 2026 result excludes $6.5 million of non-recurring items, comprising $4.9 million related to the impairment of manufacturing inventory and $1.7 million associated with the planned closure of our production support site in Évry, in France, in the Q4 of 2026.

Operating cash flow for the quarter was an outflow of $9.7 million, primarily driven by changes in net working capital, including a strategic inventory build to further strengthen supply security as well as operating performance. As a result, cash and marketable securities at quarter end were $159.5 million, a decrease of $12.3 million compared with the end of Q1 2026. Looking now at our performance for the first half of 2026, the trends we saw in the second quarter are also reflected in our year-to-date results.

Revenue for the first six months was $162.7 million, representing a 6% decline compared with the first half of 2026. For RUCONEST, revenue was 12% lower than the prior year period, and Joenja continued to deliver strong growth, with revenue increasing 37% year-on-year. Reported operating profit was impacted by a decrease in revenue impacted by RUCONEST demand and inventory destocking at specialty pharmacy level, predominantly in Q1 2026, and the manufacturing-related impairment of inventories in the first half of 2026.

Adjusted operating profit was $10.7 million, lower than in the first half of 2025. For comparability, the adjusted H1 2025 result excludes $9.9 million of non-recurring Abliva acquisition-related costs, while the adjusted H1 2026 result excludes $6.5 million, comprising of the $4.9 million impairment of manufacturing inventory and $1.7 million provision related to the site closure in France.

Compared with the first half of last year, we increased investments in R&D by $13 million. We maintained strong cost discipline. On an adjusted basis, operating expenses increased by just 1% versus the first half of 2025, despite these incremental R&D investments. Finally, operating cash flow for the first half was an outflow of $7.7 million, reflecting the combined effect of net working capital changes, primarily the strategic inventory build mentioned, and lower revenues.

Turning now to our outlook for the full year. We have revised our 2026 revenue guidance to $375 million-$395 million, a reduction of $30 million from our previous outlook, reflecting the RUCONEST stabilization and return to growth and strong Joenja growth as discussed earlier. This represents expected growth of approximately 0%-5% versus 2025.

As Fabrice mentioned earlier, nearly a year after the launch of the first oral on-demand HAE treatment, we have much clearer understanding of the evolving market dynamics, giving us greater confidence in both our forecasting and our revised outlook. At the midpoint of our guidance range, RUCONEST U.S. revenue is expected to decline approximately 3% for the full year. For Joenja, we continue to expect annual revenue growth in the high 30%s as compared to 29% growth in 2025, with Germany, Japan, and the anticipated U.S. pediatric label expansion contributing.

We remain committed to disciplined capital allocation to efficiently balance investments in our pipeline, combined with a strong focus on operational efficiency, driving short and long-term value creation. Accordingly, we have reduced our full-year operating expense guidance by $15 million to $315 million-$320 million, representing growth of 1%-3% versus 2025.

This includes more than $40 million of incremental R&D investment to advance our pipeline and approximately -- the approximate $9 million benefit from the 20% structural reduction in G&A headcount that we announced last year in October. Marketing and sales expenditure are expected to be broadly stable. For the full year, we expect cost of goods sold, including the $4.9 million manufacturing inventory impairment recorded in the second quarter, to be approximately 11% of revenue, corresponding to a gross margin of around 89%. Finally, we remain confident that our existing cash resources, together with future operating cash flows, are sufficient to fund our current development pipeline and all associated pre-launch activities. With that, I'll hand the call back to Fabrice.

Thank you, Kenneth. Let me close by putting our updated outlook into context. While we have revised our revenue expectations for 2026, the fundamentals of our business remain solid, and we have several important growth opportunities and clinical milestones ahead. We continue to believe that RUCONEST will remain a cornerstone on-demand treatment for high-burden HAE patients and a durable cash engine over the long term. This is supported by the performance we began to see this quarter, specifically the limited erosion of the active patient base, the renewed strength in patient enrollments, and the continued adoption by new prescribers. Joenja, our key growth driver, is maintaining strong sales momentum and remains early in its commercial life cycle with significant near-term commercial opportunities ahead through geographic expansion and pediatric label expansion.

We are also operating the company with much greater discipline. We have reduced our full-year operating expense guidance while continuing to invest in our most important commercial and clinical growth opportunities. We must continue to transform the organization and significantly increase our level of execution to fully capture the many opportunities in front of us. Looking ahead, we have a compelling series of near-term clinical catalysts.

As you've seen in the fourth quarter of 2026, we expect to report results from two phase II studies evaluating leniolisib in broader primary immunodeficiency populations, including CVID. Positive results could significantly expand the opportunity for Joenja and support its potential to become a blockbuster franchise. This will be followed in 2027 by the readout of the FALCON pivotal study of napazimone in patients with primary mitochondrial disease. Another program with the potential to materially increase Pharming's scale.

While we have rebased our near-term revenue outlook, we remain confident in the strength of our commercial foundations, the quality of our pipeline, and the multiple catalysts that can drive our next phase of growth. I believe these combinations position Pharming well to continue building a leading global rare disease company. Thank you.

We'll now open the floor for questions. Operator?

[Operator Instructions] Our first question is going to come from Jeff Jones with Oppenheimer.

Congrats on the strength of RUCONEST and the quarter. Could you perhaps provide some color around the commercial launch efforts for Joenja in the E.U. and how you're anticipating these to build? Maybe speak a little bit more to the magnitude of the opportunity as you expand country to country. Then for a second question, can you speak to assuming a positive outcome from the 2 PIDs trials, what that looks like and next steps moving ahead into that pivotal study? Thank you.

Thank you, Jeff. I'll ask Leverne to answer the first part of your question and Anurag for the second part.

Thank you, Jeff, good morning, good afternoon. In terms of commercial launch preparation outside of the U.S. for Joenja, we have made substantial progress in patient identification across our core 8 markets. We've identified core 8 markets that will be key for us to launch in the next couple of years. To date, we've identified about 387 potentially eligible APDS patients across these markets.

We have launched in the United Kingdom, where we have gained some scale in our capability, both from a commercial execution perspective. Our market access capabilities has grown, which we've scaled into the German launch and are preparing for the launch in Japan. The U.K. launch is proceeding at pace, and we're making good progress. German launch is underway since the 1st of July, and we have made substantial progress in acquiring funded patients on therapy in Germany.

From a Japan perspective, we are in the final stages of securing our pricing and reimbursement following approval in the second quarter. And we look forward to launching Joenja in Japan during the August timeframe.

Jeff, on your question about the two phase II studies. Again, we're expecting those results in the fourth quarter. The studies, as I've reviewed today, they have very similar patient populations in terms of one being a group of patients that are genetically defined and the other are more clinically defined. However, they have similar clinical manifestations, and we see significant overlap in the enrolled population, especially from the first study into the broader CVID study, which again, is a patient population that's about 40 times the size of APDS.

So, when thinking ahead now to what we can expect, once we have the results, we'll review those results. We're collecting a broad spectrum of endpoints to evaluate. We're also evaluating the dose regimen, and then we'll come up with a plan to review with FDA, starting with FDA, but also with regulators across Europe as well as Japan to see what a registrational study could look like. We do anticipate right now, again, pending the results of those two studies, that we would do a combined CVID study, and this would likely be a randomized control study similar to what we performed in APDS. So, I think we have a good blueprint based on the work that we've done in APDS, and again, now anxiously awaiting those final results.

The next question will come from Alyna Shamsi with Jefferies.

Hi. Thanks for taking my questions. Firstly, on RUCONEST, enrollments appear to have recovered to around pre-competitor launch levels. I was wondering if you could give a sense of what you've seen so far the first month of this quarter and whether the trend has continued. And then secondly, I just wanted to ask on Joenja. There appears to be roughly, I think, 30 identified pediatric patients in the U.S. who could be eligible under the expanded dosing schedule, if approved. How do you think we should think about the pace of converting those patients onto reimbursed therapy following that approval? Thank you.

On RUCONEST enrollments, Alyna, thank you for the question. You're 100% right. So, we've seen certainly Q2 with 84 enrollments getting fairly close to what we had in Q2 2025, which neared about 90 new enrollments. We are seeing consistency in the momentum into the third quarter. Now, in the HAE market overall, there is some seasonality. If you look back at new enrollments in the previous year or the year before that, you do see some changes in the rate of new enrollments as we go into the third quarter.

As I said, it's quite consistent with what we're experiencing deep into July so far. Importantly, we continue to add new prescribers. And what we're seeing in these new enrollments is this entrenchment of the RUCONEST position in high-burden HAE patients. These are typically either HAE normal patients, where the burden of disease is quite high, or patients with more frequent and more severe attacks, and that's where we anticipate having a really durable position, even 4 quarters after competitor launch, to continue into the third quarter.

Joenja?

From a conversion perspective, as I mentioned before, we have a substantial number of patients identified in these core markets, including certainly the U.K., Germany we're launching now, and Japan launch coming. We are assuming a fairly similar conversion rate that we've seen in the U.S. as we secure reimbursement and the commercial teams execute against our plan in the various centers, both in Germany and upcoming in Japan. Part of that will be conversion of patients that are on our EAP programs in some markets, but also pretty clear -- pretty clear identification for us in where those patients are sitting in these respective markets and what we need to do to convert them as soon as we have reimbursement.

Specifically for U.S. pediatric?

For U.S. pediatrics, similarly, what we have today is 60 identified patients between 4 and 11 years old. As Anurag mentioned earlier, the submission is divided into the higher dose and the lower dose, and what we see in the split of those identified patients, it is about 50/50. So, 50 patients in the higher dose category, 50% rather, and 50% in the lower dose category. Again, we are assuming a similar uptake what we have seen with the adult population 12 and above, converting first those EAP patients in the first few months and then continuing to convert the remaining patients that we have identified in the centers that we have.

Thank you, Alyna.

Our next question is going to come from Whitney Ijem with Canaccord.

Hi, all. My congrats on the quarter. Just to go back to the 84 new RUCONEST patients, can you talk a little bit more about those patients in terms of what they look like, severity, attack rate, is that consistent with how the RUCONEST patient has looked historically? Are they all new to therapy or some returning back from maybe trying something else?

Thank you, Whitney. Leverne?

Thanks, Whitney. So, the 84 new enrollments, as I said before, these are -- the patient population for us in terms of new enrollments have evolved over time. Right, but now we're seeing a very clear trend emerging for these high-burden patients that have high-frequency attacks, more severe attacks, patients who are more worried about high-risk attack locations like laryngeal attacks, GI attacks, and these are just the new enrollments. So, the new enrollment number does not include restarts, as you've identified, i.e., patients who are returning back to therapy. So, pure new enrollments, unique new for the first time on RUCONEST.

Got it. That's really helpful. Then moving over to CVID and PIDs. In terms of the larger patient number, clearly, very large TAM assuming success there. I guess, can you talk about any efforts in terms of patient identification or just as we think about the diagnosis rate in those, given they are larger, but not genetic, I guess how well-characterized are those patients and under the care of physicians currently, in terms of being able to access them commercially?

Sure. Hi, Whitney. This group of patients, these CVID patients, is largely already identified, and that's very different from what we experienced with APDS. With APDS, it was a newly defined disease just in the last 15 years. It required genetic testing, and it required a considerable effort in terms of educating doctors also on the importance of genetic testing. CVID, however, is clinically diagnosed, and these group of patients that we're talking about are, again, already diagnosed. They're almost always on immunoglobulin replacement therapy because that's part of one of the key manifestations is that they have low IgG levels. And therefore, really, it's a different, let's say, mechanics in terms of diagnosis versus what we've seen with APDS.

The next question is going to come from Joe Pantginis with H.C. Wainwright.

Thanks for all the updates today. Two questions. First on RUCONEST and then on Joenja. So, with regard to the current commercial profile coming into the second half, it was mentioned in the prepared comments, with the three factors. One of them was inventory normalization. I just wanted to know any anticipation for further optimization here or anything we can expect with regard to inventory and distribution going forward that might be relatively obvious to you.

Good morning, Joe. This is Kenneth here. We expect that we are in a year with a normal seasonality where we saw some inventory reduction in the first part of the year, and there will be a normal cycle with a bit of inventory build also in the year to go, but all within normal frame. Remember that when we commented on Q1, we said that 2025 was the unusual part. So, we had a normal year when it comes to the inventory.

Got it. Then for Joenja, I'm going to phrase my question very carefully. With the upcoming PIDs CVID data, which is obviously a major event for you guys, obviously you cannot market these data. However, you can leave or present these data to physicians as just sort of like a supplemental information concept. Do you have any views towards these data providing any sort of incremental boost to revenue prior to potential approval? Obviously, from an off-label standpoint.

Joe. Obviously, as Anurag said, we have those two phase II open label study that we read out in Q4, and we would be engaging with the FDA and our base assumption that we're going to have to conduct a phase III trial. Until the phase III trial read out and we receive proper approval from FDA, we won't be able to promote the data, and we don't expect any sales from CVID.

This being said, there are a lot of opportunities in APDS, as we disclosed, the many opportunities in APDS in the U.S. in adult as well with the expected upcoming pediatric and the geographic expansion should allow us to fuel the growth of Joenja very significantly in the coming years as we wait for these new indications to materialize.

The next question is going to come from Sushila Hernandez with Van Lanschot Kempen.

Yes. Thank you for taking my questions. On RUCONEST and the on-demand HAE market, how do you expect that these dynamics on new patient initiations will play out or do you expect that patients will still find RUCONEST after they have tried other drugs?

Certainly. Thanks, Sushila. From a new enrollment perspective, we think about inflows in two different ways, right? So, new enrollments or brand new patient starts and restarts. When we look at new enrollments, the vast majority of those come from, in fact, patients who've had suboptimal responses to other therapies and now switching to RUCONEST. We expect that to continue because what we're seeing in patients who have high severity of attacks, patients who have more frequent attacks, two or more attacks per month, they do require a more reliable, faster onset HAE treatment and that is where RUCONEST is uniquely positioned compared with competitive set to continue to have a position.

Okay, that's clear. On Joenja, you mentioned the 8 core markets outside of the U.S. Could you also break down or give us more color on which of the markets will be key drivers for growth ex-U.S.? And also on the VUS reclassifications, what are the next steps and when could this meaningfully add to Joenja opportunity?

On the core 8 markets in the very short term, we are especially excited about the progress we're making in Germany. We're one month into that launch, so that is going to be key for us as our next ex-U.S. market, our first European launch. And subsequent to that, the Japan launch that we are planning for August will be another key growth driver for us in the short term. Additionally, from a U.K. perspective, we continue to make progress in adoption in APDS within the U.K. One additional piece that I'll add is especially excited about the Japan market because we do have an approval for ages 4 and above, which is our first pediatric launch that we will have before we anticipate U.S. approval later this year.

Sushila, on the VUS reclassification efforts, we actually have a number of efforts that are ongoing. We have the efforts that are trying to help clinicians reclassify VUSs on a one-by-one basis. And again, that's ongoing now and that involves collecting additional data, looking at literature, family testing that can also be helpful in resolving these VUSs. That's happening on an ongoing basis, and we're seeing patients getting reclassified as a result of that. On top of that, we have the much larger project that we talked about in the past that we had partnered with Columbia on, that work has also been initiated. Once I have a little more clarity on when that's getting wrapped up, we'll be able to give you more guidance on what the timing of that, but that work is well underway.

Okay, thank you for this additional color. Just the final question. For the genetic PID phase II study, could you remind me again, how did you select these specific genetic PIDs as there are so many and which ones are more directly or indirectly involved in a PI3K delta-driven immune dysregulation?

The genetic PID study, the genes that were selected for it were all selected on the fact that there was a connection to this pathway and that these abnormalities in these genes could lead to driving of that pathway, and there was published data on that. So, that's how that group or that basket of genes was selected.

[Operator Instructions] Our next question comes from Simon Scholes with First Berlin.

Yes, hello. Good morning and good afternoon. I've got three or four questions, if I may. The first one is on the new enrollments. You've pointed out that with 84 new enrollments with RUCONEST in Q2, I mean, you're quite close to the level you were seeing in the first half of last year, which is over 90. Of course, in the first half of last year, you were seeing U.S. growth in RUCONEST of 30%, and now it's retreating somewhat. So, I think it would be helpful if you could give us the net figure, i.e., the new enrollments, less switches and drop-offs. Then also, I was wondering if I'm correct in thinking that the next EU launch for Joenja after Germany will not be until 2027.

And then I was also wondering if you could give us an idea of when you might see pediatric approval in the European Union. Just lastly, I was wondering if you could give us some more color on the manufacturing impairment of inventory, what exactly was happening there, and which product does that relate to. That's it from me.

Thank you, Simon. I'll start with the new enrollment and the outlook, the growth outlook for RUCONEST, as I understand your question well. As we've said, based on the robust underlying key performance indicator related to the resilience of RUCONEST, 93% of the active patient base maintained year-over-year, as well as the solid new enrollment that you pointed out. We expect to stabilize RUCONEST and have it return to growth. Yet, as I've explained, we see RUCONEST as a durable cash engine for Pharming with Joenja being the growth drivers for the years to come.

So, that's how we are approaching our portfolio. That's how the company is evolving from becoming a one asset company to becoming a more diversified rare disease company with a longer-term growth profile, given the number of growth catalysts for Joenja, as well as very significant pipeline catalysts for Joenja as well as napazimone. When it comes to geographic expansion, I will let Leverne provide her perspective.

In the short term, of course, we are in our peri-launch phase in the U.K., German launch is underway, and then we're looking forward to the Japan launch in the August timeframe in ages 4 and above. For 2027, as we look into that timeframe, of course, we have announced both approvals in Canada and South Korea, and we are anticipating that we continue launch progress toward Australia and Italy in 2027. So, when we look in totality at the potential for continued growth and expansion in 2027, we plan to make good progress across those markets for Joenja pediatric and as well as Joenja adult. The second Joenja question, if you could repeat that.

Was about pediatric indication in Europe. I'll let Anurag.

Yes, that's right.

Hi, Simon. Obviously, as Leverne mentioned earlier, we've identified a large number of APDS patients outside of the U.S. in these core markets, and a significant number of those, similar to what we've seen in the U.S., are pediatric patients. So, the unmet need is very similar across Europe. We're planning to bring the same data set that we have from these pediatric studies to Europe as well. And we're going to do that by beginning in the U.K., as we did with the adolescent and adult population, then we'll continue to do that across Europe.

When it comes to the manufacturing impairments, Kenneth?

Yeah. This is a matter where we have impaired for manufacturing inventory throughout the manufacturing process related to RUCONEST. This is a matter that is not concluded upon, but the indicators are that we have inventory that may not be possible to use for commercial use. We will conclude on the matter before the end of Q3, but according to our normal process, we impair for such kind of issues when we are made aware of them.

[Operator Instructions] Thank you. I am showing no further questions in the queue at this time. I will now turn the call back over to Fabrice for closing remarks.

Thank you, operator. Thank you so much for all the relevant questions. We hope that we provided additional color on our Q2 earnings. Not only about the revised revenue guidance, but also about the business fundamentals and the fact that we continue to manage a much tighter operating model that has allowed us to make sure that we allocate capital more efficiently and fully capture the number of growth opportunities and pipeline catalysts that are ahead of us. So, we look forward to updating you on our plans as those catalysts will unlock in the coming weeks and months. Thank you very much.

This concludes today's conference call. Thank you for participating, and you may now disconnect.

Good day, and thank you for standing by. Welcome to the Pharming Group N.V. First Quarter 2026 Results Webcast and Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand the conference over to your first speaker today, Fabrice Chouraqui, CEO. Please go ahead.

Thank you, operator, and good morning and good afternoon, everyone, and welcome to our Q1 2026 earnings call. I'll be joined on this call today by Leverne Marsh, our Chief Commercial Officer; Anurag Relan, our Chief Medical Officer; and Kenneth Lynard, our Chief Financial Officer. Next slide.

In this call, we will be making forward-looking statements that are based upon our current insight and plans. As you know, this may differ from future results. Next slide.

As you saw in our press release, we made important progress across the business in this first quarter despite a drop in quarterly revenue driven by RUCONEST. The RUCONEST revenue decline was largely expected due to inventory drawdown at specialty pharmacy, which we discussed on our Q4 2025 call in March. The commercial exit from non-U.S. markets also contributed to the year-on-year decline. We announced that decision last year as part of our renewed financial discipline since the commercialization of RUCONEST in this market was not financially sustainable.

Now if we look at the underlying fundamentals, we see limited interest from patients on RUCONEST to try alternative therapies. Nine months after the launch of a new oral therapy, we have retained the overwhelming majority of RUCONEST patients, and we continue to see new patients starting RUCONEST. Leverne will elaborate on this market dynamics in a few moments.

Turning now to Joenja. This product is an important growth driver still early in its life cycle. Joenja revenues grew by 34%, reflecting strong momentum, both in the U.S. where the number of patients increased by 25% year-on-year, but also in international markets.

We've also made meaningful regulatory progress this quarter, positioning us well to launch Joenja in Japan and in Europe later this year and to extend Joenja's label to the pediatric population in the U.S. After the disappointing CRL, we had a constructive dialogue with the FDA, and we've already resubmitted the sNDA for the 2 highest dose, covering a meaningful proportion of children from 4 to 11. We are also planning to submit an sNDA this summer for the lowest doses.

Finally, our disciplined cost management helped us to maintain positive cash flow from operations in this quarter despite the variability in revenues. We are maintaining our revenue guidance of $405 million to $425 million for 2026, representing growth between 8% and 13% year-on-year. Next slide.

As you can see, the durability of the RUCONEST franchise and the strong momentum and growth potential of Joenja underpin the transformation of Pharming into a profitable high-growth biotech with 2 late-stage pipeline programs offering $1 billion sales potential. RUCONEST is the foundation of our portfolio and a reliable cash engine for the future, even in an ever more crowded HAE market, given its differentiated value proposition for the difficult-to-treat patient subpopulation and it's highly manufacturing -- its highly specific manufacturing process.

Joenja is just at the beginning of its life cycle with multiple growth catalysts in APDS through pediatric and geographic expansion and the potential expansion into higher prevalent PIDs with 2 Phase II readouts later this year. Anurag will discuss an exciting presentation at the CIS conference taking place today that summarizes clinician experience treating patients with CVID with immune dysregulation enrolled in our access program.

And last but not the least, napazimone, previously known as KL1333 for primary mitochondrial disease is another $1 billion-plus opportunity with the registrational study expected to complete enrollment this year and read out next year. These commercial assets and high-value pipeline, combined with durable source of cash flow, provide a solid foundation for Pharming to become a leading global rare and ultra-rare disease company with substantial near- and long-term value creation potential.

Let me now turn it over to Leverne, who will provide deeper insights into the performance of our commercial products.

Good morning, good afternoon, everybody. Let me start with RUCONEST performance in the first quarter. Revenue was down 15% year-on-year. Importantly, as Fabrice mentioned, this was anticipated and largely driven by 3 distinct factors.

First, inventory dynamics, which reduced quarterly revenue by 8%. This reflects what we previously stated on our March Q4 call and accounts for the majority of the impact.

Second, our planned exit from ex-U.S. markets contributed approximately 3%, and this is consistent with our strategy to focus our resources where we can generate the highest return.

Third, with new treatment options entering the U.S. HAE market, we see measured impact from competition, specifically limited patient interest in trialing or switching to other therapies with many returning, and this has been in line with our expectations.

Additionally, what's important is what's happening underneath these headline numbers. We added approximately 50 new patient enrollments in the first quarter this year, and we brought on 23 new prescribers on to RUCONEST. This is a meaningful signal that clinicians continue to see the value of RUCONEST and specifically in the high attack, high severity segment and are initiating new patients even as the treatment landscape expands. Next slide, please.

On this slide, this really gets to the heart of why RUCONEST continues to play a critical role in HAE management. We know HAE is not a uniform disease. For patients on the more severe end of the spectrum, meaning those with frequent attacks, rapid onset symptoms or high anxiety around unpredictability or the attack location, the need is very clear. They require a treatment that works quickly, consistently and durably, and that's exactly where RUCONEST fits, and it's reflected in what we're seeing in the market today.

After 9 months into the launch of a new oral competitor in HAE in the U.S., the overwhelming majority of RUCONEST patients have remained on therapy. Among those who have explored alternatives, many high-burden patients are returning to RUCONEST, in particular, when response to new treatments have not been adequate. This reinforces the importance of having a dependable on-demand therapy like RUCONEST and underpins our confidence in the long-term role of RUCONEST in this evolving HAE market. Next slide, please.

So turning to Joenja. We delivered another strong quarter, building on the momentum from last year. Revenue grew 34% compared to the first quarter of 2025, reaching $14.1 million globally. In the United States, patient growth is the central driver of performance. By the end of the quarter, we had 127 patients on paid therapy in the U.S. alone, which represents a 25% increase over the first quarter of 2025, and we accelerated the rate of new patient starts to 7 during the quarter, an improvement over the additions seen in the previous 2 quarters.

The U.S. fill rate remained high at 85%, reflecting our highly effective reimbursement support and patient services process. Equally important, we continue to broaden the pool of APDS patients. We've identified 187 APDS patients older than 12 years old in the U.S. and an additional 57 eligible patients in the 4 to 11 years old group, and this represents the next frontier for growth in the U.S.

In international markets, we continue to see strong patient uptake in the U.K. and significant growth in the number of patients on government-supported access programs in other countries. This momentum sets us well to drive growth in APDS and other indications to come. Next slide, please.

Now stepping beyond the quarter, I want to put Joenja into its broader strategic context. We are building more than a single rare disease product. We are building indeed a scalable immunology franchise with multiple clearly-defined growth levers.

The first growth lever is continued expansion within APDS itself. We are still early in identifying APDS patients, and there is a significant proportion of patients yet to be identified.

The second growth lever is further U.S. APDS expansion, which includes the pediatric launch in the United States and an upside the U.S. reclassification opportunity across all ages.

Thirdly is international expansion. We are in the early stages outside the United States and upcoming launches in Europe and Japan will open meaningful new markets for us.

And finally, the fourth growth lever is life cycle and label expansion beyond APDS, specifically exponentially larger patient pools in genetic PIDs and CVID with immune dysregulation.

Taken together, these 4 levers create sequential growth engines over the coming years. APDS drives the initial growing foundation, pediatric expansion deepens penetration, geographic expansion broadens reach and new patients continue to give us access to significantly larger patient segments, which extends our platform.

Now to share more about our pediatric submission and life cycle efforts on Joenja, I will now hand it over to Dr. Anurag Relan, our Chief Medical Officer.

Thank you, Leverne. In addition to the important regulatory milestones in Japan and Europe, we made significant progress in the U.S. in our efforts to expand the Joenja labeled pediatrics for children ages 4 to 11 with APDS following the receipt of a CRL from FDA in January. As we previously explained, we believe the clinical pharmacology and analytical batch testing methodology issues outlined in the FDA letter were addressable.

We held a Type A meeting with FDA at the end of March, which included 2 APDS expert physicians, and we were pleased with the constructive dialogue and understanding of the issues raised by FDA in the CRL. The FDA also appreciated the unmet need, including the serious and progressive nature of APDS as well as challenges with clinical trial recruitment in young children with an ultra-rare disease.

We worked collaboratively with FDA to define the most expedient path forward, and we have that now with the first step being the resubmission of the sNDA for the highest doses, specifically 40 milligrams and 50 milligrams. This took place in April, in fact, on the same day that we received the FDA's meeting minutes. And as is typical, we plan to issue a press release upon FDA acceptance of the resubmission. These doses, as Fabrice mentioned, cover a meaningful proportion of 4- to 11-year-old children. An FDA decision on this is expected in 6 months or sooner.

The second step will be a new sNDA for the doses covering the lowest weight patients, which is planned for this summer. For this sNDA, we also expect a 6-month review. Next slide.

At the Clinical Immunology Society Annual Meeting this week, Pharming and our collaborators are presenting 7 abstracts, 5 expanding the evidence base in APDS and 2 that begin to provide data on a much larger opportunity in other PIDs with immune dysregulation. These include the clinical expanded access experience with leniolisib to treat immune dysregulation in patients with common variable immune deficiency or CVID and CVID-like disorders, which I will cover in more detail in a few slides. As you see, APDS is just the beginning for leniolisib. Next slide.

In addition to APDS, we continue to make progress in other PIDs with immune dysregulation, which is based on the observation of the key role of PI3K delta as an important regulator of immune cells and the imbalance in the pathway, which underlines the immune dysfunction across several primary immune deficiencies. This mechanistic understanding forms the scientific rationale for our Joenja development program.

Joenja, as you know, is currently approved for APDS where gain-of-function mutations drive a hyperactive pathway leading to immune deficiency alongside broad immune dysregulation. APDS, in fact, serves as proof of concept for the ongoing 2 Phase II studies evaluating leniolisib in other PIDs. These have significantly greater prevalence in APDS but share unmet medical needs, underlying mechanisms and disease pathology.

The programs target 2 similar populations. The first is genetically identified PIDs with immune dysregulation, which represent a prevalence that's 5x greater than APDS or more than 2,500 patients in the U.S. alone. And the second is common variable immune deficiency with immune dysregulation, which is identified independently of genetics. And this is even a larger group of patients, which is approximately 26x size of APDS or more than 13,000 patients in the U.S. alone. I'll now talk to you about the studies in the next slide.

Both proof-of-concept studies share a common design architecture, single-arm open-label dose range finding, allowing cross-study comparability. The CVID study is a multicenter study enrolling 20 patients and the genetic PID study is a single center study conducted at the NIH with 12 patients. Both studies are now fully enrolled with trial readouts expected later this year. Both also employ a 3-dose escalation design to characterize dose response and confirm the optimal dosing strategy.

The studies address 2 core objectives. First, of course, to address -- assess safety, tolerability and pharmacokinetics and pharmacodynamics to confirm dosing. Second and most clinically meaningful, to estimate the efficacy against immune dysregulation, specifically looking at the lymphoproliferation and autoimmune aspects. These efficacy endpoints are aligned with the key disease manifestations, which are focused on these aspects. In addition, we'll also be collecting patient-reported outcome measures, which were developed through a custom process involving expert input and formal interview studies with CVID patients. Next slide, please.

Ahead of these study readouts, we can see some important early clinical evidence supporting leniolisib potential in CVID with immune dysregulation being presented today at the CIS meeting. Six CVID or CVID-like patients with immune dysregulation amongst the sickest patients refractory to other therapies received leniolisib through an expanded access program for a median of 1.4 years with individual exposure ranging from 0.5 year to 2.5 years, providing meaningful duration of observation for a small cohort.

The clinical signal is encouraging and consistent across disease manifestations. Clinicians reported improvement with no patients showing progression spanning cytopenias, splenomegaly, lymphadenopathy, liver disease and lung disease. Immune profile showed reduced transitional and CD21 low B cells, confirming the meaningful PI3K delta pathway modulation consistent with the APDS experience. This biomarker data is also being collected in the Phase II studies.

Regarding safety, adverse events were generally manageable and consistent with the disease severity. While this is clinician reported data and not a prospective clinical study, the breadth and consistency of improvement across these various endpoints is a compelling early signal ahead of the formal study readouts in the second half of this year. So quite a bit to look forward later this year. And with that, I'll turn it over to Kenneth to walk through our financials.

Thank you, Anurag. I will now briefly cover our Q1 2026 results and our full year outlook. Q1 revenues were $72.4 million, down 8% year-on-year. RUCONEST revenue declined 15%, reflecting the expected U.S. inventory normalization contributing 8% decline, consistent with our expectation for 7% to 9% headwind that we communicated on the March Q4 call, as well as also our planned strategic exit from U.S. markets, which contributed 3% to the decline. Q1 is also typically the lowest seasonal quarter for RUCONEST due to ordering patterns and inventory dynamics.

Joenja revenues were strong and increased 34% year-on-year, driven by strong U.S. momentum, continued patient growth and expanding international demand. Revenue was modestly affected by inventory timing. And excluding this, growth would have been USD 1 million to USD 2 million higher.

Total operating expenses were down by 9% year-on-year. Adjusted for nonrecurring Abliva-related acquisition costs in Q1 of 2025, overall expenses were flat. This demonstrates our ability to increase pipeline investments without increasing costs overall. Adjusted operating profit declined slightly year-over-year, noting that USD 7.8 million of the nonrecurring Abliva acquisition-related costs are excluded from the adjusted Q1 '25 figure shown on the slide. And in 2026, we have incremental R&D investments for napazimone of $2.7 million included.

We generated positive operating cash flow in Q1 of $2 million, reflecting continued strong cost management and financial discipline. Total cash and marketable securities decreased by $9.3 million to $171.8 million, primarily due to a $12.3 million payment related to early termination of the DSP facility lease. For the full year 2026, we are pleased to reaffirm our expectation for total revenues of USD 405 million to USD 425 million, representing full year growth of approximately 8% to 13% versus 2025. This growth is expected to be driven by continued expansion of RUCONEST in the U.S. partially offset by the excess -- by the exit from ex U.S. markets and significant and accelerating growth for Joenja.

We delivered a strong exit to Q1 and the low percentage of HAE patients switching to competing oral therapies gives us confidence in our guidance range. Overall, we assume low single-digit annual RUCONEST growth at the midpoint of our guidance range with some pressure expected on RUCONEST revenue in Q2 and growth in the second half of the year.

For Joenja, we are well positioned for launches in Japan and Europe this year. We also now include expected U.S. pediatric label revenues later this year, previously excluded from our guidance in our outlook. We expect Joenja growth to accelerate with annual growth over 10 percentage points higher than in 2025. The pediatric APDS indication remains an important long-term driver. And for planning purposes, we conservatively assume a 6-month FDA review period following resubmission with a launch right thereafter.

We continue to expect operating expenses between USD 330 million to USD 335 million, including $60 million in incremental R&D investment to advance our pipeline. This includes up to $30 million additional for the development of napazimone. This also reflects the $9 million benefit from the 20% G&A structural headcount reduction announced in October 2025, alongside stable marketing and sales spending.

We remain very committed to strong cost management and financial discipline, prioritizing investments that support both near- and long-term value creation. There are no changes made to any other guidance assumptions, including milestone payments or gross margins. As a reminder, for Joenja, we do not assume the $10 million commercial milestone or additional milestone payments this year. Gross margin is expected to be approximately 90%. Finally, as previously stated, our available cash and future operating cash flows are expected to fully support all pipeline investments, including all prelaunch activities.

And with that, I'll now hand over to Fabrice for his closing remarks.

Thank you, Kenneth. So in summary, this first quarter demonstrated important progress across the business while reflecting variability in RUCONEST revenues. We are encouraged by the opportunity we see for Joenja in the short and long term and the potential for RUCONEST to remain a significant cash engine as an important on-demand treatment for the difficult-to-treat patient subpopulation. We have significant pipeline catalysts later this year. First, the readout of the 2 Phase II trials for leniolisib in higher prevalent PID. And second, the completion of the enrollment of the napazimone registrational study in primary mitochondrial disease.

As you've seen, the decisive steps that we've taken to improve financial discipline, including optimizing G&A headcounts are starting to deliver tangible results. With our strong commercial and development capabilities, a growth-oriented leadership team and a scalable organization, we are committed to driving sustainable revenue growth and value creation to achieve our vision of being a leading global rare disease company.

Let me now open the line for questions.

[Operator Instructions] And your first question today comes from the line of Benjamin Jackson from Jefferies.

I've got 2, if I may. The first just on RUCONEST. Could you talk a little bit more about why you think you'll see further pressure in the second quarter on that sales line? And then why you think that you -- or what gives you the confidence of returning to growth into the second half of the year beyond what you've already described? And then within that, also, are you expecting any reversal of this inventory drawdown at all that may help as a bit of a tailwind in context of that?

And then secondly, on Joenja, perhaps if you could just help paint the picture about how meaningful you think Europe will be this year and how quickly we should anticipate this ramping? Perhaps, you could touch on which countries will likely come online in Europe when and how quickly you think you can secure reimbursement there. So anything to build out that picture a little bit more for me would be super useful.

Thank you, Ben. Leverne?

Indeed. So Ben, thank you so much for the question. I think to your first one on further pressure in Q2 that we may be anticipating. So we're in the early stages of competitive entry, right, 9 months into the sebetralstat launch followed quickly by prophylactic treatments. What we're seeing is it takes a few reorder cycles. So 3 to 4 reorder cycles for us to see the full impact of trialing behavior and switching behavior. And so as we get into essentially the fourth quarter of a launch post sebetralstat, we'll start to see further impact normalize in the second quarter.

The second piece that you asked around growth in the second half of the year. Today, we continue to add both new prescribers and new patient enrollments to RUCONEST. What that tells us is there is a clearly defined subpopulation of HAE patients who are high-burden patients, so high frequency of attack patients, high attack location patients where RUCONEST continues to have a place. So despite competitive entries, we continue to see new patient generation and new prescriber dynamics in that segment.

I'll let Kenneth speak to the inventory drawdown, and I'll talk about Joenja, the question that you had on European launches. So as you know, we had a positive CHMP opinion earlier this year. We're waiting for final approval. And our first launch in Europe will be in Germany this year. So we're really excited about that launch coming in at the end of -- towards the second quarter of this year. And that will be meaningful for us because we are anticipating commercial patients, so paid funded commercial patients into the second quarter.

And then additionally, our Japan approval that we received also earlier this year, we're anticipating that launch in August of this year. So some key growth drivers for us in the second year for Joenja in addition to the pediatric approval that we are anticipating for the high doses in the U.S.

Kenneth, do you want to respond to the inventory question?

Yes, absolutely. And thanks for the question, Ben. So in 2026, we have seen the inventory drawdown, which follows the normal cycle of the year. And compared to last year, where in 2025, the inventory drawdown was lower as the previous year's build was lower as well. So we do anticipate that we are in a year that, again, is more reflective of the normal cycle where there will be inventory build during the second half of the year to basically reflect the demand. So that's how we are looking into the rest of the year.

Your next question today comes from the line of Jeff Jones from Oppenheimer.

Maybe one follow-up on RUCONEST and then on leniolisib. Can you help us maybe link the 4% drop in revenue not associated with the inventory drawdowns in the planned U.S. or the ex U.S. exit with the offset of the 50 new patients on therapy that you mentioned during 1Q? And then for leniolisib, you talked a little bit about the readouts from the Phase I/IIs that you're running currently for PIDs and CVID. Can you help us link those efficacy-related readouts to expectations around endpoints in Phase III and how we can think about expectations and the endpoints moving ahead into more pivotal aligned studies?

Thank you, Jeff. I'll take the first part of your questions on the enrollment, and then I'll let Anurag cover the leniolisib part. When it comes to the enrollment that Leverne mentioned, these are 50 new patients which have been enrolled, who will receive a script. These are not yet 50 new patients on the drug. And so there is always actually a delay between enrollment and patient on therapy. And obviously, we'll be working actively on that.

I think you should look at enrollment as patients in the pipes that ultimately will, for a large proportion, be treated by RUCONEST. And so again, seeing a significant number of new enrollment, new scripts for RUCONEST and a significant number of new prescribers I think, reinforce the recognition of RUCONEST as a distinctive treatment in the HAE on-demand category. I hope I was able to bring color.

These new patients are expected to offset the small number of patients that may adopt Ekterly. As Leverne said today, we've seen only a very limited interest from RUCONEST patients to try Ekterly, and we've seen a very small number of these patients adopting the drug. And this is obviously linked to the nature of these patients, which are -- for vast majority of them have a high burden disease and often have already failed a number of treatments.

Anurag, would you like to elaborate on the leniolisib data that are being presented today?

Sure. So Jeff, I think you have to zoom out here a bit and look at what the unmet need really here is in this group of patients. And the unmet need is all centered around immune dysregulation. And the immune dysregulation we're talking about is these aspects such as lymphoproliferation and autoimmune disease that isn't being managed adequately by immunoglobulin replacement therapy that these patients currently receive. So that's the -- those are the disease manifestations that we're looking at.

Those are, in fact, what we see in the expanded access program, these 6 patients that are being presented today at the CIS meeting, you can see the disease -- the same disease manifestations, whether it's improvements in their cytopenias, improvements in lymphoproliferation or improvements in some of the other aspects of the autoimmune disease. Those are the things that we're also going to be measuring in the -- in both of the Phase II studies.

So we're looking at lymph node size, spleen size. We're looking at the blood counts. We're looking at some of these other markers of end-organ disease activity. And those will then form the basis for the Phase III study. But it's exactly -- the endpoints are, I think, very well aligned with the disease manifestation. And again, what we see early from these 6 patients is improvement or stabilization in all of these aspects.

Your next question comes from the line of Sushila Hernandez from Lanschot Kempen.

On your revenue guidance, what could be key drivers that could make the difference between hitting the top end and the bottom end of your range? What are your assumptions here? And could you share more color on the compassionate use experience in CVID? How much do these patients resemble the patients in your Phase II study?

Yes. Thank you. This is Kenneth here. Thanks, Sushila. So I think the way to think about it is that we are anticipating 6 months for approval and launch right thereafter for the U.S. pediatric population following the submission. And obviously, an accelerated timing of the approval and launch will provide an upside compared to what we are kind of looking into now and therefore, would put us higher up in the guidance range. That will be the primary driver.

Okay. That's clear. And could you share more color on the data that was presented at CIS on the compassionate use experience in CVID? How much do these 6 patients resemble the patients in your Phase II study?

Sushila, so it's actually a great question. It's something I didn't cover, but these CVID patients and CVID-like patients in the compassionate use experience very much resemble the types of patients that are being enrolled in the CVID study, so the 20-patient multicenter study. And the reason for that is that these patients, all of them have those aspects of immune dysregulation.

Now I would say the only difference here is that this is a much sicker group than the general CVID immune dysregulation population, which is already quite ill to begin with, but this is a group that is even more -- has been even more refractory to other types of therapies. So the fact that we can see improvements here is, I think, quite meaningful and quite encouraging for us as we look ahead to the results later this year.

Your next question comes from the line of Joe Pantginis from H.C. Wainwright.

This is Josh on for Joe. So for the first one, could you guys provide more color around the proportion of the identified 4- to 11-year-old APDS patients in the U.S. So specifically, how many could be covered by the initial 40-milligram and 50-milligram resubmission? And then for the Type A meeting, did the FDA feedback change how you're thinking about pediatric dosing more broadly? Or has your overall strategy remained largely unchanged?

On the first part of the question, Leverne?

Sure. Thanks, Josh. On the first one, on the 4 to 11 age group, you can assume approximately half. So roughly 50% of that population would be eligible for the high dose leniolisib and half would be on the lower end.

Anurag?

And so Josh, on the Type A meeting and the feedback that we got and actually all of the discussions that we've had, I think it really has not changed our dosing strategy. And in fact, what -- I think based on this constructive dialogue that we had with FDA, they were -- we shared with them the efficacy that we had observed across the doses and that has allowed us to maintain the same doses in our resubmission strategy. So the lower weight patients would be maintained on -- or proposing to maintain them on the same doses that were used in the clinical trial.

And that really is tied to the efficacy that was observed in the lower weight patients, which was very similar to the efficacy that was observed in the higher weight patients. So I think that -- on that basis, we have not changed the dosing strategy. And I think we've come to an agreement with FDA on what the contents of these 2 resubmissions would be.

Your next question comes from the line of Whitney Ijem from Canaccord.

Just a follow-up to clarify for the Phase II leniolisib readouts in the second half. I just wanted to confirm, will those be read out at the same time? So it's one readout for both? Or is it 2 -- could they come at different times?

Anurag?

So the study has completed enrollment around the same time. One of the studies is 1 month shorter in duration. So it is possible that, that one, we have all of the data available slightly earlier than the other study. And once we have the data cleaned and available to evaluate, we'll have more specifics on the exact timing of that readout.

Okay. Got it. And then heading into those, can you help set investor expectations, I guess, in terms of what would be good data or what you're looking for in both of those studies, either quantitatively or more qualitatively?

Sure, Whitney. So a lot of the things that we're looking for, they are -- first of all, they're aligned with what we observed already in APDS. So we saw lymph nodes shrink. We saw spleens get smaller. We saw improvements in immune profiles. We saw improvements in blood counts, so the cytopenias, autoimmune cytopenias that occur in these patients. So we've seen that already in APDS. And that's why, again, I really think it is a very nice proof of concept for what we've already done.

And then what we know is these are -- this is also the unmet need in these other primary immune deficiencies. So we're really looking for the same things. So we're looking to see if lymph nodes get smaller. We're looking to see if the spleens get smaller. We're looking to see platelet counts or other blood cell counts increase. We're looking for other manifest -- other end-organ disease manifestations to see how they also improve. And I think this is also, again, lines up very nicely with the data that will be presented today and I shared in the slide, is that we see already in this early experience with these 6 patients we see those same types of improvements. And I think that is, again, a very encouraging early sign.

It's not a clinical trial, but it's an early sign that both based on the APDS experience as well as the 6-patient expanded access experience, the kinds of things that we can expect to see in the readouts of these 2 Phase II studies.

[Operator Instructions] And the next question today comes from the line of Natalia Webster from RBC.

I have a couple of follow-ups, please. Firstly, on RUCONEST. Just on the around 50 new enrollments that you've seen and 23 new prescribers in Q1. Do you see this as a sustainable run rate going forward?

And then secondly, I appreciate that it can take sort of 3 to 4 reorder cycles to see the full impact. But are you able to provide any quantification on what sort of percentage of your patient base has tried Ekterly and what sort of return rate you're seeing to date?

And then finally, on Joenja, you added 7 net U.S. patients on paid therapy in Q1, and I believe you previously guided to accelerating enrollment this year. Is this acceleration dependent on pediatric approval? Or are you also expecting an acceleration in adult additions in the coming quarters?

So I'm going to take. Thank you, Natalia, for your question. I'll take the first part on RUCONEST and let Leverne elaborate on the second part on Joenja. Clearly, we've seen over the past quarters really our ability to see really a sustainable stream of new enrollment. So despite the launch of new therapies, whether these are prophy therapy -- prophylactic therapies or on-demand therapy, we've seen that because of the differentiated profile of RUCONEST, we've been able to gain quarter after quarter, I think, a number of new patients. And we don't see that changing.

Specifically as the launch of Ekterly is making the on-demand market more dynamic. We see a significant increase of switches and doctors are more prone to engage with their patients on whether they are well controlled. And we see an opportunity for RUCONEST to capture even a higher number of patients that could not be controlled correctly on their current treatment.

And to complement what Kenneth said earlier, this is also a significant element to reach the upper end of our guidance. Clearly, reaching the upper end of our guidance is about the timing for the U.S. approval of the pediatric extension, but also our ability to grow RUCONEST and leverage this market dynamic with more switches.

I would let now Leverne comment on the Joenja -- on your questions related to Joenja.

Okay. Thanks, Fabrice, and thank you, Natalia. So on the Joenja acceleration, we still have significant room for growth in the 12 and above patient population, right? So as we mentioned, we added 7 new patients on therapy in Q1, and we're seeing some good sustainable momentum into Q2 already. So as you think about the adult 12 and above opportunity, we continue to identify new patients. We continue to convert those new patients, and that is a sustainable source of growth for us in the future because there's a lot of room for us to grow.

And then I think the point that you mentioned on the pediatric indication in the second half of the year will be an additional growth lever for us in the U.S., right? And then ex U.S., as we mentioned, will be the launch in Germany and the launch in Japan later this year. So I would think about the year in these sort of phased steps of acceleration in the current population, the pediatric population and the international expansion in the second half of the year.

We will now take our final question for today. And the final question comes from the line of Simon Scholes from First Berlin.

I've got a question on leniolisib and the Type A meeting. My impression in March was that you would be able to deliver the additional information that the FDA required and that probably you'd be able to make resubmissions, immediate resubmissions in both the high dose and the low dose. Could you just outline what extra work you're going to need to do on the low-dose patients until you resubmit in the summer?

Sure. I can answer that, Simon. So I think what we really -- when we met with FDA, and I think what we tried to define was the fastest way to bring Joenja to this youngest group of patients and to try to do it in a way that allowed us to leverage the data we already had. And that's why we went with this 2 submission approach that allows this 40-milligram and 50-milligram submission to already occur. In fact, we submitted it, as I said, on the same day that we received the FDA meeting minutes. So I think that was a very important outcome.

For the second group, really, this was just making sure that we had all of the efficacy data. And as I said earlier, the efficacy data that lined up very nicely with the in both the high dose and the low dose groups, or sort of the high weight and lower weight patients. So it's really just putting that data package together. I think the key piece or the key point to note is that we have an agreement with FDA on what the contents of that submission will be. And importantly, it doesn't require an additional clinical trial, this submission. So I think that's where we are, and that's why we went with this 2 submission approach. And then, we expect to make the second submission in this summer.

Thank you. I will now hand the call back to Fabrice Chouraqui for closing remarks. Please go ahead.

Thank you so much, operator. I hope we are -- we were able to provide clarity on the -- on our performance in the first quarter. As we said, we've seen meaningful improvements across the business, despite some revenue variability. I personally believe as the rest of the leadership team that we are -- those progress are really positioning Pharming extremely well for long-term value creation. And so we look forward to updating you on our plan for the short and midterm and long term as well. Thank you so much.

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

Good day, and thank you for standing by. Welcome to the Pharming Group N.V. Fourth Quarter and Full Year 2025 Financial Results Conference Call and Webcast. [Operator Instructions] Please note that today's conference is being recorded.

I would now like to turn the conference over to your first speaker, Mr. Fabrice Chouraqui, CEO. Please go ahead, sir.

Thank you, operator. Good morning and good afternoon, everyone, and welcome to our Q4 and Full Year 2025 Earnings Call. I'll be joined on this call today by Leverne Marsh, our new Chief Commercial Officer; Anurag Relan, our Chief Medical Officer; and Kenneth Lynard, our Chief Financial Officer.

On this call, we will be making forward-looking statements that are based upon our current insights and plans. As you know, these may differ from future results. As you saw in our press release, Pharming ended 2025 on a strong note, operationally and financially. Total revenues grew by 15% in the fourth quarter of 2025 and by 27% for the full year. Thanks to disciplined cost management, we delivered $26 million of operating profit in 2025 compared to a loss in 2024. We also significantly increased our cash position.

Operating cash flow came in at $55 million in 2025, putting our cash position at year-end above that of the end of 2024 level before the acquisition of Abliva.

2025 was marked by significant growth of our 2 commercial assets, RUCONEST and Joenja. RUCONEST grew 26% year-on-year and by 9% in the fourth quarter. With its efficacy, with its reliability and its rapid onset of action, RUCONEST is poised to remain an established on-demand treatment option for difficult-to-treat patients in an evolving HAE treatment landscape. Leverne will talk more about RUCONEST performance and its unique value proposition.

Joenja grew 29% year-on-year and by 53% in the fourth quarter, fueled by the acceleration of new patients on drug in the U.S., but also increased demand in international markets, including in the U.K., where the drug was launched last spring and in other countries through purchases under government-supported access program. These results underscore Pharming's transformation from a single asset company into a highly profitable, high-growth biotech with 2 commercial products and a late-stage pipeline with 2 programs offering billion sales potential.

We highlighted these programs at our Investor Day last month, offering investors unique insights to our high-value pipeline. RUCONEST is the foundation of our portfolio and a reliable cash engine for the future, even in a more crowded HAE on-demand market, given its efficacy profile on the difficult-to-treat patient subpopulation. Joenja is just at the beginning of its life cycle with multiple growth catalysts in APDS, international geographic expansion and potential expansion into much larger PIDs. Napazimone, which we used to call KL1333 for primary mitochondrial disease is another $1 billion-plus opportunity with the registrational study now well underway. This combination of durable revenue, first-in-disease innovation and an advancing late-stage pipeline positions Pharming well for substantial near-term and long-term value creation.

Let me now turn to our outlook for the remainder of 2026. As announced at our Investor Day in February, we expect 2026 revenue between $405 million and $425 million this year, representing an 8% to 13% growth with operating expenses increasing at a slower overall pace even with substantially higher R&D investment in our pipeline to fuel future growth. We expect continued RUCONEST growth for the reason mentioned earlier and accelerating Joenja growth, fueled by the uptake in APDS patients above 12 years in the U.S. and potential future regulatory approval internationally.

Regarding the U.S. pediatric label extension, we've been working to address the FDA request, and we expect to have greater clarity on the resubmission requirements and time line following the FDA Type A meeting, which is now scheduled at the end of March.

2026 is an important year for our pipeline with the materialization of potential value inflection points. We have now completed the enrollment of 2 leniolisib Phase II trials for late larger prevalence PIDs, and we expect a top line data readout in the second half of this year. We also expect to complete enrollment in the napazimone pivotal study this year to be in a position for a data readout at the end of 2027.

We are clearly determined to maintain strong financial discipline to optimize capital allocation on our growth drivers. This is critical as we strive to build an efficient and scalable organization and make Pharming a leading rare, ultra-rare disease company and deliver sustainable value for our shareholders.

Let me now turn to Leverne Marsh for deeper insights on the performance of our commercial portfolio.

Good day, everybody. Let me start with RUCONEST, where the U.S. business delivered another year of strong and resilient performance. In 2025, despite the first new wave of treatment options in the HAE market in almost 5 years, RUCONEST continued to grow as an essential therapy for patients living with severe high-frequency HAE attacks. Our strategy remains consistent, focused on high-attack patients who require fast, reliable on-demand treatment and ensure that we continue to execute against that differentiated value proposition even as new agents enter the market.

For the full year, RUCONEST delivered 26% global revenue growth and a volume growth in the U.S. of 20%, a clear indicator of the strong and durable demand for RUCONEST in the acute segment. In quarter 4, we delivered 9% global revenue growth versus the prior year quarter and a 2% volume growth in the core U.S. market, continuing the upward trajectory of RUCONEST. As expected, through Q4, we began to observe impact of newly launched therapies for HAE in the U.S. market with some patients trialing and some already returning to RUCONEST. Despite these competitive dynamics, we welcomed over 60 new enrollments in the U.S. in the fourth quarter, slightly above Q3. RUCONEST added both new patients and new prescribers in the quarter, underscoring the resilience of our position in the difficult-to-treat patient segments and the clinical trust placed in RUCONEST in real-world settings.

That said, the high burden of HAE matters for patients who have high-frequency attacks. Attacks are often unpredictable and potentially life-threatening and symptom severity often escalate within hours. Importantly, for patients experiencing multiple attacks per month or patients who experience suboptimal responses to other options, dependable rapid relief is not optional, it is essential. And this high-frequency attack segment is precisely where we have seen consistent durable use of RUCONEST over time and where we expect RUCONEST to remain highly relevant even as new treatments enter the market. To that end, a meaningful proportion of new patient enrollments in the U.S. are switches to RUCONEST from other on-demand therapies, further emphasizing the continued need that high attack patients have for an effective, reliable one-and-done therapy like RUCONEST.

And so when you put this together, the unpredictability of the disease, the high burden carried by certain patient segments, the limitations of some other acute therapies and consistently strong clinical performance associated with RUCONEST, the unique value proposition for RUCONEST remains clear. Looking ahead, we foresee some pressure on our growth early in the year, but with no change in the need for an effective, rapid onset, reliable 1-dose treatment like RUCONEST.

With that in mind, let me turn to Joenja. For Joenja, we delivered a strong fourth quarter, building on the momentum we established throughout the year. Revenue grew 53% compared to the fourth quarter in 2024, reaching $19.8 million globally. For the full year, Joenja generated $58 million, representing 29% growth year-on-year and demonstrating both sustained utilization from patients and the expanding clinical recognition and treatment of APDS.

In the United States, patient growth remained a central driver of performance. By the end of 2025, we had 120 patients on paid therapy, representing a 25% increase over year-end 2024. This steady expansion of our treated population reflects strong physician confidence, consistent engagement with patient communities and a team that executes with discipline and with urgency. Equally important, we made significant progress in broadening the pool of identified APDS patients, one of the most critical leading indicators in an ultra-rare disease. In 2025, the number of U.S. patients we identified diagnosed with APDS increased by 40, more than double the increase of 18 we saw in 2024. This growth in identified patients with APDS shows that our educational efforts, our diagnostic partnerships and our medical engagement in the U.S. are working.

Outside the U.S., we saw strengthening demand across international markets, including a solid first year uptake in the United Kingdom following the launch in April 2025. We also benefited from government-supported access programs, which allowed us to reach more patients who currently have limited therapeutic options. Taken together, these results give us a strong platform for Joenja in the years ahead.

Finally, we expect geographic expansion and the anticipated 4- to 11-year approval in the United States to be meaningful contributors to growth. These 2 catalysts remain materially important to increase the number of patients who can benefit from Joenja and expand the global footprint of the APDS business. Internationally, we've already demonstrated our ability to execute. In the U.K., where Joenja launched in April 2025, we have seen solid early uptake and [indiscernible]. That success reinforces that our teams have the capability, the infrastructure and the strategic focus needed to deliver in new markets.

In the United States, our commercial teams are fully prepared to launch Joenja for children ages 4 to 11 pending FDA approval. And importantly, we already have 52 eligible patients identified, 1/3 of them currently on therapy through our early access program ready to transition at approval. This will give us a running start and positions us for early momentum once the label is approved.

Beyond the U.S., our international organization is deeply engaged in progressing regulatory submissions and ensuring that reimbursement discussions can start when approvals are granted across Europe, Japan and Canada. Across these 3 regions, we have over 80 patients already receiving Joenja through early access mechanisms, awaiting full regulatory approval and commercial availability. This represents a significant built-in foundation for launch acceleration once those approvals are secured.

And as we're stepping into 2026, we do so with confidence. For Joenja, we have the right growth catalysts in front of us, and we have an organization that has demonstrated that it can execute launches with precision and continuity. This gives us confidence not just in the next quarter, but in the sustained global expansion of Joenja over the coming years.

And with that, I'll now hand over to Dr. Anurag Relan, our Chief Medical Officer, who will walk you through our progress across the pipeline and the upcoming development and regulatory milestones.

Thank you, Leverne. As we discussed at our Investor Day in February, PI3K delta is a master regulator of the immune system and imbalances here contribute to immune dysregulation in a number of primary immune deficiencies or PIDs. This understanding serves as the foundation and rationale for our Joenja development efforts. APDS, where Joenja is currently approved, is a primary immune deficiency caused by a genetic defect that leads to PI3K-delta hyperactivation. This results in the dysfunction of the immune system and is characterized by frequent and severe infections and a wide array of immune dysregulation consequences, as you see here. APDS is a progressive disease and leads to early mortality due to these complications with unfortunately about 25% of patients dying by the age of 30.

Based on this understanding of APDS, we have 2 ongoing Phase II proof-of-concept clinical trials evaluating leniolisib in more prevalent PIDs, which share unmet medical needs, mechanisms and disease pathology with APDS. These include the genetically identified primary immune deficiencies with immune dysregulation linked to altered PI3K-delta signaling and Common Variable Immune Deficiency or CVID with immune dysregulation, which is identified independently of genetics. And as Fabrice mentioned, both of these studies have now completed enrollment. And as you see here, APDS falls under the broader CVID umbrella diagnosis and Joenja, in fact, serves as a proof of concept for the work we are doing now in these much more prevalent PIDs.

This slide highlights the opportunity now to broaden the use of Joenja. The prevalence figures here are for the U.S., but they illustrate the larger opportunity to serve patients and underpin peak sales potential above $1 billion. We're very excited about the work that I just discussed to study Joenja in these additional PIDs with immune dysregulation beyond APDS. These address significantly larger patient populations, which are 5 to 26 times the prevalence of APDS.

In APDS, Leverne already discussed progress with patient identification and our commercial preparations for geographic and pediatric expansion. But let me update you now on the variance of uncertain significance project and the opportunity there. Following various discussions over many months involving Columbia and genetic testing labs, it became clear that the labs require additional evidence to reclassify VUSs. Understanding the consequences of VUS has remain a significant unmet need and actually a public health problem for clinicians and patients. And as you see, the number of patients with VUS continues to grow.

To complement the significant first batch of data, which were published in Cell, we are now planning new experiments to generate the data needed to allow genetic testing labs to evaluate VUSs. Following completion of these experiments, we plan to provide an estimate how many VUSs may be reclassified and how many patients may be ultimately diagnosed with APDS. In addition, the work published in Cell also suggests that the prevalence of APDS could be significantly higher than we currently estimate. We convened a global advisory board and are now initiating work to explore and better understand the prevalence of APDS as well as the spectrum of disease.

I'll now cover the progress we are making in APDS, including some of our near-term regulatory milestones. Overall, we made good progress in APDS during 2025 and early this year. While we are disappointed in the complete response with letter we received from FDA in January regarding our regulatory submission for the pediatric label expansion for Joenja for the treatment of APDS in children ages 4 to 11, we believe we can address both the clinical pharmacology and analytical batch testing methodology issues outlined in the letter. A Type A meeting has now been scheduled with FDA for later this month, and we expect to discuss the agency's feedback and align on the path forward for resubmission.

In Europe, we have filed a marketing authorization application for leniolisib for patients 12 years and older and now responded to CHMP's questions on manufacturing activities and quality controls and believe we have addressed their concerns. We now expect a CHMP opinion on the MAA to take place at their meeting later this month with potential EC approval in the first half of this year.

Regarding the Japan NDA for leniolisib for the treatment of APDS in patients 4 years of age and older, the Pharmaceutical Affairs Council meeting has recommended approval. This news was covered in The Pink Sheet, who importantly noted that this would represent the first approval for children with APDS ages 4 to 11. We now await the formal decision by the PMDA by the end of March.

I'll now turn to our next pipeline asset, napazimone or formerly known as KL1333. Napazimone has also progressed significantly in the past year. This is being developed for primary mitochondrial diseases, which is a group of rare disorders where mutations in mitochondrial DNA lead to significant fatigue and muscle weakness. Napazimone addresses this underlying disorder by normalizing the NAD+ to NADH ratio, which is abnormally low in these patients. There are a large number of these patients already diagnosed across the U.S. and large European countries where they are treated at centers of excellence and part of strong advocacy groups. And here, we have a registration-enabling study underway with endpoints agreed upon with FDA. And importantly, there was a blinded interim analysis in which both endpoints passed utility.

Since completing the acquisition of Abliva last year, we are making good progress in the second wave of the study and are on track to complete enrollment later this year with readout in 2027 and potential approval later in 2028.

And with that, I'll turn it over to Kenneth now to discuss our financial results.

Thank you very much, Anurag. I'm pleased to now provide some color on our strong 2025 financial performance and our outlook for 2026.

The fourth quarter was a strong finish with revenues of $106.5 million being 15% growth versus Q4 of 2024. This was driven by continued momentum across our portfolio, including a 9% growth for RUCONEST and a 53% growth for Joenja. Notably, Joenja annual revenues exceeded $50 million for the first time, triggering our first $5 million sales milestone payment in the quarter. As a reminder, this milestone is recorded in cost of goods sold and therefore, affected gross margin for the fourth quarter.

Adjusted operating profit was broadly stable year-over-year after several offsetting one-off items. Fourth quarter 2025 expenses include $9.3 million in expenses related to Abliva and napazimone following the completion of the Abliva acquisition this year as well as the $5 million Joenja sales milestone payment just mentioned. Excluding these items to compare operating profit on a like-for-like basis to the fourth quarter of 2024, operating profit in the fourth quarter of '25 would have been $14 million higher.

Finally, cash and marketable securities increased by $12.2 million from $168.9 million at the end of Q3 to $181 million at year-end, primarily driven by positive operating cash flow, reflecting the strength of our commercial performance.

Turning to our full year 2025 results. Our financials shows the continued strong execution of our strategy. Total revenues increased 27% to $376.1 million, driven by robust double-digit growth from both RUCONEST and Joenja. Gross margin remained stable at approximately 88% despite the $5 million Joenja sales milestone recorded in the fourth quarter.

Operating expenses rose to $311.3 million, excluding $4.1 million of one-off restructuring costs related to our G&A reduction program announced in October, operating expenses were $307.2 million and within our previously communicated guidance range of $304 million to $308 million. Importantly, when also excluding the full $29.7 million of Abliva-related expenses, operating expenses increased only 2% on a like-for-like basis. This reflects disciplined cost management. In total, adjusted operating profit, which exclude nonrecurring Abliva acquisition-related costs and other offsetting items was $36.4 million compared with a loss of $8.6 million in 2024. Excluding recurring Abliva expenses and the $5 million Joenja sales milestone, operating profit for 2025 would have been $24.4 million higher.

Cash flow from operating activities totaled $54.7 million versus being slightly negative in 2024, showing the improved profitability and cash generation of the business. Cash and marketable securities increased $11.7 million to $181.1 million despite $68 million used for the Abliva acquisition, again, highlighting the strength of our underlying operational cash generation.

Turning to our 2026 outlook. We reaffirm our expectation for total revenues of $405 million to $425 million, representing full year growth of approximately 8% to 13% versus 2025. The growth is expected to be driven by continued growth for RUCONEST in the U.S., partly offset by declining ex-U.S. revenue as we exit those markets and accelerated growth for Joenja.

For RUCONEST, quarterly revenue typically fluctuates with patient ordering patterns and channel inventory movements with the first quarter usually being the lowest. In Q1 2026, inventory drawdowns are expected to impact U.S. RUCONEST revenue growth by 7% to 9% year-on-year as market dynamics settle. This is factored into our full year guidance, which assumes mid-single-digit RUCONEST growth at the midpoint of the range. For Joenja, we expect growth to accelerate with annual growth approximately 10 percentage points higher than in 2025. The pediatric APDS indication remains an important future growth driver, and we look forward to clarity on the U.S. approval time line for patients aged 4 to 11 following the upcoming FDA Type A meeting.

In the meantime, U.S. pediatric revenues are excluded from our 2026 guidance. For operating expenses, we anticipate a range of $330 million to $335 million, including more than $60 million of incremental R&D investments. This guidance reflects -- also reflects the $9 million favorable impact from the 20% G&A headcount reduction program announced in October 2025, along with stable marketing and sales spending.

Overall, we remain committed to financial discipline, prioritizing investment that drive near- and long-term value creation for our shareholders. Because Joenja revenue is not expected to exceed $100 million in 2026, we do not assume the $10 million commercial milestone payments, which otherwise would be recorded in cost of goods sold. As communicated during our Investor Day in February and aligned with ex U.S. rollout plans, no additional milestone payments are expected. We estimate cost of goods sold at 10% of revenues, corresponding to a gross margin of 90%. Finally, available cash and future operating cash flows are expected to fully support pipeline investments, including all prelaunch activities.

With that, I will now hand over to Fabrice for his closing remarks.

Thank you, Kenneth. So in summary, we are pleased to report another strong quarter and a record year for Pharming in 2025 with $376 million revenues and a shift to operating profitability and positive operating cash flow.

Looking ahead, RUCONEST is poised to remain a constant treatment for severe HAE patients, underpinning a strong revenue base. We see clear revenue catalysts ahead for Joenja with the product well positioned to generate a significant proportion of our revenues in the future. Our upcoming clinical data readouts, including the 2 leniolisib Phase II later this year and the napazimone pivotal study readout next year, each have the potential to unlock significant value and take the company to a whole new level.

And finally, the decisive steps we have taken to improve financial discipline will support driving the positive bottom line. With strong commercial and development capabilities, a fit-for-purpose leadership team with strong new additions like Leverne and Kenneth and a scalable organization, we are committed to making 2026 another stepping stone in achieving our vision of becoming a leading global rare disease company.

Let me now open the line for questions.

[Operator Instructions] we Are now going to proceed with our first question. And the questions come from the line of Lucy Codrington from Jefferies.

To begin with Joenja growth this year, how much of that are you expecting to come from the U.S. market versus international markets? And then secondly, looking at the U.S. market, of those 61 eligible patients that are not on treatment in the U.S., how many of these do you think could be converted to paid therapy? Or how many have been -- versus how many have been considered and ruled out?

And then finally, in terms of RUCONEST dynamics, you mentioned that you have heard of patients coming back to treatment and having tried the orals. Do you have any -- I guess, it would be anecdotal commentary on how quickly the patients return having tried the orals?

Very good. Thank you so much, Lucy, for those questions. I'll turn to Leverne in a minute, actually. Let me start with the last one on RUCONEST and then we can take your 2 questions on Joenja.

It is true that we've seen some patients trying and coming back. As you know, and as Leverne reinforced, HAE is a very severe disease and patients got to be controlled and especially patients who were used to highly reliable treatment. And so when those patients try another treatment and see that their crisis is not properly controlled, they tend to come back to their previous medication very quickly because not controlling a crisis could be life-threatening.

Now when it comes to Joenja's growth, as we've said, we see the growth this year in 2026 being fueled both by the continued growth in the U.S. as well as growth increasing in international markets. It's -- obviously, the growth in international markets will come from the U.K. where the drug has been launched, new launch countries. And this will happen in a staged fashion since once we receive marketing approval, we'll have to negotiate price and reimbursement. So ultimately, a bigger portion of the growth will come from international market, but that's going to be gradual.

When it comes to more specificities on Joenja's patient funnel, I'll ask Leverne to comment.

Thank you. Thank you, Lucy, for your question. How we would think about the patients considered for Joenja or eligible for Joenja in the U.S. and the pull-through to patients on therapy, that there would be a lag there as patients are going through the patient journey, a fairly complicated patient journey, seeing multiple physicians, the enrollment and then the reimbursement process before we get to patients on paid therapy.

And so how I would think about the delta there and the opportunity, there's still a substantial proportion of patients both eligible and potentially reimbursable that would drive growth for us in the U.S. in 2026.

Maybe, Lucy, this is Kenneth speaking. Maybe I can just add out of the expected Joenja growth in 2026, it will probably be around about 70%, 75% that will come from the U.S.

So 70%, 75% from the U.S.

Of the growth in 2026 for Joenja, yes.

We are now going to proceed with our next question. And the questions come from the line of Joe Pantginis from H.C. Wainwright.

So I know might not be able to give color here ahead of the Type A, but I'm going to ask anyway. Obviously, the reasons for your discussions, as Anurag said, were the clinical pharmacology and the analytical batches. Is there anything that you would consider sort of the lead rate-limiting step here? That's question number one.

Question number two, regarding RUCONEST, you touched upon this a little bit, but I guess the RUCONEST case can be split into 2 components in my belief. So first, you have the medical component, which continues to make the case. And I'd like to touch upon the investor component and specifically your comments that patients are still seeing switches from the new therapies to RUCONEST. So I was hoping you can provide some additional color as to why those switches are taking place.

Thank you, Joe, for these questions. So on the Type A meeting, it's very difficult to speculate. I think Anurag has been clear on the questions that were raised by FDA, and we are really looking forward to engage with the agency later this month to address their feedback and discuss a path forward. So too soon to tell. Clearly, given what they've raised, we feel actually that these questions are addressable. And once again, we look forward to engaging with them.

When it comes to RUCONEST, I'll let Leverne answer your question.

So thanks for your question, an important one. So as we've seen new agents entering the HAE market in the U.S. between June and August last year, as expected, we saw some trialing of both acute agents and new prophylactic agents in the U.S. market. What we're observing in our data currently, and it's still early, is within about 3 to 6 months, some of these patterns may start to shift, and we've seen some return of RUCONEST patients that have originally adopted or trialed a different product coming back to RUCONEST.

But again, early days, and we're monitoring this closely, and we continue to execute competitively based on RUCONEST's very different value proposition for patients, specifically in the high attack segment, where they are increasingly concerned with reliability and a fast on-demand treatment like RUCONEST.

And the questions come from the line of Jeff Jones from Oppenheimer.

Congrats on the great year 2025. A couple of questions from us. You spoke a little bit to the cadence of moving patients from early access on to paid therapy. Any notable variations between Europe, Japan, Canada as you look to that? And then as you look at the other primary immune deficiencies for Joenja and the Phase II readouts that you're anticipating, can you speak a little bit about next steps? What types of additional trials might be needed and how to think about the path forward there?

Thank you, Jeff, for these questions. When it comes to access to paid therapies for Joenja in international markets, most of these markets are -- have access -- centrally driven access. So the dynamic is different compared to the U.S., where in a sense, each patient needs to deal with different payers. So in a centralized access system, things are slower at the beginning because you need to negotiate, obviously, with the authorities for reimbursement or the one you get reimbursement, then afterwards, the reimbursement process is extremely efficient. So we don't expect to see the same type of dynamic international. When it comes to higher prevalent PMDs, I'll ask Anurag to elaborate.

Jeff, so on the question about the -- what happens next. So as I mentioned, the studies have completed enrollment. We expect results later this year. The results that we're looking for, again, the endpoints that we're evaluating are clinically relevant endpoints similar to the ones that we looked at in APDS as well as other clinically relevant endpoints. As we look at those endpoints, we'll plan to have a discussion with FDA and other regulators about the path forward.

I think our base case here is that we would expect to do a Phase III randomized type of study. However, I think you've also seen from FDA some openness and willingness to look at alternative mechanisms and pathways for patients with rare diseases, especially those where there's a plausible mechanism and there's a mechanism that's understood. So those are the types of discussions that we would have with the FDA, again, once we have the data to be able to plan the path forward.

We are now going to proceed with our next question. And the questions come from the line of Sushila Hernandez from VLK.

On Joenja, you mentioned different launch dynamics for international markets. So what kind of time lines are you working with for getting these patients in Japan and Canada on paid therapy? And in the U.K., will you also start reporting the numbers of patients on paid therapy? So currently, how many patients in the U.K. are on paid therapy and how many have you identified?

So when it comes to time lines, so we've elaborated a bit on our expectations when it comes to regulatory time lines in the very near future. When it comes to CHMP opinion from Europe and PMDA approval in Japan. We'll in Japan, specifically since you asked the questions, we will be submitting a price very shortly for reimbursement, and it takes about 3 months actually for the price to be granted.

So today, we have launch time lines planned for the summer.

We will be reporting more information on the international market on Joenja in a full fashion as soon as we have launches in more than one country. So this should happen very soon. it's absolutely essential and you can count on transparency here. For the second part of your question, I'll let Leverne elaborate.

Certainly. As Fabrice has said prior, as we look at different approvals coming online at different times in this year, every country fundamentally will be a country-by-country process as the approval and reimbursement processes are quite unique for the countries that we discussed. So how we're thinking about conversion is conversion will depend on physician experience, diagnostic confirmation and testing and access, and we are building those enablers systematically with the international teams to make sure that we are able to execute upon approval.

We are now going to proceed with our next question. And the questions come from the line of Natalia Webster from RBC Capital Markets.

My first one is a follow-up on Joenja and the patients on paid therapy in the U.S. You added 18 in H1 2025 and 6 in H2. I appreciate that this takes time, but are you expecting for this rate to pick up into 2026?

Then the second question is just on costs. You're guiding to 6% to 8% growth in OpEx in 2026. And you mentioned some phasing considerations on the revenue side. Are there any particular phasing considerations for the costs through the year particularly around the higher R&D costs and G&A cost savings? And then just finally, on M&A. In the release, you mentioned continued focus on potential acquisitions and in-licensing opportunities. So any additional color on what your thoughts are there would be helpful.

Very good. Thank you so much, Natalia, for your question. So I'll start with the last one when it comes to M&A. We have clearly a number of growth catalysts, both in our commercial portfolio and in our pipeline in the years to come. So obviously, there is no urgency to do any transaction hastily to compensate for any sort of weakness. Yet, we clearly aspire to leveraging proven capabilities and a great growth platform to take that to a whole new level and make Pharming a leading rare disease, ultra-rare disease player.

And so we are constantly looking out for opportunities to expand our pipeline. Now it is absolutely essential that these opportunities, if they were to materialize, would be value accretive. And that's really our commitment to our shareholders. So it's not about actually leveraging any external growth opportunities, but making sure that anything that we would consider would be complementary, would fulfill our mission and will be quickly accretive from a value perspective.

From a cost perspective, I'll let Kenneth elaborate.

Yes. Thanks for the question. I think the way to think about it is in the 2025 baseline, we obviously had also some one-off costs that were related to the transaction of the Abliva, so nonrecurring transaction cost of about $10 million. And we also communicated earlier that we had about $4 million in costs related to the G&A reduction program. But then when you're looking into the more than $60 million incremental investments in 2026, we, of course, see the $9 million of savings in G&A come fully through. And then we have seen the impact in our planning of the strengthened capital allocation, which has allowed us to keep also marketing and sales cost flat.

So there are different dynamics that are playing in. But I think picture speaks for itself that we are fueling where we're seeing the opportunities to advance in this case, in 2026, the pipeline and are very diligent around spend discipline across all other areas.

And so lastly, coming to your question on Joenja, which is actually a very important question because, as I said, I really see Joenja taking a larger part of our revenues as the drug continue to grow significantly and realize its full potential.

You heard that last year, we reaccelerated the uptake of the drug. We had more new paid patients on therapy in the U.S. that we had in '24. Also, we've identified more APDS patients in the U.S. in '25 than we did in '24. And so this is really fueling the growth. So this year, we expect to continue to accelerate patient enrollment on Joenja and as a consequence, accelerate our revenue growth.

And the questions come from the line of Simon Scholes from First Berlin.

I've just got 2. So I was wondering if you could give us a time line on the performance and collection of the results from these additional experiments you need to perform with regard to the variant of uncertain significance. And also, are you still confident that 20% of these VUSs will turn out to be APDS?

And then just on RUCONEST, you were talking about a possible inventory-related decline in -- or inventory-related effect on sales in Q1. Is this an unusually large inventory drawdown that you're expecting to see in Q1? I mean that was my impression. And if so, how did -- why do you think you saw such a large inventory buildup towards the tail end of last year?

Thank you, Simon. So let me -- let's start with the U.S. Clearly, this is a sizable opportunity, and we are really committed to helping those patients accessing the right diagnostics. So Anurag?

So Simon, we are now planning these new experiments. These experiments, again, we're working with Columbia. They're actually going to be using new technology, new base editing technology to be able to generate different types of variants, generate more controls as they go through this process. It's too soon to tell in terms of the time lines as well as the actual number of patients that will actually be reclassified. But as this work gets underway over the coming months, we should be able to provide more details around it.

And Simon, on the inventory part, the way we're thinking about it is that there's always this quarterly fluctuation of the RUCONEST business given the patient ordering patterns and the general movements. And we have also historically, if you go back in the previous years, seen that similar dynamics in the early part of the year.

Now it's a little bit, let's say, higher in terms of inventory drawdown and dynamics this year, and we kind of attribute that simply to some of those market dynamics are kind of settling now and that inventory levels are just kind of returning to a little bit more of the normalized level. So impact-wise, it's a little bit higher, but the mechanics of how the quarters are fluctuating and the fact that the inventory impact in the first quarter are not new to us.

Very good. So listen, I think with this, we are going to close our call. Thank you so much for these additional questions, and we look forward to keeping you closely informed on our plan. There is -- there are a number of important milestones coming up. And so we look forward to reconnecting with you very soon. Thank you so much. Thank you, operator.

Thank you. This concludes today's conference call. Thank you all for participating. You may now disconnect your lines. Thank you.

Good afternoon, and welcome to our 2026 Investor Day. I'm Fabrice Chouraqui, the CEO of Pharming. We are very excited that you're all able to join us, and I really hope that you'll be able to learn more about Pharming and specifically about our financial guidance for the year as well as our high-value clinical stage pipeline programs. We are going to make forward-looking statements during this presentation, and here is our disclaimer.

I also want to remind you that this presentation is intended solely for an investor audience. As you can see on the agenda, we'll have 3 sections. In the first section, we'll provide a short business and financial update, during which we'll cover our financial guidance for the year. And then we'll have 2 longer sessions dedicated to our pipeline, one on leniolisib in high prevalence PIDs and the second one on KL1333, napazimone.

As you can see on the agenda, we have planned for a section with a Q&A at the end of each of these sections. So in just a few years, as you can see, Pharming has transformed from a single asset company into a fast-growth biotech with 2 commercial assets growing each double digit and a late-stage pipeline with 2 programs with over $1 billion sales potential each.

RUCONEST continues to grow after 10 years on the market, and it is poised to remain the on-demand treatment of choice for difficult-to-treat patients because of its mechanism of action, it replaces the missing or deficient C1-esterase-inhibitor protein and its IV administration, which provides [indiscernible] patients with the reliability they need as they suffer from more frequent and more severe crisis.

RUCONEST is also a product which is produced from the milk of transgenic rabbits, which makes its manufacturing process complex and difficult to replicate. Our second commercial asset, Joenja, is just at the beginning of its life cycle with multiple growth catalysts that will drive further growth acceleration. While we are disappointed in the FDA response to the submission of our pediatric label expansion in APDS, we are committed to bringing Joenja to this population with significant unmet need, and we are going to request a Type A meeting, which should be scheduled in March.

Joenja has also many other growth opportunities in APDS. The data published in Cell in June last year suggests significantly higher APDS prevalence and also the potential to reclassify about 250 VUS patients as APDS over time. And the expansion into larger PIDs and CVID, which will be the focus of the second session today, could unlock a much larger market. KL1333 or napazimone for primary mitochondrial disease, which is the other pipeline focus of today, is another $1 billion-plus opportunity.

The program is in a pivotal Phase II and has cleared a futility analysis on both primary endpoints. So as you can see, this combination of durable revenues, strong growth drivers and a high-value late-stage pipeline positions Pharming well for substantial value creation in the near term and in the long term.

With this portfolio and pipeline as the foundation, we are now committed to leveraging our strong rare disease capabilities to build a leading global rare disease company with a broad portfolio of rare and ultra-rare drugs and deliver on our vision. Our 2 commercial assets performed extremely well in 2025, providing the foundation for our strong financial momentum.

We announced preliminary 2025 revenue of approximately $376 million, an increase of 27% versus 2024, slightly exceeding our already upwardly revised latest guidance provided in November. With this strong revenue growth and our commitment to cost discipline, we achieved significant operating profit and operating cash flows as we stated in our latest financial report in Q3 2025. I will now ask our Chief Financial Officer, Kenneth Lynard, to elaborate on our financials and provide an overview on our 2026 financial guidance.

Thank you, Fabrice. 2025 was a strong year, and I'm happy to provide more insight into our financial performance as well as our guidance for 2026. Before doing so, let me remind you that our financial data for 2025 are preliminary and unaudited. Final results may, therefore, differ and will be reported during our earnings call for the fourth quarter and full year 2025, which we'll be hosting on the 12th of March 2026. During that call, we will get into further details on the performance of the fourth quarter of 2025.

Let me here start by drawing your attention to the right-hand side of this chart, really calling out the strong and accelerated growth in 2025. As Fabrice already mentioned, we were growing 27% over the previous year 2024. And I'm also happy to now provide the breakdown by product, starting with RUCONEST, who continued to perform very strong, reaching $318 million in annual revenues, a growth of 26% over the previous year. Joenja grew 29% and delivered $58 million of revenues in 2025.

Thereby, we exceeded the $50 million revenue level triggering the first $5 million milestone payment to Novartis. In our financials, this milestone payment is booked as part of cost of goods sold. For 2025, we expect a gross margin around 88% to 89%, excluding the $5 million milestone payment to Novartis. As earlier communicated, we are expecting our operating costs for 2025 within the guidance range of $304 million to $308 million, excluding the onetime restructuring cost of $7 million linked to the structural G&A cost reductions that we announced in October 2025.

Finally, at the end of 2025, the company had USD 181 million total in cash and marketable securities. Let's now look into the financial guidance for 2026. For 2026, we expect total revenues between $405 million to $425 million, implying full year growth over 2025 of 8% to 13%. The growth is expected driven by mid-single-digit growth for RUCONEST, including continued U.S. volume growth, partly offset by decline in ex U.S. revenues associated with our exit from these markets and furthermore, significant growth for Joenja.

Our guidance for 2026 compares favorably to analyst consensus guidance, which is approximately $398 million. We see the Joenja growth accelerating with annual growth around 10 percentage points higher, give or take, than in 2025. We continue to see the pediatric APDS indication as a growth driver for Pharming. However, until we have greater clarity on the revised time line for Joenja U.S. approval for pediatric age 4 to 11, we have conservatively removed any such revenues from our 2026 guidance.

With Joenja revenue not assuming to exceed USD 100 million, we are not assuming a commercial milestone payment to Novartis of $10 million that otherwise would have been booked in cost of goods sold. Also aligned with our ex-U.S. commercial rollout plans, we do not assume any other milestones payment payable during the year. In 2026, we expect total operating expenses between $300 million to $335 million.

This assumes more than $60 million incremental R&D investments to advance our pipeline and includes the $9 million favorable impact of the structural G&A cost reductions that we were announcing in October 2025 as well as stable marketing and sales spend. In 2026, we will continue our strong financial discipline and prioritize our investments into areas that matters the most to spark near- and long-term value creation.

We estimate for 2026, our cost of goods sold to approximately 10% of revenue or in other words, a 90% gross margin for the year. Finally, we continue to expect that our available cash and future cash flows will cover investments in the current pipeline and all related prelaunch costs. With that, we will now open for the first Q&A section.

I'm Michael Levitan, VP, Investor Relations and Corporate Communications at Pharming. Analysts and investors are welcome to ask questions during this session. Covering analysts, please feel free to raise your hand to ask a question live or use a Q&A button to type a question. Investors please feel free to use a Q&A button. We will do our best to get through as many questions as time allows. We'll now take our first question from Joe Pantginis at H.C. Wainwright.

So look, it was an unfortunate event to get the CRL, but I think the FDA asked some very important questions. So with regard to the exposure data, are these data that you have in hand that you need to provide analysis for? Or do you need to, say, conduct -- or do you anticipate conducting an early -- I'm sorry, an additional study to look at these? So I just wanted to get some sense there. And then with regard to OpEx expenses, thank you for all the details there. Do you feel that the company is rightsized currently with regard to sales and marketing?

Joe, thank you so much for your question. So when it comes to the recent FDA feedback, we have a wealth of data at hand. And obviously, we are planning to engage with the FDA at this forthcoming type 2 meeting. So there is a possibility that the data that we have will satisfy the FDA. Now it's too soon to speculate before we have this meeting.

And so we'll be able to update you on the course of action after the meeting takes place. When it comes to our cost structure and specifically our marketing and sales cost structure, we have the right level of investments behind our products, and we do not intend to increase that investments in the near term.

Our next question comes from Jeff Jones at Oppenheimer.

Just if you could provide a little bit more color on RUCONEST. You commented on single-digit growth and interested in how much of that could be driven by sales price increases versus patient numbers given -- and then a little more on the dynamics, if you could, U.S., EU as you see that play out having come off the market in Europe.

Absolutely, Jeff. So as I mentioned, really RUCONEST is poised to remain cornerstone treatment for difficult-to-treat patients. And as such, we believe that the drug will continue to grow in value as well as volume. We've taken a 3% price increase this year, and we see -- we expect also to see volume growth beyond this price increase. It's actually important to note that, that price increase was in line with CPI, not above. When it comes to the geography -- where the growth will come from geographically, all the growth will come from the U.S. That's clearly the goal.

I have a question in from Lucy Codrington at Jefferies. Lucy is asking, how much of the incremental growth comes from VUSs versus new geographic launches?

Thank you so much, Lucy, for this question. An important point of clarification indeed. As you know, we have to be arm's length when it comes to letting the clinical -- the genetic testing company work with the author of the paper. And as a consequence, it is very difficult to predict when the reclassification of those VUS patients as APDS patients will start to become effective. As such, we took a conservative estimate to take out any VUS patients in our current guidance. And as we see the progress, we will obviously update the investor community.

And one more question that came in from Lucy was KalVista has talked about switching of RUCONEST patients. Have we seen this in our data? Do we anticipate switching in our guidance?

We have seen actually a few switch, some patients on RUCONEST are so-called mild patients, and it is absolutely normal that they wanted to try an oral drug. We've also actually heard anecdotal evidence of some of those patients coming back to RUCONEST. However, we haven't seen any significant change in the bulk of the patients who are on RUCONEST.

As you know, RUCONEST is not a treatment that you take by choice. It's a treatment that you take because you need. And the majority of patients who are treated with RUCONEST have already failed other on-demand treatments. And if they are actually well controlled on RUCONEST, they often really -- they want to stay on this drug, which, to their word, often have given their life back.

Great. Next question comes in from Angela Qian at Canaccord Genuity.

I'm on for Whitney this morning. But maybe just another question on the CRL. Can you just give us a bit more color around the underexposure concern in the lower weight Peds patients? Like remind us of what the dose is and what the weight cutoff that was a concern? And how confident are you guys that you already have that data, that PK data in hand?

Thank you, Angela, for this question, and I'll let Anurag actually elaborate. It's true that the concerns raised by FDA are specifically related to the lowest 2 doses, 20 and 30 milligrams. Anurag, would you like to comment?

Sure. So again, the doses that we're referring to are the 20- and 30-milligram doses that apply to children who weigh less than 27 kilos. Now we actually have efficacy data in both of those dose groups showing comparable efficacy across doses. So children who weigh more or below 27 kilograms, we see similar efficacy including those treated with 20- and 30-milligram doses.

So we are confident that we'll be able to share this data with FDA. And of course, we'll share and review the PK concerns that they have raised and be able to address this. I think we'll be able to speak much more confidently after the Type A meeting, we have, as Fabrice mentioned, which we expect to take place in March.

Great. I think we have time for one more question in this initial section. A question coming in from Chiara Montironi on behalf of Sushila Hernandez at Van Lanschot Kempen. What do you note for the launch for the first oral HAE treatment? Any color regarding the positioning of RUCONEST?

I think what we've seen prior to the launch and after the launch is that it's a confirmation that RUCONEST is very well entrenched in a subpopulation of the on-demand market. RUCONEST is a treatment of choice for these hard-to-treat patients. Those patients who have more frequent crisis, more severe crisis, often life-threatening crisis.

Patients who need the reliability of a treatment to address their crisis rapidly with only one dose. And so that has been the consistent feedback that we have received, and that's why we believe that over time, RUCONEST is poised to remain a cornerstone treatment of choice for those difficult-to-treat patients, which account for about 20%, 20% plus of patients treated with on-demand therapies.

Good morning. I am Anurag Relan, Chief Medical Officer at Pharming, and I'm very excited now to begin our presentation on our pipeline, which will be the focus of today's session. As you see, the pipeline has evolved significantly over the last couple of years. First, we have the addition of 2 new Phase II studies with leniolisib being developed for the treatment of PIDs with immune dysregulation.

And then last year, we added KL1333, now formally napazimone being developed for the treatment of primary mitochondrial disease, both of which we'll be speaking about next. We're also moving forward on APDS. As mentioned, we are seeking a Type A meeting with the FDA to discuss the path forward to bringing leniolisib to children with APDS between ages 4 to 11.

In addition, I'm very pleased to announce that we have now completed our responses to all outstanding questions with the EMA and expect to receive approval in the first half of this year. Lastly, we continue to make progress with bringing leniolisib to Japan and other countries across the world and expect further approvals for 2026. The 2 Phase II studies I just mentioned are on track for readouts in the second half of this year.

And napazimone in our registrational Phase II program in PMD is active with more than 20 sites up and running, recruiting patients with enrollment expected to complete this year and -- which will enable a readout in late 2027. Here is the agenda for our first program that we'll be covering, beginning with the unmet need and then on to the science of the PI3K pathway and the role it plays in immune cells. And here is an overview of the diseases that we will be discussing today.

Specifically, we'll be talking about primary immunodeficiencies with immune dysregulation with an emphasis on common variable immunodeficiency or CVID. APDS, in fact, is often classified under the CVID umbrella and the experience with leniolisib serves -- the experience with leniolisib in APDS serves as a proof of concept, in fact, to treating the broader CVID population. And with that, it's my great pleasure to introduce Dr. Jocelyn Farmer next. Dr.

Farmer earned her MD and PhD in microbiology and immunology from the University of Michigan. She completed her allergy/immunology fellowship training at Mass General, and then she pursued postdoctoral research at the Ragon Institute of Mass General Brigham, MIT and Harvard, where she studied the PI3K pathway and its impact on signaling in B-cell biology.

In 2023, Dr. Farmer was recruited to Beth Israel Lahey Health as Director of the Clinical Immunodeficiency Program, where she now cares for a large and complex population of patients with PIDs. In that same year, she founded the New England Immune Deficiency Consortium to enable collaborative clinical research across broader patient cohorts, and she established her own research lab focused on B-cell biology in CVID.

This work, in fact, led her to propose exploring leniolisib in CVID based on these research findings, suggesting a shared disease mechanism between APDS and CVID. We are very fortunate to have Dr. Farmer with us today to share how leniolisib may help transform treatment across these conditions. And with that, I'll turn it over to Dr. Farmer.

Good morning, everyone. I'm thrilled to be here. So I'll be speaking to you on leniolisib, transforming treatment of immune dysregulation in primary immunodeficiencies. Here are my disclosures. Okay. So why am I here specifically speaking to you today? That was a wonderful introduction and a whole litany of degrees that I have in immunology.

But I think the top reason that I am here today is the last comment that was said, and this really came about from physician scientists who both were treating patients with CVID, which in the rare disease space is the most common primary immunodeficiency we see worldwide. and we didn't have great treatments for these patients, and we started to see a lot of parallels, both between the clinical presentation of these patients in APDS and the underlying biology, and that's what I'm going to speak to you about today.

All right. So primary immunodeficiency, that's a little bit of a complicated term. So let's step back from that. So what is PID or primary immunodeficiency. So deficiency really suggests low, and I want everyone on this call to take a pause and reinvent that term, okay? So I want you to leave here today thinking about primary immunodeficiency as more of an unbalanced immunity. So on one side of that, patients can get really terrible frequent infections.

But on the other side of that, they can also have a break in their immune tolerance. And this can lead the immune system to actually attack our own bodies. And that can be very hard for a patient both to deal with clinically and to understand. So immunodeficiency today, we're going to equate that to this unbalanced immunity. Now what comes in the door in the clinic? So in terms of primary immunodeficiency, this is a nice pictorial diagram from our European colleagues.

And the most common one that we see in the clinic is called predominantly antibody deficiency or PAD. That's that large patch of blue that you're observing in the circle. So it's most patients that we see in the clinic. Now APDS sits right up at the top. It is a very small cut of that blue circle. And so it's amazing that we have now leniolisib. But in terms of the number of patients that come in my door on a day-in and day-out basis, I want to be able to treat a large -- a much wider cut of patients.

So again, CVID is at the bottom of that blue circle, and it is the most common primary immunodeficiency in the world. So I would love as a clinical immunologist to be able to broaden from APDS to potentially all patients with CVID who are suffering from similar complications and don't have a single FDA-approved therapy for their care. Okay. So that's what PID is. Now why should you care about it? And I hope you do when you leave this call. All right. So first, I want to highlight there are no FDA-approved therapies.

This is really fresh snow when you think about a therapeutic space. Patients with immunodeficiencies do get recurrent infections, and we have good treatments to manage that. We have antibody replacement therapy that is FDA approved. We can use antimicrobials to treat their infections. We're doing pretty well as clinical immunologists here, and we can pat ourselves on the back. But where we're really falling short for our patients is the second side of their disease course.

These patients can get really catastrophic life-threatening auto-inflammatory disease. It can impact their lungs, so they can't breathe. It can impact their gut lumen, so they can have wasting to the point of needing supplementation to sustain their weight. They can have life-threatening liver disease. We really need better treatments in this space. We have no FDA-approved therapies. And quite excitingly, hopefully, to this audience, there are no products currently in development except for leniolisib.

Again, this is fresh snow. Okay. So the second part of this is that patients with CVID who experience that other side of the disease spectrum in orange that I presented on the last slide, have an 11-fold higher risk of death. It matters. So I'm going to show you that in 2 large cohorts. On the very left-hand side of your slide, this is the New York CVID cohort. And in the dotted line, you're seeing patients with those noninfectious complications compared to the solid line without.

And in the middle graph, you're looking at Germany's CVID cohort. And again, the blue line with those noninfectious complications compared to the orange line without. And you can see a clear difference there, right? So 11-fold higher risk of death if you have those non-infectious complications. And the patients themselves report a worse quality of life with those noninfectious complications. And that's what I'm showing you from our cohort on the very right-hand side of your slide.

So mental health being worse with those complications. So you don't have to take it from me. This is what patients with CVID say, and this is a quote from one individual that I'm currently treating, and she writes, for decades, I faced the systemic complexities of CVID without the benefit of any approved therapeutic treatment. It was a lonely and depressing predicament, knowing that my organs would never last long enough to see my sons grow up and perhaps make me a grandmother.

So there is an urgent and an unmet need in this disease space. Okay. So that's the downside, the depressing side of it. So can we do better? And I think that's what we're here to discuss today. So can we apply clinical lessons from APDS, this rare disease and expand it into CVID. So CVID is an umbrella diagnosis. So we use these diagnostic tools, and I'll go through them. First, low antibody levels.

So these are patients who have vaccines just like you or I, but they can't get a protective benefit from those vaccines. So low antibody levels, impaired vaccine responses, and I have to make darn sure they don't have a secondary cause that's driving that. If a patient fulfills those diagnostic criteria, then yes, I can call them CVID. But in fact, there are a lot of different varieties of disease that live underneath that broad umbrella.

So as was mentioned before, a patient with APDS might fit these diagnostic criteria, and these are the genes associated with APDS. There are also genes that link to the PI3-kinase pathway, examples being CTLA-4 or NF-kappaB1 that they will go through in detail in a moment. And those as well can live under this diagnostic umbrella. And finally, a patient can present to my clinic, and I cannot frustratingly find the genetic cause and yet they fit under this diagnostic umbrella.

And so the take-home is that the clinical spectrum of CVID and APDS commonly overlap. Okay. So we have done genetic sequencing in CVID cohorts, and this is one example of it. And when I genetically sequence those patients, in fact, I do find APDS, and that's in the yellow at approximately 4%. I also find those APDS-linked genes, those PI3K delta linked genes. That's about 20% of the patients. But the vast majority of the patients in blue still have no known genetic cause.

And we've done a systematic literature review of this and across all published studies, only about 20% of patients will leave the clinic with a genetic known identity, meaning to treat 80% of individuals with CVID who have these complications. We have to move past this to a functional understanding of how these diseases are similar. Okay. So let's step back. Do the patients look the same? Well, yes, in fact, they do. Both CVID and APDS will present with frequent infections, a lot of time ears, sinus, lung infections.

They as well will have enlarged spleens and enlarged livers. They as well will have autoimmune diseases, very commonly autoimmune cytopenias. They as well will have terrible GI complications and very frequent diarrhea. They as well will have enlarged lymph nodes that can progress to something like lymphoma if it's not caught early and managed appropriately. And they can have non-infectious lung complications such as lympho-interstitial lung diseases or bronchiectasis.

So yes, these diseases look very similar when the patients come into the clinic. So Pharming asked us to study this, and these data were presented at an abstract at last year's CIS meeting. And what we did is we took about 1,000 of our patients who we follow at the New England Immune Deficiency Consortium, and they asked us of these patients, who looks like APDS, who is with an APDS endotype, if you will. And so it turned out that about 75% of patients with CVID look a whole lot like APDS.

So we now confirm that APDS disease spectrum does clinically overlap with CVID. Moreover, we now know that end organ manifestations within CVID to go after for a Phase II clinical trial, and this is critically important. So the 2 diseases share in large spleen and large lymph nodes. So splenomegaly lymphadenopathy looks like good endpoints as well they share cytopenias, inflammatory lung disease and inflammatory liver disease. Okay. So that's the clinical spectrum.

Now let's get into the biology. I am by trade a B-cell biologist. So can we learn these similar lessons between APDS and expand that into CVID. So I want you to think about APDS like a thermostat in the B cells and the T cells, the lymphocytes of the bodies, your immune cells, and the thermostat is just set too high. So in every single cell, it is on, and this is where we have the improved indication for leniolisib. In the middle column, I want you to think about these PIK3 delta linked conditions.

And here, the thermostat doesn't start always on, but there's a faulty wire. And so the signals coming in or around it drives it up. And it makes a lot of sense then that we could use a similar drug target in this disease space, and this will be one investigational Phase II trial that will be discussed today. And in the last example of CVID, I am frustratingly not going to come up with a single gene entity and, again, about 80% of the patients that I am treating, but I still need to treat those individuals, and they deserve better care.

And so as well, we're asking if it looks like APDS and walks like APDS, but we can't find the gene for APDS, can we treat it like APDS? Okay. So these are some published data that have just come out in the last year to 2 years, and these data really start to suggest that we can. This is going to be a lot for you who are following along in your screens. So I just want you to pay attention to the highlighted boxes that I go through. So these are B cells that I've pulled out of your or my blood, healthy control blood.

They look fantastic to a clinical immunologist. You see nice maturation. You see no activation, take my word for it, okay? We then move into CVID. And it is only the patient with CVID who has those end organ complications where you're all of a sudden picking up cells in those blue boxes. These are your activated B cells, and I'll show you in the next slide.

These are the B cells that drive autoimmunity and end up causing disease in the end organs of the patients. And lo and behold, as we go through PIK3 delta linked B cells and straight into APDS, those B-cell plots start to look a whole lot similar. So there is a shared B-cell pathology in these patients. Moreover, if we look at the gene signatures that define these pathologic B cells, lo and behold, we find PI3-kinase and mTOR signaling.

So these aberrant cells, these cells that we do not want in your and my body and we don't see in healthy controls are expanded in the patients across CVID, PIK3 delta linked conditions and APDS, and they share an enrichment for PI3-kinase and mTOR signaling. Moreover, these are, in fact, the cells where we see a break in B cell tolerance, meaning these are the cells that are driving autoimmunity in the patients. And you can see that here as that red line expands.

These are just the CVID patients who have autoimmunity, and you can beautifully see that expansion of broken tolerance by the accumulation of the B cell receptor that shouldn't be there. Moreover, you can see those really nice dark connections in the APDS patient, connecting all those pathologic B cell subsets downstream to that upstream break intolerance. So there is one bad player at the very start of B cell development that filters all the way downstream to cause disease.

And in the last panel, we're showing you those B cells actually ending up in the lungs of the patients. All of that to say, if we can control that thermostat, that upstream point where these B cells start to go down a bad pathologic pathway, can we prevent, can we roll back that autoimmune disease, and we hope we can. Okay. So finally, if the clinic spectrum looks the same, if the B cell biology looks the same, can we actually use this drug in the CVID disease space.

And we have now done this in a couple of cases of compassionate use care. So I'd like to share today a single experience of a patient that I'm managing. This is a 64-year-old female. She has a diagnosis of CVID, but no known gene defect. So she sits in that 80% of patients. When I met her, she had life-threatening comorbidities, so she was getting chronic infections, but she was actually dying of lymphocytes infiltrating into her liver, into her lungs.

She had low cell counts, and so she was getting recurrent infections from this as well. She had small fiber polyneuropathy and a lot of dysregulation related to that, and she had a history of cancer as well. She had tried a lot of agents for her auto-inflammatory disease, and I'm listing them here. And none of them successfully or sufficiently were controlling her symptoms.

And there were a lot of other agents that we did not feel were appropriate to treat her with for risk of furthering her immune suppression and risking life-threatening infections in her case. So I looked at her B cells. And what I'm showing you across the bottom is PI3-kinase signaling. So to your right is more signaling and to your left is less signaling. Your or my blood is represented by the dotted line. So this is where our B cells sit.

And what I want you to appreciate is the patient in blue had as much or even higher phospho-signaling as compared to APDS. And I presented these data to Pharming and I said, if she looks like APDS, please, can I treat her like APDS, and they agreed. So we have now had her on therapy with leniolisib for approximately 1 year. So these are those bad B cells that I presented to you, okay? So you're seeing her in time across that axis, and you're going to follow her pretreatment in blue, post treatment in green.

And what we've seen is that she significantly reduced those bad B cells over the course of her therapy. Now one further point, and this I have not seen in CVID to date. On a year of therapy, she has done something even more marked, which is that she has actually brought back the production of good B cells. And so in that first seesaw I showed you, this is where we are starting to not just replace immune system or suppress immune system.

This is where we are starting to balance immune system, and that is our goal in this disease. And I want to finish with her quote. She said, leniolisib has given me hope that my immunological deficits can be stabilized and ultimately repaired. Dr. Farmer and her zealousness, which I would agree with to obtain compassionate use release of leniolisib has renewed my hope for the future and my longevity dreams can come true. Thank you. And I will now introduce Dr. Rebecca Marsh.

Thank you, Jocelyn. That was an amazing presentation. I'm so thrilled that you were able to take time to be with us today for Research and Development Day. So my name is Rebecca Marsh. I'm a Medical Director at Pharming, and I will be speaking today about Pharming and how we are acting with urgency to unlock the full potential of leniolisib to transform care for immune dysregulation and primary immunodeficiencies.

And I will say that even though I am speaking here today, I am presenting on behalf of Kevin Thorneloe and our entire immunology development core team. This is a required disclaimer. Leniolisib is being investigated for a new indication that has not been approved by the FDA or any other regulatory authorities. The safety, efficacy and appropriate use of leniolisib have not been established for this indication.

There is no guarantee that this product will successfully complete clinical development or receive regulatory approval for any new indication. I really wanted to open this part of the presentation by talking about our mission at Pharming. And that mission really is to transform the care of additional PID patients with immune dysregulation.

So I'm a clinical immunologist and a bone marrow transplant physician and my entire clinical practice centers around caring for patients with only primary immunodeficiency disorders. So this is an area that's very close to my heart. Our mission to transform the care of additional PID patients is very well founded. It is supported by clear and significant patient need, as you just heard from Dr. Farmer. It is supported by a very strong scientific rationale.

And we don't have time to talk about it today due to time restrictions, but we do have additional clinical experience from health care providers like Dr. Farmer, who have requested single patient IND treatment access to leniolisib. And we've actually treated 5 patients with CVID to date, most of them who have been on treatment now for over 1 to 2 years. The clinical trials that we've developed at Pharming really target PID disorders with immune dysregulation that's under the influence of PI3-kinase delta.

We don't have time to discuss all of the disorders that we're studying at Pharming today. So we really are focused on those that share a common pathophysiologic disease mechanism or an endotype that you heard Dr. Farmer speak to and fall under the rubric of a CVID diagnosis. And those groupings of disorders, you can see here that include APDS, genetic PID is linked to PI3-kinase delta signaling and CVID with immune dysregulation.

And when thinking about these disorders, it's really important to think about how PI3-kinase delta is really a master regulator of the immune system. And sometimes we talk about PI3-kinase delta signaling in a very simplistic manner, but it's actually really important to remember that PI3-kinase delta is not only functioning in B cells. It's actually playing a big role throughout the immune system and regulate signaling of T cells, natural killer cells, macrophages, dendritic cells, also eosinophils and basophils. I could go on, but you get the point.

And it's also orchestrating the function within individual cells on a very large basis. So PI3-kinase delta is sitting at the plasma membrane of immune cells and regulating or tuning the signaling of a whole host of immunoreceptors. These include not only important B cell molecules like the B cell receptor, but also the T cell receptor, co-stimulatory receptors like CD28. It's regulating trafficking receptors. It's regulating cytokine receptors like a JAK inhibitor would.

And because of the big role that PI3-kinase delta is playing throughout the immune system, it's regulating a whole host of different functions, including cell trafficking, cell growth, cell proliferation, cell differentiation and function, apoptosis and survival, cytokine receptor signaling and cytokine production. And so when you think about all of the roles that PI3-kinase delta is playing in the immune system, it becomes really easy to understand how any little bit of dysregulation or overuse and activity of pathways that involve PI3-kinase delta can lead to immune dysregulation pathology.

And here, we're specifically talking about the manifestations that Dr. Farmer already spoke to. So things like lymphoproliferation. So here, we're talking about patients with big spleens, big lymph nodes, patients with autoimmunity, things in particular like autoimmune cytopenias, which can be life-threatening, gastrointestinal disease, of which there are many different flavors, pulmonary disease, particularly interstitial lung disease, which can be progressive and really convey a lot of morbidity and mortality risk.

And because we're focused today on these disorders that are grouped under this shared rubric of immune dysregulation that's under the influence of PI3-kinase delta, I'm going to speak now to the clinical trials that we've developed in this space. So all of you are very well aware that we've previously completed a Phase III study in APDS, which led to the approval of leniolisib in APDS patients 12 years of age and older.

And that's important because, as you heard, APDS exemplifies a PID that's characterized by immune dysregulation. It really serves as a proof-of-concept model for understanding related disorders that we're studying. And this is just to remind you about some of our data. Leniolisib is a first-class medicine in APDS, and it really modulates or tunes down the activity of PI3-kinase delta.

And what you can see here in the blue bar is a very beautiful reduction in the total sort of lymph node lesion burden in patients with APDS who are treated with leniolisib compared to placebo there in the small gray bar. And a picture is always worth a thousand words. And so you can also see in the 2 images shown here, very nice reduction in lymph node size from prior to treatment to after 12 weeks of treatment in a patient with APDS treated with leniolisib.

And because we've seen such a good efficacy in APDS and remember that in APDS, it's caused by genetic variants that cause upregulation of function of the PI3-kinase delta enzyme itself. If we can have such a good effect in patients with constitutive activity, it stands to reason very logically that we can also address immune dysregulation in other patients who have pathophysiologic deficits in the way that the pathways are all regulated.

And so we've developed 2 Phase II trials in these 2 different disorder groups. So again, PI3-kinase delta linked disorders and CVID with immune dysregulation. And really, our Phase II trials are designed to, #1, evaluate safety; #2, evaluate optimal dosing, #3, of course, we're interested in generating preliminary data about the impact of leniolisib uncommon in serious clinical manifestations because it is our mission to really transform care for these patients and make an impact in their daily lives.

And you can see here on the left in blue bars are rates of various complications in patients with CVID compared to rates in the general population shown in orange. And so you can see that digestive system disorders, autoimmune cytopenias, interstitial lung disease, all occur at a much higher frequency in patients with CVID. On the right, as Dr. Farmer spoke to, you can see the tremendous negative impact of complications of immune dysregulation on mortality.

And as she mentioned, you can see in the top bar there that patients with CVID who develop immune dysregulation have an 11x higher risk of death compared to CVID patients who never develop complications of immune dysregulation. And then you can easily observe the negative impact of individual manifestations like splenomegaly, interstitial lung disease, GI disease, liver disease. Now the first trial that we opened was a Phase II proof-of-concept trial in genetic PIDs linked to PI3-kinase signaling.

This study was developed in very close collaboration with Dr. Gulbu Uzel with the National Institutes of Health, Unfortunately, due to time, we do not have the ability to go into all of the disorders that are shown here. Several of them you heard about from Dr. Farmer, but I will just point out that there are a couple of additional disorders that don't fall under a CVID diagnosis rubric. These are ALPS or autoimmune lymphoproliferative syndrome and also RAL or RAS-associated leukoproliferative disorder.

And these are included in this trial because the genetic lesions in these patients result in overuse of the PI3-kinase delta pathway. And we're happy to talk about that offline with anyone who has additional questions. This first Phase II proof-of-concept trial, again, was set up #1 to evaluate safety and optimal dosing. And for that reason, you can see that it is a dose escalation study. So patients start out at 10 milligrams for a month.

They then escalate to 30 milligrams for another month and then they escalate to 70 milligrams for 12 more weeks. It is a single-arm open-label study, 12 patients. Key inclusions you can see here need to be an appropriate age, need to have a pathogenic or likely pathogenic variant in any of the genes that are shown. They need to have clinical manifestations that we're targeting and have likelihood to treat.

So cytopenias, lymphoproliferation in the form of either splenomegaly and/or lymphadenopathy or interstitial lung disease. Key exclusions are shown. Patients cannot have had a stem cell transplant, and they can't be on really immunosuppressive medications other than we do allow just a little bit of steroid. Notably, after completion of the Phase II trial, all patients do have the option to continue into a separate 3-year open-label extension study and most patients do choose to move on because they're receiving some benefit.

Now the next study that we designed was in very close collaboration with Dr. Jocelyn Farmer, who you heard from earlier. You'll note that I intentionally overlaid these 2 slides so that you can see how similar they are because there is a lot of overlap in some of the disorders that are included in that first study, namely CTLA-4, NF-kappa B, B10. So again, patients are escalating dosing over the course of the trial.

There is an extra month of treatment in the CVID study to really allow us more time to estimate efficacy in terms of liver disease. Key inclusions are similar, except that patients do not have to have a genetic diagnosis. They really just have to have a clinical diagnosis of CVID, and then they need to have disease manifestations that we're targeting and have high likelihood to impact.

We have a few more exclusion criteria really designed for safety, so patients cannot have severely low T cells or NK cells. These are the shared Phase II objectives and endpoints that are really geared to support pivotal trial design. So you can see here again, the first objective is really safety. So we're assessing safety through standard AE monitoring. We're also looking for tolerability, and we're working hard to confirm the dosing strategy in these populations so that we're best positioned in the Phase III program to be successful.

And so we've got very detailed PK and PD assessments that are part of both of these Phase II studies. We're also estimating the clinical efficacy of leniolisib for immune dysregulation. So based on the clinical manifestations that Dr. Farmer outlined, we're paying very close attention to changes in lymph node and spleen size changes. We're looking very closely at improvements in blood cell counts. We're using very detailed CT scoring of lung disease to really analyze the impact on interstitial lung disease.

We're looking at typical pulmonary function test. And then we've got some other readouts that I don't have time to talk about today. We are also working very hard to evaluate the mechanistic impact of leniolisib and then to also pilot correlative biomarkers, scoring systems to help us in our Phase III effort. So for the mechanistic impact, we're doing some very detailed phenotypic evaluation of B cells by flow cytometry. We're also looking at detailed phenotypic changes in T cells.

We're correlating biomarkers that really play into the mechanism of disease in CVID with immune dysregulation, so things like CXCL13, interferon-gamma, soluble IL-2 receptor. And then we're actually piloting a modified scoring system that's used in the immunology space to help grade disease for patients with immune dysregulation. And then we've developed several custom patient-reported outcome tools to really capture how patients are feeling in their day-to-day lives.

Now this is just a little bit of quick epidemiology to help you understand the impact that we are hoping to be able to make. And we did a really good job taking a deep dive into many different sources of epidemiology. And so we spent a lot of time with our colleagues at the ESID registry. We worked with the USIDNET registry in the North America. We did a comprehensive literature review. We've also talked with many primary immunodeficiency key opinion leaders.

And as you can see here in the second column, these are the references, and these are the estimates from those. And so at the end of the day, the diagnosed targeted population per million for the genetic PIDs linked to PI3-kinase signaling is about 7.5 per million. Now it's important to remember that CTLA-4, NF-kappa B, B10 are also included in the estimates for epidemiology for CVID. And again, these are the references shown here where we're basing our numbers. And you can see that overall, we're estimating the total CVID population to be about 106 per million.

Those who develop immune dysregulation is about 50%. So that gets us to 53%. And then based on Dr. Farmer's work, we estimate that about 75% of those patients have an APDS-like endotype, which brings us to 39. And so when you put everything together, we really have a tremendous opportunity to be able to transform the care of PID patients with immune dysregulation at a population estimate of about 44 per million. So we are all extremely hopeful and excited and looking forward to bring forth transformative care for these patients.

And with that, I will close and say simply that leniolisib for PIDs with immune dysregulation has the real potential to bring unmet need patients a good treatment. PI3-kinase delta is a master regulator of the immune system and targeting PI3-kinase delta can hopefully modulate the underlying immune dysregulation in PID patients. And we are on track, as Anurag mentioned, to deliver top line data in the second half of this year, showing the impact that we are hopefully making for these patients. Thank you, and we'll be happy to take some questions and have some conversations.

Thank you, Rebecca. [Operator Instructions] First question comes from the line of Joe Pantginis at H.C. Wainwright.

My first question is for Dr. Farmer, if you don't mind. And maybe Anurag would like to chime in as well. So Dr. Farmer, you said that there's really a dearth essentially 0 compounds being developed for these indications outside of leniolisib. So why do you feel either from a scientific MOA or clinically, there is such a dearth of pipeline assets? And then do you see any potential impact or even off-label use for other B-cell targeting assets, say, for APRIL or what have you?

Yes. Great questions all around. So in the data I showed with the mortality, that was really a landmark study. And the follow-up study in Germany was just published last year. So I think for a long time, we were just kind of patting ourselves on the back as clinical immunologists that we fixed the infections, and it really took those decades of epidemiologic data saying we weren't doing enough to really unearth that this clinical problem existed. So I think that's part of the delay.

I think the second has been the concept that you could come into a patient with a low immune system and use what's classically thought of as an immune suppressive agent. So we do use off-label B-cell targeting. We use rituximab, we use agents. It takes me about 6 to 12 months to get them approved, a lot of my time. And there are patients, right? So if I give rituximab, I take away the bad B cells.

COVID was very humbling during that time, right? So I wasn't able to immunize those patients to new pathogens once I take the B cells out. So there are risks to those therapies. I think what's so exciting to me here is that there is the opportunity to immune modulate without overtly immune suppressing. So in that patient example that I showed you, actually, I've reconstituted, I brought back B cells that are able to make hopefully functional antibody for the patient in time.

So my hope is that's our future that we're able to modulate more than suppress. But yes, we do use agents off label, not to the point where I think I can sustain that in routine clinical practice. And certainly, we would welcome FDA-approved therapies that we could routinely get through for these patients in a much more expedited fashion and again, focusing on ones where we don't see an increase in infection risk.

And just a quick question, if you don't mind, for this PID genetic study. Can you discuss the variability of steroid use and how you're controlling for that?

Yes. So the patients are allowed to stay up to 25 milligrams a day of prednisone, and that's really just for safety reasons so that if they need a little background steroid to make it into -- coming into study, we do allow that to come in. So it's not a significant amount of steroid, but we do allow a little bit of background.

Our next question comes from Jeff Jones at Oppenheimer.

The -- as you're looking at patient selection across the various phenotypes, is there a way to look directly or more directly at PI3K delta activity and pathways to try for patient selection? And then maybe to expand on some of the commentary on Rituxan and some of the off label thinking about BTK inhibitors and things like that, how all these either play a role today or might play a role as we look at patient population selection here, both for the trial and beyond?

Yes. Pharming pushed me up very hard to look at the phospho-signaling, which I can certainly do. It's an assay I've done for years. It's a tough assay. It's one that's really tough to bring to kind of clinical development because it's so varied. What I've nicely shown you in that second to last slide is that, that pathway activity links with the proportion of atypical B cells. So over time, you can start to use that more functional second assay, which is much more feasible.

We already do that in routine clinical care to start to pick out these patient populations. And so you're 100% correct. What's convergent across all 3 of those arms, APDS, PI3K delta linked disorders and CTLA-4 that get the non-infectious manifestations that we think about bringing on to trial is that they absolutely share those expansion of cells that are high in PI3-kinase signaling. And we will show it in the preliminary work, of course.

My hope is over time, we can divorce ourselves from having to do the complicated assay and move into those readily available clinical assays. In terms of your second question, it's great. That question gets brought to me a lot with the BTK inhibitors. So as Dr. Marsh mentioned, these -- we have dysregulation of both the B cells and the T cells in this condition. So leniolisib is really fortunate and then it crosses over both of those.

So when I use rituximab, I can -- it benefits the debulking of the bad B cells, but I can't hold the patient at bay for long periods of time. I have to use a concomitant T cell inhibitor to do that. So with the BTK, you're going to hit B cells, you're going to hit innate immune cells, you hit macrophages. You leave the T cells uninhibited. And I think we will have to see if that isolated B cell targeting approach is enough to get us there.

I think it's yet to be determined. I like the fact that we have a long experience of using off-label both B cell and T cell targeted agents in this disease, and that has seemed to work over longer periods of time. So I like leniolisib in that it's not single lineage specific because this disease looks to be across multiple different lineages of lymphocytes.

And as part of the clinical trials, we do look at phospho-AKT and phospho-S6 so that we can really correlate the impact of various levels of baseline pathway activity with clinical trial response outcomes. But we actually are not expecting that to necessarily be a prerequisite for what Jocelyn has mentioned and what I mentioned that really the ubiquitous nature of involvement in PI3-kinase and various pathways that are involved in the pathophysiology of immune dysregulation. It's really going to be acting in multiple ways probably.

Next question will come from the line of Lucy Codrington at Jefferies.

I think you may have actually ended up answering one of them in the subsequent presentation. But in terms of the proportion of CVID patients that do have the immune dysregulation or the noninfectious complications, I think it was subsequently said to be 50%, but if we could just confirm that. And then in the patient, the compassionate use patient that you talked about, you showed the kind of change in the B cell profile.

But I guess -- I'm sorry if I missed it, were there any clinical benefits seen in her symptomology in that 1 year? And then my final question, I guess, what constitutes success in the Phase II trials? So for example, if you weren't to see any signs of clinical efficacy, but you did see the mechanistic impact that you were looking for, would that still be enough to drive you to go into a Phase III?

[indiscernible] which was related to the proportion of CVID patients that have symptoms of immune dysregulation also. And we did mention that, that was approximately 50% and then Dr. Farmer, I don't know if you want to answer the second question.

Yes. I'm sorry, not taking for a special slide for that. I was kind of letting the patient speak for herself. But yes, so especially the liver disease, the natural history of that is progression over each subsequent year. And so we've held the liver disease stable, given this woman essentially a year of her life back. Spleen has held stable. Lungs have had no advancement during that time.

I think it's yet to be determined whether that will be the single agent forever more in her condition. Her T cells doubled. She cleared lung COVID for the first time. She was antigen positive for, I think, over a year. So she was able to do things like attend her children's white coat ceremony and be outside of the house more. And so all of those were huge wins. I think can we hit the next benchmark to say we've completely restored; she can respond to vaccines.

No, I don't think we've hit that yet. but I am encouraged with the data I see so far. And again, this is a progressive disease. So I usually say to my patients, if we can hold it in its tracks, I've saved her life, we've won. If I can reverse it, icing on the cake. But I think first goal is can we start to hold patients where otherwise you'd be listed essentially for a liver transplant. So that would be the win.

And I think, Lucy, your third question related to what constitutes a win in the overall program. And really, what we're looking for is improvements in the hallmarks of the disease. So I think you heard clearly from Dr. Farmer and Dr. Marsh, what those disease manifestations are, both from a B cell perspective, but also from a clinical perspective.

So we really are looking for improvements in lymphoproliferation, the types of things that we've seen in APDS patients, improvements in their cytopenias, improvements in some of the other end organ damage manifestations, whether it's the lung disease or the liver disease. Those are the types of things that we'll be looking for in this study and be able to guide us further.

I think we have time for 2 more questions. First one comes in from Chiara Montironi on behalf of Sushila Hernandez at Van Lanschot Kempen. It's a question for Dr. Farmer. Within the PIDs linked to PI3K delta and CVID, can you comment on how many patients have symptoms so severe that they actually need treatment?

Yes. So it will be most. So I think Dr. Marsh did a nice job of laying out kind of -- and I was trying to with the shading on that slide. So when you think about APDS, again, that's your thermostat always on. Those patients uniformly need treatment when they have that genetic diagnosis. When you move into patients with CTLA-4 deficiency with NF-kappaB1, NF-kappa B is a bad gene to have.

If you are a CVID patient, the vast majority of those patients will need to go on to therapy. And then when you move into CVID, if you sit at a large academic tertiary care center, it's approximately 2/3 of the patients we see with CVID that actually need this therapy, but across all comers, yes, 50%. So that's kind of the breakdown, if that makes sense, from absolutely every patient with APDS needing it down to what you've been quoted as the 50% in CVID.

And then final question for the chat. In the absence of an increase in PI3K delta signaling, what is the mechanistic rationale to support leniolisib will provide benefits?

So -- I can answer. So to be clear, it does -- they do have increased PI3-kinase signaling. So that was the phosphoflow I showed you. It's just hard to make that your metric. It's very variable. If you take my B cells, I've done this assay for years, it's a very variable assay. It depends on the stimulation of the B cells. It's better to do fresh than frozen, so you can picture how difficult that can be. So the pathway activation is there.

That is what is there. In CVID, it is there in the cells that I showed you on that last slide that are atypical. They're going down that bad pathway. And so I think the larger question is, are we beholden to always doing this complicated assay? Or can we move one step above that and say, if we define these pathologic B cells as inherently having this high PI3-kinase signaling, can we start to just take that as a firm known entity?

And then can we start to treat all patients that have these convergent B cells with a drug that beautifully targets these pathologic B cells. And I think probably and hopefully, we can. But just to be absolutely clear, we do see the increased activation of the pathway in the patients that we are targeting on these trials. Is that correct? Yes.

We'll now be turning to our next agenda item on today's schedule, and that's to discuss napazimone or KL1333, which is being developed for primary mitochondrial diseases. Again, these are rare disorders with significant unmet need, and napazimone is really positioned to become the first standard of care for this disease. There is a pivotal study ongoing, and you'll hear more about that study and what the opportunity really represents for Pharming. And with that, I'd like to now introduce Dr. Amel Karaa.

Dr. Karaa is an internist and clinical geneticist by training, currently the Director of the Mitochondrial Disease Program at Mass General Hospital in Boston, where she oversees clinical care, clinical research and trials for patients with mitochondrial disease. She is the recipient of the United Mitochondrial Disease Foundation Fellowship.

She is the former past President of the Mitochondrial Medicine Society, past Chair of the United Mitochondrial Disease Foundation Scientific and Medical Advisory Board. She is also a founder and a Board member of the Mitochondrial Care Network, a U.S.-wide network overseeing expert centers for patients with mitochondrial disease and the founder of TREAT MITO, a clinical trial and research consortium for patients with mitochondrial diseases. Dr. Karaa?

Thank you very much, and good morning to everyone. I just wanted to start by disclosing that I am a consultant for Pharming, and I do receive a clinical research grant as well. And what I'll share with you today reflects my own opinion as an expert in clinical and research with patients with mitochondrial disease and do not reflect at all my institution or my university.

So my goal today is to frame primary mitochondrial disease as a serious genetically defined metabolic space with real unmet needs, measurable endpoints and a growing therapeutic momentum. Mitochondrial diseases are not virological curiosities. They are a distinct class of inherited metabolic diseases formally recognized within the International Disease Classification of Inherited Metabolic Disorders.

What makes them unique is that they are -- the genetic mitochondrial dysfunction sits across multiple organs and causes a systemic presentation that is broad of clinically impact and not a narrow niche indication. While genetic mitochondrial dysfunction is cross and multisystemic, secondary mitochondrial dysfunction caused by other rare genetic conditions and other environmental and toxic factors are also primordial mechanisms in multiple other diseases.

So therapies for primary mitochondrial disease can potentially benefit other conditions where mitochondrial dysfunction is present and vice versa. So what makes mitochondrial diseases a bit unique is this dual genome input that they have. They can be caused by mutation in either the mitochondrial DNA or the nuclear DNA. Mitochondrial DNA disorders typically cause adult-onset disease and are maternally inherited whereas nuclear gene defects are typically causing pediatric cases that are Mendelian of inheritance and recessive in nature.

There are about 37 mitochondrial genes that can cause disease and about 400 nuclear DNA genes that can cause mitochondrial disease. So as you can see, this is a hugely heterogeneous genetic condition. This also naturally segments the disease within the market by gene inheritance pattern, age of onset and trajectory, which is highly favorable for drug development and orphan strategies as well as life cycle expansion. I now want to ground this a little bit in a real patient. I invite you to meet Regina, one of my patients.

Regina has a mitochondrial myopathy caused by the mutation 8344A>G. Regina has a strong family history of other members also affected by the disease given that this is a mitochondrially inherited disorder. Over the years, Regina had affected movement, hearing, speech and all function that allow her to socially interact, leading her despite supportive care to lose independence, employment and to have inability to socialize, including with her own family. This is not a unique story to Regina. Most of our patients do have similar disease burden and have a lot of morbidity and mortality. I will invite you to listen in her own words to what Regina has experienced.

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Now we are going to hear the impact that mitochondrial disease has on Regina's day-to-day life.

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So as you can see, what comes across from these 2 short videos is, one, the delayed diagnosis. This is not uncommon but is improving tremendously in 2026 and in the past 10 years due to the advent of more genetic testing. It also highlights the cumulative disability. By the time these patients are diagnosed, the disease burden is already very high. And it creates urgency for disease-modifying therapies. So how do we diagnose these disorders that are so heterogeneous and so complex?

Well, to this day, we don't really have a good biomarker to diagnose mitochondrial diseases, and we heavily rely on genetic testing. This has been the gold standard for the last 10, 14 years. The recommendation as of 2026 is that whole exome sequencing with mitochondrial DNA sequencing or whole genome sequencing be the first-tier testing. However, utilization of these sequencing methods can be hindered by insurance coverage, at least in the U.S.

And despite the use of these large-scale genetic testing, there do remain cases with -- who remain molecularly undiagnosed, owing to the fact that there are probably many more genes to be discovered that cause mitochondrial disease. So after the diagnosis and during the process of the diagnosis, we do rely on other measures that look at the mitochondrial dysfunction biochemically. In the last 5 years, GDF15 and FGF21 have emerged as potential biomarkers.

They do lack sensitivity and specificity, unfortunately. And then we do rely on tissue pathology, which primarily includes muscle biopsies, specifically for a subtype of mitochondrial DNA disorder called mitochondrial DNA deletion syndrome, where the deletion of the mitochondrial DNA can sometimes only be detected on muscle tissue. We also rely on tissue pathology when we discover a new variant of unknown significance where we need more functional assessment to better interpret the pathogenicity of the variant.

Obviously, due to the multisystemic nature of the disease, a full survey of all end organs has to be done, which includes major organs like the brain, the heart, the kidneys, the eyes and so forth and so on. So patients need to undergo a very comprehensive assessment. Mitochondrial diseases are relentless. They are progressive and impact mortality over the course of the lifespan. A published paper from the Mitochondrial Medicine Society did show that mortality in primary mitochondrial disease patients is very high compared to age- and sex-matched individuals.

And it is constant across the subgroups of mitochondrial disease with a bimodal distribution affecting early mortality for the pediatric cases as well as mortality in the mid-20s to mid-50s for the adult patient. Mortality increases over time, but -- and progression remains heterogeneous but measurable. And we now do have natural history studies that can support this data.

On the cellular level, the biology is well characterized now. Primary mitochondrial disease disrupts multiple cell functions, including dysfunction of the OXPHOS metabolism leading to low ATP production and energy failure, increased mitochondrial oxidative stress, impaired mitochondrial trafficking, biogenesis, dynamics and includes defective mitophagy. These are all druggable. And we're no longer asking whether mitochondria matter but deciding which lever to pull.

And the result of the dysfunction is that the same energy failure manifests differently across organs, but the underlying driver remains a shared one and causing organs of highest energy demand to be first affected and to cause severe central nervous system, heart, muscle, eye, GI and kidney problems. Any symptom that you can think of in any organ that you can think of can be affected by mitochondrial disease in one way or another.

Studies have actually shown that on average, a mitochondrial disease patient has 16 different symptoms at any given time. So there's a huge morbidity from this disease. These are some illustrations of more typical red flag symptoms that we do see in our patients. The first panel represent a brain MRI from a pediatric patient with Leigh syndrome, showing typical bilateral lesions in the basal ganglia. The second picture is the retina of a patient with Leber hereditary optic neuropathy, a mitochondrial DNA patient with hyperemia of the vessels and atrophy of the optic nerve.

The third panel shows a muscle fiber with red rimming that represents proliferation of mitochondria called ragged-red fiber, which is pathognomonic for mitochondrial disease when present at high percentage for age. Then you see a rimmed erythrocytes precursor cells filled with iron-laden mitochondria, showcasing the sideroblastic anemia that some patients have. The middle panel shows a very dilated column of a patient who has severe GI dysmotility.

The pseudo-obstruction happens without any anatomical obstacle. And then finally, a cardiomyopathy with a thickened heart, as you can see here within the septum and the left ventricle. So what are the symptoms that are most meaningful to patients? We asked this question several times as drug development efforts started. We wanted to really to understand what was most meaningful to patients to treat if we had a drug that could solve it all.

And consistently across all the registry information that we have access to and the studies that we have done, muscle weakness and fatigue come at the top of these complaints. Patients want to have their fatigue, and their muscle weakness fixed because that is what is most impactful for their day-to-day lives. These are now measurable and reproducible and strong and have some validated outcome measures and strongly limit the daily function and are well correlated with day-to-day activity of the patients.

So what has been achieved since drug development has taken off in primary mitochondrial disease, we now better understand what this fatigue looks like in patients with mitochondrial disease. This is a well-run study that was done in the context of the FALCON study where patients clearly characterized their fatigue that can be multimodal affecting the brain, affecting physical fatigue, energy and muscle fatigue as well.

These have very different impacts on day-to-day life, including effect on schooling, effect on work, effect on housework, effect on relationship and social interactions. And this creates a vicious circle where these impacts further impair the -- and heighten the fatigue perception and vice versa. So in the setting of the FALCON study, multiple fatigue questionnaires were reviewed, and the PROMIS Fatigue Mitochondrial Disease Short Form was created and was -- not created, validated because it's a PROMIS tool that has been already in existence developed by the NIH, but it has been validated in this specific patient population.

And after cognitive debriefing, we do feel that it strongly captures the fatigue experience of patients with primary mitochondrial disease and hopefully can show meaningful change over time. So now we do have validated disease-specific outcome measures for fatigue, which is the most common complaint for these patients. So how common is mitochondrial disease? It's actually more common than people think. Population studies show prevalence higher than many assume.

In studies, pathogenic mitochondrial DNA variants are present in about 32 million to 40 million people worldwide. So these are people living with these variants with or without symptoms developed from these variants. And of those, about 1 million to 2 million will go on and develop full-blown mitochondrial disease of different severity and different organ involvement.

And then when we dig deeper into these mtDNA disorders, the mitochondrial DNA mutation 3243, which is the most common mitochondrial DNA mutation, represents about 300,000 to 400,000 patients within that group, followed by the single large-scale deletion, which represents about 100,000 to 150,000 patients carrying disease caused by this deletion.

And so together, they represent the majority of mitochondrial DNA disorders, and they also represent the targeted population by the FALCON study. So how do we manage and treat our mitochondrial disease patients? Despite decades of research, no approved therapy is available. And the recently approved drugs have extremely limited indication and are not able to support the broader group of primary mitochondrial disease.

So support remains -- treatment remains largely supportive, trying to minimize energy losses and optimize energy gains by recommending that patient eat healthy, sleep well, keep themselves hydrated and exercise, which exercise is very important because it's the only intervention that has scientifically been proven to improve OXPHOS and mitochondrial biogenesis within organ tissues.

So what is the therapeutic landscape looking like these days? It is exciting because there's diversity of approaches now in the development, targeting multiple different cellular mechanism, including antioxidant, targeting biogenesis, nitric oxide modulator, targeting mitophagy, membrane stabilizer and even gene therapy for certain mitochondrial DNA disorders. The box -- the red boxes highlight the active programs as of 2026.

There aren't as many as they used to be, but these remain active programs that have a high excitement for the community, and we're hoping that we will get more and more drugs approved over time. In the last 5 months, we had 2 recent approvals in ultra-rare subset of mitochondrial diseases. We have Forzinity that was approved for Barth syndrome and KYGEVVI that was approved for TK2 deficiency.

Both these are ultra-rare subgroups of primary mitochondrial diseases that will target very, very small numbers of patients. But these 2 approvals are very exciting because they are not just important clinically, but as precedent setting signaling for the field with showcasing that regulators are open to engage and willing to approve drugs when endpoints and unmet needs cross path. So what do we -- what does the ecosystem of mitochondrial medicine look like in the U.S. and worldwide?

We have a well-organized ecosystem in the U.S. We have centers of excellence and expert networks that oversee the majority of our patients with mitochondrial disease. We have a Mitochondrial Medicine Society that is very active putting forth guidelines of -- for diagnosis and management, acute and chronic for primary mitochondrial disease.

We had a North American Mitochondrial Disease Consortium with an 11-year registry for mitochondrial disease and more recently, TREAT MITO, which is the consortium for clinical trial readiness that has started a large-scale prospective natural history study that is FDA compliant to serve as external arms and to better understand the natural history of the disease as well as to help support endpoint development. This is coupled with patient organization that are sophisticated partners for academia and industry.

They drive awareness through education. They have registries sometimes of their own. They have annual disease conferences, and they run a lot of successful patient support program. So we have a landscape that is ready for trial execution, which lowers the risk for patient enrollment and ready to go.

And with that, I would like to leave you with this message. Primary mitochondrial diseases are not a single problem with a single solution but is no longer an intractable one. The science is real. The patients are ready, and the regulatory path has been opened, and we are all here ready to make this work. Thank you.

Thank you so much, Amel. That was an excellent introduction and overview of mitochondrial disease. I'm Magnus Hansson. I'm a Medical Director at Pharming, and I'm heading up the napazimone program. The first time I learned about mitochondrial disease was actually 21 years ago in a very odd location, very remote village in the Austrian Alps. And I was there to pick up a technique from my PhD thesis on mitochondria.

And I never heard about mitochondrial disease during med school, but at this small conference, there were actually 2 physicians working on mitochondrial disease, one, diagnosing, this was before genetic testing was widely available and one treating patient. And he's actually taught a lot of the physicians we now work on and is soon an active investigator in our study. So that's a nice connection.

But already then, I learned how devastating when the mitochondria energy production is insufficient, how devastating diseases can follow. So several years later, when I first encountered KL1333, which we now have a nice name for napazimone, I was super excited about the mechanism of action because I saw in that compound and that mechanism, the potential to actually have a true meaningful impact on people with mitochondrial disease.

So I will speak today about the drug development program for napazimone. So napazimone is an investigational drug that has not yet been approved or has not been approved. And we are right now doing the clinical trials to establish safety and efficacy. So I will talk about those components, first with the mechanism of action, that's the basis for how we have targeted the program.

But then how we have been very careful in selecting a targeted disease population, fit-for-purpose clinical outcome assessments and then built in derisking strategies for the program. So the reason I was excited about napazimone was that it specifically targeted something that is key to the energy deficiency in mitochondrial disease. And that is the low and disrupted NAD+/NADH balance. In the leniolisib program, we target the balance of the immune cells.

Here, we target the balance of what regulates energy in the cell. So with the mutations that cause a large subset of mitochondrial disease, mtDNA mutation affecting the OXPHOS system of mitochondria, that leads to this low NAD+/NADH ratio. And that drives a decrease -- could stop to the energy production and also inhibits the endogenous compensating mechanism, the so-called mitochondrial biogenesis pathways.

And that leads to these debilitating symptoms that we focus on, such as fatigue and the progressive organ dysfunction. And very commonly, as you heard from Dr. Karaa, is the muscle weakness. And this significantly impacts the activities of daily living. So digging a bit further on that mechanism of action and why I'm excited about it is that you can see from these illustrations how central NADH and NAD+, the 2 versions of NAD is in energy metabolism. So it both mediates the energy production and regulates it.

In the central image there, we have OXPHOS dysfunction caused by these mutations causing mitochondrial disease. And that creates a block in this pathway. So it leads to kind of a halt of this energy production system where we see an accumulation of NADH and a relative deficiency of NAD+. Now what is really a hallmark of mitochondrial dysfunction in general is that we see an increase in lactate. So the cells have a small rescue system where they can produce lactate from pyruvate.

So that's also a hallmark of mitochondrial disease and a hallmark of the dysregulated NADH/NAD+ balance. Napazimone has been designed to restore that balance. So it provides an alternative pathway to convert NADH to NAD+. And that is done by redox cycling of the compound. And that also directly feeds into the OXPHOS system. So in vitro, when we look at patient cells, we see activation of the mitochondrial biogenesis or restoration of the mitochondrial biogenesis pathways.

As you can see from this published paper, when we explore this in patient cells and compare that to wild-type cells, you see here 4 different graphs. First, how the patient cells, in this case, from MELAS patients, that's syndrome associated with the most common genetic mutation for mitochondrial disease.

We see how the NAD+/NADH ratio has decreased and how that then leads to a decreased mitochondrial mass, a decrease in those components of the electron transport chain, the OXO system that is coded or affected by that mutation and then an overall decrease in the energy production. After treatment with KL1333, napazimone, we see a restoration of the NAD+/NADH ratio, leading to an increased mitochondrial mass, a specific increase of those proteins that were downregulated or decreased and then an overall increase in energy production.

So how do we then translate that benefit at the cellular level to a benefit for patients? So as we heard early in the program and which Dr. Karaa referred to, from the patient perspective, subjective and debilitating fatigue and muscle weakness are really the 2 most common and highly highlighted symptoms of mitochondrial disease. So we decided to explore those already in Phase I.

And we saw promising differences between the active arms and the placebo arms, both with reduction of fatigue and a signal of improvement of muscle function. And we also looked at biomarkers and as I mentioned, lactate pyruvate is a marker of that NAD+/NADH dysfunction that is a consequence of mitochondrial dysfunction. And we decided then to look more recently closely at this. So a couple of weeks ago, we presented this data in Italy.

So based on the Phase I data, we took the samples we had from all-time points and built a pharmacokinetic model, and we use that model and compared to all the lactate pyruvate samples from Phase I. And we see from that data a clear exposure response relationship that is a nice confirmation of target engagement by the drug. Okay. But moving over, the -- as Dr. Karaa also told you, a lot of the treatment remains supportive.

So from that extent, it hasn't changed that much from 21 years ago. Diagnosis has certainly improved, but still a lot of the treatment remains supportive. And we also see the same picture when we interview health care providers that most patients unfortunately need to find a way to deal with the condition and the high unmet need. Here scored on a scale is really scored -- really towards the top of the scale. So moving over to our drug development program.

So we have been really careful in selecting the target population and then matching endpoints to that. And as I said, try to derisk the program as far as possible. So if we first look at the patient population, you recognize the same image here where we have a subset of mitochondrial disease. So this is category 6 mitochondrial DNA-related disorders. And the reason we specifically focus on them is that they impair OXPHOS function. So they are a good match to the mechanism of action of napazimone.

We also focus on those mutations causing multisystemic disease. And you can see in the table here that we listed the 3 most common but also include very similar type of mutations that are less common. And if we look further at those 3 mutations alone, we can see that the prevalence of those, they account for more than half of the total adult patient pool. They're associated with different symptoms -- syndromes. But what they all have in common is that both fatigue and muscle weakness myopathy is very common in all.

This slide summarizes the clinical trial program for napazimone. In the center of this program is, of course, the ongoing FALCON study. So this is a randomized blinded placebo-controlled study, and we work closely with the regulatory authorities to make sure that this has a pivotal study design. This study will be followed by an open-label extension that will open in the second quarter of this year, and that will ensure that all patients who complete the FALCON study will have access to continued drug treatment.

Looking more specifically at the derisking components we've built into the FALCON study, we knew that it was really important to carefully select not only based on the genotype, but also on the symptoms, the patients experience to make them fit for purpose for the 2 study endpoints that the 2 primary endpoints we have in the study that reflect fatigue and myopathy in the lower extremities. So we have an extended running period during the extended screening period.

And both at the beginning and the end of that period, the patient has to meet certain thresholds for symptom severity. An important other component of the derisking strategy is that we have separated myopathy and fatigue evaluation. So we have 2 alternative primary endpoints. And the study will be positive and demonstrate benefit if either of those demonstrate statistical significant difference compared to the placebo arm.

Then we had an opportunity to have an interim analysis, which was an important milestone from the program and a bit more details on that. That was performed by a fully independent data monitoring committee. They evaluated safety, but they also evaluated not efficacy. We didn't test for efficacy, but we did do a futility analysis of both endpoints. And what was really encouraging was that both of the primary endpoints passed this futility threshold.

And we are, therefore, very confident as the study continues the treatment duration, and we increased the study size from 40 that led to the interim analysis to 180 in total, we will have a really strong data set. So they recommended us to continue the study as planned. The safety and tolerability profile were acceptable. And if we look overall at the safety from the completed studies, 3 Phase I study and the first part of the FALCON study, we see a beneficial and benign safety profile.

And looking at the full FALCON-WAVE-1 data at week 48 confirms that information from the Phase I studies. So of course, we had the opportunity to learn from previous studies that were completed in the field. And most importantly, the mechanism of action to target the underlying pathology is critical. But we also learned a lot about how to target the disease population and how to match specific endpoints to that.

When we designed the program, we had in mind, of course, that the target product profile will be attractive to both patients and also prescribers. And now when we interview these 2 groups, we also see that, that pans out. So we get very good feedback from both groups, highlighting that it's a very promising mechanism and that the endpoints we study are meaningful for the patients. Going back to the prevalence of the population.

So as Amel indicated, for being a rare disease, this is a relatively common rare disease. And if we just look at our subsegment, the FALCON trial inclusion criteria, that's more than half of the entire adult population, and that corresponds to more than 30,000 diagnosed patients with these mutations, the addressable patient populations in the U.S. and the major European markets. So in summary, our program for mitochondrial disease. It targets condition with significant unmet medical need.

And as Anurag mentioned, we are positioned to become the first standard of care in mitochondrial mtDNA-related disease. Super excited about the pivotal study. It's ongoing. We've passed the positive interim analysis, and we have had that aligned with the regulatory authorities. So we believe this program is a significant value creation for patients with mitochondrial disease as well as Pharming. Thank you.

I see some questions have come in. [Operator Instructions] The first question we have comes from Chiara Montironi on behalf of Sushila Hernandez at Van Lanschot Kempen. Can you -- any more color on the status of recruitment on the FALCON study?

The recruitment is going according to projections. So our target is to complete the recruitment by the end of the year and to have the study readout 1 year after the placebo-controlled phase is completed.

Next question from Jeff Jones at Oppenheimer.

Really appreciate the detailed presentation. Could you speak a little bit more on the PROMIS score and what is a clinically meaningful change and what you're hoping to show there? And maybe a little bit the same question on the sit-to-stand score, the degree of change you need to see there?

Would you like to begin and then Dr. Karaa.

Yes. So what is inherently good with the PROMIS fatigue questions is that each question has an inherent meaningfulness to the patients. And that's what we established when we developed the short form and also then cognitively debriefed it. So what we've set the threshold for inclusion in this study is about standard deviation worse than average population. And I mean the study is fully blinded, but we see really interesting trends in the blinded data.

The specific number for what is clinically meaningful in the regulatory setting, that is something that we will use the data and make correlations with kind of global assessments to discuss with the FDA. So that question, what is clinically meaningful has several nuances to it. It, of course, has to reflect what is meaningful from the patient perspective.

And a lot of the exploratory endpoints we have in the study as well as exiting to use has the purpose to establish that number. Yes. And the same is true for 30-second sit-to-stand. So what is good with that endpoint is that it reflects a type of movement, which is very functional for many activities of daily living. And we will do the same process for that endpoint to correlate it with other exploratory endpoints and use the study data to show that.

I would add to that, that it's not -- it was specifically -- the PROMIS fatigue score was specifically selected because that is a tool that the FDA knows well that has a long history of standardized measurements in other diseases and meaningful change in other diseases, including neurological diseases that are very similar to mitochondrial disease, which will be used to extrapolate at some point.

And then like Magnus said, the anchoring within the clinical trial is going to help support what meaningful change looks like at the end of the trial. And what I wanted to add is that in parallel to the FALCON study, we are conducting a natural history study through mitoSHARE, the patient registry and collecting PROMIS fatigue scores on patient every 3 months also. And that is also going to help us identify what a meaningful change is. Same is true for the 30-second sit-to-stand.

We do now have cohorts of primary mitochondrial diseases that have been doing the 30-second sit-to-stand for 5 years, and we do have more standardized values of what the deviations are within this patient population. And we're also doing that within our parallel natural history study, where we are asking patients to do the 30 seconds sit-to-stand at home. And so we're cross validating these 2 endpoints, not only within the trial, but also in a parallel separate natural history study using the exact same criteria for patient selection as the FALCON trial.

And Magnus, I think you partially addressed it, but maybe also just comment on the degree of impairment that these patients have at baseline with both of these measures.

Yes. And that's one of the critical components of the study design that we have thresholds for inclusion. And we've set them to be a standard deviation worse than the population mean. And that has, of course, 2 reasons to ensure that the patients really have an appropriate severity of those symptoms, but also to make the scales in themselves sensitive to change because I think that's often been a problem in previous studies that you apply different questionnaire, different assessments, but you really don't know if you are in a range where you will have sensitivity to change. And we thought about that process really carefully.

Okay. One more question from Lucy Codrington at Jefferies, and then there's one final question after that.

Just wondering if you could remind us in terms of the FDA involvement in the design of the study and any risk -- potential risk in terms of the endpoints and/or this being considered a pivotal study? And then just secondly, and again, apologies if I've missed this, but with regards to the endpoints and kind of relates to my earlier question for the -- sorry, I lost my mind. In terms of is stabilization considered success. Or do you need to see improvement here?

Thank you. Great questions. And if I start with the FDA involvement. So throughout the development of the protocol, we had very close interaction with the FDA. And one of the first interaction was the concepts of the disease to study. So the concept is the regulatory language for which symptoms are meaningful to the patient. I think the first important agreement was that fatigue in itself is sufficiently important to have as a primary endpoint.

Then we added the sit-to-stand test as another independent endpoint and also align that with the FDA. But it also, of course, included the appropriate sample size, the duration of the study, the validation plan. And before we embarked on the initial validation of the PROMIS Fatigue scale, we submitted the whole interview guidance to the FDA. So they've been heavily involved in the whole design of all components of the study.

Thank you. I think that largely addresses the next questions, which were the FDA views on the endpoints and also what the patients think. So with that, I think I'd like to turn it over to Fabrice for some closing comments.

Thank you, Michael. So as this meeting comes to an end, I'd like to thank you all for your attention today. Coming off strong growth momentum and financial performance in 2025, we were pleased to share with you our initial 2026 financial guidance, including, as you saw, a meaningful increase in revenues driven by the anticipated accelerating Joenja growth and the continued RUCONEST growth.

We have clear and significant revenue catalysts ahead for Joenja, and our renewed discipline in capital allocation will help drive the bottom line. I hope that you've got deeper insights into our high-value pipeline today with the opportunity for you to hear directly from Dr. Farmer and Dr. Karaa, who are world-renowned clinical experts in their respective fields.

We have 2 important clinical data readouts in the near term, starting with the 2 leniolisib Phase II readouts in the second half of this year and the readout of the napazimone pivotal study by the end of next year, each having the potential to unlock significant value.

With our proven commercial and development capabilities, a fit-for-purpose growth-oriented leadership team and a scalable organization, I truly believe that Pharming is more than ever poised to achieve its vision of being a leading global rare disease company. Thank you for your attention. We can now close this Investor Day.

Good day, and thank you for standing by. Welcome to Pharming Group N.V. Third Quarter 2025 Results Conference Call and Webcast. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Fabrice Chouraqui, Chief Executive Officer. Please go ahead.

Thank you, operator, and good morning and good afternoon, everyone, and welcome to the Pharming's Q3 2025 Earnings Call. I'll be joined on this call today by Steve Toor, our Chief Commercial Officer; Anurag Relan, our Chief Medical Officer; and Kenneth Lynard, our new Chief Financial Officer.

On this call, we will be making forward-looking statements that are based upon our current insights and plan. As you know, these may well differ from future results. As you saw in our press release earlier today, we delivered another very strong quarter. Total revenues grew by 30% in the third quarter of 2025 versus the same quarter last year, and operating profit jumped to $15.8 million, nearly 4x last year's result. Operating cash flow came at $32 million, putting our cash position almost back to where it was at the end of 2024 before the acquisition of Abliva. Our strong top line growth was fueled by the continued significant growth of our 2 commercial assets, RUCONEST and Joenja.

RUCONEST grew 29% year-on-year, fueled by continued strength in new prescribers and in new patient enrollments, even amid the launch of a new oral on-demand therapy in July. This reflects RUCONEST's unique value proposition for severely affected HAE patients, which Steve will elaborate upon in a minute. Joenja third quarter revenue increased by 35% reflecting the 25% year-on-year growth in patients on treatment and our increasing success in finding new APDS patients. The drug continues its uptake in the 12-year plus APDS segment. And when looking ahead, we anticipate adding new sources of growth with the pediatric indication, the reclassification of the U.S. patients and our geographic expansion. The strong momentum for our 2 commercial assets support an upgrade to our full year 2025 revenue guidance to $360 million -- to $365 million, $375 million from the previous $335 million, $350 million, for which Kenneth will provide more details later in the call.

Finally, the recently announced significant reduction in G&A headcount follows through on our plan to optimize capital deployment to high-growth initiatives to fully capitalize on our significant growth prospects. Before we review our commercial and financial results in greater detail, I'd like to highlight that our Q3 performance reflects our strong growth foundation. In just a few years, Pharming has transformed from a single asset company into a fast-growing biotech with 2 high-growth commercial products and a late-stage pipeline with 2 programs with over $1 billion sales potential each.

As we've seen, RUCONEST continues to grow double digits after 10 years on the market. Its unique value for severe HAE patients and specific manufacturing process make it a reliable cash engine to fund our future growth. Joenja is just at the beginning of its life cycle with multiple growth catalysts. The recent data published in sales suggests significantly higher APDS prevalence and the expansion in larger PIDs and CVID could unlock a much larger market. KL1333 for primary mitochondrial disease is another $1 billion-plus opportunity with a positive futility analysis in the ongoing registrational study. So this combination of durable revenues, first-in-disease innovation and late-stage pipeline positions Pharming well for substantial value creation in the near and long term. With this portfolio and pipeline as the foundation, we can leverage our strong rare disease capabilities to build a leading global rare disease company and deliver on our vision.

I'll now hand over to Steve, who will discuss our commercial progress during the quarter and elaborate on the continued strong growth of RUCONEST and Joenja.

Thank you, Fabrice. Good morning, everybody. As Fabrice said, RUCONEST has delivered another very successful quarter with high double-digit growth of $82 million in revenue, which is up 29% on Q3 of last year. The strong growth is being driven by the continued increase in prescribers quarter-on-quarter. New prescribers are recognizing the value RUCONEST brings to patients suffering with moderate to severe HAE, and this underpins our consistent prescriber growth over the years. In fact, we've added an average of 22 new prescribers in the past 6 quarters, which leads directly to the high level of new patient enrollment and the vial volume increase over prior year, which is at 28% versus the first 9 months of 2024.

Pharming's sustained success unabated by the recent launch of the oral product reflects RUCONEST's unique profile and strong differentiation in the acute on-demand HAE market. RUCONEST remains an important treatment option for moderate to severe patients who experience more frequent attacks, which explains the continued strong momentum and our confidence in the product's long-term growth prospects. As a reminder, RUCONEST is a highly effective product serving all patient types, type 1, type 2 and normal C1, specifically those patients suffering from frequent moderate to severe debilitating HAE attacks. They've also typically failed other single pathway-specific targeted acute therapies such as Icatibant, which have not been effective for them, often leading to the need to redose to stop their HAE attack. As the only recombinant C1 protein replacement therapy, RUCONEST uniquely addresses the root cause of HAE, providing strong differentiation versus single pathway targeted therapies. This differentiation is why RUCONEST is a cornerstone treatment for HAE attacks.

You can see in the photographs on this slide an actual RUCONEST patient, and this is exactly the type of patient I mean, with a more severe course of disease attacking frequently and having to redose on other therapies along with her recovery as she resolves the attack. HEA patients with the disease profile I've described need RUCONEST on hand, which through its IV mode of action delivers a bolus of C1 straight in the vein, which is critical for them. As a result, by using RUCONEST, patients get complete resolution in a single dose for 97% of their attacks. Half of those patients actually get complete attack resolution in 4.5 hours with the vast majority within 24. That efficacy is both critical and reassuring, and that is direct feedback from the patients we serve.

Switching gears to Joenja. As with RUCONEST, we've delivered another strong third quarter. We achieved high double-digit year-over-year revenue growth of plus 35%, generating $15.1 million in revenue for the quarter. The number of U.S. patients on paid therapy is up 25% versus Q3 2024. And importantly, we've identified 13 additional APDS patients in Q3 alone, which shows our ability to keep building the patient funnel in this ultra-rare disease. We're finding patients faster than we did in 2024 with a total number of APDS patients in the U.S. now at 270. Importantly, the resulting significant increase in patients versus 2024 on patients consistently high adherence to therapy is driving this strong revenue growth. The launch of Joenja in the U.K. is also going well, and this is an important first step as we execute our focused geographic expansion plans.

Let's now review the next significant inflection point, which is the pediatric launch in the U.S. for patients aged 4 to 11. The FDA has granted priority review of our application to expand the label and assigned a PDUFA date or an approval date of January 31, 2026. Our preparations for launch after the expected approval in January are on track. As we approach the U.S. pediatric launch, the team has already identified 54 patients diagnosed with APDS aged 4 to 11. 1/3 of those patients are already on therapy through Pharming's early access program and with many others likely to go on therapy soon after launch. So this represents an important growth driver for Pharming, which starts in just a few months.

I'd like to now hand over to Anurag, who will discuss our development programs and the forthcoming data presentations at the American College of Allergy, Asthma and Immunology later this week in Orlando.

Thanks, Steve. In addition to the commercial successes in the quarter, we continue to advance our pipeline in the past 3 months. In APDS, as you mentioned, Steve, the FDA granted priority review for our sNDA for 4- to 11-year-old children, underscoring the seriousness of the disease and the potential to offer a new treatment option with leniolisib. We also have regulatory filings under review in Europe, Japan and Canada with approvals anticipated in 2026. We have 2 Phase II proof-of-concept studies for PIDs with immune dysregulation, and these are also on track for readouts in the second half of '26. And then our newest addition to the pipeline is also progressing nicely, KL1333 in a registrational study for primary mitochondrial disease, where enrollment and site activation are advancing, and we continue to expect to read out in late 2027.

As you recall, there was an important publication in Cell in June. This work has implications for the variants of uncertain significance or VUS reclassification work, which is ongoing by the labs. The publication in Cell, however, also opens another potential avenue to expand the APDS population. Specifically, the paper found more than 100 new gain-of-function PI3K delta variants. What surprised the researchers was that these gain-of-function variants were much more commonly found in population databases, suggesting an APDS prevalence up to 100x higher than current estimates as well as a broader set of clinical symptoms. This raises a number of key questions to determine how these variants may cause disease, including which variants cause clinically meaningful gain of function, what symptoms and diseases do these variants cause and how do we find patients with these variants. We started a number of activities now to help answer these questions. First, we're convening a global KOL at [ AG Board ] this month to address how these variants can cause disease. In parallel, we're sponsoring work to build a predictive AI-driven model that could identify patients who could benefit from targeted PI3K delta inhibition with the goal then to be able to apply the model to large EMR databases. And given the significant findings, we can actually identify more gain of function variants with newer base editing technologies. Generating additional variants will be important not only to understand the broader prevalence, but also for the ongoing VUS resolution project. So much more to come on this exciting work.

We also have new data being presented at the American College of Allergy, Asthma and Immunology. There are 5 posters on RUCONEST where we performed a reanalysis of our clinical trial data with recently used definitions of key endpoints. These data highlight the key symptom benefits in HAE patients experience with RUCONEST across a number of clinically relevant outcomes. In addition, an indirect treatment comparison with sebetralstat will be presented, providing additional evidence for the unique benefits that RUCONEST offers HAE patients. On the APDS side, we have posters describing the treatment burden of the disease on both patients and caregivers. We also have a number of posters on Joenja with real-world data highlighting key benefits, including a reduction in infections. Lastly, ahead of our expected pediatric approval, we have new data in this 4- to 11-year-old APDS population, showing important outcomes, especially on quality of life improvement seen in the study.

I'll turn it over now to Kenneth, our newest member of the team, to review our financials.

Thank you, Anurag. As the new CFO, I'm excited to have joined Pharming at such an exciting time and have the opportunity to provide more color on our strong financial performance and outlook.

Q3 was an excellent quarter with revenues at $97.3 million, up 30% versus the same quarter last year. We saw double-digit revenue growth for both RUCONEST and Joenja. Gross profit grew by 33% to $90.2 million, mainly due to the higher revenues. And accordingly, we recorded a gross margin of 93% versus 91% same quarter in 2024. Our operating profit with a slight adjustment, as it's noted here on the slide, almost increased to 4x to $16.0 million compared to $4.1 million last year. That came from growth in revenues, the improved gross margin and well-managed operating costs. Cash and marketable securities increased from $130.8 million at the end of the second quarter to $168.9 million at the end of Q3. This increase was driven by significant cash flow from operating activities with $32 million. And as Fabrice mentioned, the total balance of cash and marketable securities is now back in line with the end of 2024 prior to the Abliva acquisition.

Our year-to-date consolidated financial numbers for the first 9 months show continued strong execution of our strategy. Total revenues grew by 32% to $269.6 million due to strong double-digit revenue growth for both products and gross profit grew by 35%. Operating expenses increased by $29.2 million, excluding $20.4 million of Abliva-related acquisition expenses and our operating expenses were up by only 4%. Adjusted operating profit, excluding nonrecurring Abliva acquisition-related expenses compared -- was $29.7 million, which compared to a loss of $15.3 million for the first 9 months of 2024. Cash flow from operating activities was $44 million in the first 9 months of the year.

Following the strong results for the first 9 months, we are raising our 2025 total revenue guidance to $365 million to $375 million, up from $335 million to $350 million. This implies full year revenue growth between 23% to 26%. The increase is due to continued strong performance and outlook for the remainder of the year. We continue to expect total operating expenses between $304 million to $308 million, this assumes constant foreign exchange rates for the remainder of the year, includes $10.2 million of nonrecurring Abliva acquisition-related transaction expenses and excludes approximately $7 million in onetime restructuring costs related to the implementation of our G&A reduction plan. We continue to expect that our available cash and future cash flows will cover the current pipeline and related prelaunch costs.

Going forward, we'll further accelerate setting the foundation for strong financial discipline with investments into areas that matters the most to spark near- and long-term value creation. On a personal note, I came to Pharming given my deep belief in its mission to bring life-changing therapies to rare disease patients and so the strong potential to develop a leading global rare disease company. I see great opportunity to sharpen our focus on profitable growth, effectively allocate capital to maximize return on investments and improve transparency and predictability in our financial reporting.

And with that, let me hand back now to Fabrice for closing remarks.

Thank you, Kenneth. So in summary, we are really pleased to report yet another strong quarter, reinforcing the strength of our business for sustainable growth and long-term value creation. As you heard from Kenneth, as a result of this performance and our outlook for the remaining of the year, we are raising again our full year guidance. Looking ahead, RUCONEST is poised to continue to grow and to remain the cornerstone treatment for severe HAE patients, underpinning a strong revenue base. Joenja is well positioned to generate a significant portion of our revenues in the future given strong growth and the additional opportunities we are actively unlocking. Our high-value pipeline is advancing rapidly with a clear objective to deliver 2 potential blockbuster assets, creating a meaningful value creation catalyst for shareholders. And we are also taking decisive steps to enhance financial discipline, including optimizing G&A headcount to ensure efficient capital allocation and maximizing our return.

I'd like to end this call by expressing my sincere gratitude to Steve Toor for his contribution to Pharming over the past 9 years. We look forward to his continued support as an adviser to the company, and we are very excited to welcome Leverne Marsh as our new Chief Commercial Officer to drive the next phase of commercial growth. Let me now open the line for questions.

[Operator Instructions] First question comes from Jeff Jones of Oppenheimer.

Congrats on a really strong quarter. Two questions from us. With respect to RUCONEST, can you speak to any impact you're seeing from the new oral that has come on to the market? Where do you see it being adopted? Do you anticipate any pressure on your patient base? And then for Joenja, you mentioned that 1/3 of the pediatric patients already identified are currently on therapy through early access. Any impact on revenue from these patients when the product is formally approved next year?

Thank you so much, Jeff, for your question. So on RUCONEST, I mean, clearly, we don't see RUCONEST competing head-to-head with sebetralstat. And so that's why I cannot comment on how sebetralstat is doing. As I mentioned, I believe we have a highly distinctive value proposition that serves a different type of patients, more severe patients. And this is due to a unique mode of action that replace the missing, the deficient protein underlying the biology of the disease and a very specific mode of administration. As such, I believe that many more patients could benefit from RUCONEST, many more patients who are not yet well controlled on an on-demand treatment. And that's the vast majority of the RUCONEST patients. These are patients who have not been able to be controlled appropriately with other treatments and ultimately got the efficacy that they needed with a treatment with RUCONEST.

When it comes to the pediatric, the question on Joenja and pediatric, as you rightly said, we have identified already 54 pediatric patients in the U.S. and about 1/3 of them are on our early access program. We expect to convert these patients, those patients who are already on the drug fairly quickly. And as such, which is typically what you see in rare disease, in ultra-rare disease, we expect somehow a bolus of patients to come on drug. This will then add to the patients that are already identified that we will strive hard to ensure that they can benefit from RUCONEST. And then will come additional patients, pediatric patients that we are committed to identifying. So the normal sequence where you have, first, patients who are on access program that will convert, second, patients who are already identified that will probably come on drug if the doctors decide so. And then new patients that you identify. So really, that sequence will probably happen next year.

And given the number of patients that we have already identified, 54, it's a large number, we believe that pediatric, the expansion of the pediatric -- the label to the pediatric population will be a significant growth driver that will add to the current source of business in adults in the 12-year plus segment.

Next, we have Lucy Codrington from Jefferies.

I've got a few, if I may. So just following then on RUCONEST, and apologies if I missed this at the beginning of the call, I was late joining. The plan to stop RUCONEST outside of the U.S., have you given a time frame on when that will become effective? And then just in terms of the competitive threat from Ekterly, given -- I'm totally understanding your -- the different positioning of the drugs. But how often are typically HAE patients seen by their specialist for them any -- if there were to be any switching for that to potentially become apparent?

And then moving on to Joenja. In terms of the VUS opportunity, are you happy with the rate at which the -- this -- I mean, my understanding is we might start to see VUS patients in the second half. And I noticed that the guide no longer -- the kind of details with your outlook no longer kind of suggest that. So is that something that you think is now more likely to be pushed into 2026? And what is the process for VUSs outside of the U.S.?

And then if I may, 2 more. Just in terms of the compliance rates on Joenja, I think before it's been roughly around 85%. Is that something you're still happy with? And then just in general, your rate of progress identifying patients, what do you think the anticipated peak could be within the U.S.? Sorry for so many.

Thank you, Lucy. I'll try to cover all your questions. So I'll start with RUCONEST and your questions related to the delisting of RUCONEST in some countries in Europe. We plan to complete this by the first half, first quarter -- end of the first quarter, first half of next year. When it comes to -- and again, this is really driven by the fact that we don't see the commercialization of RUCONEST in these countries that's financially sustainable. Given the number of growth drivers that we have, we hope to be financially disciplined and ensure that we deploy our capital appropriately. Obviously, we are working with all stakeholders in those countries to ensure that those patients will be able to access the right treatment and if needed, ensure continuity of supply of RUCONEST through compassionate use access mechanism.

When it comes to Ekterly, I mean, I said that clearly, for me, the RUCONEST and Ekterly are serving 2 different types of patients. And as such, I don't see a second threat for RUCONEST. I mean, RUCONEST is a drug that has a unique mode of action that replace the missing or deficient protein underlying the biology of the disease. RUCONEST has a very unique mode of administration that allow a very fast onset of action. And as such, it has a unique value proposition for more difficult-to-treat patients. That's why the vast majority of patients on RUCONEST are more severe patients, are patients that often have failed other treatments, are patients that need actually that level of efficacy, that speed of onset to really address their more frequent and more severe crisis.

All right, moving to Joenja and your question about the U.S. as Anurag said, test labs are in ongoing conversations with the researchers, which published this paper in Cell. And we expect that over time about 20% of the U.S. patients to be reclassified as APDS. We have obviously to remain arm length, obviously, to what's happening and hope that the discussion will progress well and that we will see some patients being reclassified.

Outside the U.S., the process will be the same. Test labs will have to, again, understand the data, incorporate the data, identify patients who are carriers of those newly identified variants. And if those test labs feel that those patients needs to be reclassified, then they'll call the doctors and then the doctors will probably reach out to the patients. The adherence rate is -- we don't see any change actually in the adherence rate for Joenja. It is actually remains extremely strong and around the magnitude that you have mentioned. When it comes to patient identification, you're right that we're very pleased to see that our efforts continue to pay off and that we have added 13 new APDS patients in Q3. We have identified 13 new APDS patients in the U.S. in Q3. That shows our capability to identify patients in this ultra-rare -- suffering from this ultra-rare disease.

You asked about the peak. I mean, there are in the U.S., if you consider the prevalence, at least 500 patients suffering from APDS. On top of it, we've said that we expect that 20% of the U.S. patients actually could be reclassified as APDS, and that could increase the potential of this population by 50%. And then on top of that, Anurag mentioned the efforts that we are making to really leverage the work that has been published in sales and which suggests that APDS prevalence may be far higher. And that could be actually an upside. So again, I think there are some very concrete numbers I've shared with you. And on top of it, the potential upside, which we cannot quantify today. The authors suggested up to 100x. Again, this needs to be verified, and you can see that we have a very concrete and solid kind of action to be able to come back to you with more next year. I hope I addressed your question, Lucy.

Next we have Sushila Hernandes from Van Lanschot Kempen.

This is [ Maridith ] for Sushila from Van Lanschot Kempen. I have 2 questions. First, given your more disciplined approach, what are your priorities for capital allocation? Can we expect another M&A transaction similar in size to Abliva? And second, how is your basket PID trial progressing? And when can we expect top line?

Hi, thank you, Sushila. Thank you for calling out the disciplined capital allocation. That's true. And hopefully, it was very apparent. And with Kenneth joining, clearly, I'm extremely happy that given his track record, I'll be able to really embed that mindset, which is absolutely essential if you want to run a high-performing organization. I think as you see, we have a number of growth catalysts in our commercial portfolio in the short term. We also have a number of pipeline catalysts next year and the year to come. So when it comes to value inflection point, growth catalysts, we have a lot, and we are committed to showing that we can execute.

Now it is true that we have higher ambitions, but there is no rush actually in doing any M&A. Obviously, given the strong growth platform, our ability to generate cash, the very strong capability platform that we have built over the years in clinical development, in supply chain, in commercial, in access, I believe we can be much more ambitious, and we should be looking at the continued expansion of our portfolio and our pipeline. And as such, we are continuously looking at potential opportunities to expand our portfolio and pipeline. So there is nothing planned. There is no rush. Anything that we would want to do will have to be value accretive for our stakeholders and shareholders. But clearly, this is something that we keep in mind. It is part of the work that we're doing. And if we find the right opportunity, obviously, we will engage with our shareholders.

And I think you had asked also about the basket PID trial. And if you remember, this is a study with multiple genes that can drive the PI3K pathway, a Phase II proof-of-concept study. And this study is actually progressing very nicely. We continue to expect readout from the study in the second half of '26. So a very exciting program, along with the CVID program, both on track for second half '26 read out.

Next we have Joe Pantginis from H.C. Wainwright.

This is Josh on for Joe. So I just wanted to ask a question about the new formulation. If you could give any more color on this new pediatric formulation for the 1- to 6-year-old group? And if there's any specific manufacturing hurdles that you may need to clear for this formulation?

Josh, so we have indeed a new pediatric formulation for the youngest population, again, because this youngest population of children wouldn't be expected to be able to follow a tablet, which we currently have available for the older kids as well as the adolescents. For this youngest population, the formulation is granules. And so these granules, we've manufactured them, we've done PK work on them, and we're going through the -- we've actually completed the study with this 1- to 6-year-old population. So we expect to follow a similar process in terms of the regulatory path. And obviously, we've engaged with FDA, both with discussions on the formulation, but as well as on the study design. So I think all of it remains on track.

Next, we have Natalia Webster from RBC.

Firstly, I just wanted to ask around your revenue guidance uplift, just confirming how much of this comes from better-than-expected RUCONEST versus Joenja. And then in particular, for RUCONEST, how you're expecting that to develop into Q4 and 2026, given that you're not seeing much pressure from competition and also continue to see increases in prescribers and patients there?

My second question is on Joenja and the international rollout. It seems that this is contributing around 11% this quarter. So curious to hear a bit more about how that's evolving and how you expect that mix to evolve over time?

And then thirdly, just around the RUCONEST withdrawal from ex U.S. markets. Are you able to comment a bit on the savings you'll make from this and where you plan to redirect those resources?

Thank you, Natalia. So when it comes to our revenue guidance, as Kenneth said, it was driven by the continued strength of our business that we've seen in Q3 and throughout the year in 2025. So obviously RUCONEST plays an important role because of the size of the drug, of the RUCONEST revenues in the total size of the revenues. But this upgrade is driven by both, obviously, the continued performance of RUCONEST and also the continued performance of Joenja. As Kenneth said, the new guidance suggests a growth for the year between 23% and 26%. We have not yet provided guidance for next year. But as we mentioned during the call, we expect RUCONEST to continue to grow as it's serving a differentiated population and has a unique value proposition for these more severe patients. And obviously, the acceleration of the growth of Joenja. Acceleration because until now we were able to source patients from only a unique source of business, the 12-year-old plus APDS patient population and that tomorrow we'll be able to unlock new source of business with the expected expansion of the label to the pediatric population that will add a significant number of patients. We have already identified 54 patients. That's a large number of patients. 1/3 of whom are already on drug, which we'll be able to convert, I hope, and fast. And then obviously, having already identified patients, these patients are more likely to be put on drug, and we will continue our efforts to identify more patients.

And then we have other growth opportunities that we have elaborated upon in detail, the U.S. and then the geo expansion. That was actually one of your points. I think the launch in the U.K. is going very well. So we are very encouraged to see this. I think that shows our ability to launch a drug like Joenja in other countries. We have selected 8 markets outside of the U.S. where we believe we can develop a significant business for Joenja. And so we will roll out this strategy. Obviously, we are -- we will be -- we will make sure that reimbursement authorities in these countries reimburse the drug at the right price. It's absolutely. So the goal is not to launch just for the sake of launching. We have access program in place to allow patients to benefit from the drug at the present time. Obviously we are not a philanthropic company, and we need to have our drug reimbursed, but it cannot be done at any cost, and we will be working actively on this.

When it comes to the RUCONEST withdrawal, as I said, we have to be more disciplined in the way we allocate our capital. We felt -- clearly we felt that maintaining the commercialization of RUCONEST in these countries was not financially sustainable. We'll take great care to ensuring -- great attention to ensure that patients can continue to access the right treatment. In terms of financial implication, it's difficult to quantify. It's going to be minimal. I mean you know that actually the vast majority of revenues came from the U.S. So I don't expect meaningful impact whether on the top line and in the bottom line, this is actually combined with our financial discipline efforts to really manage our cost structure more tightly.

Our last question comes from the line of Simon Scholes from First Berlin.

I've just got 2 questions. So you recorded a gross margin of 92.7% in the third quarter, which I think compares with 90% in H1 and 89% in '24. I was just wondering how we should think about the gross margin in your existing markets going forward? So do you think this 93% is sustainable going forward?

And then you also say in the presentation, I mean, you said you've got -- you've seen an increase in more severe frequent attack patients. Does that mean that these more severe frequent attack patients are actually increasing as a proportion of the overall number of patients?

So I'll start with the latter, and I'll let Kenneth actually elaborate on the gross margin point.

So it is true that RUCONEST is serving a quite distinctive population in the on-demand market, more severe patients. And by more severe patients, I mean, patients who are having more severe crisis, often life-threatening crisis and more frequent crisis. And so that's basically the bulk of the patients. And so as the sales of -- as the revenue of RUCONEST developed, we see that pattern being reinforced. So RUCONEST is a drug that is primarily used on more severe patients, patients who are having more severe crisis, more frequent crisis. And I don't think that, that will change. I think there will be other treatment options for other type of patients.

And RUCONEST will be able to continue to serve those patients, leveraging, again, the reliability that is built among this patient category and with prescribers. And I think that also illustrates the fact that quarter after quarter, although 10 years on the market, we see more prescribers using the drug.

When it comes to the gross margin, I'll let Kenneth elaborate.

Yes, thank you. Thank you, Fabrice, and thanks for the question. It's obvious that we have a high gross margin and it's impacted also by the mix of sales and across different geographies. As you see, so to say, the Joenja share growing and faster growing than RUCONEST, we're having a benefit coming from that. So we don't want to kind of give specifics in terms of the forward-looking performance, but I think you have seen kind of a slight increase on a continuous basis as we start to build out the Joenja sales to a larger extent. So I think Q3's performance is very encouraging, but we are not at this point of time giving the specifics around forward-looking, but think about it in that context of the Joenja share growth.

That concludes the Q&A session. I will now hand back to Fabrice for closing remarks.

Thank you very much, operator. Thank you all for attending this call and for your continued interest in our company. With that, I'll close the call. Thank you.

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