Beam Therapeutics Inc Stock

Good morning, and welcome to Beam Therapeutics Conference Call. [Operator Instructions] Please be advised that this call is being recorded at Beam's request.

I would now like to turn the call over to Holly Manning, Vice President of Investor Relations and External Communications.

Thank you, operator. Good morning, everyone, and welcome to Beam's conference call to review initial clinical data from the Phase I/II study of BEAM-301 in patients with glycogen storage disease Type 1a presented at the ESGCT Annual Congress. You can access slides for today's call by going to the Investors section of our website, beamtx.com,

With me on the call today with prepared remarks are John Evans, our Chief Executive Officer; Dr. Amy Simon, our Chief Medical Officer; and Dr. Giuseppe Pino Ciaramella, our President.

Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties and other factors, including those set forth in the Risk Factors section of our most recent annual report on Form 10-K and any other filings that we may make with the SEC.

In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. Except as required by law, Beam specifically disclaims any obligation to update or revise any forward-looking statements even if our views change.

With that, I will turn the call over to John.

Thanks, Holly. When Beam was founded nearly a decade ago, it was driven by a bold belief that a new generation of genetic medicines could transform the treatment of serious genetic diseases. This opportunity is much bigger than one treatment, one disease or even a handful of diseases. We believe this is the start of a new era of medicine, one in which we address disease at its genetic source with onetime therapies that potentially prevent a lifetime of disease progression. These medicines can free patients from the burdens of chronic treatment, and in so doing, they can also lower lifetime costs for the health care system.

We know patients and their families want to move on from their disease. Physicians and payers want a treatment that prevents further decline and reduces the expense of chronic disease management and regulators want to enable these therapies to reach the people who need them. At Beam, we saw this coming and have positioned our company to lead this new era of medicine.

Underpinning this vision is base editing, designed to make precise changes to DNA without creating double-strand breaks. This precision is capable of producing consistent gene sequence outcomes and durable correction following a single treatment.

The promise of base editing treatment is profound. By fixing genetic disease at its root cause, we have the potential to deliver transformative disease modification or even functional cures for patients with highly predictable outcomes.

Today, our vision for base editing is becoming a reality. Over the last several years, base editing has moved from an emerging scientific concept to a potential new class of medicines being administered to clinical trial patients across a growing range of serious genetic diseases.

Just 3 years ago, we treated the first clinical trial patient in our sickle cell disease program with the goal of enabling a life free from the constant burden of pain crises and organ damage that is sickle cell disease. That program is now progressing toward a potential regulatory submission.

Last year, we made history by demonstrating for the first time, genetic correction of a disease-causing mutation in a patient and establishing clinical proof of concept for our first in vivo liver-targeted therapy for alpha-1 antitrypsin deficiency or AATD. That program is now in pivotal development.

That same year, Baby KJ became the first person in the world to receive a personalized on-demand base editing treatment designed specifically for a unique genetic mutation through the incredible work led by the team at the University of Pennsylvania and Children's Hospital of Philadelphia.

And today, we mark another important milestone with initial clinical data for BEAM-301, showing what targeted genetic correction could mean for people living with glycogen storage disease type 1a.

Individually, each of these is a remarkable milestone in the history of medicine. Collectively, they showcase the coming era of genetic medicine in which we have the potential to correct the root cause of disease once and for all in a huge range of conditions from people living with more common genetic diseases like sickle cell disease and AATD to those with ultra-rare conditions that until now were not commercially viable and ultimately even a single child.

To put this transformation into context, I'd like to share a little more about the life of a person living with glycogen storage disease type 1a. Because their bodies cannot maintain normal glucose levels during fasting, people with GSDIa must take carefully timed doses of cornstarch throughout the day and night to maintain blood sugar levels. And since their glucose levels are constantly dropping, missing even a single dose can result in severe hypoglycemia with the potential for seizures, coma or death.

That means daily life is organized around constant vigilance. Patients and caregivers monitor glucose levels, manage repeated dietary dosing and set their alarms to go off every few hours all through the night to prevent a potentially life-threatening event.

One parent of a GSDIa patient told me she hasn't slept through the night once since her child was born because like so many GSDIa parents, she is part of the first line of defense to make sure her child gets through each night safely.

By correcting the underlying mutation, our goal is to restore the body's ability to reduce glucose on its own. For patients and families, that could mean freedom from around-the-clock cornstarch dosing, more stable glucose levels and the ability to sleep through the night without the disease dictating every decision. That is the potential of treating genetic disease at its source. Amy will share some of the promising data from the BEAM-301 clinical trial in patients with GSDIa later in this presentation.

Over the past decade, we have built the core capabilities needed to bring these potentially transformative medical outcomes to patients at scale. Our editing and delivery technologies are highly adaptable and reusable, and they are delivering consistent preclinical and clinical results.

In fact, across 4 of 4 distinct programs, we have now translated our preclinical findings into clinical proof of concept. Each success strengthens the platform by generating translational and clinical experience and by establishing technical foundations that can be applied to the next program. Now that this flywheel is running at speed, each new program has the potential to be faster, more efficient and more likely to succeed.

In addition to the breakthrough science and technology underpinning our platform, 2 other factors are essential to expanding our impact across more diseases and patients, our internal manufacturing infrastructure and an increasingly flexible regulatory environment.

I'd like to take a deeper dive into each of these now. First, we recognized early that the traditional model for developing and manufacturing genetic medicines would not support the scale of our ambition or the potential of this technology. Gene editing is a highly complex therapeutic modality with many critical components that must be precisely engineered.

That is why we made the decision in 2020 to begin building out fully integrated internal production capabilities for CRISPR medicines, spanning editor design, automation, computational biology, process development, manufacturing and quality release.

The silicon chip industry famously relies on fabs, highly specialized manufacturing facilities that fabricate the complex silicon chips underpinning the computer, Internet and AI revolutions. Our vision is to create a fab for CRISPR genetic medicines.

Today, those capabilities allow us to move from the design of a new editor through the production of clinical and potentially soon commercial material within one vertically integrated organization.

Just as important, the assays, procedures and manufacturing experience established through one program can be cross-referenced and reused across all the programs that follow, helping us avoid redundant investment and serve even more patient populations in need of therapies.

These capabilities are already paying off in our 2 most advanced programs. Both are now in pivotal development and target large patient populations. In sickle cell disease, risto-cel has the potential to be a highly differentiated onetime therapy and Beam's first commercial launch.

Because we create customized base edited cell products using each patient's cells, owning the manufacturing process has been critical to shaping the patient experience and improving manufacturing outcomes as seen in the BEACON trial. It also led us design for commercial scale from the start, and we've already expanded capacity to meet potential demand.

The same facility now manufactures our investigational base editing therapy, BEAM-302, a new kind of treatment designed to directly correct the exact DNA misspelling that causes disease in most patients with AATD. BEAM-302 has the potential to become the first onetime therapy addressing both the lung and liver manifestations of AATD.

Through these programs, we also have built a substantial base of validated assays, manufacturing processes and quality systems designed to support late-stage development and potential commercialization. This foundation can be cross-referenced, adapted and extended as we advance the next generation of programs through our platform.

With all the momentum for base editing in the clinic, our focus now shifts to reaching as many patients as possible with this technology. While sickle cell disease and AATD are large enough to follow standard regulatory paths, the traditional regulatory model doesn't work for many genetic diseases. Some like GSDIa, affect relatively small populations, while others like PKU are caused by many different mutations within the same gene.

Luckily, the FDA has been closely following this new technology as well. And in recent years, they have advanced multiple new frameworks with the potential to accelerate our ability to treat more patients with base editing medicines.

Some of these approaches enable us to cross-reference platform information across programs, avoiding needless duplication of effort and vastly simplifying the path to clinic for new editors.

Other guidance frameworks, such as the plausible mechanism pathway, allow us to treat populations of patients who may have different mutations with different base editors, but still combine them into a single efficient clinical program.

Together, these new approaches at FDA represent a paradigm shift in drug development away from evaluating each product in isolation and toward recognizing the cumulative evidence generated across the common components in a validated platform. And what Beam has been building for the last decade positions us perfectly for this potentially dramatic expansion in the reach of genetic medicines.

So now we have a programmable technology for gene correction, a capability for complex CRISPR manufacturing at scale and an FDA that is working to evolve the pathways to help us go faster.

As is commonly noted, rare diseases are individually rare, but collectively common. Sickle cell disease and alpha-1 antitrypsin deficiency are among the more prevalent genetic diseases. Yet together, they represent only a small part of that total. The rest is spread across thousands of genes representing millions of potential patients in the U.S.

Each of these diseases is rare on its own, but together, they are one of the largest areas of unmet need in medicine. And most of these diseases have a clear genetic cause. Historically, that fragmentation has been the barrier.

Now our platform and new regulatory pathways together have the potential to change that. Instead of treating each new mutation as a fresh start, we can add new patient populations onto the foundation we've already established. That lets us pursue opportunities across the full spectrum of genetic disease from common mutations down to single patients.

Today, we'll focus on 2 examples of what that looks like in practice. In GSDIa, we are developing our base editing candidate, BEAM-301 for a severe mutation found in approximately 300 patients in the U.S. Initial clinical data suggests that by correcting that mutation at its source, we can restore the body's own ability to produce glucose following a single treatment.

Importantly, 2 of 3 patients at our second dose level reached the maximum time limit in a fasting challenge without becoming hypoglycemic, and they have eliminated their cornstarch use, exactly the kind of outcome we dreamed of when we started this program. We believe this outcome validates the potential of base editing for this disease and also provides another data point for the success of our LNP delivery platform.

And thanks to the FDA's platform regulatory approaches, we now have a potentially efficient path to advance a medicine for this patient population that would be difficult to serve through conventional drug development.

With BEAM-304, our investigational base editor in the metabolic disorder phenylketonuria, or PKU, we are extending that model across multiple mutations within the same disease. Rather than developing each editor as an entirely separate product, our approach is designed to build from a common technological, manufacturing and regulatory foundation with the potential to reach a much broader portion of the PKU population over time.

These are 2 different expressions of the same strategy, using the accumulated capabilities of our platform to make genetic correction possible across progressively broader and more diverse patient populations. Today, we'll begin with GSDIa and the initial clinical data for BEAM-301.

With that, I'll turn the call over to Amy.

Thanks, John. GSDIa is an autosomal recessive metabolic disease caused by mutations in the G6PC1 gene that disrupt glucose-6-phosphatase or G6Pase, a key enzyme involved in maintaining glucose homeostasis. GSDIa can result from a single point mutation in G6PC1 with R83C representing one of the most prevalent disease-causing mutations and one associated with the most severe form of the disease.

GSDIa patients with the R83C mutation cannot effectively maintain normal blood glucose during periods of fasting and can become severely hypoglycemic within just 2 to 3 hours without food or corn starch. As a result, patients rely on frequent meals and slow digesting cornstarch throughout the day and overnight in order to maintain glucose levels and prevent severe hypoglycemia.

Despite intensive dietary management, patients remain at risk for serious consequences of hypoglycemia, including seizures, metabolic crises, coma and death. GSD1a also results in the accumulation of glycogen and other metabolites in the liver, which can lead to liver enlargement, renal insufficiency and other long-term complications.

BEAM-301 consists of an mRNA encoding an adenine-based editor and a guide RNA encapsulated in a lipid nanoparticle or LNP that directed the liver to the precise location of the R83C mutation in the G6PC gene.

BEAM-301 is designed to directly address the root cause of GSD1a by precisely correcting the disease-causing point mutation back to the normal sequence. This correction is intended to restore functional G6Pase activity, enabling the liver to once again convert stored glycogen into glucose and maintain normal blood glucose levels during periods of fasting.

We have previously shown that in preclinical studies, a single dose of BEAM-301 resulted in a significant and durable improvement in survival in a humanized mouse model of GSD1a carrying the R83C mutation. These findings provided important preclinical evidence that correction of the underlying mutation could translate into meaningful disease modification. We have now reported initial clinical data that demonstrated clinical proof of concept.

Moving to our study design, BEAM-301 is being evaluated in a Phase I/II open-label clinical trial to investigate its safety, tolerability, pharmacodynamics, pharmacokinetics and efficacy in patients with GSD1a, who are homozygous or compound heterozygous for the R83C variant and have had at least 1 episode of hypoglycemia in the last 2 years.

The primary endpoint is safety and the key secondary endpoints are change from baseline in the time to hypoglycemia in a monitored controlled fasting challenge and change from baseline in starch supplementation.

As of August 17th, 2026 data cutoff, 6 patients had received a single intravenous infusion of BEAM-301, including 3 patients treated with 20 milligrams and 3 patients treated with 40 milligrams with a median follow-up of 7.6 months across both cohorts. Their baseline characteristics are shown here on Slide 19. At baseline, these patients could only fast for a brief period of time, a median of 2.7 hours before encountering significant hypoglycemia defined as a glucose less than 60 mg per deciliter.

As John mentioned earlier, these patients require frequent cornstarch supplementation to maintain their glucose at safe levels. Patients in the trial required a median of 6 cornstarch doses in the 24-hour period, meaning approximately every 4 hours throughout the day and even at night, these patients need to have cornstarch supplementation.

Turning to safety, BEAM-301 demonstrated an acceptable safety profile at both the 20 mg and 40 mg dose levels with no dose-limiting toxicities, treatment-related discontinuations or Grade 4 or 5 treatment-emergent adverse events. The most frequent treatment-related events were infusion-related reactions, or IRRs, and transient transaminase elevations, consistent with the known safety profile of intravenous LNPs.

All transaminase elevations resolved without intervention and with the exception of a single Grade 2 AST elevation, all transaminase elevations were grade 1. The use of shorter-acting steroids as premedication, which is typical in this patient population may have contributed to the Grade 3 IRRs observed and the steroid premedication has since been modified.

Now turning to efficacy. BEAM-301 demonstrated dose-dependent improvements in time to fasting hypoglycemia, a key measure of glucose regulation in GSDIa in a controlled fasting challenge. The median fasting duration increased from 2.9 hours at baseline to 4.3 hours at day 36 in the 20-milligram cohort and from 2.5 hours to 15 hours in the 40-milligram cohort.

Importantly, 2 of 3 patients treated with 40 milligrams reached the protocol-defined maximum fasting duration of 15 hours, consistent with restoration of endogenous glucose production following a single treatment with BEAM-301.

The third patient in the cohort did not show an increase in fasting duration. We hypothesized that this lack of response may be secondary to the patient's elevated BMI, which could reduce hepatic drug exposure or to lower overall editing as this patient is a compound heterozygous carrying the R83C mutation. We expect to learn more as we advance to the next cohort at the 60-milligram dose level.

The improvements in glucose control -- the BEAM-301 treatment were also accompanied by reductions in both the amount and frequency of daily cornstarch supplementation that were most pronounced in the higher dose cohort. 2 of the 3 patients in the 40-milligram cohort were able to eliminate starch supplementation entirely. For patients and families living with GSDIa, this removes an enormous daily burden.

These patients can now sleep through the night without setting alarms to take cornstarch and go to school without carrying bags with premeasured doses of cornstarch that must be taken at timed intervals throughout the day,

Taken together, we believe these initial data demonstrate clinical proof of concept for BEAM-301 and support its potential to address the root cause of GSDIa with a onetime therapy. By targeting the underlying enzymatic defect, a single dose demonstrated restored hepatic glucose metabolism with the potential to enable normal fasting tolerance and lasting freedom from starch supplementation.

If these results are further validated as we continue to dose additional patients, BEAM-301 has potential to prevent severe hypoglycemic episodes, limit the chronic complications of glycogen accumulation and free patients from around-the-clock disease management.

Based on these initial results, we are continuing to enroll patients in the 60-milligram cohort to further characterize the safety and efficacy profile of BEAM-301 and inform dose selection. Given the promising initial clinical results we've observed together with the severity of GSDIa and the rarity of the R83C patient population, we also plan to engage with the FDA on identifying a potential path to approval for BEAM-301. Those discussions will help inform the evidence required to support a potentially modest pivotal expansion with the ongoing Phase I/II study.

Beyond the progress in GSDIa, BEAM-301 is also helping us to build a growing base of expertise in rare metabolic liver diseases that can extend across multiple programs. Many of these diseases share common biological pathways are cared for at specialized metabolic treatment centers and have similar aspects of disease management, such as requiring strict dietary management.

The experience we are gaining translating editing into evidence of restored enzymatic activity, working with these clinical communities and patients and their families and advancing liver-targeted investigational therapies can therefore enable us to leverage some adjacencies and learning from one indication to the next.

Over time, we believe this growing expertise can create meaningful synergies across non-clinical and translational research, clinical development and commercialization. Shared clinical networks can support future programs, while focused commercial and market access capabilities could ultimately serve multiple metabolic indications. These capabilities reinforce the broader platform we have discussed today. Each program can advance an individual medicine candidate, while also strengthening the underlying foundation for those that follow.

With that, I'll turn the call over to Pino to discuss how we are applying this model in PKU.

Thank you, Amy. The data Amy has presented provides a compelling example of the model that John described earlier. At its core, the power of our platform is the ability to carry knowledge and capabilities forward. Each program adds to our understanding of editor design, delivery, translation, manufacturing and clinical development. Those learnings in turn, increase our confidence and inform how we advance the next program.

BEAM-301 benefited directly from the foundation established through BEAM-302. With BEAM-304 in PKU, we're extending that model further by applying a common platform across multiple disease-causing mutations within the same indication.

On Slide 28, we've illustrated what this looks like in practice. BIAM-304 builds on the LNP, messenger RNA and guide RNA delivery capabilities validated clinically through BEAM-302 and now BEAM-301. The manufacturing experience from those programs also informs how we produce and advance the BEAM-304 candidates.

But PKU introduces another important dimension. Rather than developing a medicine for only the most prevalent mutation, we are designing a family of editors intended to address multiple mutations through a shared technological manufacturing and clinical foundation.

The shared components in these editors mean that we can expect consistent preclinical and clinical outcomes, and we can accelerate development with a shared delivery platform, and internal manufacturing platform and a single clinical development framework. This creates the potential to reach progressively more patients without rebuilding the entire development model for each new variant.

PKU is an inherited autosomal recessive metabolic disorder caused by many different mutations in the PAH gene. In the United States, there are approximately 20,000 people living with PKU.

And we are excited to announce today that we have identified our third development candidate within our BEAM-304 program targeting a third undisclosed PKU mutation. This comes just months after the unveiling of our first 2 development candidates earlier this year, emphasizing how this flywheel is able to move faster and faster.

Together, the editors in the BIM-304 program have the potential to treat up to half of PKU patients in the United States, and we have active research efforts to address additional pathogenic PKU mutations over time, potentially covering a majority of all PKU patients. This approach to creating a more efficient path to serve the genetic diversity of PKU is fundamentally different from a conventional single product strategy.

At a product level, each BIM-304 candidate contains an editor and guide RNA designed for a specific PKU causing mutation. Across those candidates, however, we intend to preserve common attributes wherever possible, including the LNP delivery system, physical chemical characteristics, pharmacokinetic and biodistribution profile and manufacturing processes. This consistency is important because it creates the potential to leverage non-clinical evidence across related product variants rather than repeating the full development package for each one.

Our proposed approach is to establish the broader safety profile through BEAM-304A, the first variant planned to enter clinical development and then use that accumulated knowledge to inform the development of subsequent variants. This is the practical application of a platform model, customize what must change for the patient's mutation while carrying forward the evidence and infrastructure that remain relevant.

Our preclinical results across the first 3 variants demonstrate the remarkable consistency of base editing technology and support this approach. In mouse models corresponding to 3 different disease-causing mutations, treatment with potentially therapeutic doses produced potent correction and normalized blood phenylalanine levels. This data informed the selection of BEAM-304A, BEAM-304B and most recently, BEAM-304C and supports our belief that the underlying platform can be adapted across variants, while continuing to generate predictable biological outcomes.

We have designed the Phase I/II study to reflect this platform approach. Earlier this year, the FDA cleared a single IND for BEAM-304, enabling us to evaluate multiple BEAM-304 candidates under one clinical protocol. To start, we will evaluate BEAM-304A in a dose escalation phase, allowing us to characterize safety and tolerability, evaluate reductions in blood phenylalanine levels and the potential for diet liberalization and identify an optimal biological dose.

Subsequent BEAM-304 candidates could start with the optimal biological dose established with BEAM-304A rather than repeating the full dose exploration process for each new variant.

Each candidate can then seamlessly advance into a collective dose expansion phase for pivotal development. This approach creates a potential path to move efficiently from one mutation to the next and progressively extend the reach of BEAM-304 across the PKU population.

We hope you've come away today with both a sense of our vision for what is possible with Beam's platform and the significant near-term value drivers within our portfolio that are bringing this vision to life.

Our 2 lead late-stage pipeline programs address large markets and are advancing towards important milestones with risto-cel on track for a potential BLA submission and first commercial launch and the pivotal study for BEAM-302 is underway.

At the same time, our next wave of clinical and preclinical programs is building on the validated editing technology, vertically integrated manufacturing infrastructure and expanding clinical experience established by the programs that came before.

Importantly, we are well funded to reach key inflection points across each of these programs. Together, we believe this combination of near-term execution and a platform that learns and repeats positions Beam to become a leading genetic medicine company.

To close, everything we do at Beam is ultimately about the people who could benefit from this medicine. I want to thank the entire Beam team for the work that brought BEAM-301 and BEAM-304 to this point as well as our investigators, clinical sites, partners and advocacy organizations around the world.

We'd also like to thank our PKU collaborators, Kiran Musunuru and Rebecca Ahrens-Nicklas at Penn and CHOP. Most importantly, we're grateful to the patients and caregivers who participate in our trials and make these programs possible. Thank you for joining us today.

Operator, please open the line for questions.

[Operator Instructions] Our first question coming from the line of Alec Stranahan with Bank of America.

Congrats on the updates here. Two from me. One on the GSD program and then one on the broader platform. So I guess on the dose escalation, thinking about the 60 mg cohort, what does this need to show for you to choose it over, say, the 40 mg? And is there a capability to expand maybe an 80 mg cohort as well? And when will we see data from the 60 mg?

And then more broadly on the pipeline, I guess one on AATD. A competitor recently announced some alignment for their registrational trial that has a full approval with 2 years and 1-year interim analysis to support a potential accelerated approval. Any thoughts here vis-a-vis the alignment that you struck for your program in terms of time lines and just overall sentiment from your conversations with the FDA would be great.

Yes. Thanks. So maybe I'll take this in a couple of parts. So let's start with GSD1a and 301. Maybe, Amy, do you want to talk a little bit about what we've seen at 40 mg, which is obviously quite dramatic and then the plan to go to 60 mg. And then Pino, if you want to expand at all on our thoughts about path to market here? And then I'll cover the 302 question after that.

Sure. So at 40 milligrams, we're seeing, as you can see, dramatic effects. We are now having 2 patients at the 40 mg dose completely weaned off cornstarch. Keeping in mind, they've been on 6 doses throughout the day. In addition, they are now fasting for over 15 hours or 15 hours, which is the maximum time point.

So from that, you can see that we have restored G6Pase activity and endogenous glucose production, which is quite significant. However, we just want to make sure that we're not leaving any further efficacy on the table. And the reason I say that is there is restoration of glucose metabolism and then there's also restoration of any kind of alterations in the metabolic pathways such as hypertriglyceridemia, hyperuricemia and increased lactate.

And while we have very promising results for that right now as well, sometimes that takes a little longer to see. And so we'd like to be able, during this important dose escalation phase, make sure we understand the safety and efficacy of our choices for our optimal biologic dose.

So of course, to date, we've also seen acceptable safety at the 40 mg cohort, and we'd like to examine that as well. Once we see the totality of data from both the 60 mg and 40 mg cohorts, we'll make the decision of what is the optimal biologic dose to take forward.

Pino.

Yes. And in terms of moving this program forward to licensure, as Amy mentioned, obviously, we want to see the totality of the data, including the 60 mg, and then we will have a conversation with the FDA to move this program forward.

Given the rarity of the disease, obviously, we hope to move this program forward as efficiently as we possibly can and obviously, with the FDA support moving forward. So -- but we're very, very encouraged by this data. And obviously, the 60 mg could also provide some additional clarity on the individual compound heterozygous person that didn't respond like the other 2.

That's right. So yes, I mean, I think when you see data like this, I think if you compare this to what has been seen in this field before, this is obviously quite dramatic. So this is a moment where you sort of say, we're pretty sure this is a potential drug. We want to get to patients as quickly as we can. We have to then finish off the experiment here to identify the dose for the FDA. But I think this will be a very -- we will be working to make this an accelerated pathway.

To your other question about 302. So yes, we've seen that report. I think, obviously, alpha-1 is going to have a lot of different competitors in it. Everybody is going to try to sort of figure out their path. I think until we see more details on protocol design, it's too early to say. That said, BEAM-302 is obviously setting a precedent here. We're -- that's sort of the benefit of being in the lead. We get to sort of lay down tracks that that the field can use.

And so as you know, we're already in our pivotal cohort, which will be a 1-year follow-up for accelerated approval and then follow other outcomes for the longer term. So we think we look forward to learning more about others while we stay focused on just accelerating our 302 path as quickly as we can.

Our next question in queue coming from the line of Samantha Semenkow with Citi.

Congrats on the 301 data and all the progress. I also have 2 questions. Just first on 301. I'm wondering if you could just share a little bit more detail around some of the safety events that you observed, particularly the IRRs and the rhabdomyolysis. Just wondering how we should think about these AEs? Was it the LNP driving it or the construct? And any comparisons you can make to BEAM-302 since both of these programs use the same LNP?

And then second question, just bigger picture, you really outlined some nice long-term sort of views for how to think about pipeline growth within various ways that you can maximize that for base editing. I'm just wondering, how should we think about the cadence of new programs over the next several years as we think about longer-term sort of growth for the business and just maintaining that growth long term?

Yes. Thanks, Great. So I'll take the second question after, but let's start with Amy on the safety and talking through the steroid experience, the IRRs and then also rhabdomyo (sic) [ rhabdomyolysis ].

Sure. So in general, I think what we're seeing in BEAM-301 is fairly consistent with what we see with LNPs in general with both having IRRs and transient transaminase elevations as being the most common findings. I think what's a little bit different is the severity of the IRRs was, as you can see, slightly greater, meaning that there is, let's say, more intensity or longer duration of symptoms, which were typical and seen in our other studies. So for example, fevers, chills, body aches, those types of things are all still very common. They may be lasting a little bit longer.

In general, we do think this relates to the fact that we are using a different type of steroid premedication in this population. And it turns out that long-acting steroids are really to be avoided in this patient population because they can cause risk of severe metabolic decompensation, particularly lactic acidosis. As a result, shorter-acting steroids were used as a premedication by all of the investigators.

Once we realized that there was differences probably relating to the use of those kind of shorter-acting less potent steroids, we've since made adjustments to the steroid regimen to ensure that those shorter-acting steroids now provide the same duration of coverage and same potency that we would have seen with dexamethasone. So that's the answer to your question about the IRRs.

As far as the rhabdomyolysis, in that case, we actually don't even think that technically that met criteria for rhabdomyolysis. So in that case, we would think it's more elevated muscle enzymes or elevated creatine phosphokinase. And the reason is to really hit rhabdo, you have to have a CPK that's greater than 1,000 with myoglobinuria, electrolyte and creatinine abnormalities, and that was not the case.

So we think that this patient potentially developed this from having some muscle pains and aches, which can cause the release of muscle enzyme or CPK. So really not concerning and not by the investigators thought to be related to BEAN-301, but more to the inflammatory profile of just getting muscle aches and pains with an infusion-related reaction.

As far as the transaminases, we're seeing really mild Grade 1 elevations in transaminases of ALT. And the one person that had a transient Grade 2 AST elevation was that patient who had the muscle enzyme elevation, and it turns out that AST can come from muscle and is not as specific to the liver as ALT. So overall, I would say that this profile is very consistent other than the slightly more severe IRRs with our other LNP profiles that we've seen and with other LNPs that have been dosed in clinic.

Yes. Thanks, Amy. So yes, so I think that is an important point. I think our LNP experience just continues to grow. We continue to be very pleased with what we're seeing in the safety overall for this platform. And then because we get to reuse these capabilities again and again, it really bodes well for obviously, 302 and 301, but any programs we bring forward from here.

Shifting back to your platform question, yes, I mean, that's sort of what we're so excited about here that again, you have the predictability and reusability of these technologies where, again, you're using the same kind of delivery every time with these LNPs. We can make them in the same way in our manufacturing facility. And once you get a base editor into a cell, it's going to edit. We know that in vitro. So you start to have this flywheel kick in where we have increasing confidence that things we make can work. And that is incredibly valuable in our industry, where risk is really the thing that killed you over and over.

On top of that, you have the fact that costs drop. It's quite expensive to do this the first time, but then doing it a second time, you're just literally rerunning the same kinds of things that you ran before. In some cases, as Pino outlined, you start to just cross reference them. you don't even have to rerun the study. And that can be the case in things like acute tox or certain assays, et cetera.

So the time line to start new programs, the cost to start them and the uncertainty that you face when you start new programs is all dropping dramatically as we get going here. So in terms of cadence, I think we can't guide there. We're more likely to keep things a little closer to our best until we're ready to talk about them as we've been doing with PKU, for instance.

But I think you can certainly expect that's the whole point of the talk I gave that we see a really incredible opportunity to address an incredibly wide range of potential genetic disorders in any organ that we can reach with this technology, obviously, starting with the liver, but certainly not stopping there. There's a lot of patients who need help, and we think these transformative effects can be brought to many, many conditions.

Our next question coming from the line of Brian Cheng with JPMorgan.

Maybe just 2 from us as well. Just going back to the poster, can you talk a little bit about the triglyceride excursion that we're seeing here? Is that something that you expected based on what you saw in the clinical study? I mean in the 40 mg, it seems that there's a pretty wide spread of triglyceride excursions. I mean maybe perhaps it's due to end of 3. Just curious if you can talk a little bit more about what you expected? And then we have a follow-up.

Yes. Amy, do you want to talk about triglycerides?

Sure. Yes. So I think when you think about what's going on with this block in G6Pase that happens, you get a buildup of G6 phosphate. And from that buildup, it then goes down alternate pathways that it gets diverted to. So for example, that you expect then with the block that there's increased triglycerides, increased lactic acid, increased uric acid.

And as you relieve that block and as you increase G6Pase activity, the very first thing that you should see is that you actually get glucose metabolism restored. These other types of pathways need to be sometimes restored in longer periods of time because there's a lot of kind of counter pathways that have been upregulated over time. There's hyperinsulinemia and other things because these patients are often overconsuming starch to keep their sugars in the euglycemic range. So there's a lot of different pathways that are kind of intersecting being upregulated.

Once you relieve the block, it does take some time for these things to then kind of have their throughput. And so I would argue the first thing that you can see benefit from is this ability to fast, which is quite striking.

And just to keep in mind, when you ask someone to fast who has GSD1a, they usually at the most, can fast 2.7 hours. These people are going 15 hours and not only are they going 15 hours, but their lactate levels are near normal. Keep in mind that these patients don't even have normal lactate levels when they're not fasting before treatment. So this is quite amazing and suggests that some of these other pathways that have dysfunction are now being actually impacted positively.

I think it's going to take us a little time to definitively know what's going on with triglycerides as more glycogen, et cetera, gets kind of then taken out and then converted to glucose because keep in mind, they've had tons of glycogen accumulation over a lifetime. And so we expect over time to actually see triglyceride levels going down. We expect the cholesterol levels to go down. And what we saw in the fasting challenge for their lactates to remain normal.

So given that there's a lot going on, that there is dietary adjustments also going on, I think it's going to take a little time until we see how their triglycerides actually settle out.

Okay. And then a quick follow-up on the third patient in the 40 mg cohort. Just given what you saw with that third patient, is there any specific protocol that you're implementing in the study going forward? Meaning are you excluding -- are you enforcing a cutoff for BMI? Are you continuing recruiting patients with compound heterozygosity? And just curious if you have any thoughts about that? And how does -- if that's the case, whether that has any potential to the addressable population?

Yes. Amy, do you want to just cover the sort of -- why don't we summarize the hypotheses around the third patient and then just talk about the path forward and whether any changes to the protocol being made.

Yes. So I mean, in general, our hypotheses are exactly what you said, which is, is it due to the fact that this patient had a BMI that was quite outside of what we had seen before, so over 50, whereas I believe the mean was around in the 20s, mid-20s. And so this is quite a high BMI. These patients can have very large livers as well. And because of that, given that we have fixed dosing, one hypothesis would be that the overall liver exposure that this patient saw was, in fact, lesser. So that is one hypothesis.

The other hypothesis is that this is a compound heterozygous for the R83C mutation. And so is it possible that you had editing that was more robust at one of these mutations that they had, et cetera.

I think going against that is the fact that we had a compound heterozygous that was in the 20 mg cohort that is one of the patients that had not only a very good response, but it was very similar to a homozygous patient. So from that perspective, looking at our 20 mg data, we don't see a difference in response between the compound [ het ] and the homozygous patient. However, we're still looking into this. We will plan to dose in the 60 mg cohort, both patients that are compound het as well as homozygous and see if there's any further information that we can get from that.

I think your point about the BMI is quite interesting. I think that's something for us to think about. Unfortunately, this patient population can have obesity because they're taking so much cornstarch that they're trying to keep their blood sugars up, and this can lead to kind of almost overweight because of this high cohort -- cornstarch.

So I don't know at this time that we're ready to limit the inclusion criteria, but it will pending the 60 mg dose, get us to think about whether we would change our dosing paradigm if your weight was above a certain BMI or if a patient with a certain BMI. So I would say stay tuned on that. We'll learn a lot more as we dose the next cohort.

Our next question coming from the line of Yanan Zhu with Wells Fargo.

Congrats on the data. Three quick ones, if we may. First, regarding editing efficiency at the 20 mg and 40 mg level. Is there any estimate based on the data? And the body weight aside, do we think for the same body weight patient, the editing efficiency could translate across different indications such as between this indication and AATD.

The second question regarding your level of comfort in terms of the IRR in the 60 mg cohort. I was wondering with this updated steroid regimen, what's the comfort level? And have you happened to have dosed any patients there yet? And what's the initial takeaway there?

And lastly, on PKU, I was wondering, it sounds like the initial cohort of study will be on mutation A. I was wondering, as you add on additional mutations, could multiple mutations be added at the same time to increase the pace for expanding to mutations? Or is it still one mutation at a time?

Yes. Great -- great question, Yanan. So maybe we'll go to Pino first for the first and the third. So Pino, any comments on how we think about editing efficiency in GSDIa? And can we draw conclusions from other programs to this one. And then maybe if you also want to talk about how we will be introducing some of these newer PKU editors over time. Yes.

Yanan, thanks for the question. Yes, obviously -- so we don't know specifically what is the editing rate. So we haven't done any biopsies in order to be able to do that. What you will see, however, that at the 40 mg, obviously, the 2 responders responded extremely well. So clearly, reestablishing the full functionality of that system.

In terms of translatability, I mean, this is basically a different guide, first and foremost, and obviously, different guide have got different potency. It is potentially a different editor. So really, the one important thing that the best translatability is the fact that you're seeing the same LNP and very similar doses that can be used across the board because essentially, the safety, obviously, is preserved with the exception, obviously, of the steroids that I'm sure Amy will address in terms of your question.

So what we do know is that what is translatable is that the preclinical to clinical translation is proving to be very robust and solid. And so now we have very good ways of predicting starting doses, levels of efficacy that we are expecting to see. And so that gives us confidence for the future programs as we develop new combination of guide and editors.

Excellent. And then Amy, do you want to talk a little bit about just any thoughts about as we go to a 60-milligram dose, do we think the IRR issue is solved at this point with the adjusted regimen or anything we're watching out for [indiscernible]?

Yes. I mean I definitely think that the optimization of both potency and duration of steroid coverage has definitely helped. And so I do feel that both we feel pretty confident about it. Obviously, the DMC, SRC agreed with us and the PIs agreed. And for that reason, we feel very comfortable going up to the 60-milligram cohort. And I think that it's something that, obviously, we take safety very seriously -- very seriously and it's something we'll be monitoring.

But it's good to know that these investigators now all have experience with both delivering an LNP as well as with managing these IRRs, which, in general, have been, as you mentioned, very manageable for these sites. So stay tuned on the 60 mg cohort, both in the safety and efficacy profile.

Yes. Well said, I think it's just a general just kind of comment that I have that I think these LNPs are really doing quite well. And this is a great delivery modality where we're talking about temporary headache, fever, flush kinds of infusion reactions or lab abnormalities on the LFT front in return for a onetime dose that gets to potentially transformative durable efficacy like we're seeing here. It's a pretty good delivery vehicle. We're quite happy with it.

[Operator Instructions] And our next question in queue coming from the line of Michael Yee with UBS.

I'm going to ask one question, 2 parts. I guess, as it relates to the outcome of the studies in terms of the regulatory framework, could you just maybe talk a little bit about the type of discussion or the openness of the FDA to have a very rapid type of a pathway given a very ultra-rare disease. And if that endpoint would probably be the cornstarch endpoint or is it hypoglycemia endpoint, maybe just talk a little bit about what you're envisioning there because I could see this being very fast.

And then the second, if that's the case, could you comment a little bit about the commercial framework given the 300 patients, I think you cited on one of the slides and how you think about the commercial opportunity from a prevalence standpoint? And is that how you're thinking about and how we should be modeling things?

Yes. Maybe I'll just -- I'll jump in on this one. So I think -- I mean, we clearly are going to talk to the FDA about going as fast as possible here. And I do think this program is quite well aligned with the kinds of things they've signaled in the past about a willingness to look at small data sets and going quickly for very severe rare populations. That's several of our other programs. We're also, of course, going to be seeking approval based on our initial trial.

And I think this -- we expect this would be potentially no different. So even as we have the 60-milligram cohort, we'll be working out a couple of these questions. We'll also be looking to enroll pediatric patients. I'm sure that we might be eligible for pediatric review voucher. These are all important aspects. It really is all in the context of how do we get this to patients as quickly as we can, and we do expect the FDA will be partnering with us on that. So I think that we should see that.

I've actually -- already forgotten your second question. What was the second one?

Yes. Given a potential path to approval, which we would be excited on [indiscernible].

Oh, yes, commercial.

Commercial framework given the 300 patients and yes.

Yes. So that is -- so this is 300 like real patients. I mean we -- I think the epidemiology might have suggested it's actually more like 900 if you do the math, but I think we wanted to be as realistic as we could. But this would be 300 like diagnosed patients, all of whom need treatment. This is a severe mutation uniformly. So we think that's quite important and exciting. So with a relatively efficient clinical path, we think there's plenty of patients there to generate a meaningful commercial market.

Obviously, if we have treated everyone, then that goes away. But I think this is just an example of one of the many kinds of programs we can generate as part of this platform. So yes, I think I'll just leave it there. But I think clearly, the value here for patients is quite significant, and we're quite eager to see this reach everyone with this mutation in disease.

Our next question in queue coming from the line of Maury Raycroft with Jefferies.

[ This is James ] on for Maury. Congrats on the results. Just a 2-part question. How many patients have you enrolled so far in the 60 mg cohort? Do you plan -- also do you plan to dose more patients at the 40 mg so you have a sufficient data set to compare against? And when do you expect to have enough 60 mg follow-up to meet with the FDA on the path forward?

And then separately for PKU, the IND cleared in mid-June, but there isn't any trial post on CT.gov. Is it reasonable to assume that you started activating sites and recruiting patients at this point? Or what are the gating factors for starting the study?

Yes. So maybe, Amy, do you want to cover the first one, and I can talk about the time line of PKU?

Sure. So currently, we're open for enrollment for the 60 mg cohort. We're not really giving guidance on how many patients we've dosed, et cetera. You asked a really good question. I mean most of our cohorts are N equals 3, but we have the option to go up to an equal 6 per cohort.

So we probably, as you indicate, we'll dose a minimum that N equals 3 in the 60-milligram cohort and then decide what our next step is, which could include getting more information at 40 mg, as John indicated, could mean opening pediatric cohort.

So I would say stay tuned on that, but we plan to get that data, and as John indicated, have an interaction with the FDA sooner than later so that we can, as he mentioned, get to patients efficiently as possible because as you can see, there's a tremendous unmet need and especially in that younger population, where sometimes they have to have feeding tubes to keep their glucose up overnight. So we expect this will be one of those programs that hopefully, the FDA agrees with can move fast because this is a rare population with significant unmet need.

Yes. And then for PKU, I think as we said at the time of the filing, so this is one where we actually -- this will be a pretty fast path program overall with the exception of opening the first site. So this is -- we're going to be in the U.S. We're going to be in big academic centers. So this isn't one, where you go to England or New Zealand as sometimes people do. We want to be in the big metabolic centers with diagnosed patients who have their genotypes. So that's where to focus. Everything is very much on track.

But I think at the time, we always said it would be -- this isn't a 3, 4 months to start the trial. It's 6 to 9 months to get those first sites open. So we're looking at sort of end of year and first part of '27, most likely, but all on track. And then from there, it's pretty fast. As I said, we think there will be a dose escalation. As you can see, we think we're getting better and better at this LNP understanding. And so we're looking forward to that.

And of course, at the same time, we're treating patients and looking for that early data set, and that should be pretty definitive in terms of are we on track for success there. And then from there, there's some kind of expansion where, again, in PKU, all you have to do is show phenylalanine lowering and some amount of diet normalization and that those are full approval endpoints. So I think it sets us up for another fast path push like we've done elsewhere.

Our next question coming from the line of Adhi Sikand with Evercore ISI.

It's Adhi on for Cory. Could you maybe characterize the editing profile of BEAM-301 with respect to if any bystander edits or off-target editing was seen as discussed in the AATD program?

Yes, Pino?

Yes. No, we see no bystander editing and the off-target profile is completely acceptable for moving forward. So no -- the AATD situation is quite different given the density of [indiscernible] in the particular editing window, but it's not the case for GSDIa.

Our next question in queue coming from the line of Myles Minter with William Blair.

Congrats on the data. I know you haven't done liquid biopsies, but do you have a sense just from your PK modeling and PD modeling what the expected range of G6PC1 enzyme activity is that you're getting across 20 mg, 40 mg and 60 mg 301 doses. I think previously, you said from preclinical studies that 11% enzymatic activity is required for metabolic restoration. So just trying to understand where 20 mg, 40 mg and 60 mg is predicted to get you.

Yes, Pino?

Yes, you're right. So there are various models that predict basically something around 10% is enough to restore the activities. As you've seen in the 40 mg, we are expected to be above that meaningfully. So we will see, obviously, with the 60 mg, whether we can also see responses in additional compound heterozygous, which, as Amy explained, we've already seen some positive response in a 20 mg patients. So we'll see how it goes. But we are meaningfully above the 10% for sure.

Our next question in queue coming from the line of Patrick Trucchio with H.C. Wainwright.

This is Luis in for Patrick. I was thinking about the addressable population here. So the R83C mutation about 300 to 900 patients, but there's also other mutations Q347X is a common one as well. I was thinking if you're thinking -- how you're thinking about BEAM-301 future development, is it possible that you can have a similar development protocol -- umbrella protocol like you have for PKU in where you have multiple INDs for multiple mutations using the same platform? And how do you expect to develop that? What's the cadence of development for those additional mutations?

Yes, it's a great question. But it comes back to the addressable market here. So I think absolutely correct that the same platform rules may apply. So that's something that we would consider in the future, really just have to meet with the GSD community and understand kind of the unmet need of the different mutations and sort of the level of applicability of what we can bring. And then obviously, the regulatory frameworks are there, we believe.

And as a reminder, even going back to our PKU situation, it's not even multiple INDs. In the PKU case, it's the same IND multiple editors. So that's kind of the big breakthrough here in the new paradigm shift that we're seeing in how the FDA is treating these platforms. So for sure, with GSDIa that will be something that we will consider in the future as we work with this community.

And our last question in queue coming from the line of Luca Issi with RBC Capital Markets.

This is Cassie for Luca. And we have a quick one for BEAM-301 for the team, given what you have observed preclinically across the programs in terms of translatability of PK/PD from animal models to patients, would you expect the dose response curve going from 40 mg to 60 mg to mirror the magnitude going from 20 mg to 40 mg or at least proportionally, we appreciate 20 mg to 40 mg is obviously doubling the dose versus 40 mg to 60 mg maybe a smaller step up -- or would it be more like what we saw with the top 2 doses in AATD that some kind of ceiling effect already achieved with the 40 mg dose from -- back in AATD was the 60 mg dose and here the 40 mg dose. From what we heard on the call earlier, the 60 mg dose is perhaps making sure no efficacy [ that's ] on the table. So I just wanted to -- [ you will bring up that ].Any color much appreciated.

Yes. I think a simple way to think about this and invite others to comment if they have anything to say is just that we've just about maxed out efficacy that we can see in terms of the 2 endpoints we're measuring, which is cornstarch reduction and time to hypoglycemia through a fasting challenge.

I think there was a question actually a lot earlier that we didn't quite answer, which is we do think that of these endpoints available to us, time to fasting hypoglycemia is probably the harder endpoint. It's more well controlled. And so when we think about approval pathway, that would probably be the favored one. cornstarch reduction is, of course, also quite meaningful and important to these patients.

So I think in the 2 to 3 -- 2 of the 3 patients at 40 milligrams, there's not an obvious room to improve, obviously, that we've sort of maxed those out. It's really just the third patient where -- whether it be BMI, as Amy mentioned, or is it something with the genotype, we just have to learn that. I mean most of those hypotheses suggest that more exposure would probably help. And so that's really the goal of the higher dose cohort. But we're learning a lot as we go, and we'll look forward to updating you as we get that data.

Thank you. And there are no further questions in the Q&A queue at this time. I will now turn the call back over to Mr. John Evans for any closing remarks.

Thank you. I really appreciate all the engagement. We just couldn't be more excited about this data set, obviously, for patients with this mutation. As I said in my remarks, it's just such a terrifying disease. And we think that this is the kind of potentially transformative and profound effect that we want to achieve for patients like this. So as I open, you can really start to think about moving beyond your disease, moving beyond chronic therapy and moving on with your life. So that is our vision as a company.

And as I also said, I think that the manufacturing platform, the FDA rules and of course, this technology itself that we're using, we think, really position us to focus in the years ahead on bringing this kind of outcome to as many patients as possible across genetic disease from the rarest [ cause of ] mutations to increasingly common disorders. So we look forward to partnering with you all on this journey and hopefully making a big impact on medicine and on patients in the years to come.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation, and you may now disconnect.

I'm Sam Semenkow, one of the senior biotech analysts here at Citi. And it is my pleasure to be hosting Beam at Citi's 2026 Biopharma Back To School Summit. I'm joined by John Evans, CEO; and Sravan Emany, CFO. John and Sravan, welcome, and thank you both for being here.

Thanks for having us.

So why don't we just start by level setting. You've made a lot of progress across the pipeline this year. Just tell us where the company stands today and what we can expect through the end of the year and beyond.

Yes. Great. So Beam has made a lot of progress. We're moving very quickly now across a broad range of programs, all building off of this very dynamic platform that we've created. Using base editing, of course, next-generation CRISPR 2.0 technology for more precise gene editing, but then building that into a delivery and manufacturing machinery that is now quite mature. So doing both ex vivo cell therapy but also now in vivo lipid nanoparticle part programs and manufacturing all of that internally. So it's a very significant capability we've built.

The programs are now moving very quickly. So Risto-cel, our sickle program is really awaiting its final data cut from a now fully enrolled and dosed BEACON trial that will become a BLA filing right around the end of the year, which will be our first BLA. So that will be an update we're excited to share. Then in vivo programs, on the liver, we have been 302, alpha-1 antitrypsin deficiency. We just have shared sort of new data there, showing really dramatic consistency of that program as we continue to add patients. That's now a pivotal cohort. We're enrolling patients. We dosed our first patient in July. By the end of the year, we hope to have significant progress on enrolling that 50-patient cohort and continue to move that program forward towards patients. Behind that is BEAM-301 which is a program for glycogen storage disease 1A, the R38C mutation. There we'll have first data, first in human data this year on a couple of dose cohorts for that program, another sort of metabolic type of mutation that we're going to try to correct.

And then finally, also Vivo PKU, BEAM-304, we now have an open ID. So we're now opening sites as we speak and hope to begin screening patients towards the end of this year. And obviously, then that will become a clinical program to follow. So lots going on, lots to talk about, but we're seeing this flywheel continue to gain momentum on both the payload technology and our delivery manufacturing capabilities.

Yes, absolutely. So as you said, lots to get into, why don't we start with AATD. So yesterday, you did share data an updated data cut. And our takeaway kind of what you said is that it seems to be quite durable in that the level of AAT and MAT induction that you're achieving just continues to be within the range of that protective NZ phenotype. So maybe it would be helpful just to hear a little bit of the feedback from ASR. Walk us through how physicians are viewing the data, how impactful they believe achieving these levels of AAT and MT are for patients.

Yes, it's a great question. So there's been a lot of enthusiasm and I'd say ERS is no exception. We're hearing from physicians around the world, certainly our investigators, but more than that, that this looks like the profile they've been waiting for. There's been -- this patient community is really overdue for some better therapies. And when you ask them sort of what is the ideal outcome, they will say, well, we need something that raises our AT into the protective -- above the protective threshold -- teams into the teens because that is the place where there are no patients who have those kinds of levels.

We want to raise it by creating M, the norm protein, which we know is functional, and we'll protect their lungs. At the same time, we want to be reducing Z as much as we can -- that's a toxic protein, both for the liver, but we've learned a lot more recently about its disruptive effects systemically, causing inflammation and interfering with the protection of normal you want to be inducible, right? So when you get sick and as you could go up and we have shown that. And then, of course, you want it to be durable. Patients -- these patients have been on chronic therapy, their whole lives, taking weekly augmentation. They're very hungry for a onetime cure, and that is what we believe we're offering. So lots of excitement, I think, as the physician and patient community, and we continue to see that operationally in our BEAM-302 trials.

And so one thing we heard after the presentation yesterday is maybe a little bit of confusion on the assay used to quantify AHV and MAT. It can make cross-trial comparisons perhaps a little difficult and maybe even comparing your own data cuts difficult. So maybe just talk about whether Tuburdity or LC/MS is better assay. Why are you using both? And maybe clarify if we're seeing a decrease in AAD levels or if it's just an assay difference.

Yes. Great question. So there are multiple assays available. And I think the important point is to step back and see that they're actually telling the same story across the board. We do change back and forth between the bits. So turbidimetry is the classic in the deal. This is literally taking protein in liquid, shaking it up and seeing if it disrupts light scattering. So it's a fairly crude sort of old assay, but it is used by the clinicians very frequently. So that's the standard. If you're going to get diagnosed with ATD, you're going to use turbidimetry to do so. But they don't check AT levels very frequently. It's kind of a one-off.

So for our first academic conference presentation, which yesterday, we thought turbidimetry makes sense because it could be familiar to the clinicians, and they would fully understand it. LCMS is different. That's, of course, mass spec, and we need LCMS to discriminate between the kinds of AT, right? So if you want to see how much you have, how much Z you have turbidimetry can't do that. So we need LCMS at least for that. And so you've seen some of our LCMS data reporting that. Our expectation is ultimately, even things like total AT level for the FDA, they will also want LCMS. And so we have been bridging our way over to that assay. I expect we will -- you'll see more of that from us in the future.

Right now, we're validating it for pivotal stage but it gives fairly similar answers. There is definitely for these assays, there is a 10% wiggle as you think about sample to sample and also AT levels themselves drift up and down for these patients on that order of magnitude. So I definitely don't see -- there's no change in our levels, I think that you should interpret here between 16%, 14.5%. It's all basically mid-teens. And as we have seen, it's quite durable. So once you see those set points, I think you'll see them sustained.

Right. Okay. What patients tend to achieve is what they tend to keep?

Exactly.

And so then looking forward, there's a lot of competition in AATD. The space has quickly become quite crowded. You remain well ahead of competitors entering pivotal studies. But other companies are also developing gene -- therapies. And so how do you see 302 positioned outside of being first to market against all the competition?

Yes. So I think the success of BEAM-302 is definitely going to invite competition, and they will be coming. We have the fortune of being well ahead. So we've been up against some different costs of medicine. So RNA editing is one that we've been facing. I think we're now moving past them in operations, we're now into pivotal trials or any editing is still more of the early stage development. By and large, the numbers they've produced have been positive clearly for patients, but maybe numerically not where we're at in terms of both level [indiscernible] amount of being produced, the amount of production in the -- so then you look to the DNA editing field.

And as I said, I think the DNA editing is maybe more where the ideal target product profile lives for the patients and for the community. And they are, as you noted, BEAM-302 is in pivotal trials. We will have a clear first-in-class advantage. We're about 2 years ahead of our most advanced competitors, but there are going to be others. By and large, it isn't clear to us where the opportunity for differentiation clinically really lives. There will definitely be a competition around who can maybe have the higher AAT level and that will be something that people focus on. The reality is all of our patients are already above the protective threshold, right?

So there's no evidence that there's any clinical difference once you get to that state or going a little bit higher, it also isn't clear to me exactly how much higher you can go. I think we'll learn as we see some of the competitor data. But I think it's clear to me that editing a lot of the liver in these patients. You can get patients to that protective threshold. You can get them into the teens. I don't think it's going to be possible to get people to 30, which is kind of where normal would live. But again, it's all good because patients are protected now.

Beyond that, I think BEAM-302 is doing everything we needed to do. So I think we're looking forward to pressing on the accelerator and staying certainly ahead of the competition and bringing a new product to patients as quickly as we can. All that said, competition is good for patients. We're always welcoming of more entrants. They certainly deserve more options.

And just maybe double-click on that a little bit about the AAT level. I mean, do physicians recognize that there -- it's going to be difficult to clinical differentiation, say, if you have 2080 versus your 14, 16, depending on the asset. Like how do you think it will be viewed by physicians when they're trying to make treatment decisions.

Yes. I think it's got quite well understood. So these physicians have thought a lot about the clinical genetics here, right? So ZZ is the profile of a patient. They live in the 6 -- 5, 6 range in terms of their [indiscernible] levels and their parents, right, the people who are carriers who maybe have 1 copy of Z, but the other is of M, they are in the teens. And this is called MZ. And so an alpha-1 expert intimately knows what ZZ patient is like versus an MZ carrier, and then, of course, MM is the normal. And there's been extensive literature that these community groups have done to understand what is the relative risk of each of these groups. And it is a very settled question that MZs do not have progressive disease, they're perfectly stable where they may have a little bit of high risk is if they are heavy smokers, for instance. So if you have a second hit you can see a little faster decline, but that's really the extent of it.

So I think at the end of the day, I think if we're all in sort of the MZ neighborhood or better, I think that that's going to be a wash from a competitive perspective.

Got it. Okay. And then how important is it to lower Z levels? Z have its own pathologic effects?

It does. And I think that is actually an increasingly important part of the story here where, of course, we want the total [indiscernible]. And then we like the fact that it's inducible so when you get cyclical even higher still. But it's really the quality of the AAT that was being produced in the body. Meaning, in our case, we're getting 93% M circulating and only 7% Z. And that's because we have lowered Z by about 84%. That's really helpful. It's helpful obviously to the liver. Z is the thing that's building up in the liver and causing toxicity. But it's increasingly clear and Dr. [indiscernible], who is on our call yesterday morning was speaking to this that Z is a bad actor systemically. It causes polymers. And those polymers are basically inflammatory and they lodge in tissues and they cause the local inflammation.

They can also bind to and actually inhibit the natural AT from doing its job to stop [indiscernible]. And so they can actually frustrate them from doing its job. So I think there are lots of sort of emerging ideas that the less you have the better systemically. And so our ability to do that is an important part of the product profile.

And so how is enrollment going in the pivotal cohort? I feel like you've commented that it's going quite well. I'm wondering if you could just speak to some of the engagement that you're hearing from your investigators based especially on the back end of this updated durability data?

Yes. It is going well. I think we have great enthusiasm. We're at 14 sites across 6 countries now. We've been adding more sites in the U.S. in response to demand. And yes, as I noted, there's -- almost each site has a list of patients who are interested and are willing to travel for this therapy. I think it's very clear we've gotten on the map with the community. So nothing more to say other than what we feel confident in the enrollability of the cohort, and it's moving quickly.

How long does it take to get a patient off the list and into the trial? Is that site dependent on their capacity? Or is it your ability to like be able to dose them? How does that work?

Yes. It's more the -- I mean, the site obviously has capacity. I have to work through it. The patient has to go through screening, I mean, that's probably the biggest thing. So we just want to make sure they meet the inclusion criteria that they're stable and all the right medical things are at. You then have to wash them out, right? So they're generally on augmentation, particularly in the U.S. and we are washing those patients out. So you want to get the augmentation out. That then gives you a clear view of their true baseline in terms of alpha-1 levels, all Z, of course.

Then we take a baseline phase, right? So then we're going to take a series of measurements to make sure we have a good average of what their set point is. And then you can treat. So I think there are definitely a few steps to go before the dosing. But as I said, -- we're already in the dosing phase. We had our first dose in July. So this has all been ongoing now throughout '26.

And it's a little early to maybe start this conversation about the commercial strategy. But how are you thinking about initial launch strategy? Where are these AATD patients typically treated? Are they concentrated in centers of excellence? Or do you need a community referral program? Or are they all of the above? How are you starting to think about actually targeting this in a commercial way?

Yes, it's not too early at all. I think we actually think about this a lot. So there's probably at least 100,000 patients in the U.S. are ZZ genotype, that's our target population. Of those, we know about 10,000 to 15,000 are diagnosed, okay? So it's a largely underdiagnosed disease still and of the 10,000 to 15,000, maybe 9,000 are on augmentation, something like that. So the large majority are taking therapy, but everyone is pretty educated about their disease that they've got the diagnosis. So that's your initial addressable market, right? And that launch will be primarily through the academic key opinion leaders, the AATD treatment centers, these are specialists, right? This is still a rare disease. And that's clearly a very biotech friendly kind of launch. We know these folks. We're working with them now. They're partners with us. So we feel quite capable of moving there, and that's a large addressable market, right? If you think about 10,000 to 15,000 patients at gene therapy pricing.

From there, though, we were not done yet, right? So we need to think about how do you find the other 85,000 to 90,000 patients who are not yet diagnosed. Now some of them may be ZZ but not yet symptomatic, right? And that would be a group that we'd want to find and treat before they get the disease, right? But many are symptomatic, but they've just not completed the diagnostic odyssey. So they may be living in a respiratory clinic, may had COPD diagnosis. They may just be primary care and be complaining about fatigue. There's an awful lot of that out there. And so that is more of a diagnostic campaign that would happen over the subsequent years. I think of the analogy to like a TTR CM, right, where you have you have to go find those patients, educate them, get them to the right centers and then you can treat.

Got it. Okay. That makes sense. And that's a really large opportunity if you can improve those diagnosis rates over time ATTR.

Yes.

Okay. And so you have alignment with the FDA on your path to accelerated approval. Just wondering if you could just walk through your engagement with FDA thus far and overall regulatory strategy and thoughts on the confirmatory study as well.

Yes. FDA has been great. I know it's been turbulent over there and investors have had a lot of questions. But I always remind people that the commissioner is not our reviewer. We have had actually a lot of consistency in our reviewers over the last several years in these programs, that's true for sickle cell and for alpha-1. And I think, by and large, as I have always experienced, I think the FDA really -- if you bring them really good science and really good medicine, they are very eager to help and do it in a thoughtful way. You just have to find a way to help them satisfy their demands, which is they have a lot of statutes they have to live up to, and that's good. So they've been great. So they're working closely with us for years now.

I think it's an example of that. We got RMAT designation, which is sort of the breakthrough therapy for advanced therapies. We have this CMC program called CDRP, where we get also extra advice from them. I think they're clearly understanding that base editing is a very frontier kind of technology. And so they need to be very proactive with us to help us understand how to get it ready for filing, and that's been incredibly helpful. And then as you noted, we're now in an accelerated approval pathway. And that, of course, relies on their guidance to say, yes, this could make sense and we align with them on that path.

And again, I think this is not a big stretch to see this as an accelerated approval candidate. Accelerated approval is an approved statute for the FDA to use when you have enough biomarkers and science to suggest you are likely to have clinical benefit, which can then be confirmed in a confirmatory trial. While here, we have any number of biomarkers all pointing in the right direction, all exceeding the threshold that would say this person should no longer have the disease. So I think it's a very clear candidate for that. So I don't feel like we got a special favor. I think it was actually kind of right down the middle. Then we will have to come back and we are doing so to design the confirmatory trial, which will help them establish the functional outcomes that they will want to see in coming years, and that will be the next step of the process.

Before I move on to the rest of the pipeline, is there anything else AATD-related that you think is important to really highlight?

It's a great question. I mean I think mostly just to step back and kind of remember like what's going on here. I mean, this is the first time, as far as we know in history that we have a drug that can not just intervene genetically, which has been kind of the new wave of medicine, but literally rewrite a sequence of the genome back to normal. It's a profound event, and I think it's gotten a lot of interest. And so as excited as I am by AATD, I'm equally -- maybe it's a good segue, equally excited about that paradigm and our ability to now use what is effectively a platform technology to now march through mutation to mutation, always in this case, maybe the same organ using the same delivery technology, the same editing technology to increasingly, predictably and reliably make these same kinds of interventions from our patients.

So I think I think we're opening a door here to a whole new kind of medicine, which is very exciting.

It is a good segue because next, I want to spend a little bit of time on PKU. And particularly, what you're alluding to is that FDA sort of pathway or platform, multi-mutation sort of IND essentially. So maybe talk a little bit about the PKU opportunity. There -- you're nearing your Phase III initiation later this year and just frame a little bit how you're leveraging that regulatory flexibility, specifically for here and then maybe even expand it beyond in your plans for additional indications.

Yes. So you had asked before about regulators. So this is an example where the science makes something possible and the regulators are following that science, right? So with LNP delivery, right? We have a synthetic highly predictable delivery vehicle, and we have an RNA payload and of a certain LNP, if we run the preclinical tox again and again and again, even when we're changing the order of letters of the RNA, it doesn't change the acute tox, right? It's always the same. So it's highly predictable and repeatable. And then for the payload, the base editor again, we can change the guide RNA around, you'll have different on and off-target edits. So you have to check those, of course, but the acute tox, the manufacturing, it's all going to be identical, right? So that's a true platform that allows us to have high confidence every time we do it the next time.

And so this -- so beginning under Peter remarks, actually, in the prior administration, he was really at the forefront of saying, "Wow, okay, this should enable a different kind of medicine, right? We should be able as regulators to sort of see one set of studies with one editor, let's say, -- and once it looks good, we should give you credit for that. You should have to repeat all those studies every time. And in fact, even more than that, you should be able to say, I'm going to make the same genetic change, but just a different mutation but that should live under the same program, right, every time. And so this was sort of very forward-looking of Peter to start laying this out, but then some of the best ideas and government are the ones that survive administration change.

Then we're now the Trump administration, Dr. Mackay comes in, and he says, "This is amazing. Now let's take this to the next level and talk about pause mechanism pathway, which is exactly this point, which is we know that if I'm fixing PKU, the PAH gene and I'm correcting a mutation that's causing high phenylalanine, it doesn't matter which exact point mutation I fixed. It's going to have the same effect. And therefore, if you show me once or show me twice that it works, the third, fourth, fifth time, I'm going to give you credit that you can just build on that same foundation. And that's where we're living now. So a very, very exciting new world. So as you noted, we have an open IND for BEAM-304. This is to correct point mutations in the PKU gene PAH.

We would expect, again, as with Alpha-1 that a single dose ought to be able to fix enough enzyme that you can then metabolize molality normally and hopefully get patients towards a functional cure. And then this IND already has 2 different editors in it, right, treating 2 different mutations. They'll be slightly different patient populations, but all mixed up into 1 trial. And then as we qualify and bring forward new editors, we will then add numbrer 3, number 4, number 5 some of that in development, some of it on the commercial market. And again, it's a very new paradigm we learned about this together with the FDA, but it's very much right down the middle of what they were trying to outline with the plausible mechanism path of the guidance.

When you bring a new mutation onto the market, let's say, you're already approved with like those first 2, how does that work? Do you have to do just a very short study? Do you now have to do a study at all?

So we'll see. In theory, if you really read their guidance, it may not need clinical trial at all. I mean, I think we'll have to see. But what you -- I'm sure will have to do is you will need to show some amount of potency information may or may not involve more animal studies even, right, but at least in vitro, possibly in vivo, and then in vitro off-target asset, you'll have to sort of make sure you've shown for this specific guide, here's the off-target pattern and everybody is comfortable it that and then you move forward. But the whole point is to avoid having to redo clinical trials, right? And in fact, if you think about it, in the limit where this is going is ultimately individualized editors, right? That's the end game. We call it end of 1. And we've already seen that with Baby KJ that the CHOP team in Pennsylvania did there, by definition, you can't do a clinical trial on the commercial market because you would have treated the patient. There's no 1 left to treat. It's a unique mutation.

So I think in theory, this system is designed to not need the clinical testing every time. So long as you have a plausible mechanism for the effect should be the same every time. And you're seeing consistent effects, I think then the FDA will give you that runway in Latitude.

Yes. No, that's exciting. Excited to follow that as you progress it. But maybe just to go back to PKU as an indication you've selected, what makes it ideal for a base or to come in outside that there's multiple mutations that you could target.

Yes. It's a high unmet need disease. Patients are generally not controlled despite available therapy is an extremely life-disrupting disease. You really can't eat normal foods. There's all sorts of social impacts of that and in the many ways in which you are generally uncontrolled, it modifies your executive function and cognitive ability sometimes very deeply. And so it's a really tough disease. There are some products that work okay for some patients. You've had these BH4 cofactor types of products, Kuvan. Now [indiscernible] has a little bit more of an impact. But still, you have dietary restrictions. It's not getting that all the way to a functional cure. We've tried gene therapies. They generally didn't work.

AAV has been a tough platform to see that come through. So at the end of the day, I think a onetime LNP containing a base editor if we can fix enough of the enzyme. We ought to be able to open up the spigot and start the flux metabolizing phenylalanine and just drain it out of the body. No matter what you've eaten I mean that's basically the concept and that would be a onetime durable effect.

Right. Okay. A big change for those patients. We're running out of time, so I want to make sure that we talk a little bit about sickle cell because you are nearing that BLA filing. And I do -- even with me feels like it could be overlooked sometimes, so how are you preparing for commercialization? How should we think about that early launch? We've learned a lot from Casgevy, but what can you do to really drive perhaps even a more successful launch than Casgevy?

Yes, good question. I'm going to have Sravan cover this one.

First of all, thank you for asking the question. We always appreciate the focus on Risto-cel. I'd say a couple of things. One, would be remiss to acknowledge it. We just hired a new Chief Commercial Officer. Eric Foster who just joined us from Ardelyx, really excited. Lots of experience in [indiscernible]. I would say from an overall organization perspective, we're very focused on the launch. It's a whole student body effort right to make sure this happens, whether that's building systems, processes coming up with plans in terms of manufacturing from a capacity perspective and a quality perspective. So every part of the operations aspect of the company is very much gearing up for the launch. And so that's the back end. I think on the front end, I think we've increased the presence that we have from a medical perspective and from a field perspective. And I think that ramp will continue into next year as we get closer. Operationally, also, we're very much focused on submitting our BLA as early as the end of this year, maybe it slips a little bit into the early next year, but as early as the end of this year. With, hopefully, a quick review and launch.

And I guess just from a total market opportunity, I guess, how should we think about that just given what we know on the slow Casgevy launch? You have a lot of differentiation in various parts of the process. But how should we be thinking about what that actually looks like in terms of revenue?

Yes. I don't think our views on this have necessarily changed. We think -- I still think this is a blockbuster potential as a whole from a peak sales perspective for Beam. Our cuts for the patient population that Risto-cel can treat already assumes some amount of selection. There's 100,000 patients that we think in the United States with sickle cell disease. We think about 10,000 patients are about the right patient population size for risk to sell and that assumes these are the people that are willing to step through conditioning to get there.

With respect to the competition, it's not just Casgevy, it's [indiscernible] ut I think what we've seen is we're coming in -- being the third to market here, we get the opportunity to learn from their approach. We also get to ride some of their hard work in terms of seeding the market, whether it's working with hospital systems to build contracts and sign contracts, processes within the systems themselves. Some of those things are now hospital systems across the country, all have familiarity with this therapy, at least the ones that do treat the sickle cell patients and the ones we'd start out by marketing to. So I think that from our perspective, we see the potential there. We think our differentiation will carry the day, whether that's our ability to get to a 60-40 fetal hemoglobin to sickle ratio, our resolution of anemia or time to engraftment being about 2 weeks, 16.5 days. Just overall, I think we feel really good about what we have, and we think we have a potential for real class preference.

Yes. Looking forward to that. And you've also prioritized in vivo as your next approach in sickle cell disease recently. So I'm just wondering if there's an update or you could share just where that program stands? Like how close to moving this into the clinic as a quick follow-on for risto-cel is the company?

Yes. Look, I think we wouldn't have made the decision we did our announced at the start of the year if we didn't feel confident that we have a path forward. I think we're in the process of making sure we have it right before we nominate it as a drug candidate. And when we do have -- feel like we're there, we'll come back to the market share but we're -- I mean, I think it's at some point, stay tuned is my response.

I work on my patients. Okay. All right. Well, I think we've covered a lot here, maybe just turn it back to you, John, for any closing remarks that you might have and to recap the runway and just the positioning that Beam has over the next 12 months?

Yes. So it's been a great discussion. I think we've covered a lot. I'd maybe add to the near term that we will also have first-in-human data for another metabolic disorder GSDIa again, fixing a mutation here, R83C, that's BEAM-301. That will be a couple of cohorts of data and that will be this year. There, Ultragenyx had a recent approval, looking at cornstarch reduction. That's an okay endpoint. We're also thinking about time to hypoglycemia. So I think that's a near-term point. Long term, I think we have runway into mid-29, we're well financed. We will have a commercial sickle product by then. We know I think alpha-1 will be right around the market around that time. We haven't tightened that up yet, but we'll do so in the future.

If you think about the speed with which we can get sickle launch, then an alpha-1 accelerated approval, PKU is pretty fast, too. I mean it's obviously it's entering the clinic will be behind those, but not far behind. It's a pretty efficient development process. So we think all 3 of those are blockbuster potential franchises where we can make gene editing into a real business and become a sustainable multiproduct company. And all of that is using the same platform that is now built. And as we talked about a little bit along the way, I think the opportunity to now exploit that platform and target it now at many other diseases and continue to grow on that base is just what's so exciting for us on the long term.

Well, lots to look forward to there. So thank you so much, John and Sravan for the time. This has been wonderful. And I appreciate it.

Thank you.

Good morning, and welcome to Beam Therapeutics Conference Call.

[Operator Instructions]

Please be advised that this call is being recorded at Beam's request. I would now like to turn the call over to Holly Manning, Vice President of Investor Relations and External Communications. Please go ahead.

Thank you, operator. Good morning, everyone, and welcome to Beam's conference call to review updated clinical data from the Phase I/II trial of BEAM-302 in patients with alpha-1 antitrypsin deficiency presented today at the ERS Congress. You can access slides for today's call by going to the Investors section of our website, beamtx.com. With me on the call today with prepared remarks are John Evans, our Chief Executive Officer; Dr. Amy Simon, our Chief Medical Officer; Dr. Gerry McElvaney, a physician from Beaumont Hospital and an investigator in the BEAM-302 trial; and Dr. Giuseppe Pino Ciaramella, our President.

Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties and other factors, including those set forth in the Risk Factors section of our most recent annual report on Form 10-K and any other filings that we may make with the SEC.

In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. Except as required by law, Beam specifically disclaims any obligation to update or revise any forward-looking statements even if our views change. With that, I will turn the call over to John.

Thanks, Holly, and good morning, everyone. At Beam, our vision is to provide lifelong cures for patients with serious diseases. We are working to realize that vision by developing 1-time genetic medicines that precisely correct disease-causing mutations and address disease at its source. The promise of our base editing technology is becoming increasingly tangible across our growing and maturing pipeline. Today, we're excited to share detailed and updated clinical data for BEAM-302, our lead liver-targeted genetic disease program and the most advanced genetic medicine in development for alpha-1 antitrypsin deficiency, or AATD.

For the first time, we are showing BEAM-302 data at a major medical congress, and we're honored to bring these findings to the global AATD and respiratory communities gathered in Barcelona at the European Respiratory Society Congress, or ERS. As you'll hear shortly, this data set gives us even greater confidence in the differentiated profile of BEAM-302 and its potential to transform the treatment paradigm for people living with AATD.

Beam was founded on the idea that precise changes to individual bases in DNA could fundamentally alter the treatment of serious genetic diseases. Base editing is designed to make those changes without creating double-strand breaks in DNA. This precision is intended to produce consistent gene sequence outcomes and durable correction following a single treatment with the potential for less genotoxicity than traditional gene editing approaches.

Together, these attributes are central to what we call the power of predictability, the ability to design genetic medicines with precise and reproducible biological outcomes for patients. The profile we're seeing with BEAM-302 reflects these fundamental advantages we set out to achieve with base editing. The power of predictability is more than a scientific concept. It's also our strategy for building a durable and scalable genetic medicines company. BEAM-302 is an example of that strategy in action. The same core capabilities that underpin BEAM-302, including our base editing platform, LNP delivery technology and internal manufacturing expertise can be leveraged across current and future programs, increasing confidence and speed from one to the next.

Our goal is not simply to develop a single successful medicine. It's to create a repeatable model for advancing precision genetic medicines efficiently, predictably and at scale. We are already applying that model across 3 major areas of opportunity, each with large addressable underserved patient populations and blockbuster potential for differentiated 1-time therapies. Starting with sickle cell disease, our multiwave approach begins with risto-cel, a potential best-in-class ex vivo transplant, where we expect to file a BLA as early as the end of this year.

With a differentiated clinical program and internal manufacturing capabilities, risto-cel is poised to enter an established market with significant demand. Behind it, we are applying our targeted LNP expertise to an in vivo sickle program that has the potential to reach the vast majority of sickle cell disease patients. In AATD, which is the focus of today's call, BEAM-302 is the only genetic medicine in pivotal development and has the potential to be the first 1-time treatment addressing both the lung and liver manifestations of the disease.

Our newest major program is in phenylketonuria, where we are taking a multi-mutation approach with BEAM-304 to address the majority of patients living with this disease. PKU has few treatment options and an established regulatory pathway for approval. BEAM-304 leverages our industry-leading in vivo LNP capabilities to advance multiple base editors within a single clinical program and represents an important foundation for our growing interest in base editing for metabolic disorders. Together, these 3 programs demonstrate the breadth of what is possible with our base editing platform and represent multiple meaningful opportunities to create value for patients, physicians and shareholders over the near term.

Turning to Slide 8. BEAM-302 is the lead program within our growing liver-targeted in vivo portfolio, where our platform capabilities create meaningful synergies across programs and have enabled us to efficiently advance multiple clinical programs in parallel.

This portfolio also includes BEAM-301, another liver-directed base editor for metabolic disease, which aims to correct the severe R83C mutation in glycogen storage disease Ia with first-in-human data expected later this year. Before I turn it over to Amy to provide an overview of AATD and our BEAM-302 clinical program, I want to highlight a few key takeaways from the data shared at ERS today. First, BEAM-302 continues to demonstrate the potential to become the first 1-time treatment to address both lung and liver manifestations of AATD through direct correction of the disease-causing mutation. With follow-up now out to 2 years, treatment with BEAM-302 has demonstrated durable restoration of normal AAT physiology, including production of corrected M-AAT for the first time that is both functional and under normal physiologic control in response to inflammation. A single dose of 60 milligrams BEAM-302 led to total AAT levels above the protective threshold and substantial reductions in mutant Z-AAT and circulating Z-polymers.

In addition, the safety profile remains consistent with our prior experience and expectations for LNP therapies. Taken together, these findings reinforce our confidence in BEAM-302 as a potential first-in-class, best-in-class 1-time treatment for AATD. With that, I'll turn the call over to Amy.

Thanks, John. Alpha-1 antitrypsin deficiency, or AATD, is a serious genetic disease caused by mutations in the SERPINA1 gene. In the most common severe form, the PiZZ genotype, mutant Z-AAT accumulates in the liver, while too little functional AAT reaches the circulation. This creates 2 distinct consequences: progressive liver disease from the accumulation of the toxic Z-AAT protein and progressive lung disease from too little and poorly functioning AAT in circulation to protect the lungs.

Despite affecting more than 100,000 people in the U.S., treatment options remain limited. Current augmentation therapy replaces circulating AAT but does not address the underlying production of mutant Z-AAT or restore the body's natural regulation of AAT. Weekly augmentation is intravenous and is the only approved therapy for lung disease. There are currently no approved treatments for the liver manifestations of AATD.

Clinical genetics gives us an invaluable benchmark for what meaningful correction could look like. Patients with severe PiZZ disease have very low AAT levels, well below the 11 micromolar protective threshold, and substantially elevated risk of both emphysema and liver disease. By contrast, as shown here on Slide 12, MZ and most SZ carriers generally have AAT levels above the 11 micromolar protective threshold and do not develop progressive disease without the presence of additional risk factors, such as smoking or obesity. This provides a clear therapeutic goal, move patients from the severe PiZZ phenotype towards a carrier-like state associated with substantially lower disease risk.

BEAM-302 aims to do exactly that by correcting the disease at its genetic source. Delivered to the liver through a lipid nanoparticle, or LNP, the BEAM-302 base editor is designed to directly correct the E342K mutation in SERPINA1, converting the disease-causing PiZ mutation to the normal PiM allele. Through that correction, our goal is to restore AAT function and address the full spectrum of AATD. That means providing functional M-AAT for the first time in circulation, increasing total AAT above the protective threshold, substantially reducing toxic Z-AAT, and restoring the body's ability to increase AAT naturally during periods of inflammation. Taken together, these objectives have the potential to address both the lung and liver manifestations of AATD. And with base editing, we can potentially accomplish all of this with just 1 treatment providing durable long-term benefits.

Importantly, the clinical and regulatory strategy has advanced alongside the clinical data. Last year, we reached alignment with the FDA on a potential accelerated approval pathway for BEAM-302 with the primary endpoint expected to be based on AAT biomarkers evaluated over 12 months. To support that pathway, we plan to enroll approximately 50 additional patients in a pivotal cohort in the ongoing global Phase I/II study. We continue to partner with the FDA on the confirmatory trial design and have also been accepted into the agency's CMC Development and Readiness Pilot program.

Our flexible Phase I/II trial design allowed us to move rapidly from dose escalation into pivotal development. The open-label dose exploration and dose expansion clinical trial was designed to investigate the safety, tolerability, pharmacodynamics, pharmacokinetics and efficacy of BEAM-302. Part A evaluated patients with AATD-associated lung disease, and Part B evaluated patients with mild to severe liver disease with or without lung disease. As of August 17, 2026, 38 patients were dosed with BEAM-302 across Part A and Part B.

As you'll hear from Dr. McElvaney in a moment, the ERS presentation included data from 29 patients treated with a single dose BEAM-302 in the dose escalation portion of the study, including 21 patients from Part A and 8 from Part B. He will also provide additional data that was not presented in the corresponding ERS ePoster, which builds on the late-breaking presentation. Data from patients in the Part A multi-dose cohort and the Part A expansion cohort were not included. A global pivotal cohort known as Part C is now dosing patients across an established network of more than 14 sites in 6 countries.

With that, I'm pleased to introduce Dr. Gerry McElvaney, who currently serves as an investigator in the BEAM-302 trial. Dr. McElvaney is a Professor of Medicine at the Royal College of Surgeons in Ireland, Head of the Irish Centre for Genetic Lung Disease at Beaumont Hospital in Dublin, and Founder of the Alpha-1 Foundation of Ireland. He is a world-leading expert in AATD research and translational medicine, and we're so honored to have him on the call with us today. Dr. McElvaney?

Thank you, Amy. Today, I'm very pleased to share updated data from the Phase I/II study of BEAM-302 that were reported at the ERS Congress earlier this morning in both an oral presentation and an ePoster. Having treated alpha-1 patients and worked on alpha-1 therapies for decades, this is really an exciting time for the field given the number of emerging transformative therapies such as BEAM-302, which are now available.

BEAM-302 has been studied in a first-in-human Phase I/II clinical study enrolling patients with both the lung and the liver manifestations of alpha-1 antitrypsin deficiency.

Patients aged 18 to 70 years with homozygous ZZ mutation and sufficient lung function with blood alpha-1 antitrypsin levels lower than the protective threshold of 11 micromolar were enrolled. In Part A, patients with a clinical diagnosis of emphysema but no liver disease were enrolled into dose cohorts of 15 milligrams up to 75 milligrams BEAM-302. In Part 2, patients with a clinical diagnosis of alpha-1-related liver disease and fibrosis without cirrhosis received 30 or 60-milligram doses.

The key study endpoints are the rates of treatment-emergent adverse events, including serious events. Blood Levels of total and mutant Z alpha-1 antitrypsin including polymeric Z and M alpha-1 antitrypsin, functional AAT, and other measures of disease activity and treatment efficacy. As of the June 24, 2026, data cutoff date, 21 patients have been enrolled in Part A and 8 patients in Part B. And now we report the safety and efficacy data for all 29 patients enrolled.

At the data cutoff, the safety profile of BEAM-302 was consistent with that of lipid nanoparticle-based therapies with grade 1 to 2 infusion reactions and predominantly grade 1 elevations in liver transaminases being the most common adverse events related to treatment. There was one grade 3 elevation of liver transaminases that occurred in Part B in a patient with underlying alpha-1 antitrypsin deficiency liver disease that was without abnormal bilirubin and resolved completely without intervention. There were no serious adverse events related to BEAM-302.

In Part A, a single dose of BEAM-302 led to sustained increases in total alpha-1 antitrypsin levels above the 11 micromolar protective threshold. In the 60-milligram cohort, mean total alpha-1 antitrypsin increased from 5.0 micromolar at baseline to a steady-state mean of 14.4 micromolar and a median of 15.2 micromolar. The increases in total alpha-1 antitrypsin were durable with the longest follow-up out to 18 months. Similarly, in Part B, the post-treatment steady-state circulating total alpha-1 antitrypsin mean and medians were 13.5 and 13.8 micromolar, respectively, compared to a baseline of 4.7 micromolar. These measures were above the protective threshold.

Importantly, increased total alpha-1 antitrypsin in circulation was functional. The functional levels of alpha-1 increased in a dose-dependent manner up to 60 milligram, and those increases were durable throughout follow-up. Human neutrophil elastase levels decreased in a dose-proportionate manner also. Mutant Z alpha-1 antitrypsin was significantly and durably reduced after treatment with BEAM-302 with an 84% reduction in circulating Z alpha-1 in both Part A and Part B 60-milligram cohorts.

Treatment with BEAM-302 also led to a significant decrease in circulating Z alpha-1 protein aggregates referred to as Z-polymers from baseline in the 60 milligram cohort. This reduction in Z-polymers was to levels at or below that found in the MZ genotype as seen with the dashed gray line. Circulating Z-polymers have been shown to correlate with liver disease severity and also to amplify lung inflammation by inducing neutrophil recruitment.

Following treatment with BEAM-302, newly produced corrected M alpha-1 antitrypsin comprised the majority of alpha-1 in circulation. The proportion of M alpha-1 antitrypsin at steady state was 93% following treatment with 60 milligram in both Part A and Part B, exceeding the approximately 80% M alpha-1 antitrypsin portion associated with the MZ genotype.

Here, we demonstrate that following BEAM-302 treatment, alpha-1 antitrypsin protein production remained under normal physiological control as evidenced by the inducibility of alpha-1 in a patient who experienced a respiratory infection roughly 8 months after treatment.

This patient had been dosed with 60 milligram of BEAM-302 in Part A and achieved a steady-state mean total alpha-1 antitrypsin level of about 14 micromolar through month 6.

At an unscheduled visit around month 8, the patient presented with a respiratory infection, resulting in elevated CRP and a concomitant increase in total alpha-1 antitrypsin level, which is upregulated to protect the lungs from damaging proteases. As the infection resolved, the total alpha-1 antitrypsin levels trended back down along with the CRP values by the month 9 scheduled visit. Importantly, the patient's favorable alpha-1 antitrypsin composition of approximately 95% M alpha-1 was maintained before, during and after the respiratory infection.

In conclusion, BEAM-302, the first therapy in pivotal development to correct a disease-causing mutation, offers a potential 1-time treatment for both the lung and liver manifestations of alpha-1 antitrypsin deficiency by restoring SERPINA1 function. BEAM-302 at 60 milligrams in Parts A and B was well tolerated with mainly transient grade 1 transaminase elevations and mild-to-moderate infusion-related reactions.

It achieved durable increases in total alpha-1 antitrypsin above the threshold of protection. It increased functional alpha-1 antitrypsin levels and decreased neutrophil elastase activity. It reduced Z alpha-1 antitrypsin and Z-polymer levels and induced M alpha-1 antitrypsin production in circulation. It led to an increase in alpha-1 antitrypsin during a respiratory infection, indicating that alpha-1 antitrypsin protein production remains under normal physiological control. The pivotal cohort of patients with AATD-associated lung disease with or without liver disease is now currently dosing patients globally using 60 milligrams of BEAM-302.

As a physician, my idea of the ideal treatment for alpha-1 antitrypsin deficiency would have the potential to meaningfully change the disease course for patients by addressing the following key aspects. It should elevate total alpha-1 antitrypsin above the protective threshold to markedly decrease the risk of emphysema and liver disease in those without additional risk factors. It should improve the composition of alpha-1 antitrypsin by producing high levels of functioning M alpha-1 antitrypsin whilst also reducing toxic Z and Z-polymer alpha-1 antitrypsin, which is associated with disease.

And finally, it should enable further induction of M alpha-1 antitrypsin during acute inflammation when it's needed to contain tissue-damaging proteases. What is encouraging about the BEAM-302 data is that we are seeing evidence of all these effects. While longer follow-up and additional clinical experience are important, these findings suggest that BEAM-302 has the potential to move patients towards a biology that more closely resembles that of carriers with substantially lower disease risk. With that, I'd like to thank all the patients, investigators and study teams who have contributed to this work.

Thank you, Dr. McElvaney. It is a pleasure to have you here with us today. As you've heard, the robust dose escalation data generated with BEAM-302 continue to support its potential to address the critical aspects of AATD, including the correction of the underlying mutation, restoration of AAT function, reduction of disease-driving mutant Z-AAT and durable treatment with a 1-time therapy. Taken together, these findings strengthen our confidence in BEAM-302 as we focus on execution of the pivotal development program.

At Beam, our commitment to the AAT community extends well beyond BEAM-302. We continue to invest in life cycle opportunities while working alongside leading patient, research and regulatory organizations to advance the broader field. That includes our participation in C-Path CPA-1 consortium with the FDA to help identify clinically -- clinical efficacy endpoints. Our work with the Alpha-1 Foundation and Alpha-1 Europe Alliance to incorporate patient perspectives into clinical development, and our support of AlphaDetect to help improve detection and diagnosis. Together, these efforts reflect our long-term commitment to advancing care for the AATD community.

More broadly, we're entering an important period of execution across Beam. As you've heard today, executing the pivotal cohort for BEAM-302 is a key priority, along with the submission of the BLA for risto-cel as early as the end of the year. At the same time, we're advancing the next wave of the pipeline with BEAM-304 study start-up activities underway, initial BEAM-301 data expected by year-end and continued progress in our in vivo HSC editing program.

And we're doing this from a position of financial strength with $1.2 billion in cash as of June 30 and an expected runway into mid-2029, supporting the anticipated risto-cel launch, BEAM-302 pivotal development and clinical proof of concept of BEAM-304.

To close, everything we do at Beam is ultimately about the people who could benefit from these medicines. I want to thank the entire Beam team for the work that brought BEAM-302 to this point as well as our investigators, clinical sites, partners and advocacy organizations around the world. Most importantly, we're grateful to the patients and caregivers who participate in our trials and make this progress possible.

Thank you for joining us today. Operator, please open the line for questions.

[Operator Instructions]

And our first question will come from Yanan Zhu with Wells Fargo.

This is Jeff on for Yanan. Congrats on the data. For the one Part B patient with grade 3 liver enzyme elevations at 60 mg, were the timing and resolution consistent with what you would expect from an LNP [Technical Difficulty] mediated liver enzyme elevation? And just a quick clarification. For this data [Technical Difficulty] AAT was measured by turbidimetry rather than LC-MS, which was used in previous data disclosures. Which assay will you be using in the pivotal Part C cohort and then data disclosures going forward?

Thank you, Jeff. Amy, do you want to handle those 2?

Yes. Thank you. The patient had, as you know, an underlying history of AAT-related liver disease. We saw that the LFT elevations began to increase around day 14 and peaked around day 28-ish and then recovered spontaneously. Again, nothing too out of the norm, we saw, in general, LFT elevations, if they were going to happen, anywhere from day 3 to day 14 as the start of those elevations and then typically would start to decrease or recover by 2 to 4 weeks post-treatment.

As far as your question about turbidimetry, yes, we used turbidimetry this time, which is something that is used often in the clinic and it's something very familiar to clinicians. So we felt like using that was something that, especially at a medical meeting, something that was very useful to do. We will continue to report turbidimetry and we will also be optimizing LC-MS for our pivotal cohorts.

I think that one may serve more for a regulatory function, which is that LC-MS is often something that is looked at as preferred by the regulatory authorities given that it is actually measuring the mass of [Technical Difficulty] so we may still wind up doing both the assays. And going forward in our presentations, it's TBD how we will present them.

And the next question is going to come from Maury Raycroft with Jefferies.

Just wondering, in the prior cutoff, the mean steady-state total AAT in the Part A 60 mg cohort was 16.1 micromolar versus 14.4 in the new ERS analysis. As the number of patients reaching 12 months increased from 3 to 5, can you clarify whether this reflects a longitudinal decline in AAT levels or longer follow-up or differences in assay methodology or the steady-state calculation?

Yes. Thank you. Amy, do you want to cover that again?

Sure. We actually think that in general, we've seen once patients go up after day 28, we tend to see quite durable alpha-1 levels. As you know, alpha-1 is not something that is kind of very rock solid. It's something that is fluctuating based on how a patient's immune system is, whether there's inflammation. And so we think this difference between a 14.4 versus 16.1 is within the kind of normal variability you might see and feel that this is not a significant change.

And can you confirm the proportion of patients treated with 60 mg in Part A and Part B who remained above the 11 micromolar protective threshold through their latest follow-up, including at month 12?

Everyone has been above the 11 micromolar protective threshold.

And the next question will come from Alec Stranahan with Bank of America.

Good to see the progress. I guess just from a regulatory perspective, do you think Z or M-AAT levels are most important to show for an impact on disease? And when you think about enrollment is the 50 -- is the target of 50 U.S. exclusive? Or do you plan to open ex-U.S. sites as well to help expedite global submissions?

Yes. Thank you. So just covering the latter one. So this is a global cohort. So we're absolutely in multiple countries and double-digit sites around the world to enroll this. On the question of endpoints, maybe, Pino, if you want to talk a little bit. I mean the bottom line is, of course, we think the critical piece of this drug is to be achieving carrier status where you're well into the teens, you're above the protective threshold. You have the MZ composition that we like and the Z reduction.

So those are all critical pieces of what we think is so predictive of clinical benefit here and therefore, supportive of the approval pathway we're pursuing. Pino, do you want to talk to how we think about the specific endpoints within that push with the FDA?

Yes, sure. Obviously, as you pointed out, it's important to demonstrate the entire physiology. And clearly, total AAT levels above the 11 micromolars are an important data point, but they don't describe the full extent of the correction that we're making. And obviously, the ratio between M and Z and importantly, the reduction of Z is very important to show also a potential benefit to the liver in addition to the lung.

And as Dr. McElvaney has pointed out, the reduction of Z-polymers are also very important.

So we intend to measure all of those parameters and obviously provide a very complete picture about the effect of BEAM-302. Exactly which endpoint is going to be the primary versus secondary, frankly, we have not disclosed that as you can imagine, this will be a competitive piece of information that we obviously hold true. And eventually, there will be also a confirmatory trial. We're discussing very actively with the FDA exactly what the design and importantly, which endpoint we will be using as part of that.

And the next question comes from Eric Schmidt with Cantor.

Congrats on the consistency of these data sets here. Another question with regard to the pivotal cohort C. Can you talk about any differences in enrollment criteria between Parts C and A, B? And then are you actually doing densitometry or any other measurements in Part C that could support full approval?

Sure. Amy, do you want to cover that?

Sure. So our inclusion criteria is really meant to encompass the spectrum of disease for alpha-1 patients. And so in this regard, the criteria, you have to have evidence at least by CT scan of emphysema, you can have normal pulmonary function. So just some evidence of lung disease, you can also have liver disease. So in this case, we want to be able to have both and show that we have efficacy across the broad disease manifestation. As far as you asked about...

Densitometry.

Densitometry -- those are involved in all of our studies. So we'll be collecting CT densitometry in our Phase I/II studies. We'll be collecting CT densitometry as well in the pivotal study.

And the next question comes from Samantha Semenkow with Citi.

Congratulations on the progress from me as well. I have another one on the pivotal cohort. I'm wondering if you could just speak a bit to the enrollment cadence that you're seeing so far, particularly since there are several other trials that are enrolling patients or about to start enrolling patients within the overall development landscape. And then when do you think you'll be in a position to guide on top-line data from the pivotal cohort?

Yes, that's a great question. And maybe, again, Amy, you can maybe expand on this. I think overall, the enthusiasm for the drug has been quite high, and we've seen that continue. So maybe, Amy, if you want to talk a little bit about what you're seeing and we can also speak to no decisions made yet in terms of any top-line outcomes from the pivotal cohort. But go ahead, Amy.

Yes. So this is a global study. And I have to say the amount of enthusiasm for this has been outstanding. What we're hearing from [Technical Difficulty] their lines from their own clinic, they're now getting calls from out of country, out of state, depending where they are. And they said they've never seen anything quite like this. We're getting to the point where people are demanding more slots. And obviously, we're trying to do that. So we have not seen a problem.

I think we are first in pole position here because we've been in the clinic now for quite some time. I think that's been very helpful. And we continue to expand the sites that we are opening because we know that, as mentioned before, a confirmatory trial is not that far behind. And so I think we have a lot of momentum.

And our next question will come from Michael Yee with UBS.

This is Matt on for Mike. Congrats on the update. Just curious to any updates around your thinking on the requirements for a confirmatory study. I know there's sort of an active conversation with the FDA, but thoughts around FEV versus functional outcomes. And then also just curious if you'll need to do any kind of like natural history work or any kind of controlled study down the line as well and some of your thoughts there, too.

Yes. Maybe I can just handle that. I think that is very much an active conversation with the FDA. We do anticipate needing to run a confirmatory trial given that the cohort C is an accelerated approval strategy. And all of the endpoints you described as well as things like CT densitometry, which we've talked about in the past are of interest. So that's something we will work through with the FDA. We have to be operationalizing that trial by the time of the filing for the accelerated approval, as you may know. And so that gives us some time to get it designed and up and running.

So obviously, our operational focus right now is the cohort C, but we will be -- have plenty of time to get that trial locked and then opened in time to then complement the study. And ultimately, we do know that the community is going to be very interested in functional outcomes. And given our profile here, we're quite confident that we will be able to show stabilization of this disease over the long term, consistent with what we believe could be a functional cure.

And the next question comes from Cory Kasimov with Evercore.

So I wanted to ask about the 11 micromolar bar and your 60 mg steady-state medians were 13.8 to 15.2. But the poster out shows the per patient minimums were 11.0 in Part A and 11.1 in Part B, so sitting right at what's thought to be that protective lower threshold. If the field's view of adequate AAT drifts higher post the upcoming SPARTA data, does your 60 mg dose still clear that patient by patient? Or is it possible you could potentially need dose headroom or looking to dose further?

Yes. I'm wondering -- so maybe I'll answer this to start, and then I'm wondering if maybe I could invite Gerry to say a few words about the profile we're achieving and how he sees this relative to what we need to do for patients. I think that might be a good opportunity. Just to answer the question, I think SPARTA, as you rightly point out, is testing standard augmentation versus high-dose augmentation. I would just remind people of the very different profile of augmentation. On augmentation, the number you care about is that trough level because you're not going to go up when you're sick. So that's all you can get. That's not the case with us, right? These numbers are floors. And when you're sick, as we have shown, you will go up higher.

And so I actually think that high-dose SPARTA is probably a closer parallel to what we're achieving physiologically than the low dose. And we do hope it can show some benefit. Also, of course, augmentation does nothing for the Z protein, which is still being produced by the body. So maybe with that preamble answer, I'd invite Gerry to say maybe just give some perspectives on what he -- how he views this profile and how it might compare to augmentation.

Thank you very much. I would certainly agree with what you've said there. I think one of the most interesting things about the Beam result is that it's mainly M alpha-1 antitrypsin, a very small amount of Z alpha-1 and phenomenally decreased polymer levels. But that's really important because Z alpha-1 is less efficient at inhibiting proteases. It's slower. And if it's in polymer form, it's unable to inhibit protease. So the more M alpha-1 you can get, the better. So put it another way, 11 micromolars in a Beam individual is much more effective as an antiprotease and anti-inflammatory than 11 micromolars in a person receiving augmentation therapy.

And the next question is going to come from Luca Issi with RBC.

Congrats on the data. Maybe Amy or Giuseppe, just circling back on the prior question, can you talk about the kinetics of the ALT and AST post-infusion? When you kind of compare and contrast those kinetics between patients with and without liver manifestations, like are the curves like generally superimposable with like Cmax narrowing the curve generally comparable with one another? Or should we assume the patient with liver pathology tends to have a little bit of higher levels versus the patients without liver pathology. Again, just asking the questions in the context of obviously the grade 3 being in patients on Part B stuff. So any color there, much appreciated.

Yes. Amy, do you want to try that one?

I mean we really don't have that many patients to be able to comment fully about that. I do think that we know and maybe after I'm done, I'll have Gerry comment, that once you have alpha-1 antitrypsin deficiency and you have known liver involvement that your response to medications and your liver can be quite susceptible to kind of, I would say, almost kicks or inflammation.

And so I think this is not that inconsistent with, number 1, what we see with getting a lipid. And then number 2, in someone who has alpha-1 antitrypsin deficiency with known liver involvement of then having to process that lipid and having inflammation may occur as well.

And so overall, this was a little bit higher than the typical grade 1. TBD, what will happen with other liver patients because right now, we've only dosed, I think, about 5. But on the whole, we think the safety overall is largely still grade 1 in the B patients that we've seen to date with the exception of this patient. And maybe, Gerry, you can comment on what you see in your patients with underlying alpha-1 antitrypsin deficiency-related liver disease.

Yes. So that's an important point. I think people with alpha-1 antitrypsin deficiency-related liver disease tend to have retention of Z alpha-1 or Z-polymers in the liver. And that makes them somewhat sensitive to certain inflammatory processes. So for example, if you start an individual with alpha-1 on an antibiotic, he may get a flare up in his liver function test as well. But it usually settles down. It's something that, that happens, but we don't see it as being a major contributor to the ongoing process in these patients. You notice that in Part B, none of the patients had cirrhosis. So they had a certain degree of liver disease, but not the really severe liver disease that we sometimes see.

And the next question is going to come from Sami Corwin with William Blair.

Congrats on the data. I guess I was curious that there was a change in Z that was great -- that was dose-dependent, that was greater than the patients treated at the high dose, but that didn't necessarily translate into a greater reduction in Z-polymers. So I guess I was curious as to why and what the implications are for that. And then Dr. Gerry is kind of continuing off of the messaging you've been saying, do you think that increasing the steady-state AAT levels would add further benefit? Or does it not matter as long as the M-AAT is still increasing during periods of acute inflammation?

Sure. So maybe, I guess, Amy and Gerry, if you want to talk a little bit about Z-polymer reduction and then the question about raising from steady state.

Yes. So the Z-polymer story is one that's evolving, but there's some very interesting data coming out now. So if you look at Z individuals, and you got a person who's got the same level with less polymers. They less -- the people with less polymers have less inflammation. And we've actually done a study comparing MZ individuals to SS individuals. We got exactly the same levels of alpha-1, exactly the same anti-elastase capacity, but the SS individuals with no polymers. And the less polymers you have, the less inflammation you have and the less -- decrease in lung function you have.

So we have good evidence now that polymers actually impact upon you in a number of different ways. Obviously, they impact upon the liver, but they're also pretty useless in inhibiting elastase or having an anti-inflammatory effect. And then on top of that, they're very potent neutrophil chemoattractants, so they're pro-inflammatory. So anything you can do to decrease polymers is a good thing.

And I wasn't quite sure I followed the question about increasing the steady state. I think the key points, again, there that we've highlighted is just the AAT physiology, this is an acute phase response protein. We want it to go up when people are sick, and we have shown that. Obviously, you get a higher level at a basal level with BEAM-302 treatment, then when you're sick, it goes even higher. And then the key point is that you're maintaining the quality, let's say, of that AAT, the over 90% M that's completely consistent between that new basal level and when it's upregulated, meaning you're getting all -- almost all M production and not increasing Z. And so to Gerry's point, we think that, that's the quality of the AAT we're producing is quite significant for the effect within the body.

I am showing no further questions at this time. I will now turn the call back over to John Evans for closing remarks.

Thank you very much. So thanks for your attention this morning, and thank you, Gerry, for joining us and for your great insights. We're clearly very pleased with the consistency of the data here with what we've shown previously, achieving what we believe is a protective level of AAT, normalization of the AAT profile for M and Z, the natural regulation and now the reduction of these harmful Z proteins, the aggregates, just showing the overall profile that we think is really, as Dr. McElvaney said, the ideal profile that we're trying to deliver for patients suffering from this terrible disease.

As well, very pleased with the operational momentum in the trial moving deeper into our pivotal experiment here and looking forward to bringing this to patients as quickly as we can. So thank you again for your time and look forward to speaking again soon.

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

Capital Market. Today is a great privilege to have Beam as part of our 2026 Global Healthcare Conference. Representing the company, we have John Evans, Chief Executive Officer. John, thanks so much for joining us. How are you doing today?

Doing very well. Thank you, Luca.

Great. Long list of questions here, but maybe before we go into specifics, it would be great if you can maybe start a little bit big picture about what progress has the organization made recently and kind of what's ahead here for Beam?

Great. Yes. So it's great to see you all. So Beam Therapeutics is a next-generation gene editing company. We're working on a new form of CRISPR called base editing. And so this allows us to make single letter changes in genes on a permanent basis without needing to make a double-stranded break. This lets us make many more kinds of edits, more therapeutic edits, more precise edits, including doing things like correcting mutations back to normal rather than just knocking things out. We are pursuing this in a variety of different places, ex vivo and in hematology for the treatment of sickle cell disease. Our lead program, Risto-cel, is moving towards market, and we'll talk a little bit about that. I'm sure we'll have a BLA filing as soon as the end of this year, followed by a research effort to move sickle cure in vivo using some of our LNP capabilities.

On the liver side, our second major focus area, we have a variety of different programs. The lead program there is alpha-1 antitrypsin deficiency. This is BEAM-302. And here, we are correcting the single-letter misspelling in the alpha-1 gene back to normal. And this is the first time actually that anyone has been able to do that. We're really thrilled about that. Huge population, incredible level of unmet need really due for better therapy.

Following on to that and building on that platform will be a variety of other liver programs. We have BEAM-301 for glycogen storage disease Ia, that we'll have data this year. And then we're just going to be filing an IND this year for our third liver program targeting PKU, editing some of the mutations there and another sort of major opportunity. And so we're thrilled with the early progress.

I think the data has been very much confirmatory of the way we think base editing should work. And then the beautiful thing about this platform is it's very predictable, right? So once it begins working in the clinic, there's every reason to believe it will continue to work in exactly the same way, whether that be the fact that the editing, once it's in the cell, can edit the DNA predictably or the fact that an LNP, once you've delivered it safely to the liver and effectively, you can do that again and again for different programs.

So in many ways -- in some ways, we've made a lot of progress. In other ways, I feel like we're just at the starting line of our vision because now we get to take that flywheel that has been built and apply it in more and more places with increasing amounts of confidence.

Got you. Got you. That's super helpful overview. Maybe let's double-click on alpha-1 antitrypsin. Maybe just remind us what data you have seen so far? And then maybe just if you can talk about dosing. It's, again, my understanding that you guys have tried to go a little bit higher than the 60 milligram, either by doing a 75 milligram or a 60 plus 60. I think that experiment maybe didn't pan out the way you were hoping for, but maybe what are the lessons learned from kind of going higher and then we can go from there.

Yes. So I think -- so the first data we showed a year ago was after 3 dose cohorts. So we went from a low to a medium to a sort of medium high dose, and that was 60 milligrams. And as you recall, that was shown to be a potential functional cure, like we had reached the threshold of efficacy we were looking to get to. So at 60 milligrams, we achieved over 11 micromolar of alpha-1. That's the sort of magic threshold people talk about because basically, anyone who is a carrier or better, a carrier is someone who only has one copy of the mutant gene and they don't have the disease, they live above that line. And anyone who has the disease who has progressive lung and liver damage, generally live below that line, they're in the single digits.

So we have gotten all of our patients up there. So then the subsequent experiment as you're referring to, I just consider it to be good drug development. You really have to get your dose right, right? And you have one shot at that. And so what we basically said is, okay, 60 is clearly a possible dose. And then we want to do some experimentation around that, sort of pushing the dose higher, trying 2 doses and doing more 60s just to confirm where are we on the curve in terms of our maximum PD effect.

And the bottom line is somewhat as we sort of anticipated, we clearly have sort of saturated the pharmacodynamic effect here for the drug already at 60. So 75 didn't add much of anything. It was still well tolerated, which was great. The 2x 60 didn't add much either and the second dose was not as powerful as the first dose. So clearly, that's not getting anything. So the bottom line is we confirmed that 60 was where we want to be.

That larger data set showed 60 milligrams to deliver an average alpha-1 level at 16, and that's very consistent with what a carrier would have. We had a percentage of M, the normal protein in the body up around 90-plus percent, which is in excess of what a carrier would have, an MZ person. And Z had been reduced by 84%, okay? So we had clearly and dramatically changed the disease physiology to at least a carrier physiology, someone who would not have the disease, and that's the basis from our confidence that we think we've put these -- these patients in a position where they shouldn't have any progressive disease going forward.

Got you. Got you. That's actually super helpful. I think you already alluded to it, but I think this is important for kind of the broader field of gene editing. Why was the 60 plus 60 like the second time around, maybe not as well tolerated as the first time around? Obviously, you dosed the two, I believe, I think it was 8 weeks apart from each other. So you would have thought that the first kind of lipid nanoparticle will be kind of completely washed out from the system. Like why was that maybe not as well tolerated as first dose?

Yes. It's hard to know. I think certainly, that's true by the preclinical data, 8 weeks should have been enough to have kind of a clear background, right? And yet, we did see a little bit of response. That said, these are non-normal livers. I mean this is alpha-1. So alpha-1 livers are different in terms of their physiology, they're kind of -- their macrophage biology is different. There's all sorts of things that may have sort of retained some sensitivity given that time period. I don't have data on this, but I feel fairly confident that just a longer time period would probably resolve that.

Also just to note that the things we saw were not showstoppers. I mean we saw higher infusion-related reactions, so more like grade 2s where you're giving a Motrin to handle some soreness. And then we had basically one patient who gone to a grade 3/4 AST/ALT. But it was asymptomatic. They never went to the hospital. There was no bilirubin and it resolved very quickly, right?

So again, a sign that those livers weren't quite back to normal. Back to my first comment, obviously, given that we didn't see a dramatic change in the pharmacokinetic outcome, there's no reason to pursue it. But I think for the field, nobody should draw from that conclusion that re-dosing LNPs is not possible. It clearly is. Moderna does it all the time. Intellia has re-dosed patients successfully. I expect we will as well. So in fact, we still intend to go back and redose the patients in our trial at the 15- and 30-milligram level who have received subtherapeutic doses and will need to get the full dose at some point soon.

But in that case, you're not going to go higher than whatever is the 75 milligram? Or is that to receive like 60 you're going to get 15 or is that...

No. Usually, what you do is you -- once you sort of settled on the final dose, in this case, it would be 60, then at some point, you would go back and just give them 60. We wouldn't...

Go higher than that. Okay. That makes sense. Maybe one last one on safety, if I may. I think this is super important for the broader field here given that you're obviously pioneering in this space. So what can you tell us about the kinetics of the kind of liver elevations? Obviously, it's kind of somewhat physiological to see some of the liver elevations with LNP. What can you tell us about what you have seen there? And how are those kinetics of the ALT and AST elevations compare between patients that have liver involvement versus patients that don't have liver involvement. Obviously, it's a complex indication. There's a liver manifestations, there's a lung manifestation and so on. So just maybe walk us through the kinetics and how the two -- the magnitude of the elevations compare between the two buckets.

Yes, it's a great point. So -- and I want to make sure people understand. So we're all learning about LNPs in real time. So there has been this concern from a couple of the programs or one of the programs that Intellia has been running the TTR program where you saw an unusual LFT signature that was maybe late appearing, right, around day 28, okay? So that -- as far as I know, that's the only time that's been seen. I think Intellia has spoken to it. That's a specific issue related to their editing and that target, which I do not think is LNP related broadly.

Pretty much every other LFT signal that I can think of, including this one, classic LNP signals is just it goes up fast and then it comes down fast, right? It's really the kind of mass action of putting a lot of lipid into the liver all at once and the liver gets inflamed. The key is you want to see them within days coming down rapidly, and you want to see no bilirubin change, right? Because that shows you the liver function has not been affected. It's still processing bilirubin, et cetera. And that's exactly what we saw, right, in this case. So I think nothing out of the ordinary, just a sign that the liver was still sensitive, I think of it and not fully [indiscernible].

Sure. Okay. That's helpful. Maybe let's talk about bystander editing. That's something comes up in every conversations we have with investors. Maybe remind us what kind of work you have done to really make sure that not only you have this like level that are above this magic number of 11 micromolar, but the fact that the actual protein is functional. Maybe just remind us what kind of work you've done there?

For sure. So with base editing, you can, in some cases, get an additional edit in addition to our target edit if there's a second, in this case, A, within the editing window. With alpha-1, we know that can happen in the most common such outcome in addition to the pure correction of the Z mutation back to M, which is the main thing we're trying to do is sort of a neighboring change, which basically we get a mixture. You'll get some just M and you get some of this what we call M variant. But we -- this is the fingerprint of the drug. We've known this for a long time. So we've had plenty of time to really characterize that variant and show that it is normal and comparable to the M. So it is secreted normally. It is functional. We've done structural biology showing that it folds and that its structure is the same as the normal.

It turns out that variant position is actually commonly varied in the human population. There are 6, 7, 8 different variants you can find in people. The one that we're making is found in people and not associated in disease. And it's just a permissive sort of surface residue on the protein. I think the most important data we have shown is that when we showed the functional data, we showed that we had very high levels of functional data consistent with what you would expect to see if it was just the M and ours was the mixture of M and variant.

So that shows you that the M variant is clearly functional and contributing to the total functionality we have. We just gave an encore of our top line data, and there's a nice chart in there, you can see where we're showing direct -- using the serum from these patients, direct inhibition of human neutrophil elastase, very dramatic drop, very quick by this alpha-1 sort of mixture that we're creating. And so again, showing you it's clearly functional.

And I forget, have you disclosed the ratio between the variant and the wild type? Or is it...

It's comparable to what we see in preclinical models. So you see some amount of M and some amount of M variant.

Okay. Okay. Okay. That's helpful. Maybe let's talk about going forward, the pivotal trial. It feels to me that the level of alpha-1 that you get in the serum is a little bit of a function of the baseline characteristics and the higher is the alpha-1 at baseline, the higher is kind of the boost. And I appreciate at the end of the day, you need to have as many patients as you possibly can about this level micromolar. So can you enrich the study in some capacity to kind of stack the odds in your favor and try to maybe enroll or maybe exclude patients that have baseline level below certain thresholds? Or how should we think about that part?

I think -- yes, it's a great point. And I think you're probably thinking about this correctly. I don't know exactly how hard and fast to rule it is. But generally, my read of our data is that, yes, there is a spread. And it's true even at the baseline, Z patients live anywhere from 4 to 6 or 3 to 7, it's kind of a range. And if you were low on that range, then you get edited, you're probably low on the resulting range. And if you were high in that range, you're probably high in the resulting range. And that's just, I think, physiology, patient to patient. The key for us is to make sure that every patient regardless of where they are, gets above the therapeutic threshold is in the teens, looks like a carrier, right?

Because I want to be able to say every patient has been functionally cured. And the great news is that is what we're seeing, right? Now could you game that? Yes, of course, you probably could. And we're certainly not excluding any patients on the basis of their AAT levels. So we take them all. I think, especially for small N like early data sets, you certainly want to look at the baselines and understand that a patient start from a high place and go to a high place. That's definitely important. Where we're at, we've now treated 29 patients total and counting. So your ability to play those games goes away with larger N. I mean we've already converged on what I would consider to be a typical average baseline, and we're going to treat another 50 patients, that will only continue to happen.

Got you. Got you. Super helpful. You guys came forward early this year about alignment with the FDA and a path to accelerated approval. Again, you guys have talked about biomarkers and maybe you haven't offered the specifics, but we can all think about like total alpha-1 and M and Z and the whole nine yards. How do you feel about that, especially in the context of the never-ending headlines around the FDA? Is your alignment? We've seen the companies obviously complaining about moving the goalposts and whatnot. How do you feel that the FDA is fully on board, everybody is on board, both the reviewers are on board and the top of the house are on board and not like top of the house changes, like walk us through your level of confidence around this accelerated approval?

It's a great question, and it's something we're all obviously watching. I think that -- I think the outgoing leadership actually had some really good ideas about modernizing the FDA and some specific policies like the plausible mechanism pathway that I think are actually quite helpful to Beam and to base editing. Of course, some of those were also a continuation of work that was done under the Biden administration by Peter Marks. So it's actually bipartisan, kind of where that's going. So we're obviously eager to see how this goes. I know there's been a lot of anxiety over some of the late flip decisions that have happened and impacted some folks. So that's -- hopefully, that stabilizes, and I expect it will.

I think the good news in a way for alpha-1, it's true of sickle as well is we're not doing anything unusual here. right? So we're -- so our alpha-1 path is not reliant on the plausible mechanism pathway, right? Nor I think hopefully, will I have to worry that somebody is going to rug-pull us at the end, right? I mean I think it's just -- this is a classic accelerated approval. And the review team that we're working with is not the folks who have left. It's professional FDA reviewers. They've been there for years. We've worked with them consistently over the last several years. That's also true in our sickle program, by the way, very stable review team, and they're doing a great job, very constructive.

So I think not too much worry here, but of course, I want the whole situation to stabilize. In the case of alpha-1, as I said, classic accelerated approval pathway, you have all sorts of biomarkers that tell us that we are likely having a curative benefit for these patients, right, that you would predict. That's the whole point. And that includes the alpha-1 levels, the total getting up into the carrier range, the M, the M percentage that we're creating, the reduction in Z, the fact that it's functional, the fact that it's inducible, all of that together shows you that you've basically recapitulated the physiology of a carrier versus a patient, and we know that carriers are stable. So that should be enough for an accelerated approval. The FDA has seemed very amenable to that. The main pushback they pushed towards us was to have 12 months of follow-up. They know that alpha-1 levels can bounce around. They want to make sure they have a good longitudinal series, perfectly reasonable. So we'll enroll 50 patients, follow them for a year and then bring it in.

Got you. Got you. That's helpful. What's the -- I think one of the components here for the accelerated approval is like, yes, I'm going to drive level of alpha-1 above certain thresholds. However, there's a little bit of debate around augmentation therapy now with this data with Inhibrx and Sanofi, they kind of a little bit of raising the bar on like the total level that can drive in the serum. And so there's a debate around like trough versus what you achieved. So I do feel that as you try to advocate for accelerated approval, it will be important for you to show that this liver benefit is not just theoretical, but it's actually there. So can you maybe speak about some of the endpoints that you're now doing? Obviously, biopsy will be invasive, as it will be difficult to enroll patients and whatnot, at least for now. But what are you measuring to actually prove in addition to emphysema type of potential benefits you also have a liver benefit?

Oh, for sure. So I think -- so first of all, on the Inhibrx program, so yes, they do achieve these high levels. Of course, as you know, because it's a chronic therapy, you have to worry about the trough level. And then it's also not inducible, right? So that trough is as good as it's going to be when you really need it when you're sick, right? So we -- our trough is different. It's really a floor. And when you're sick, you get more, right? And so it's a very different kind of dynamic way of looking at the numbers. And so I think -- and equally, right, the Inhibrx is not a natural protein. It is an FC-bound set of AAT proteins. What is the bio-distribution of that? Does it show up in the right places? Is it fully active? I think there are probably a lot more questions there, right? For us, everything about our situation, you can rely on the MZ genetics to tell you what that should be. So I think we have just a higher background credence and probably less to prove in some of these ways.

All that said, then, yes, on the liver, we definitely believe there will be clinical benefit here as well. I think it's a key differentiator for our class of drugs, right? We're going to simultaneously help the lung and the liver. With the liver, we're trying to drop the Z protein and relieve the liver as much as possible. And we're clearly doing that. We're getting Z levels down to or below what an MZ carrier might have. And again, they don't generally have progressive liver disease of any kind. How will we show that?

So we are doing biopsies in the Part B patients. As a reminder, the great news of Part B was that so far, all the Part B patients have been -- have tolerated the drug the same as Part A. So that despite having livers that are advanced in their disease, doing the LNP dose didn't change the safety or efficacy, which is great news. It means that our Cohort C is going to be an all-comer cohort where everybody comes together. So -- but in the Part B, we are doing biopsies before and then 6 months and 12 months. So we should be able to measure are there resolution of aggregates? Are we seeing any fibrosis change over time.

I think over the long term, those are endpoints we may be able to develop. And of course, there is about 10% of the population in alpha-1 who are liver only that for whatever environmental reason, their liver got sick before their lungs. That's the group we don't have in our registrational cohort. So we'd have to go back and do something like that for them anyway.

Can you also do MRIs or is biopsy kind of the go-to or the trials are too short to actually show a benefit biopsy?

It's an emerging field. This has been pioneered a little bit by Takeda with RNAi drugs, which of course, liver only in their benefit potentially. But that endpoint work will be applicable here. You can do some imaging, there's FibroScan, there's other things there. But I think biopsies end up being important to kind of directly measure fibrosis as well.

And the primary point of that Takeda Arrowhead trial is biopsy, right? So it kind of makes sense. Maybe just quickly, early days, but kind of fun to start talking about approval and maybe pricing. You have obviously a very interesting model, which is one and done. Obviously, augmentation therapy is a comp to a certain degree out there. Maybe big picture, how you're thinking about pricing? And will payers appreciate the longer-term pharmaco-economic value of doing one and done or they will rather pay less for something that I got to pay for 1 year like I guess like because I'm assuming that you're going to ultimately price higher than what's the price of augmentation therapy for 1 year, given it's one and done. So like will the payers get it?

Yes. It's a great question. There's no question we will price higher than the 1 year of augmentation, right? I mean the whole one-and-done model has to do that. Payers are very sophisticated. They want to deliver cures and great medicines to their patients, and they do the math, right? I mean that's kind of what the business is. They're really good at math. And so when we generally -- when we bring them a great value story with strong pharmacoeconomic argument, they can understand it and they will get behind it. And we've actually seen this play out in sickle, right?

So in sickle cell disease, you know that the lifetime cost of a patient is $5 million, $10 million given all the expensive medicines and the loss of productivity and of course, the hospitalizations. And even ICER, [ institute of cost-effectiveness ], which is a fairly conservative body said over $2 million price in sickle made sense.

And as far as I know, there have been no reductions on price in the sickle market. So we're on speeding up authorizations and things like that. But ultimately, that's the price that the payers have said they're willing to pay, and that includes CMS and Medicaid, right? So this is a broad consensus. Alpha-1 is basically similar, right? And we've published some data showing the lifetime cost for an alpha-1 patient can be anywhere from -- depending on their course, kind of the $4 million to $5 million to $8 million over time.

So certainly, we think that's suggestive of genetic medicine pricing. Of course, it's too early to talk specifically about that, but I do think that we feel strongly about the pharmacoeconomic value of what we're doing and the value to patients. And of course, relative to augmentation, we would have more sources of value as well, right, not just the one and done, but obviously the liver plus the lung, more of a deep resolution of the situation. So bottom line is, I think it's definitely a good value story, and we're very eager to bring it forward.

Got you. Super helpful. I know we're unfortunately almost out of time here. Maybe a quick update on sickle cell disease. Tell us what's next for this program. And then we've seen headlines from Tessera or other companies that are kind of working in vivo and there's a broader enthusiasm around in vivo more broadly in oncology, we're seeing a lot of transactions that went on there. So like I guess, give us an update on your ex vivo approach. And what's the latest thinking to pivot to in vivo?

For sure. So as our ex vivo, Risto-cel, BLA as early as the end of this year. We think we have a really incredible manufacturing process, which is what the market is really looking for and asking for. That's been a struggle so far with some of the early rollout of some of the other agents. We know our vein-to-vein time is just over 4 months, which means we can treat patients quickly and with high predictability. Part of that is base editing, part of it is the manufacturing. So we're very enthusiastic about what that can do for patients. Of course, that is to treat the severe patients, right? There's about 10,000 we think, maybe more, maybe less, who are eager to get that kind of therapy.

And that's a multibillion dollar a year opportunity to bring an exciting product forward, and that's what Risto-cel will be. Nonetheless, of course, we're very eager to go treat the other 90,000 patients with sickle cell disease who for a variety of reasons are just not quite in that bucket where they will choose the transplant-based option, but they'd be a great fit for something that is in vivo and more scalable. And so we're also working on that, of course.

And there have been data out there. We've seen some of that. We have some of our own. It's obviously a bigger challenge to get to hematopoietic stem cells in the body with an LNP than it is initially in the liver, of course. And now people are getting the T cells pretty well. We think HSCs are coming. And now will it work as well as our ex vivo at first? We'll see, right?

It just depends on the translation. I will say that with LNPs, remember, it matters what dose you're giving, right? So in preclinical studies, it's always important to see that they disclose the dose. And if they didn't, you have to sort of see how close to the finish line they really are. But I think it's going to happen. I mean we're quite active there, of course.

We have the ex vivo capability of Risto-cel. But of course, Beam is also an LNP company. We're an in vivo company. Everything else we're doing is in vivo. So I think we've got a lot of tools in the toolkit for that one. And certainly, our commitment to the sickle community is long term, and we expect to be bringing waves of programs forward to try to cure everyone on a global basis over the long term.

Got you. And on that note, I have a lot more questions but over time. John, I appreciate you joining us. Thanks, everyone, for joining us here at RBC Conference, and we'll talk soon. All the best.

Thank you, Luca.

Good morning, and welcome to Beam Therapeutics Conference Call. [Operator Instructions] Please be advised that this call is being recorded at Beam's request.

I would now like to turn the call over to Holly Manning, Vice President of Investor Relations and External Communications.

Thank you, operator. Good morning, everyone, and welcome to Beam's conference call to review top line clinical data from the Phase I/II trial of BEAM-302 in patients with alpha-1 antitrypsin deficiency. You can access slides for today's call by going to the Investors section of our website, beamtx.com.

With me on the call today with prepared remarks are John Evans, our Chief Executive Officer; Dr. Amy Simon, our Chief Medical Officer; Dr. Jeff Teckman from St. Louis University; and Dr. Giuseppe Pino Ciaramella, our President.

Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements for purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual events or results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties and other factors, including those set forth in the Risk Factors section of our most recent annual report on Form 10-K and any other filings that we may make with the SEC.

In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date.

Except as required by law, Beam specifically disclaims any obligation to update or revise any forward-looking statements even if our views change.

With that, I will turn the call over to John.

Thanks, Holly, and good morning, everyone. At Beam, our vision is to provide lifelong cures for patients suffering from serious diseases. We believe base editing uniquely positions us to fulfill that vision through onetime durable genetic medicines that correct disease at its root cause while delivering predictable and reproducible outcomes.

One year ago, we established clinical proof of concept for our onetime in vivo base editing therapy BEAM-302 in alpha-1 antitrypsin deficiency or AATD, and accomplished an incredible milestone for the field of genetic medicine, delivering to our knowledge, the first ever genetic correction of a disease-causing mutation in DNA.

Today, we're excited to share a compelling and robust data set from 29 AATD patients treated with BEAM-302 in the ongoing Phase I/II study. These updated data further strengthen our belief in the best-in-class and first-in-class potential of this onetime therapy and pave the way for the advancement of BEAM-302 into pivotal development.

Beam was founded on a simple but powerful idea that making precise, single base changes in DNA could fundamentally change how we treat many serious genetic diseases. Base editing allows us to correct mutations without creating double-strand DNA breaks. Our goal is to translate that capability into onetime genetic medicines that durably and predictably restore normal gene function.

We believe that predictability is not just a scientific advantage. It's a strategic one. Predictable outcomes can streamline R&D, reduce development risk, support regulatory efficiency and ultimately build confidence among physicians, patients and payers. Over time, we believe that impact can ripple across the entire health care ecosystem. That same predictability also allows us to build a scalable platform for developing multiple genetic medicines.

Many of the core components of these therapies can be reused across programs, so that once we demonstrate success in one setting, we can apply those capabilities to additional diseases with greater efficiency. In that way, we're not simply advancing a single therapy. We're building a repeatable engine for developing multiple genetic medicines over time.

Our liver-targeted in vivo portfolio is a clear example of this platform in action. Now with 3 core programs that are in or nearing clinical development, BEAM-302 in AATD, the focus of today's discussion, as well as BEAM-301 for glycogen storage disease Ia and BEAM-304 for phenylketonuria, all leverage our LNP delivery capabilities, enabling us to apply the same core technologies across multiple programs and moving them forward efficiently through emerging regulatory pathways.

Today's data further underscores the strength of our industry-leading in vivo liver-targeted precision gene editing technology and our ability to efficiently and rapidly execute to advance to pivotal development for BEAM-302.

Before turning the call over to Amy to walk through the results in detail, I'd like to briefly highlight a few key takeaways from the data set we are reporting this morning.

First, treatment with BEAM-302 continues to demonstrate robust and durable efficacy with more patients at higher doses and longer follow-up. In the single-dose 60-milligram cohort where patients have follow-up out to 12 months, we observed meaningful increases in both total and functional AAT, achieving steady-state mean levels of 16 micromolar and once again, with all patients above the 11 micromolar protective threshold that is associated with lung health.

In addition, treatment resulted in substantial reductions of approximately 84% in mutant Z-AAT, the toxic protein responsible for the liver manifestations of the disease and that in circulation can also contribute to lung disease. Most importantly, these patients now produce corrected M-AAT for the first time as seen in a clear shift in circulating AAT protein composition to approximately 94% corrected M-AAT, consistent with correction of the underlying genetic mutation. All of these findings are consistent with AAT profiles seen in MZ genotype carriers, people who do not have severe AATD nor progressive disease and are not at elevated risk for lung or liver disease without secondary factors like smoking or obesity.

Second, we now have strong evidence that AAT production is inducible following BEAM-302 treatment during periods of inflammation when it is most needed as expected from BEAM-302's mechanism of action. In one patient, AAT levels increased to approximately 30 micromolar during a respiratory infection and critically retained the corrected AAT composition of approximately 95% M-AAT, suggesting the edited gene does indeed function under normal physiologic regulation following treatment with BEAM-302. This is the strongest induction result yet observed after a genetic treatment in AATD showing that treatment with BEAM-302, not only elevates basal AAT levels to a new floor similar to carrier levels, it further provides a dynamic capacity in the body to generate even more AAT whenever it is most needed. Restoring the AAT acute phase response in these treated patients offers a fundamentally different treatment profile from that seen with augmentation therapies and shows the power of precision-based editing to correct all aspects of this disease.

Third, BEAM-302 continues to demonstrate a well-tolerated safety profile across the single dose cohorts with Grade 1 transaminase elevations being the most common adverse event. Based on the strength of both the safety and efficacy data, we have selected 60 milligrams as the optimal biological dose for our pivotal cohort, which we plan to initiate in the second half of this year.

Taken together, we believe these findings reinforce the potential for BEAM-302 as a best-in-class and first-in-class onetime treatment for AATD.

With that, I'll turn the call over to Amy to go through these BEAM-302 findings in more detail.

Thanks, John. Alpha-1 antitrypsin deficiency, or AATD, is a serious genetic disorder caused by mutations in the SERPINA1 gene, which affects the production of alpha-1 antitrypsin, or AAT, a protein made in the liver that is secreted into the bloodstream to protect the lung from inflammation and damage.

The most common severe form of AATD results for mutations in the Z allele, known as PiZ, which is caused by a single G to A point mutation in the SERPINA1 gene. This results in the extraction of a pathogenic variance of AAT known as Z-AAT that misfolds and aggregates in the liver leading to liver damage and disease such as cirrhosis, and you'll hear more about this from Dr. Teckman shortly.

The Z-AAT made in the liver is poorly secreted into the circulation and less effective in inhibiting neutrophil elastase, leading to total circulating levels of AAT that are 10% to 15% of normal in homozygous PiZZ individuals. As a consequence, the lung is left unprotected from neutrophil elastases and other damaging proteases that can cause progressive lung destruction, resulting in early onset emphysema. So in this disease, it is caused by too much abnormal AAT that gets stuck in the liver and too little AAT that gets out in the circulation.

The current standard of care for AATD for patients with lung disease primarily consists of treatment for emphysema, such things as bronchodilators, inhaled steroids, oxygen therapy and with severe cases requiring lung transplantation.

The only approved treatment today, plasma-derived AAT or augmentation therapy requires weekly intravenous infusions to achieve static levels of AAT, lacking the natural upregulation of AAT, so important during infection and inflammatory processes such as respiratory infections.

While augmentation has been shown to slow lung disease progression, it does not stop it, nor does it prevent ongoing liver damage and has no impact on the Z-AAT aggregates in the liver or circulation.

Treatment for liver disease is limited to supportive care as there are currently no approved therapies. In severe cases, liver transplantation remains the only option. The PiZZ genotype accounts for over 95% of severe AATD cases. And despite affecting more than 100,000 individuals in the U.S., only about 10% of people living with this disease have been diagnosed.

As shown in Slide 12, clinical genetics provides critical information on a wide range of AAT levels and highlights why reaching the protective threshold of greater than 11 micromolar for AAT in circulation is critical for decreasing disease risk related to AATD. Patients with the severe PiZZ genotype have 2 copies of the disease-causing mutation, leading to a high risk of developing both emphysema and liver disease. These patients have very low levels of AAT between 3 to 7 micromolars shown in orange. All of their AAT is in the mutant Z-AAT form, which is much less effective and can form polymers in circulation, leading to lung inflammation and injury.

In the middle are individuals with just 1 mutant PiZ copy referred to as MZ or SZ individuals. And in this case, the majority of these individuals had AAT levels above 11 micromolar.

On the right-hand side of the slide, you can see how these genotypes correspond to lifetime risk for emphysema and liver disease. People with the PiZZ genotype are greater than 30x more likely to develop emphysema, and greater than 20x more likely to develop liver fibrosis or cirrhosis. Conversely, an SZ or MZ individual's risk is only marginally greater than a person with no mutation, and disease in these individuals requires the presence of additional risk factors, such as smoking or obesity.

These genotype characteristics are important as they help define what the critical goal posts are for efficacious AATD treatment. Any treatment that can achieve carrier range or better levels of AAT greater that 11 micromolar protective threshold along with further upregulation of the gene during inflammation would eliminate risk of progressive disease and would represent a functional cure of severe AATD.

Our base editor consists of 2 components, an mRNA encoding an adenine-based editor protein and a guide RNA that directs it to the precise location of a Z mutation in the SERPINA1 gene. Both are encapsulated in a lipid nanoparticle or LNP for delivery to the liver. Once in the liver cells or hepatocytes, the base editor precisely and directly corrects the misspelling, so it changes the A base into G base, converting the disease-causing PiZ mutation back to the normal functioning PiM form.

By correcting the root cause of AATD at the most proximal source, the DNA, we believe that BEAM-302 has the potential to deliver on the critical aspects of a onetime transformational genetic medicine.

First and foremost, our goal at BEAM-302 is to have a person make corrected and properly functioning M-AAT that gets into the circulation so that it is above the protective threshold of 11 micromolar, which as described earlier, is informed through genetics and was clinically accepted as the basis of augmentation approval.

Second, BEAM-302 aims to treat the full spectrum of AATD disease manifestations by significantly reducing mutant Z-AAT levels as much as possible to prevent aggregates in the liver and blood that can lead to ongoing organ damage.

Finally, AAT needs to be available in a dynamic manner, meaning that during periods of inflammation or infection, AAT levels need to be able to increase in order to combat lung destruction from unopposed proteases generated from inflammatory cells such as a neutrophil elastase protease. This is not possible with existing therapies like augmentation.

With those goals in mind, we designed a robust Phase I/II trial to assess early safety and efficacy of BEAM-302 and enable dose selection in patients across the spectrum of AATD.

The dose escalation base of the study is structured in 2 parts. Part A includes patients with lung disease to establish an understanding of the safety in patients without clinically evident liver disease, followed by Part B, which includes patients with mild-to-moderate liver disease with or without AATD-associated lung disease.

As of the February 10, 2026, data cutoff, we have treated a total of 29 patients across both Part A and Part B, representing a meaningful update from our proof-of-concept data last year where we presented data from 9 patients.

In Part A, we have completed a 15 mg cohort with 3 patients dosed for 12 to 18 months of follow-up, a 30 mg cohort with 3 patients, each with 12 months of follow-up, a 60 mg cohort with 6 patients followed for 5 to 12 months, a 75 mg cohort with 9 patients followed for 2 to 9 months and a multi-dose cohort evaluating 2 doses of 60 mg given 8 weeks apart, which included 3 patients followed for 84 days or 28 days after the second dose.

In Part B, we completed a 30 mg cohort with 3 patients followed for 4 to 5 months and dosed 2 patients in a 60 mg cohort. The first patient had 3 months of follow-up and the second patient was dosed after the February 10 data cut and is included in the safety data throughout the DLT period, but excluded from the efficacy data.

Turning to safety. Single-dose BEAM-302 demonstrated a well-tolerated safety profile at doses up to 75 mg. Importantly, the safety profile was consistent in patients across all single-dose Part A and Part B cohorts. In the 26 patients treated with single-dose BEAM-302 from 15 milligrams up to 75 milligrams, no serious adverse events, dose-limiting toxicities or Grade 3 or higher adverse events were observed. All treatment-emergent adverse events were mild to moderate.

Grade 1, asymptomatic transient elevations in ALT and AST were observed within the first 28 days in some patients. In addition, Grade 1 and Grade 2 infusion-related reactions were observed and all resolved within a day.

In the multi-dose cohort evaluating 2 doses of 60 milligrams in 3 patients, we observed a higher rate of events following the second dose of BEAM-302. One patient experienced Grade 4 ALT and Grade 3 AST increases within days of the second dose, which were asymptomatic and resolved without treatment.

The Grade 2 ALT increase occurred in another patient, which also resolved without treatment. No clinical signs of liver dysfunction or bilirubin increases were observed in any patient. Transient Grade 2 IRRs occurred in all patients.

Turning to efficacy. Treatment with BEAM-302 led to durable increases in total AAT into the MZ carrier range at single doses of 60 milligrams or greater. Here, we show steady-state mean total AAT levels by dose, which is the mean of each patients total AAT levels measured by an LC-MS assay from day 28 to the month 12 visit or until the patient's last visit is earlier than 12 months.

In the 60 mg cohort, where we have now just 6 patients with follow-up out to 12 months, we observed a steady-state total AAT mean of 16.1 micromolar. In addition, all patients consistently and durably demonstrated mean steady-state total AAT levels above the 11 micromolar protective threshold.

In the 75-milligram cohort with 9 patients and follow-up out to 9 months, we observed a steady-state total AAT mean of 14.4 micromolar. Increased total AAT in circulation was functional as demonstrated by a functional AAT assay based on neutrophil elastase inhibition.

The full change from baseline in total AAT was comparable between the 60 mg and 75 mg single dose cohorts, suggesting near saturation editing at doses greater than or equal to 60 mg.

BEAM-302 was designed to increase total AAT by inducing the expression of corrected M-AAT while at the same time, stopping the expression of mutant Z-AAT. As shown here, mutant Z-AAT was durably and significantly reduced by 80% at steady-state compared to baseline in the highest dose cohorts.

As a result, newly produced corrected M-AAT comprised the majority of total AATs in circulation with 94% M-AAT in the 16-mg cohort and 91% M-AAT in the 75 mg cohort. This exceeds the AAT profile seen in people with the MZ genotype with 80% M-AAT and 20% Z-AAT in circulation do not have disease unless there is a second injurious insult.

Moving to Part B, patients with AAT-related liver disease show similar efficacy trends as Part A patients without liver disease. In the 30 mg Part B cohort, 3 patients achieved a steady-state mean total AAT of 12.5 micromolar, of which 75% was newly produced M-AAT, representing a 51% reduction in mutant Z-AAT.

In the 60 mg Part B cohort, only 1 patient was efficacy evaluable at the time of the data cutoff. That patient achieved a steady-state mean total AAT of 17.2 micromolar and similar to the 60 mg part A cohort, 95% was newly produced M-AAT, driven by an 86% decrease in Z-AAT.

In the multi-dose cohort, we observed an efficacy profile consistent with a single-dose 60 mg cohort. The 3 multi-dose patients achieved a mean of 16.5 micromolar of total AAT at day 84, which was 28 days following the second dose of 60 mg of BEAM-302.

In addition, the mean Z-AAT reduction was 80% and the newly produced M-AAT was 93% of total AAT. Together, these early data suggest that a single dose of 60 mg BEAM-302 has achieved near saturation editing.

As I highlighted earlier, one of the goals of therapy with BEAM-302 is to restore the physiologic control of AAT during inflammation, which is when lungs require higher AAT levels to maintain protection against tissue-damaging proteases. Here, we show strong evidence of inducibility of AAT in a patient who experienced a respiratory infection roughly 8 months after treatment with BEAM-302. This patient was dosed with 60 milligrams of BEAM-302 in Part A and achieved steady-state mean total AAT of about 16 micromolar through month 6.

At an unscheduled visit around month 8, patient presented with a respiratory infection, resulting in elevated CRP and a concomitant increase in total AAT to approximately 30 micromolar. After the infection resolved, their total AAT levels trended back down along with their CRP values by their month 9 scheduled visit.

Importantly, the patient maintained consistent AAT composition of 94% M-AAT before, during and after the respiratory infection.

This case study shows clearly that there are 2 distinct assets at AAT protection offered by BEAM-302 treatment.

First, the achievement of a new basal AAT level above the protective threshold achieved within 28 days after treatment. Second, the ability to produce significantly more proactive M-AAT on demand during periods of inflammation or infection.

In summary, we are encouraged by these robust and comprehensive BEAM-302 clinical data now in 29 patients and follow-up out to 18 months. These data demonstrate that a single 60-milligram dose of BEAM-302 led to durable correction of a PiZ mutation, resulting in increases in total AAT to mean of 60 micromolar, above the therapeutic threshold of 11 micromolar and into the MZ range. Production of corrected functional M-AAT in circulation for the first time and significantly decreased mutant Z-AAT by approximately 80%.

Treatment with BEAM-302 enabled production of corrected and functional M-AAT that was under normal regulatory control as shown by the increase in AAT that occurred in response to inflammation in a patient with a respiratory tract infection, enabling the body to naturally regulate AAT as needed.

And importantly, BEAM-302 was well tolerated with an acceptable safety profile at all single doses tested to date in 26 patients. Based on the strength of safety and the efficacy profile of BEAM-302 in single-dose cohorts, 60 milligrams was chosen as the optimal biological dose for the pivotal trial, which we plan to initiate in the second half of this year.

Pino will provide more details about the next steps for pivotal development shortly. Taken together, we believe these data demonstrate the potential for BEAM-302 to be a transformative onetime treatment for AATD that could meaningfully impact both the lung and liver manifestations of the disease.

With that, I would like to turn the call over to Dr. Jeffrey Teckman. Dr. Teckman is a Professor of Pediatrics and Biochemistry at St. Louis University School of Medicine and a recognized world leader in alpha-1 antitrypsin deficiency. His over 30 years of research and clinical care has focused on the mechanisms of liver injury in AATD and improving the diagnosis and clinical management of patients across the disease spectrum. We're pleased to have him with us today to provide a clinical perspective on the disease, the needs of patients living with AATD today and how emerging genetic medicines could reshape the way this disease is treated in the future.

Dr. Teckman, over to you.

Thank you, Amy. It's a pleasure to be here. On a personal note, I've been working on alpha-1 antitrypsin deficiency for a long time. When I first started, we didn't even know how this disease worked in the liver, let alone, a concept that we would have cures on the horizon. And it's very exciting to see how much has happened. I think the question to first start with is why alpha-1 antitrypsin deficiency now?

There are a lot of conditions. There's a lot of interest in biologic treatments. Why this disease? Well, first of all, there's increased awareness in the liver disease and the hepatology field. There has been a lot of talk about "steatotic liver disease," our new word for fatty liver disease, steatotic liver disease. And there's a recognition that metabolic genetic liver disease like alpha-1 antitrypsin deficiency actually caused steatotic liver disease. And as more people with steatotic liver disease are being evaluated, there's more testing going on for specific causes like alpha antitrypsin deficiency.

The lung disease of alpha-1 is well known, but not -- the patients are not fully diagnosed. And the treatment options, while they exist are suboptimal, there is protein replacement as we'll talk about but it does not return people to wild type. It's very expensive and it's burdensome to patients.

What's also unique about alpha antitrypsin deficiency is the patient community is highly centralized. There is a very active foundation, the Alpha-1 Foundation. They have national meetings. They have a registry. They have a therapeutic development network, and they're a major mover in research and treatment and in lobbying for alpha antitrypsin deficiency. So these factors together really make this a great time to be developing treatments for alpha-1.

Next slide. So just as a background reminder, the alpha-1 gene, the SERPINA1 gene has hundreds of variants. M being the normal wild-type allele, which is MM is 96%, 98% of the population in the United States and Europe. The Z allele is by far responsible for 90% to 95% of disease. People sometimes also talk about the S allele, which is the intermediate disease allele, which also when present with Z especially, it could be related to disease. But really, the vast majority of disease are individuals who were ZZ.

Next slide. As you might recall, the liver disease in alpha-1 is a storage disease and the lung disease is a serum deficiency. That's why it's called alpha-1 antitrypsin deficiency because it was originally identified as a serum deficiency, but the liver has too much.

Next slide. So this is just a schematic of alpha-1 protein processing in the liver. On the left side, you see a normal wild-type MM individual. That's the endoplasmic reticulum of the hepatocyte, the little black wavy lines are nascent polypeptide chains of AAT protein, and it folds into its secretion-competent conformation. That's the little knot. And then it's secreted into the blood in huge quantities. So the adult liver makes 2 grams per day of alpha antitrypsin.

On the right side, a ZZ individual is still synthesizing the same number of nascent polypeptides, but they do not fold efficiently into the secretion-competent conformation. So only 15% of the peptides reach a secretion-competent conformation are secreted. The rest accumulate in the ER of the hepatocytes. Now most of those polypeptides are degraded by proteolysis pathways within the hepatocytes. But for reasons we're not totally sure, some accumulate and form these unusual, what we call polymers of protein, which are highly cytotoxic to the cell. And so again, you have the situation where the liver has too much, but the serum has too little.

Next slide. So these are photomicrographs of human ZZ liver. On the left side is H&E. On the right side is what we call Periodic Acid-Schiff with digestion or PAS with digestion. So the PAS stains glycogen and glycoproteins red purple and the digestion washes the stain out of glycogen. And so if you have an accumulation of glycoproteins in the cell, which is shown there by the inclusions, what we call globules. So that shows the accumulation. Sometimes those are what 100% made up of Z protein in the polymerized conformation. Sometimes those accumulations are larger than the nucleus. So it really is very toxic to the liver cell.

Next slide. So what's the risk of liver and lung disease? And it is complicated. So let me just walk you through the slide for a second. So if you look at the top and from left to right is the odds ratio, that's shown at the very bottom. And you see the line there on 1. So that's the same risk as MM individuals. So at the very top, you see MZ. And MZ individuals have a modest 1.7-ish odd ratio increase of liver disease and cirrhosis. We think of MZ being a genetic modifier of other liver diseases. Most of those people have other kinds of steatotic liver disease, NASH, other things like that.

The risk of lung disease in MZ, again, it shows there, it is between 1.5 and 2. But really, that's just smokers. Nonsmokers who are MZ appear to have no increased risk of lung disease. If you again, if you go down a little further on FZ, so the cirrhosis risk for lifetime for FZ might be odds ratio of 3 over MM individuals, so increased, and emphysema, again, between 1.5 and 2.

So at the bottom in ZZ, the risk of fibrosis cirrhosis lifetime, the odds ratio is more than 20%. So significantly increased over the general population. And likewise, with emphysema, somewhere between 30 and 40 odds ratio increased risk compared to MM individuals. So what's really interesting about the data is that we appear -- in this treatment, you appear to be able to make people at least MZ, if not better. So that would eliminate 95% of the risk, which is incredible and very exciting and something that we're anxious to see how it turns out with further study.

Next slide. So this just sort of says over time, over a lifetime, because what's interesting also about this disease is it affects different people, different ages differently. So on the vertical is the incidence of medically significant disease in the ZZ individual at a certain age and then you have age from left right across the bottom. So early in life, ZZ babies and children can develop liver disease. But it's only about 20% of ZZ individuals have enough disease to come to medical attention in childhood.

And then the risk of liver disease in young adulthood and new onset liver disease is very low, but it goes up later in adults and again, become significant as a lifelong risk.

With regard to lung disease, you do see an increased risk of childhood asthma but not emphysema in ZZ children. The lung disease really starts to become evident in the 30s and older. And then again, the lung function decline in alpha antitrypsin deficiency is greater than the MM individuals general population. No, not everyone has -- who's ZZ has accelerated lung function decline. But it is well known that it is higher. And really even if you're a nonsmoker.

Next slide. So I wanted to go back and touch on how the American Association of Liver Disease, AASLD, which is the worldwide leader in liver disease science. So just in the last couple of years, we've changed the way we look at "fatty liver disease." And it's not just a nomenclature change, but it's really a recognition change. So we call it steatotic liver disease overall. And this, again, is the official sort of scheme, which not only shows metabolic dysfunction associated with steatotic liver disease, so that's individuals with obesity, high lipids who then develop MASLD as well as alcohol, but it's also recognized that increasingly that monogenic diseases like alpha antitrypsin deficiency, you see in the red circle on the right, contributes to the steatotic liver disease group of patients.

And so this has really led to an increased focus on diagnosis because it's on clinical grounds to a hepatologist, just history, physical exam, basic lab tests, you can't differentiate alpha antitrypsin deficiency from MASLD or alcohol, you really need to test for it specifically. And that's being increasingly recognized, especially as treatments are rolled out, it's going to be tested for even more. And we've seen that in a lot of rare diseases where when there's no treatment, the testing is modest. But when new treatments are available, there's a huge spike in testing.

And we saw that actually in alpha antitrypsin deficiency in the late '80s and in the '90s when the protein replacement for the lung disease became available. There was a dramatic increase in diagnosis. And we went from just a few hundred people on replacement therapy to thousands and thousands on replacement therapy in just a decade as a result of more treatment.

Next slide. So as we said, the liver currently has no approved treatment to supportive care and liver transplant if liver failure becomes untreatable. And the lung disease does have the protein replacement, which is an intravenous product. It's fairly burdensome and it doesn't do anything for the liver, right, because the liver is a storage disease and the lung disease is a serum deficiency. So this really brings up how the patients are really ready for new treatment options.

And there seems to be significant interest among patients on IV replacement therapy to move to something more permanent such as a DNA-targeted treatment, which would be equal, if not better, to the protein replacement.

I think one of the key concepts which has been touched on is the alpha antitrypsin protein is an acute phase reactant. So it can increase 3 up to 5 fold in serum with inflammation. So -- and that seems to be very important in the pathology -- pathophysiology of preventing damage because if you get inflammation of the lung and pneumonia, then you make a lot more alpha antitrypsin to protect those tissues from injury. And that's part of the normal physiology. People on IV protein replacement don't infuse more when they're sick. They just have that same dose. So they don't get that boost.

And we see that in some of the data, that there is an acute phase reactant boost, which will probably be much more effective at protecting the lung. And not require weekly infusion. So there's -- there seem to be a lot of interest in patients for this kind of intervention.

Next slide. So again, just touching on the community, the Alpha-1 Foundation, their registry, their therapeutic development network, their funding of research and their support with government. I personally have been to the FDA a number of times as part of delegations from the Alpha-1 Foundation to discuss therapeutic development to discuss how these treatments should be evaluated and how important it is to treat both the liver and the lung. So these are very exciting developments. I think the community is going to be very excited about the data that we've been discussing. And I think we're very, very excited to see, not only improved treatment, but cures for this disease.

Next slide. So again, in summarizing our key takeaways, alpha antitrypsin deficiency has a wide range of presentations over a full lifetime, from infantile liver disease to emphysema in older adults. It's way underdiagnosed but increasingly being recognized, not only in lung disease, but also in liver disease as a result of increased focus on steatotic liver disease. There certainly is unmet need. Even though there are treatments, they're suboptimal. And these are very exciting developments. And we look forward to the next steps.

Thank you, Dr. Teckman. It's a pleasure to have you here with us today. As we disclosed in January, on the heels of significant regulatory engagement over the course of last year, we have reached alignment with the U.S. FDA on a potential accelerated approval pathway for BEAM-302.

To support the future BLA submission, we anticipate enrolling approximately 50 additional patients to be treated with BEAM-302 in an expansion of the ongoing Phase I/II study. The primary endpoint is expected to be based on AAT biomarkers evaluated over 12 months.

Continuing our track record for efficient and rapid execution, we're moving forward with multiple parallel efforts to maintain momentum in the ongoing Phase I/II trial in preparation for initiating the pivotal cohort, which we expect to do in the second half of 2026.

To start, now that we have selected 60 milligrams as our optimal biological dose, we plan to enroll additional patients in an expansion of Part A as well as continue to enroll patients in the 60-milligram cohort in Part B. This allows us to not only grow our safety database, but also to provide new sites in the U.S. with BEAM-302 experience prior to initiating the pivotal cohort.

At the same time, we're actively working to complete the pivotal protocol amendment. And recently, we completed site activation at multiple U.S. sites. This builds on our already extensive global site network spanning 12 sites and 6 countries.

At Beam, our commitment to lead in innovation for the AATD community extends far beyond one program. In addition to our focus on advancing BEAM-302 to patients as efficiently as possible, we continue internal R&D efforts for future life cycle management. We're also deeply involved in the advocacy and research communities and serve as a member of C-Path's CPA-1 consortium in collaboration with the FDA to accelerate AATD research by identifying clinical efficacy endpoints. And as a collaborator with Alpha-1 Foundation and Alpha-1 Europe alliance to educate about gene editing and obtain a critical input on clinical trial design and patient experience.

As we look ahead to the rest of the year, 2026 is shaping up to be a milestone-rich period for Beam, with multiple value-driven catalysts on the horizon across our growing clinical portfolio. First, we remain focused on advancing our lead programs, including progressing BEAM-302 towards pivotal development in the second half of this year, following the data that we shared today.

Second, we expect to continue advancing the pipeline with key development milestones across several programs that leverage the same platform capabilities.

And finally, we are doing this from a position of financial statement with a balance sheet that we believe supports the execution of our commercial, clinical and development plans over the coming years.

To close, at Beam, everything we do is driven by our commitment to patients. The promise of base editing is not just about innovation. It's about transforming lives and enabling people to live the lives that were meant to live. And we are deeply committed to our vision of developing onetime life-changing therapies for patients.

I'd like to thank the entire Beam team for their tireless efforts and exceptional teamwork in advancing this program from inception to today.

I'd also like to acknowledge that these findings today will not be possible, wherein not for the individuals whose lives we aim to change, people living with AATD.

We'd like to thank all of our partners, including the investigators, the clinical site staff, our clinical development and manufacturing partners, the Alpha-1 Foundation and other advocacy organizations around the world, and above all, each of the patients and caregivers who have taken part in our trials and made today possible.

Operator, please open the line for Q&A.

[Operator Instructions] Now first question in queue coming from the line of Cory Kasimov with Evercore ISI.

This is Adhi on for Cory. In the multi-dose cohort, how should we interpret the absorbed transaminase elevations? Are these events primarily a function of cumulative LNP exposure through repeat dosing? Or there is any residual concerns around the safety profile that could impact the future dosing strategies as well?

Yes. Thank you. Great question, and I'll pass that to Amy.

I think with one event such as that and the fact that it has very swift onset and a very rapid resolution along with some cytokine increases, we think it's likely driven by the inflammatory response to the second load lipids. However, given that I've mentioned, it's just a limited number of patients, we're not entirely sure. But I think what's important is the LFTs resolved very quickly back to normal, and there was no evidence, for example, that the patient had symptoms, required any intervention.

And in the end of the day, I think that this is something that we think we didn't see with the single dose, which is very reassuring. And we've now dosed, I want to remind people, 20 patients at the 60 mg and 75 mg doses with really just very consistent Grade 1 elevations in LFTs. And I also just want to note that seeing Grade 1 elevations of ALTs or even Grade 2 are not really predictive of more severe events in the future, such as things like DILI. So I think from that perspective, we feel very reassured at this point in time with our single-dose and our optimal biologic dose chosen of 60 mg times 1.

And our next question coming from the line of Maury Raycroft with Jefferies.

Congrats on the great data. Wondering if you can talk more about just explanations for why the AAT levels at 60 mg are higher than your last update, increasing from 12.4 to 16.1. Is it due to higher baseline AAT or dynamics with longer follow-up, maybe a combination of both.

And do you have a good understanding of the rate of AAT levels reaching steady-state after dosing. And do you think that could continue to improve with longer follow-up?

Sure. There's a lot in there. I mean I think maybe the first comment I'll make, and then I'll invite Amy to expand on it is, there's obviously a very significantly updated data set since last year. So we went from [ n of 3 to now n of 6 ] with much longer follow-up plus obviously expanding on the other dose areas as well.

So I think we commented last year, actually we felt that the few patients we had at 60 were probably a little on the low end and I think you've seen that sort of normalize here.

In terms of how the overall data set has matured, I mean, I think that we see a lot of stability in the levels that we're achieving and that is quite consistent with the mechanism of action of the drug.

Yes. I mean I do think that over time with more patients, we are seeing probably in the mean baselines that are more kind of what had been reported in the literature. So instead of having baselines of around 5, we're kind of up in the range of about 6 micromolar at this time. And I will say that once people hit day 28, they tend to kind of remain fairly stable from day 28, you can see all the way out now to as far as month 12.

What we don't know yet is will the people who are at the lower doses, let's say, the 15 or 30 mgs, which are not close to kind of editing saturation, will they continue to increase over time because of the potential theoretic survival advantage that the cells that have corrected M-AAT would have over those that still have Z-AAT.

But given the slow turnover in the liver of a T half-life of maybe 365 days, those drifts upwards over time in AAT levels may take a little time to see. In other words, 1 to 2 years, maybe kind of more along the line to what we need to see. But we're very pleased that we're seeing very strong steady-state levels and people maintaining those gains now in a durable manner.

Our next question coming from the line of Samantha Semenkow with Citi.

Congrats on all the great data and all the progress. I have a question for Dr. Teckman. Dr. Teckman, it would be great to just have your thoughts on what is most important here from an efficacy and safety standpoint in your view for a gene editing therapy specifically.

When you look at the emerging profile for BEAM-302, how compelling does that mean 16.1 micromolar in total AAT. There's a few other additional gene editing therapies in the pipeline, and I would love to get a sense on whether you think pushing that total AAT higher, if that's possible, would impact your view on the BEAM-302 profile as we see it thus far?

Dr. Teckman?

Yes, good question. And I think something that I've been thinking about and others have been thinking about. I mean certainly, there's some element of a continuum there. So more probably better. On the other hand, the curve of that line, it's not straight, right? I mean it's actually a curve. And as we talked about and at the level that we're seeing, it's at least MZ and that eliminates 95% of the risk. And plus, it's better than that because MZ people half the protein they're making is Z. And in this situation, we see that really almost everything in the liver at that dose is converted and then you have the acute phase reactant response preserved or restored.

So higher levels give some better protection? Possibly. But this seems pretty good. With regard to future treatment, hard to say, but this looks pretty exciting.

The -- it's commonly -- I mean we've discussed this at the FDA going back a decade, what should the target be and a lot of people have said, well, if you make people into carrier better that you've eliminated the vast majority of disease. So yes, I think it's pretty exciting.

Our next question in queue coming from the line of Eric Schmidt with Cantor Fitzgerald.

Some of the main values you've produced here are really impressive. So congrats on that. I guess I'm wondering if there are any patient-specific factors that either lead to better or lesser gene editing efficiencies or whether maybe there's limited variability?

And then as a follow-up, Pino mentioned that sites have already been activated in the Part C pivotal portion of the trial. I think some would probably claim that, that means the trial has already started, but what else are you guys waiting for to give us the green light on the go ahead there.

Sure. Maybe I'll take the first one and Pino can clarify on the second one. So I think the -- I don't think there's much to say yet on patient-specific factors. Generally, if anything, the results have been quite consistent across all types of patients and particularly now, not missing the point that the Part B and Part A patients, that's probably the biggest factor we were already controlling for in the trial, where a Part D patient has known significant liver burden. But as you've seen in the safety and efficacy of the 60-milligram dose has been comparable there, which is very exciting. So by and large, very consistent, frankly, across the full range of spectrum of patients in this disease. Pino, in terms of the site network and then the path to getting the trial open.

Yes. I invite Amy to comment as well. But fundamentally, we've made a protocol change, and we're in the process of the IRBs and the sites to review that and to improve it. Obviously, we submitted that to the FDA as well. And they don't necessarily need to provide the input, but it's obviously always helpful to provide a little bit of time for them to comment if they choose to do so.

So fundamentally, it's just the process of activating all the sites, making sure that we review this, we get the approval. In the meantime, we are continuing, as I mentioned, some additional Part A treatment as well as Part B, and I think that will provide basically almost like the training ground, if you will, for some of the U.S. sites. So they will be ready for the pivotal trial. Amy, anything else that I may have missed.

Yes. Just to clarify, just so people know the footprint that we're using is global, and that footprint is the exact same footprint we've used for the Phase I/II study. So when we talk about site activation for the pivotal, these sites have already been open for the Phase I/II study and now we'll just wind up conducting the pivotal with, as Pino mentioned, an amended protocol.

And so the good news there is a lot of these sites have already had experienced dosing people, kind of figuring out how to do the study, and this allows us to move superfast because we don't have to then go to new sites that haven't been familiar with BEAM-302 or that then we have to wait for sites to come on board and contract, et cetera. So I think we're going to be able to move very fast using our existing global site network.

Our next question coming from the line of Brian Cheng with JPMorgan.

Can you tell us a little bit more about how the additional 50 patients will be split across the lung and liver phenotypes in the expansion portion? And we know there's also a change in the way how you analyze total AAT here. Previously, you used turbidimetry and then here you use mass spec. Just curious if there's any potential influence in how we interpret total AAT levels.

So to answer your first question, I believe you wanted to know how the breakdown would be in the pivotal study for patients. And in that study, what we're requiring is that everybody have evidence of emphysema. So they don't necessarily have to have abnormal pulmonary function test, but they have to have at least CT scans and emphysema. They do not have to have liver disease, but they can have liver disease. And so what we're hoping here is we now have a pivotal cohort that is a spectrum of disease. So those with lung disease with and without as well liver disease.

So it won't be divided into a Part A, B or altogether. And we feel that our studies that we've done in Part A and B really assure us, to John's point, that the safety and efficacy should be the same, whether or not you have liver disease.

To get to the second point, we are using LC-MS because it's the preferred assay by the FDA to assess total AAT in circulation and enables us to test the AAT composition. So with turbidimetry, you can only just look at AAT. But with LC-MS, we can look at this composition of M-AAT, Z-AAT. And that's very important because it's not just the total AAT matters, but what is it made of?

And so from that perspective, that's why we're switching to this. Now in general, the values tend to be similar. But again, you would have to have each assay compared to each other. It's not enough to say like our LC-MS assay versus turbidimetry done at another hospital. So we have our own validated assays, and we tend to do our assay side by side, and turbidimetry will have a role because it's a very quick turnaround time. So we need that for things like eligibility and other things. But as far as endpoints go, it's going to all be LC-MS based.

Our next question coming from the line of Yanan Zhu with Wells Fargo Securities.

Congrats on the data. So I have a question for the doctor and a very quick follow-up regarding an earlier question for the company.

For the doctor, could you talk about what proportion of your AATD patients are candidates for this gene editing treatment? And how many of them do you think would be interested in proceeding if you prescribe?

For the company, the quick follow-up is on the Grade 4 liver enzyme question asked earlier. I was wondering, can you talk about the time course of this event? And how is it similar or different from the other Grade 4 liver enzyme elevations seen by gene editing peers?

Great. I'll start out. This is Jeff Teckman. Yes, I think there would be a lot of interest from patients. I think that like with a lot of new therapies, the use would expand over time. Most alpha-1 patients come to medical attention because of lung disease, at least in the past. And so there's a significant group of lung disease diagnosed patients. And as we said, there is treatment with protein replacement, but it's suboptimal and a lot of lung physicians don't even use it.

I talked to a patient last week who probably would benefit from it, but his doctor told them not to be on it because he didn't like it or something. So I think a new thing that's not going to be weekly infusions and burdensome, but is really going to return people to an excellent defense of the lung, I think people will be very interested in that. And I think there will be interest in people, especially as time goes on and it becomes more established, be interested in people from switching from infusions over to a one and done that really would be superior, at least that's our initial impression of the data.

With regard to the liver, I think that it's extensive and would -- more study would help us understand the impact. But there are a lot of people who are going to be diagnosed more frequently coming up. And again, if we have something to offer them, that is going to be powerful, and it's going to drive diagnosis.

I mean speaking to the liver doctor, I mean, we test just as an example, for Wilson's disease all the time, even though Wilson's is 10x more rare than alpha antitrypsin deficiency, but it has a treatment and if you can give it to people and save their life. So we send billions of Wilson's treatments for the 1 out of 1,000 that comes back positive. In this case, there will be way more people with alpha-1 that we would identify and then bring the treatment to bear. So I think it's patients, especially over time, as we establish better data, are going to be very interested.

In answer to the second part of the question about the time course for the Grade 4 LT elevation, this is very rapid. The LFT started to increase within 2 days. They probably peaked within 5 to 7 days and were within normal limits even by the next visit at month 4. And so this is a very rapid up-down. And as mentioned, the patients had no symptoms, was followed as an outpatient. There were no changes in bilirubin. And so again, I think this time course is more consistent with what one might see and what has been seen before with LNP dosing.

You asked about contrasting it a little bit to what's been seen, and I think you're referring to the Intellia data with some Grade 4 elevations. And from what we can tell from what's out in the public domain, it seems like those are occurring later in time and being picked up about 1 month post dosing or so. And so I think this is quite distinct from that.

I will point out as well that, as you can imagine, there's been no impact to efficacy either. So we don't think this is something that's like an antibody-mediated type of thing. We think this is more of a response by the body that you might see when you got a lipid load like after a COVID vaccine, et cetera, so more of an inflammatory response that's transient.

Our next question coming from the line of Mani Foroohar with Leerink Partners.

A couple of quick ones. One, we've seen a lot of dynamism in response to inflammatory insults, at least one patient you presented today. How should we think about what that might imply in terms of functional outcomes and clinical profile in a larger, longer pivotal study? And then I have a quick follow-up.

Well, I think -- I mean, just to clarify the question, I think -- I mean, clearly, we do think this is a dynamic mechanism. The gene is quite dynamic. It's one of the central parts of the acute phase response to inflammation. And I think you actually said it well in the question. I think we think it's a fundamental part of the value proposition of the mechanism of action of this drug to, I think as we said, not only get you to a new floor, but have you be able to respond over time.

We will know when there is an induction event because we're also monitoring CRP, right? So we're looking at inflammation in real time. So you can tell the difference between a patient who's giving you the read on their new basal level over the long term, which gives you a sense of what the levels have been changed to after therapy versus when someone is having an inflammatory event and the spike that happens as a result of that.

Maybe just one point of clarification. The 16 micromolar steady-state level importantly does not include the 30 micromolar spike that has been seen. So just to give you a sense, that 16 is really very much basal, a steady-state level measured over several months without incorporating the acute response.

Our next question coming from the line of Michael Yee with UBS.

This is Matt on for Mike. I wanted to ask one for the doctor, maybe an add-on to a prior question. And could you just talk about how you use IV augmentation therapy now, what the weekly burden looks like for patients. And I'm curious whether new or longer-acting recombinant augmentation could change that? And then just overall, how does that compare to a onetime therapy like gene editing from a patient perspective?

Sure. So I'll just say, I'm a liver doctor. I'm very familiar with the lung disease. So I don't prescribe -- personally prescribe protein replacement for alpha-1, but I'm very, very familiar with it. The -- until recently, it's all purified from human plasma. And yes, people have to have IV started or they have to get a port and it's disruptive to travel and things that people want to do. And again, I wouldn't underestimate what the problems with the therapy are.

Like I said, it helps people, but it doesn't return people to wild type and such that many people in the pulmonary field don't use it because they don't feel that the risk-benefit and cost ratio is even worth it. I don't agree with that, but that is a strong opinion among lung doctors -- some lung doctors.

With regard to the recombinant or long-acting, that might actually be a bad thing because as we've said, when you're sick, you need more alpha-1. It gets used up. So we didn't really talk about this the actual physiology. But -- so when alpha-1 antitrypsin protein does its job, which is to inactivate neutrophil proteases. So when neutrophils are moving through tissue as part of their attack against bacteria, they use proteases to open the pathways in the tissue. And alpha-1 is present in the fluid between cells and in serum to inactivate that so that, that effect doesn't spread as well as when neutrophils phagocytose, and there's some leakage of proteases. So again, alpha-1 is there so that it protects. So when you have an active infection, you use up and when alpha antitrypsin protein, its mechanism is it binds -- it's a suicide binding to a molecule of neutrophil elastase, for example, or other neutrophil proteases.

So you use it up. So if you have the long-acting, I mean, it's great that it has a long half-life in circulation. But if you get -- if you're getting infusions once a month instead of once a week and then you get an infection, your next infusions is for 3 weeks, you're suddenly unprotected because you used up all the alpha-1 that you've got.

So the acute phase reactant response and restoring that theoretically would be a major advance in lung protection. Again, we have to see the data. But I mean, people have thought about this and hoped that there was something that would restore the acute phase response in this disease for a long, long time.

And there are even people who are on protein replacement, who in the past, especially would hoard it and then try to infuse more when they were sick because they felt like they -- when they got sick that they had a step down in their lung function. So I think this is important, and I don't think the long-acting replacement is going to nearly match at least if these results are borne out, the infusion is not going to be as good.

And our next question coming from the line of Luca Issi with RBC.

Congrats on the progress here. Maybe, John, kind of high level, any quick thoughts on the competitive landscape here? I'm wondering what was your reaction to GSK return the rights to Wave. But maybe on the other side, also your thoughts on YolTech which I believe in China showed more than 20 micromolar of total protein, I believe it just 45 milligrams. So any thoughts there, much appreciated.

And then maybe super quickly, Giuseppe, on the regulatory side. Again, I appreciate there's a path here for accelerated approval on AAT biomarkers. But what's the bar here that the FDA is looking for? Do you need to show all patients above 11 micromolar? Do you need to show a specific ratio between MN Z? Like any additional color on what the FDA is looking for here, much appreciated.

Yes. Thanks for the question. So I'll take the competitive one as you noted. So we think we're in a very strong position. This is going to be a huge indication. We have a very clear first-mover advantage. We're now up to almost 30 patients and moving directly into a pivotal trial now with alignment on the FDA for the path to market. So that puts us several years ahead of everyone else.

There obviously will be more players, as you noted. I think the RNA editing field, I think we await more data to see if those agents can produce the kind of profile we're seeing here.

I think we clearly believe that this will be a best-in-class relative to that, but look forward to seeing more. And then for future DNA editing agents, obviously, I mean, YolTech, a couple of patients reported in China. We have to wait for more there, only one of which was at the level you described. Other DNA agents moving into the clinic over the course of this year, we would probably get some data in a year or so. I think we have a very strong lead over them. I think the most important thing is the fact that as Dr. Teckman was commenting on the risk levels, we think we've done what we needed to do to get rid of the risk of disease. So it doesn't clearly, to me, leave any room for a lot of improvement that would be detectable in any kind of reasonable clinical experiment you can do.

I mean I think we've -- that's the whole point of getting the carrier here is unless someone is a smoker or something like that, you're not going to see any progression in the disease whether you're -- where we are now or anywhere else that people can try to get to.

So bottom line, I think it puts us in a very strong position. The other thing competitors talk a lot about, as you know, is bystander editing and variant. I think we are very confident, as we've shown before in our preclinical data that the variant acts completely normally relative to the normal protein. And I think we have a lot more data now in the clinic building up that we can share over time. So that, I think, will also not be a source of competitive advantage over time.

In terms of the pivotal cohort, maybe I'll pass that one to Pino to address.

Yes. Look, in terms of what is approvable, there is no real sort of hurdle specifically in terms of the levels or MZ ratio that the FDA requires, certainly not expressed to us.

I think the way we handle the conversation with the FDA, we shared the data that we shared with you in last year. And basically, we asked the question, if you saw this in the pivotal trial, will this be approvable? And the answer is yes.

So the data that you see today is very consistent with that, and we do believe that there is approval. Obviously, in the pivotal trial, we will need to see consistent sort of responses to this data. And if we do so, we do believe that, that is approval.

Our next question coming from the line of Alec Stranahan with Bank of America.

This is Matthew on for Alec. Congrats on the data.

First one from us, I guess, just curious the percentage of bystander or passenger edits. Is it similar to the previous update at 60 milligrams and sort of how do those pan out at 75 milligrams in the multi-dose cohort?

And then maybe a quick one, double-clicking. Curious whether you're seeing those with higher AAT at baseline have more pronounced increases in total AAT or the proportion. Just trying to dig in there a bit.

Yes, maybe I'll handle that. So I think, again, nothing different clinically than we've seen preclinically in terms of the editing profile and the outcomes. And that's true at 60, 75 and multi-dose 60. So again, those are all quite comparable.

And then just your -- I guess, your question about baseline and just sort of patients higher or lower baseline. We do think that, that's probably physiology, right, that a patient who lives at the high end of maybe their baseline is going to be a higher outcome after editing versus low and low. But it's very small end, so you'll obviously be learning more over time about those nuances.

Next question in queue coming from the line of Whitney Ijem with Canaccord Genuity.

This is Angela on for Whitney. We'll add our congrats. Just curious, are there -- has there been any discussion with regulators in terms of wanting to see an acute phase response in the pivotal? Will there be any endpoints related to that?

And then I guess, at this point, are there any more conversations that need to be had with the FDA? Or did they have all the feedback in terms of getting the pivotal started?

Yes, I'll take that. The answer to your second question is, no, we don't need to have any further interactions. I think we have clarity on what it takes to do the pivotal trial and what would be acceptable. And there was no specific conversations around needing to see an acute response in pal. However, we'll keep on monitoring, and we do believe that on average, we're expecting to see that just by virtue of the fact that people are exposed to various infections and so on. So we think it will be part of that data set, but it's not a specific requirement.

Our next question coming from the line of Myles Minter with William Blair.

Congrats on the data. My question is actually for Dr. Teckman. I was just wondering whether you're aware of the SPARTA trial that's going to read out at the end of the year for a double dose of AAT augmentation therapy. I know it's measuring lung function and liver with a doctor. I understand that.

But if that did show functional superiority with higher dose, does that move the 11 micromolar sort of bar that we're looking for, for efficacy associated with serum AAT levels that's the target here. Just curious if your thoughts there.

Right. So you're referring to the double-dose trial, which has been going on for a while. So yes, this is the -- the dose of augmentation -- protein augmentation therapy was arrived at almost 40 years ago. And the reasoning behind that has sort of been reworked and the thought -- part of the thought behind why augmentation doesn't return people to wild-type is that the dose is too low.

And also, when you talk about the dose and the levels reached, people are -- obviously, you give it and it goes down over time until the next infusion, right? So it was natural to somebody finally do a higher dose. It's hard to get payers at this point to pay for higher dose or double dose.

I think there has been some preliminary evidence that released from those trials, which might probably better, but it doesn't return the acute phase reactant thing. So I think there's more to do there. There's still the infusion burden. Infusion would be longer, it would be more expensive.

And the other thing we really didn't touch on so much is that there is this data and idea that the Z protein polymers are actually damaging to the lung. So in the liver, it's definitely a storage disease. There is evidence that there's polymer deposition in the periphery in blood vessels and in the lung. And there's evidence that these little polymers are chemotactic for neutrophils and alpha-1 emphysema is known to be more neutrophilic than the usual emphysema. So there's some evidence that this actually is a thing.

So getting rid of the circulating Z, 95% as was shown, that might also help the lung as well. And of course, protein replacement doesn't do that. So I think the protein placement has helped some people over the last 40 years, but I think it's ready to be replaced by better things. I don't think it's going to continue on with some of these new treatments, which are going to be so much better.

Our last question will come from the line of Patrick Trucchio with H.C. Wainwright.

This is Annabel on for Patrick. Congrats on the data. I guess I was wondering if you could comment on what drove the numerically lower AAT, the 14.4 versus 16.1 micromolar at the 75 versus 60-milligram cohort? And what drove the lower number instead of just a plateau? And then on the side of near saturation editing at 60 milligrams, do you have any direct measurement of editing efficiency in the liver? Or is this inferred from circulating protein biomarkers?

So I'll close with that here. So I think the -- on the latter, it's all inferred. We don't have editing rates yet. We'll pick that up over time with biopsies. But I wouldn't read too much into the 14.4 versus 16.1.

I think that if you look at the aggregate AAT levels across 60, 75 and the multi-dose 60, you look at the percent M we're all in that sort of low 90s, 90, 95. You look at the Z reduction, we think that those are more comparable than not, and they certainly overlap statistic significantly. So I don't think we're picking up any real signal there. Most likely, obviously, with more follow-up, we'll learn more over time.

And I will now turn the call back over to Mr. John Evans for closing comments.

Thank you very much. So yes, I want to thank you all for your time. It's an exciting day. We're so pleased to see this continue to mature and really looking forward to partnering with the community to getting this to patients as quickly as we can. I want to thank Dr. Teckman for joining us and for the great and insightful commentary and help along the way, and we look forward to sharing more of this with you as this moves forward. Thank you very much.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.

Good morning, and welcome to Beam Therapeutics Conference Call. [Operator Instructions] Please be advised that this call is being recorded at Beam's request.

I would now like to turn the call over to Holly Manning, Vice President of Investor Relations and External Communications. Please go ahead.

Thank you, operator. Good morning, everyone, and welcome to Beam's Conference Call to review updates announced this morning in conjunction with our fourth quarter and year-end 2025 financial results. You can access slides for today's call by going to the Investors section of our website, beamtx.com.

With me on the call today, with prepared remarks are John Evans, our Chief Executive Officer; Dr. Amy Simon, our Chief Medical Officer; Dr. Gopi Shanker, our Chief Scientific Officer; Sravan Emany, our Chief Financial Officer; and Dr. Kiran Musunuru from the University of Pennsylvania. Our President, Dr. Guiseppe Pino Ciaramella, will join for Q&A.

Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties and other factors, including those set forth in the Risk Factors section of our most recent annual report on Form 10-K and any other filings that we may make with the SEC.

In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. Except as required by law, Beam specifically disclaims any obligation to update or revise any forward-looking statements even if our views change. With that, I'll turn the call over to John.

Thanks, Holly, and good morning, everyone. At Beam, our vision is straightforward, but ambitious: to provide lifelong cures for patients suffering from serious diseases. We believe base editing has the potential to deliver on that vision through onetime durable genetic medicines with predictable and reproducible outcomes. Today, we're excited to share several important updates that bring us closer to accomplishing this mission. First, leveraging our platform to bring forward a new and innovative development program to address a serious genetic disease, phenylketonuria, or PKU, and second, further solidifying our balance sheet to support the anticipated commercialization of a potentially transformative onetime base editing therapy for sickle cell disease.

Beam was founded on a simple concept: aimed at rewriting broken genes back to normal. Base editing is a next-generation form of CRISPR that allows us to make precise single base changes, resulting in predictable edits without the need to make double-stranded breaks in DNA. With consistent gene sequence outcomes conferring potentially lifelong benefit, base editing enables predictable, reproducible outcomes for patients. This scientific foundation underpins everything we do.

Predictability is a theme you'll hear throughout today's discussion. We believe it is a powerful driver of progress, not just for patients, but across the broader health care ecosystem. Predictable outcomes can streamline R&D, reduce development risk, accelerate regulatory pathways and ultimately improve confidence and deliver value for physicians, patients and payers alike.

Base editing is a highly modular and scalable technology. This means that the core elements of our therapies can be reused again and again. And once they are proven to work the first time, we expect to have a higher probability of technical success as we expand to other genes and other diseases over time. So the power of predictability is built into our business from the start. This is not a one-asset story. It is a repeatable, reproducible model. And as you'll see today, we are now applying that model across a growing pipeline. One of the clearest examples of this platform in action is our liver-targeted portfolio. We have built leading lipid nanoparticle or LNP capabilities to enable efficient in vivo delivery to the liver that can be leveraged for multiple programs, allowing us to move faster with each successive candidate. We're excited to share today that we're expanding this franchise with an innovative new development program for PKU called BEAM-304. BEAM-304 exemplifies how we can leverage base editing to directly correct not just one but multiple disease-causing mutations over time. PKU represents an important strategic expansion of our portfolio and an ideal application of our platform. To start, we have the technology and expertise that positions us well to address this condition. PKU is often caused by a single-point mutation in the phenylalanine hydroxylase, or PAH gene, exactly the type of error base editing is designed to correct. PAH is primarily expressed in hepatocytes, making it highly addressable through LNP delivery, which is an area where we have an industry-leading expertise. There also remains significant unmet need despite available therapies in a large population of approximately 20,000 individuals in the U.S. and many more around the world. As Gopi will describe in a moment, our initial focus will be on targeting the 2 most common mutations found in almost half of patients with PKU. In addition, taking advantage of novel and emerging regulatory pathways, we believe our innovative development approach gives us the potential to address mutations found in a majority of PKU patients over time. Blood phenylalanine or Phe reduction has been accepted as an endpoint for full approval in both the U.S. and Europe, providing an attractive opportunity for both early clinical proof-of-concept and an expedited path to market. Taken together, PKU is a compelling opportunity to demonstrate the scalability of our platform and to deliver potentially transformative therapeutic options to patients.

With that overview, I'll now turn the call over to Amy to provide additional context on the clinical manifestations of PKU and current standard of care.

Thank you, John. PKU is an inherited autosomal recessive metabolic disorder caused by mutations in the PAH gene, which results in the loss of PAH activity, failure to metabolize or break down phenylalanine, referred to as Phe, leading to elevated Phe levels in the blood, which can cause neurotoxicity. In the United States, PKU is typically identified at birth through the federally mandated newborn screening program, and genotyping of these patients is increasingly common as it can guide therapy. As shown in the large arrow, the severity of PKU depends on the amount of residual PAH enzyme function an individual has, which determines their pretreatment Phe levels that can range from 360 to 1,200 micromolar, with classifications ranging from hyperphenylalaninemia to mild, moderate or classic or severe PKU. Guidelines in the United States recommend patients maintain Phe levels below 360 micromolar across their lifetime. But as I'll show on the next slide, many patients struggle with uncontrolled disease, particularly as they age.

People living with PKU can face a significant impact on their health and quality of life as very elevated Phe can have serious neurologic and cognitive consequences. In children, very elevated Phe can result in impaired brain development, intellectual disability and seizures, with some of these manifestations being irreversible. In adolescents and adulthood, where adherence decreases dramatically and many patients are lost to follow-up, increased Phe can also have detrimental health consequences, such as cognitive impairment, headaches, anxiety and depression.

As you can see in the chart on the right, the majority of pediatric patients are within the recommended blood Phe levels of less than 360 micromolar up until about the age of 12. But this percentage steadily decreases with age and as adult, only about 25% of patients remain under control.

For pregnant women, strict control prior to conception and during pregnancy is required to prevent maternal PKU syndrome, which can result in severe irreversible fetal harm such as microcephaly and congenital heart defects. There remains a significant unmet need for new treatment options to address PKU that offer better control of Phe levels and that are less burdensome to patients and their families. Phe exists in most foods, including meat, dairy, grains, vegetables and fruits. Thus, people living with PKU must follow a severely restricted diet limiting protein intake from foods to only 5 to 10 grams per day, which, as you can see from the chart on the right, would mean 1 egg and a slice of bread. Instead, they require medical food without Phe, shown in the lower right-hand panel, to get their needed protein. Medical food is often poorly tolerated and very expensive. Patients with more mild disease and some residual PAH enzyme activity are able to take BH4, a cofactor used to stimulate the PAH enzyme to reduce their elevated Phe levels. However, people living with more moderate to severe disease would require enzyme replacement therapy to decrease their Phe to reach target. This type of therapy must be administered as a daily subcutaneous injection, and it often takes at least 1 to 2 years for patients to achieve target levels. Overall, this occurs in only about 60% of the patients. In addition, it requires frequent labs to adjust treatment based on diet and Phe levels and the discontinuation rate is high due to immune reactions and hypersensitivity. While these treatments help manage the disease, they are not curative and impose significant burden on the patients, leading to diminished quality of life and compliance. To guide our development strategy in PKU, we have anchored our target product profile to establish regulatory precedents, the literature, including the updated ACMG clinical guidelines for PKU diagnosis and management and direct feedback from clinicians treating this disease.

Importantly, the regulatory precedent in PKU is well established. Blood Phe reduction has been accepted as a surrogate endpoint for full approval in both the U.S. and EU. Within this context, a successful gene therapy would be expected to achieve significant and sustained Phe reduction below 360 micromolar, be well tolerated, enable normalization of diet, enabling people to get off of medical foods, which really has the potential to meaningfully improve quality of life. Ideally, this therapy would be delivered as a onetime treatment. These elements define the target product profile we are pursuing with BEAM-304.

I will now hand the call over to Gopi to discuss our base editing approach and early preclinical data demonstrating what's possible with BEAM-304.

Thank you, Amy. As John said earlier, PKU is an ideal expansion of Beam's genetic medicines pipeline and application of our platform technology. I'm excited to share the incredible rapid progress that has led us to the cusp of clinical development today.

In the United States, there are approximately 20,000 people living with PKU. To date, we have already identified 2 development candidates within our BEAM-304 program, targeting the 2 most prevalent PKU mutations, including R408W, which is the most prevalent. Together, these candidates have the potential to treat nearly half of PKU patients, and we have active research efforts to address additional pathogenic PKU mutations over time, covering a majority of all PKU patients. We plan to utilize an innovative development approach in which multiple mutation-specific base editors are developed within a single clinical program. With this approach, we believe that Beam has the potential to create a scalable path to get transformative therapies to the majority of patients with PKU as efficiently as possible.

BEAM-304 leverages our proprietary and clinically validated base editing technology together with our internally discovered and optimized LNP delivery system to precisely target hepatocytes in the liver and directly correct the disease-causing mutations. This technology is adaptable, utilizing a unique guide RNA for each mutation, while the rest of the components of the therapy can stay largely consistent. The advantages of LNPs as a delivery mechanism for liver genetic diseases are multiple. They can be dosed in an outpatient setting by an intravenous infusion. They are titratable and redoseable if necessary, and benefit from a synthetic and highly scalable manufacturing process. Once optimized, LNPs provide a predictable and reproducible platform for both tolerability and dose projection. LNPs also offer a more manageable cost of goods. At Beam, we have built significant expertise in LNP optimization of both internally developed and externally sourced lipids and have internal GMP capabilities to manufacture at scale in our North Carolina facility.

The BEAM-304 program builds on foundational work conducted in collaboration with Dr. Kiran Musunuru's lab at the University of Pennsylvania, which first established preclinical proof-of-concept for base editing in PKU. After adding our in-house capabilities in base editing and delivery, we have now advanced BEAM-304 to IND-enabling activities in less than just 2 years. We are pleased to have Dr. Musunuru here with us today to discuss this work as well as his pioneering work on the development of customized genetic medicines for rare diseases.

This slide highlights the preclinical data supporting BEAM-304, which demonstrate the potential of base editing to correct underlying PKU mutations and rapidly normalize plasma Phe levels. On the left, you see results from a mouse model carrying the R408W mutation. And on the right, data from a second prevalent mutation, which we refer to here as mutation B. Following a single dose of BEAM-304 at 0.3 milligrams per kilogram, we observed a rapid reduction in plasma Phe levels by day 7. In both models, plasma Phe levels were reduced below the therapeutic threshold, effectively normalizing levels in animals consuming an unrestricted standard protein-containing diet. These reductions were accompanied by robust on-target editing in the liver, consistent with correction of the underlying PAH mutation.

Here, we show the dose response relationship between on-target editing and plasma Phe reduction. As dose increases, editing in the liver rose in a predictable manner with even relatively low levels of editing sufficient to drive Phe below the therapeutic threshold. We are eager to advance BEAM-304 into the clinic and have already completed productive pre-IND interactions with the FDA.

Structured similarly to our BEAM-302 and BEAM-301 clinical programs, the planned Phase I/II study will be an open-label, single ascending dose trial initially in PKU patients with the R408W mutation. The study is designed to achieve early clinical proof-of-concept of plasma Phe reduction, establishing a potential path to market and laying the foundation for expansion of the program to additional mutations. Key endpoints will include safety, tolerability and reduction of blood Phe concentration. We expect to file the IND for BEAM-304 in 2026 following completion of pre-IND activities.

As we've laid out here today, our goal is to develop a onetime treatment for as many PKU patients as possible. Our underlying technology, manufacturing process, clinical learnings, regulatory path and commercial infrastructure for R408W will directly inform and support an efficient path forward for additional mutation-specific editors. In addition, our work in PKU builds upon our growing expertise in metabolic disease, along with our experience in GSDIa and has the potential to enable continued expansion into other metabolic disorders.

With that, I'd like to formally introduce Dr. Kiran Musunuru. Dr. Musunuru is a Professor of Cardiovascular Medicine, Genetics and Pediatrics at the Perelman School of Medicine and the University of Pennsylvania, and was recently appointed as the Co-Director of the Penn Orphan Disease Center. A practicing cardiologist and geneticist, his research focuses on genetics and genomics of cardiovascular and metabolic diseases with a particular emphasis on developing gene editing therapies. Dr. Musunuru is widely recognized as a leader in applying CRISPR and other genome editing technologies to prevent and treat heart disease. He also played a central role in the development of world's first personalized base editing therapy to treat an infant known as baby KJ, marking a landmark advance in precision medicine for ultra-rare genetic diseases.

Over to you, Kiran.

It's a real pleasure to have the chance to speak to you today. I've been working with my friend and colleague, Dr. Rebecca Ahrens-Nicklas at the Children's Hospital of Philadelphia, or CHOP, for several years now to develop personalized gene editing treatments for a variety of inborn errors of metabolism, including PKU. I should start by emphasizing the poor metabolic control achieved in patients with PKU under the current standard of care, even at an academic medical center where patients are receiving specialized care from a team of metabolic physicians. We looked at data from patients with PKU treated at CHOP, specifically all individuals with at least one copy of the PAH R408W variant, which is the most frequent variant causing classic PKU, that is severe PKU. We found that the majority of patients had at least a single Phe measurement above the recommended safety zone indicated here by the dotted line, 360 micromoles per liter. About 30% of patients had lifetime average Phe levels above the recommended maximum Phe level. There's clearly enormous unmet medical need here. There are more than 1,000 PAH variants cataloged in patients with PKU worldwide, and many are potentially amenable to adenine-based editing, meaning that like the R408W variant, they could in principle be corrected by A to G edits, either on the sense strand or the antisense strand. Rather than focus on the top few most frequent PKU variants, Dr. Ahrens-Nicklas and I chose to initially focus on a lower frequency variant, the PAH P281L variant. Early on in our work using a humanized mouse model with PKU caused by the P281L variant, we found that treatment with an LNP test article with an mRNA encoding an adenine base editor and a guide RNA specific to the variant caused the elevated Phe levels in these mice to be entirely normalized by 48 hours after treatment. This got us excited about the prospect of addressing not only the P281L variants, but a broad range of disease-causing variants in the PKU population.

Since then, Dr. Ahrens-Nicklas and I have found promising adenine-based editing solutions for other variants, which together comprise a majority of PKU patients. It's not hard to envision using the same LNP formulation, slightly different versions of mRNAs to cover a family of closely related adenine-based editors and individualized guide RNAs, effectively, variations on the same drug product to treat all these patients. That said, Dr. Ahrens-Nicklas and I are very committed to the idea that no patient should be left behind. Our goal is to be able to rapidly develop and validate a corrective editing therapeutic for any PAH variant in any patient with PKU. Solving a small number of variants isn't enough. What about the 1,000-plus other variants that have been cataloged? And that actually understates the problem. Here's a figure from the most comprehensive study of PKU variants worldwide published in 2020, plenty of data from some parts of the world like Europe, and then whole stretches of the globe from which there are little data, for example, the entire African continent and large parts of Asia. This highlights that you can't make gene editing therapies for patients if you have no idea what genes and variants are causing their diseases. As gene sequencing becomes more broadly accessible, we can be sure that many more PAH variants will be identified. It won't be feasible to design gene editing therapies for these patients beforehand for many of these patients will need to be able to make these therapies in real time. The problem is even more acute in another set of diseases on which Dr. Ahrens-Nicklas and I have been working, the urea cycle disorders. Variants in the genes encoding any of the 6 liver enzymes and the transporter shown here, which together comprise the biochemical pathway that converts the toxic ammonia that results from the breakdown of dietary protein into nontoxic urea, can cause very high blood ammonia levels shortly after birth, which in turn cause irreversible injury to the brain, coma and death. In principle, all 7 of these urea cycle disorders could be addressed by doing corrective editing in the liver, just like PKU. But these are ultra-rare diseases, and most of the patient's variants are N-of-1 and N-of-few. And so the treatments would need to be highly personalized, and in most cases, made rapidly in real time once a patient has been diagnosed. It goes without saying that the current regulatory framework was never intended to handle this type of personalized therapy and that regulatory innovation is needed. Dr. Ahrens-Nicklas and I have been extensively engaging with the FDA over the past couple of years, having interact in pre-IND meetings about gene editing therapies for patients with PKU or any of the 7 urea cycle disorders as well as a single patient expanded access IND for an infant with a urea cycle disorder, through which we were able to make a personalized adenine-based editing therapy for the patients in just 6 months. I'm not going to get into the details shown here, but instead give you the highlights over the next few slides. I should note that we've published some of our FDA interactions, the briefing books and written feedback, in the paper cited here in the American Journal of Human Genetics a few months ago so that everyone has access to them. We first asked the FDA whether we could include multiple PAH variants in the same IND application, a single application using the same LNP formulation, slightly different adenine-base editors and individualized guide RNAs. They were agreeable to this, opening the door to a so-called umbrella clinical trial. We then asked the FDA whether we could add new PAH variants to the umbrella clinical trial in real time, submitting rapid IND amendments that include only in vitro cellular on-target and off-target data with no animal data at all. And they were agreeable to this concept, and it lays the foundation for an eventual approval of a full therapeutic editing platform for PKU.

Finally, we asked the FDA if we could bundle all 7 urea cycle disorders into a single clinical trial under a master protocol. There's a primary IND with the master protocol and then gene-specific secondary INDs that heavily cross-reference the primary IND and to which new variants in any of the 7 genes can be added in real time. We think of this as an umbrella-of-umbrellas clinical trial. And our hope is that the FDA will be open to an accelerated approval with a relatively small number of subjects, either through the newly announced plausible mechanism pathway or another pathway. In all, we think this is a very positive development for the ultra-rare disease space and are excited to move forward with this kind of clinical trial for the urea cycle disorders with funding support from the NIH's Somatic Cell Genome Editing program.

Thank you, Dr. Musunuru. It's a pleasure having you here with us today. I'll now turn the call over to Sravan to discuss today's financial updates.

Thanks, John. In addition to PKU, today, we shared another important update that further strengthens our balance sheet and reaffirms our belief in the commercial potential of risto-cel, our investigational autologous cell therapy with potential for best-in-class profile for the treatment of sickle cell disease. This morning, we announced a strategic financing agreement with Sixth Street that provides up to $500 million in long-term non-dilutive capital to support the anticipated launch of risto-cel. The facility includes $100 million funded at close, up to $300 million available upon the achievement of certain regulatory, clinical and commercial milestones for risto-cel and an additional $100 million subject to mutual agreement during the 7-year term. Repayment of the principal is due in early 2033. This structure strengthens our balance sheet while preserving flexibility and enhancing our ability to both commercialize risto-cel as well as fund future growth and innovation across our pipeline. With this latest announcement, we have established a foundation of financial strength for sustainable growth. We ended 2025 with $1.25 billion in cash, cash equivalents and marketable securities. With the anticipated minimum draw of $200 million from the Sixth Street facility, we now expect our runway to extend into mid-2029. This supports Beam's pipeline execution through key anticipated milestones, including the launch of risto-cel, the BEAM-302 pivotal plan and clinical proof of concept for BEAM-304. We remain focused on being efficient with our investments, including building focused commercial capabilities ahead of the anticipated risto-cel launch and positioning BEAM-302 for a potentially accelerated path to market.

Finally, our pipeline is wholly-owned and addresses significant markets. Combined with our platform-enabled approach, we believe this provides a clear path to long-term value creation and sustainable growth. I'll turn the call back to John for closing remarks.

Thank you, Sravan. We believe our PKU program clearly illustrates the power of Beam's genetic medicines platform. By correcting the genetic cause of the disease, base editing is a potentially ideal onetime solution for patients with this severe disease. Further, we believe we'll be able to take advantage of the modularity of our platform to ultimately address additional mutations supported by emerging regulatory precedents. Like our other programs, BEAM-304 is a precision medicine with potential for early proof-of-concept in the clinic and a predictable pathway to a large initial market poised for significant growth.

As we look ahead to 2026, we believe BEAM is well positioned to realize the power of predictability across our growing portfolio. For our lead programs, we are accelerating the path to approval and look forward to providing updated Phase I/II data and next steps for BEAM-302 pivotal development in alpha-1 antitrypsin deficiency this quarter, followed by the anticipated submission of the risto-cel BLA as early as year-end.

In addition, we continue to advance and expand the pipeline. We expect to file the IND for BEAM-304 for PKU, report initial BEAM-301 data in GSDIa, complete the BEAM-103 healthy volunteer study and continue advancing our in vivo HSC editing efforts this year. As Sravan outlined, we are doing this from a position of increasing financial strength with a strong cash balance and new long-term non-dilutive capital from Sixth Street to support risto-cel. At Beam, everything we do is driven by our commitment to patients. The promise of base editing is not just scientific innovation, it is the potential to deliver onetime life-changing therapies to patients in need. We are grateful to all of our partners, employees, investors, physicians and above all, the patients who are participating in our clinical trials for making this work possible. Together, we are building a future where serious genetic diseases can be treated precisely at their source in a personalized and predictable manner to bring new options and new hope to patients with serious genetic diseases.

Operator, please open the line for Q&A.

[Operator Instructions] Our first question comes from Samantha Semenkow with Citi.

Congratulations on all the progress. I just wanted to talk a little bit about the regulatory path forward and addressing multiple mutations. From a Beam-specific perspective, how should we think about the opportunity and the time line to moving beyond the R408W mutation into other mutations?

And then just with the strategic financing for risto-cel, does this allow you to reallocate more of your existing capital to additional liver-targeted indications? And how should we think about the rollout of those additional programs?

Yes. Thanks, Samantha, and great questions. So maybe to start, I'll ask Gopi and then Amy to talk a little bit about how we see additional mutations rolling over time, first in research and then in the clinic. And then we'll come back and have Sravan talk a little bit about what this allows us to do financially. Gopi?

Thanks, John. Thanks, Samantha, for the question. On the additional mutations, our research efforts are already underway for other mutations beyond the first 2 mutations that I described. And we expect the time lines could be fast given that we are primarily changing the guide RNA. We believe this platform approach can act as a flywheel where we get faster and more efficient for each subsequent mutation. And based on our initial interactions with the FDA, we expect to be able to bring multiple mutations forward within one program.

Also just to add to what Gopi has said, I think as a first step, it's been very gratifying to work with the FDA, very collaborative in order to kind of get their feedback on this whole process. And I think our intention is to get proof-of-concept in PKU with the R408W mutation. And then we'll continue to work on adaptive trial design to accelerate development in some of the other mutations that also impact patients with PKU.

This is Sravan. I'll tackle the finance question. So I think we're really confident this financing gives us a lot of flexibility with the long-term non-dilutive capital to support the commercial launch and subsequent revenue generation for risto-cel. And I think you kind of hit the point, which is, it also enhances our ability to redirect our capital to the growth of our pipeline. For a novel platform and technology like ours, it takes a lot of fixed investment to get to at this point. But we really feel like the subsequent programs that are on top of our platform are exciting, and we look forward at some point in the future when they're ready to be shared to show.

Our next question comes from the line of Maury Raycroft with Jefferies.

I'm going to move to the next question. It comes from the line of Eric Schmidt with Cantor.

A couple of questions on 304 as well. First, it sounded like Dr. Musunuru's lab may have been first at kind of reducing the practice of base editing for some of these mutations. Is there some IP associated with either R408W or others that the company has access to?

And then second, in terms of the predictability of the platform, that seems to be the theme today. Does 304 use the same ionizable lipid or even same or similar lipid nanoparticle? What can you say about the delivery there relative to, say, 302 or 301?

Yes, great questions. I can handle those 2. So yes, so I think we will have access to all of the IP that we need here. Certainly, there is a lot of pioneering work from Kiran's lab to point the way in this indication. Obviously, a lot of work has happened at Beam in the last few years, as Gopi said, to then make these industrial and leverage all of the platform capabilities that we have as well.

In terms of the LNP, so yes, so it's broadly the same kinds of LNP approaches that we use with 302, 301. We do have our own a ionizable lipids at this point as a company, which we expect to use. But the way we make them, the formulation, the approach as well as the internal manufacturing, we'll all be leveraging the work that we've done for 302 and 301 as well.

One moment for our next question, it comes from Yohan Zhu with Wells Fargo.

A couple of questions. I wanted to take advantage of the presence of not only the company, but also Dr. Musunuru On the line. Yesterday, FDA provided a draft guidance for individualized therapy. One thing that's not quite clear is how rare [ does ] the disease has to be to qualify for this new framework? I am wondering within the PKU range of mutations, are there any that are some or a lot of the mutations would have fall under this new framework? And if I may, 2 quick technical questions. For the 304 product name, are there going to be 2 different guide RNAs targeting the 2 different mutations or the same guide RNA? And if you can also talk about in your preclinical work, the presence of bystander editing, that would be great.

Great. Thank you, Yanan. Yes. So I think you're touching on some of the more innovative aspects of what we're doing here, which is quite exciting. So maybe I'll ask Dr. Musunuru First to say a bit about yesterday and the plausible mechanism pathway. And then Gopi, maybe you can cover the multiple guides in the bystander [indiscernible].

Yes. Thanks, John. So my perspective on the plausible mechanism that was announced yesterday is that it's primarily talking about potential approvals of platforms. And so you have to make a distinction there that it's about ultra-rare diseases, at least that's what is explicitly stated in the guidance, for which it is not feasible to do standard randomized clinical trials. And there are a bunch of conditions that are set there as to what particular types of diseases might qualify under the plausible mechanism framework. But it's ultimately geared towards either accelerated or potentially full approvals, in this case, because we're talking about gene editing therapies, we're talking about biological license applications. It's not necessarily prescriptive about clinical trial designs per se. And so what I should say with respect to PKU is that there's some ambiguity there. So if you're talking about urea cycle disorders, which I mentioned during the presentation, those are very clearly ultra-rare diseases. You're talking about perhaps a few dozen patients at most who are born in any given year who might be amenable to this type of gene editing approach. What's less clear is with a disease like PKU, where there's a wide spectrum of mutations, there are relatively frequent mutations where potentially you could contemplate doing a standard randomized controlled trial. But then if you go to the other end of the spectrum, there are N-of-1, N-of-few type scenarios that would be individually considered ultra-rare. And so I don't think it's clear. I'm not sure the FDA necessarily has thought about this so much. Dr. Hoeg, the acting CDER Director yesterday during the press conference when asked about this very issue, demurred to some extent and said that the agency doesn't want to be prescriptive, at least at this point as to what distinguishes ultra-rare from rare. She expressed openness to the idea that it doesn't necessarily need to be an ultra-rare context in order for the plausible mechanism framework to apply, but he didn't give much specificity. And I would point out again that this is a draft guidance, not the actual final guidance. And so there will be 60 days in which members of the biomedical community can give feedback. And I expect this will be one of the issues where they will receive a lot of feedback. And so we'll have to see what the final guidance says.

The other last point I would make is that, as I mentioned during my presentation, my academic group has been having interactions with the FDA about clinical trial designs. I outlined some of them. Those predate the announcement of the plausible mechanism framework, both what happened yesterday as well as the original New England Journal of Medicine article published by Dr. Makary and Prasad back in November. And so those clinical trial designs where one can include multiple variants in the same IND under a single umbrella clinical trial, those are relevant regardless of whether the disease itself would qualify for the plausible mechanism framework or not. The clinical trial designs will stand on their own. It's very clear that the FDA is open to those types of designs, whether there are going to be accelerated approvals under the framework that was announced yesterday, less clear. I think that would entail discussions with the agency on a case-by-case basis.

Our next question is from...

I just wanted to add one...

One moment. I think we have -- we wanted Gopi to answer the second half of Yanan's question. Gopi, over to you.

Yes. Thanks for the question. So the 2 mutations that I described today, the guide RNAs are unique. And in general, for this program, we expect to be developing mutation-specific guide RNAs and editors. So the guide RNA will be unique for each mutation, but they'll all be part of a single clinical program. That's how we intend to carry this forward. And on the bystander profile, even though we didn't disclose details today, we feel confident about the on-target editing and the benefit risk profile.

And Amy, did you want to add something to Kiran's discussion?

I would just indicate that we've had also very good meetings with the FDA, and they're supportive of this platform approach where multiple variants could be treated under one single program or one type of IND. So I think that it is something that, although it's not necessarily the same as a plausible mechanism, they're clearly showing interest in adaptive designs to enable basically acceleration to patients.

Our next question comes from Cory Kasimov with Evercore ISI.

This is Adhi on for Cory. I wanted to ask a question on sickle cell given the new financing. The recent increase in uptake of approved ex vivo therapies, can you help frame your current view of peak penetration or sales for ex vivo modality? And specifically, what market share assumptions do you currently expect for risto-cel, assuming its differentiated profile continues to hold?

Yes. Thank you. So maybe I'll have Pino talk a little bit here about our view for risto-cel. Of course, we wouldn't be giving market share or other specifics like that at this stage. But I think we do have -- we have been watching, obviously, the market evolve and have a lot of perspective on that. So maybe, Pino, you want to talk a little bit about how the market is coming along and what we think [ about ] risto-cel?

Yes. Thank you, John. Yes, I guess what we have seen about the market is consistent with some of our sort of intelligence gathering that we've been doing over the last year or so. And that is that clearly, there is a significant demand for a program such as the risto-cel that we're developing. And that's -- as you can see, there are basically patients waiting in order to do that. Also, other aspects of the market are very positive, like, for instance, to our knowledge, nobody has been refused the payment despite the fact that these treatments are north of $2 million. What has been a situation so far has been the somewhat limited ability to support the demand that exists on the basis of the manufacturing process that the current programs seem to have. And in particular, what we have seen is that many patients have had to go through several rounds of mobilization before they're actually being dosed. And so that causes also limitation on the overall capacity of the system as well as not making the money essentially on behalf of this company. We have really from the get-go, optimized our manufacturing process very strongly so that you can see our median mobilization cycle is only one. And that's also likely helped by the fact that we don't make double stranded break. So we do believe that we have a very competitive product and that it will hopefully help to satisfy the significant demand that exists for these products.

One moment for our next question, it comes from the line of Whitney Ijem with Canaccord Genuity.

This is Angela on for Whitney. Maybe jumping over to the AATD. Can you just help us set expectations into the upcoming readout? How should we all be thinking about what is good in terms of AAT levels from the 75 and the 60 milligrams double dose?

And then for the pivotal, I guess, how confident are you that we'll have what we need with the next data update to pick a dose and move forward into the pivotal?

Yes. Great. So I'll handle that one. So we're obviously on track to give that update. I think we've shared prior, there will be a pretty comprehensive set of data there. So as a reminder, for that trial in alpha-1, so with 302, we're dosing additional 60-milligram patients, just given the strength of the data we showed last year and then continue to explore dosing schedule, looking at a 75-milligram dose and a 2x 60. So we'll put all of that together. And as a reminder, what we're looking to see there is, is there any evidence of increases in alpha-1 sort of versus how close are we to saturation in the liver already. So that will be sort of part 1. We'll also be looking at patients with -- this is all sort of Part A with lung. We're looking at patients in Part B who have the sicker livers. We're trying to see if there is similar efficacy and safety as in Part A. And then depending on what we see there, there's certain things we can think about. We'll also be, of course, showing durability. So we'll have a significant amount of time now with patients who are in the update from last year out 12-plus months and then a range of follow-ups from there.

So I think in terms of your second question, I think we said before, we do expect to have sufficient insight over the course of the beginning part of this year to finalize dosing schedule and anything else that need to go into the protocol. I expect that the data set will be hopefully helpful there, and we have it or we'll be able to have it soon. But it's [ not we're ] limiting at this point. We're already operationalizing the accelerated approval cohort and that can just take in the input from the rest of the part of the Phase I/II. So that is very much on track for getting started.

Our next question comes from the line of Brian Cheng with JPMorgan.

First, just on responses in PKU. Do you have a sense of how well these R408W carriers behave and respond to current options like Kuvan, Sephience or Palynziq in the real world? And any thoughts on their uniformity in terms of response to a base editing approach?

And then second, just on the Phase I/II design, can you talk about the age range you're thinking of recruiting here? And how quickly can you get to the newborn at the time of their diagnosis?

Yes, great question. So as a reminder, the mutations we're going after are really in the classic kind of severe PKU part of the market. So maybe, Amy, if you could speak a little bit to for those patients, responsiveness to current therapies, and then a little bit of how we think about getting to different age ranges over the course of the clinical trial.

Sure. Thanks, John. So it turns out that the first mutation, the R408W is called classic or more severe because the amount of PAH enzyme activity is really almost 0. And so from that perspective, these patients would not respond to things like BH4 or co-factors that you mentioned because that requires some residual enzyme activity in order to have any types of utility. And so typically, that would be for more mild or moderate cases and not necessarily for this R408W. There is, as we mentioned, the enzyme replacement therapies, but these are quite cumbersome. And even then only about 60% of patients after a couple of years of therapy can even get to the target below 360 micromolar. So even in those patients with this cumbersome therapy, we're still not addressing and getting people to have full diet liberalization with the therapies that are available.

As far as the pediatric population and getting into those patient populations, I think the FDA has shown signs of being very collaborative. And typically, when we do go into these patient populations, we will stage [ gauged ] a little bit and typically start either at 18 and above or, for example, sometimes you can get an indication directly to go to 12 and above. And then once you get some data, then working with the regulators to then be able to open up cohorts that are younger and younger. And some of this also can be done with some, obviously, PK/PD modeling and other kind of things to kind of figure out dosing, et cetera. But we are very confident that we will be able to get to the patient population that, frankly, would benefit tremendously from this because those are the patients who are having brain growth in development, and it's critically important that they have their target levels less than 360, even though we have increasing evidence that adults and others should be treated for a lifetime with the goal of being under 360 given impact on cognitive and executive function.

Our next question comes from Luca Issi with RBC Capital Markets.

Congrats on the progress. This is Cassie on for Luca. A quick one on A1AT. I appreciate that you are DNA editing and some of your competitors is RNA. But what is your read on GSK returning the rights on A1AT? And also maybe a longer question for A1AT's pivotal, has the FDA discussed with you their minimum requirements for representative U.S. enrollment? If -- correct me if this is not right, please, we see on fda.gov that the Phase I/II are ex U.S. Would this mean that your pivotal of [ NL50 ] will have to be mostly from the U.S. if the agency does require a majority of patients in the approval package to be U.S. patients? Any color there is much appreciated.

Yes. Thanks. I can handle some of those. So the first question on RNA editing, I mean, I wouldn't want to comment on another company's situation. I think you just have to ask them. I think our belief remains that, all things equal, that having a one and done for alpha-1 is going to be a preferable target product profile if you can achieve it, which we believe we can. And then obviously, just doing head-to-head on the different data sets that have currently been disclosed, we continue to believe that BEAM-302 has shown the best-in-class data in terms of alpha-1 levels as well as the composition of that -- of those levels as well between MD production.

So in terms of U.S. ratio, I think it's probably premature to talk about that. I think we are -- we obviously have an open IND. We will be active in the U.S. That will be a big part of the entire trial going forward, along with the ex U.S. regions that we're in. So we'll certainly be keeping an eye on that and make sure that anything we need for U.S. approval will be satisfied, which I'm sure.

Our next question comes from the line of Sami Corwin with William Blair.

Congrats on the progress. I was curious for the clinical development in PKU, if it will be required that patients have 2 copies of the same mutation. And if not, how that could impact the range of benefit observed?

Yes. Great question. Maybe, Gopi, do you want to talk a little bit about the preclinical work we've done on that subject? And then Amy, if you want to expand on that [indiscernible]?

Yes. Thanks for that question. As you saw in the dose response data I showed, the level of correction that is required in order to reduce Phe levels below the therapeutic threshold is relatively modest, and that is one copy of PAH gene corrected is sufficient. A large number of patients do -- are compound heterozygous, so they will have 2 different mutations on each of their alleles, and it's sufficient to correct one of them. And to model such patients, who've actually used compound heterozygous mice, meaning mice that have 2 different mutations, but we were only correcting one of the mutations and then demonstrated that, that was sufficient in order to reduce the Phe levels to below the therapeutic threshold.

One moment for the next question, we have Maury Raycroft from Jefferies.

Congrats on this update. Maybe just a quick one. For the in vitro data that you have for the different variants, can you just provide more specifics on how much of that you already have? And I don't know if there's any more practicalities you can comment on for how new variants are going to be added into this Phase I/II study and how the Phase I/II is going to work from like a dosing standpoint to adding these new variants?

Yes. I think -- I mean, maybe I'll just give the high-level answer, which is, we are quite far at this point through all the preclinical preparations. We've already had interactions with the FDA, which have been supportive of this approach, which has been very encouraging. And I think as you've seen, we've guided to IND filing this year. So clearly, we're in the final steps here. And then I think the other piece about bringing more mutations in over time, I think we obviously are going to start with 2, but there is an understanding that we can then append additional mutations into the same IND over time. That's basically the framework that has been put forward here. And so as the research team brings them along, we can then adaptively put that forward. Some of the nuances of exactly how we manage the trial over time and mix these different populations together on our approval pathway is obviously some of the work that Amy and her team will do in consultation with the FDA, and that's where we're going to continue to sort of pioneer this. But we feel quite confident, especially with the well-precedented endpoints in this disease that we will be able to do that.

Got it. And for dosing, is there anything from the AATD study that just kind of informs where you can start out with dosing here?

Yes. Either Gopi or Amy, you want to talk about sort of initial dose selection and escalation?

Yes. I mean I think, again, it depends a lot on what we see in our nonclinical, and we do PK/PD modeling. And obviously, it's unique for each kind of LNP and drug product that you make. And so I think we're just going to base it on kind of those analyses like we have in the past for 302 and 301.

I think you can expect it to be standard would be what I would say.

And maybe I can just add that as you saw in the preclinical work, we were able to bring Phe levels down to below the therapeutic threshold at relatively low doses of LNP. So we expect to be able to do the dose finding relatively efficiently.

Our next question comes from William Pickering with Bernstein.

First is, could you explain why a lower editing rate seems to be needed here compared to, say, sickle or AATD and any risk that translating to humans? And then on OpEx, could you just ballpark how much incremental OpEx you'll be taking on over the next couple of years to advance the PKU program? And how does that scale with the number of unique mutations you take into the clinic?

Yes, good question. Maybe Gopi, why don't you start with the first question just about the low threshold for [indiscernible] here? And then, Sravan, do you want to talk about how PKU appears in our cash planning and runway guidance?

Sure. So PKU is caused by what's called recessive loss of function mutations, which means both copies of PAH need to be nonfunctional in order to have PKU. And it's often not required in diseases such as this caused by recessive loss of function mutations to have full restoration of the enzyme activity in order to reduce the phenylalanine levels. And as you saw from the mouse data, it's sufficient to only get modest levels of the enzyme activity restored in the liver for the enzyme to then reduce the phenylalanine levels and to be active. And you see this in other diseases in addition to PKU as well.

And then on the question about runway in operating expenses, I would say that first, and I guess the most important thing, PKU is already baked into the operating runway guidance we provided at the start of the year and updated today. And that we're just at this point in time, probably not going to disclose the level of detail around cost by program as it's kind of balanced across the entire portfolio. And I think I mentioned already as a platform company, we've got a lot of fixed investment. But as we evolve as an organization, start to see some of the benefit of taking advantage of that platform as subsequent programs come online.

Yes. And if I could even just underline that last point. I think it's generically as the platform gets built that an entirely new program is easier and faster and more efficient and more likely to succeed when we do it at the second time or the third time or the first time. And I think we're already experiencing that to a degree with PKU BEAM-304 coming after 302 and 301. The adding additional mutations within the same program is even more efficient, right? I mean the flywheel now is simply an additional guide RNA, some minimal testing and then you're off the races. So we do think these are continuing to drive down the kind of incremental cost of the additional editor as we continue to mature the platform.

One moment for our next question, that comes from the line of Alec Stranahan with Bank of America.

Just a couple from me. Maybe just a follow-up on the plausible mechanism pathway. I know ultra-rare was mentioned. Curious if you have any thoughts on the FDA comments on plausible mechanisms, specifically related to AATD. This seems consistent with the biomarker-driven [ patient ] path you're pursuing, but any additional thoughts relating to the applicability to AATD would be great?

And then just given the increased attention on vector safety in the liver, could you maybe talk a bit more about your LNP for the PKU program? Any structural modifications you're making here, specifically thinking for optimizing safety and specificity?

Sure. So maybe on the first point, so I think, as Kiran already mentioned, I think the plausible mechanism pathway is sort of one way that the FDA anticipates getting these sorts of programs to approval, but it's not, of course, the only way once you're in this sort of platform world. I think with alpha-1, we can say that we think we're taking a, frankly, more traditional path, which is an accelerated approval pathway [indiscernible] root cause of disease, followed presumably by some kind of confirmatory experiment. So we don't need an innovative new pathway for that. That's pretty traditional. That said, obviously, it shows that what we're doing in alpha-1 is broadly aligned, I think, with the kinds of programs working on the kind of root cause of disease that the FDA is clearly leaning in on. And then lipid nanoparticle, I mean I think broadly, I think we think that LNPs are the best available option for the liver in terms of getting there. We think we've got a lot of expertise in that area. And I think as I mentioned before, we're building on that clearly with the 304 IND and look forward to updating you over time.

Our next question comes from the line of Michael Yee with UBS.

This is Matt on for Mike Yee. Maybe one on the next-gen sickle cell program. It seems like in vivo has maybe leapfrogged ESCAPE in terms of priority. Could you just speak to what goes into choosing the right next-gen program for sickle cell? And what gives you confidence in the in vivo program and the HSC targeting that you might use there? Just any you can say there would be great.

Sure. Pino, do you want to maybe just talk a bit about our prioritization of in vivo and prospects there?

Yes. Definitely, the consideration here is the fact that with LNP, of course, we can deliver a product much more easily than an ex vivo approach, and therefore, it would provide support for a larger number of patients if the efficacy, obviously, were proven to be equal or certainly manageable from a disease point of view. I think the important aspects of -- and because we're making progress, frankly, and preclinical studies would suggest that, that can also move relatively quickly in clinical studies. And therefore, that's what is guiding us to making that choice. We also have opportunities, obviously, to further enhance the engraftment rate, if you will, of an LNP with the use of our ESCAPE-like technology as well. So I think that gives us the confidence at this stage to move that program as quickly as possible. And obviously, we're doing everything we can to move it at speed.

One moment for our next question, it's from the line of Patrick Trucchio with H.C. Wainwright.

Luis here. A question on -- for the go and no-go decision for 103 in healthy volunteers, how are you thinking about that? And comparing to the in vivo editing in HSCs, how are the efficiency -- the editing efficiencies compared?

Sure. Pino, do you want to talk a little bit -- I think you just sort of talking about this about the role of ESCAPE, obviously, broadly, but also in the in vivo context.

Yes. Also, the initial question was not clear, but I heard the healthy volunteers. So...

Yes, 103, yes.

Yes, 103. So what we're doing with the healthy volunteers is basically, we are dosing just the antibody component of the ESCAPE technology. This is the anti-CD117 antibody. And what we are doing there is in addition to obviously confirm the safety of that antibody, we're also developing a PK/PD model that would guide us the dosing in the context of the sickle cell patients that we plan to test in subsequent studies. We do not have any editing in that particular healthy volunteer study. And the other thing to confirm is that by having the additional edit that essentially protects the edited cells from the binding of their antibody, it gives us the opportunity for edited cells to basically survive over the unedited cells even in the context of an in vivo delivered technology.

And the efficiencies compared to the in vivo program?

The efficiency, do you mean, of editing in combination...

Editing the 2.

Yes, it's very high. So it's comparable.

Thank you, ladies and gentlemen. This will conclude our Q&A session for today. I will pass it back to John Evans for final comments.

Thank you all. It's obviously a lot of exciting updates. We continue to be really pleased with our momentum here across the board and very excited about what's ahead. I also want to thank Dr. Musunuru for joining us and for all of his pioneering work along with his colleagues and Dr. Ahrens-Nicklas for really opening the door to some of these new approaches. I look forward to continuing the partnership. So thank you all for your time.

This concludes our conference. Thank you for participating, and you may now disconnect.

Good afternoon. Thank you for joining us for another session at the 44th JPMorgan Healthcare Conference. I'm Brian Cheng, one of the senior biotech analysts here at the firm. On stage, we have the CEO of Beam Therapeutics. I'll now pass the mic to their CEO, John Evans, for a short presentation, followed by a live audience Q&A. John, the stage is yours.

Thank you very much. So yes, my name is John Evans, here to tell you about Beam Therapeutics and some of our medicines. And I'm going to talk about the power of predictability in the technology that we're using. So as a reminder, I will be making forward-looking statements today.

So at Beam, our vision is to provide lifelong cures for patients suffering from serious diseases. This is gene editing for rare and common disorders. This means the potential for onetime curative therapies with lifelong effects. And this is a platform that can potentially create a large number of medicines over time. So it's been a remarkable 12 months for base editing, and I just want to walk you through some key events.

So at the very end of 2024, we revealed data of base editing for severe sickle cell disease, showing dramatic results. Shown here is Brandon, patient #1 on that trial, who was treated at Boston Children's Hospital. Just a couple of months later in March, we published the first data for base editing and alpha-1 antitrypsin deficiency using BEAM-302. This is in vivo editing this time. And now for the first time, we're literally rewriting a broken gene back to normal, which has never been done before.

Two months after that, a team at the Children's Hospital of Philadelphia published dramatic results where they created a customized base editor for a baby named KJ, who -- the editor was only developed over the course of about 6 months while the baby was being born, and it worked.

So you have three very different settings, very different context and yet base editing went 3 for 3, okay, with dramatic results. And that's not an accident, okay? And I think it's a sign of the predictability and the power that this technology can bring.

So at Beam, we're not surprised. So Beam was founded around this technology. It's a simple concept, but it has many profound implications. So with base editing, we're using CRISPR to target within the genome precisely. But once we get there, we're not going to make a double-stranded break or a cut. We're instead going to make a single-letter change in the gene, and we are going to have total control of those strains.

This has a couple of outcomes. So first, we're going to have consistent gene sequence outcomes. So we're going to know the gene sequence that is going to result from our edit in every case. Second, this will be, of course, durable. We're going to have lifelong correction, onetime curative potential.

And finally, because we're not making the double-stranded break, we're going to have less genotoxicity. The cells are going to be healthier, potentially happier than in traditional gene editing.

So you put all that together and what we believe we're going to have is more predictable and reproducible outcomes for patients. So if that's possible, what could that mean? So we think that the products that we're going to create here that have that predictability are going to have profound ripple effects across the health care and biotech ecosystems.

So first, the predictability that we're predicting here is going to mean streamlined R&D cycles. That means reduced development risk. We're going to be able to predict that this drug ought to work every time. That's going to shorten timelines and make our investment more effective.

Second, regulatory acceleration. The FDA is more than willing to work with you to move programs to patients faster so long as the science is really clear. And here, it is, and we're already seeing this FDA open up the door to more flexibility for these kinds of medicines.

Third, physician confidence. These are not drugs where you might get a 10% or 20% response rate. These are drugs where everybody responds and everyone has a profound impact from this editing. That's going to mean predictable safety, durability and efficacy that can give physicians confidence.

Of course, patients are also very interested in that same kind of predictability. And they're eager to be done with their disease. They want to get that benefit and hold on to it. And the unique part about lifelong cures is the patient doesn't have to worry now about maybe their insurance is going to change or they're going to lose access to their chronic medication. They're going to get that benefit, and they're going to be able to rely on that benefit for the rest of their lives.

Finally, payers. We all know we need to be more efficient in our health care spend, and we're so confident that the profound changes and the lifelong changes that we're going to provide here are going to reduce lifetime health care utilization costs across the health care system with outcomes to back it over the long term. Payers are going to be very supportive of that, and we think that will be another tailwind in favor of this kind of therapy.

So beyond that, there are also advantages to Beam as we build a company around this technology. So this is a true platform. So what does that mean? That means that base editing is easily adaptable. Once we've made it work in one target, one cell type, it's very quick to then put it on to the next target and you have an entirely new program.

Delivery technology, things like the LNP we use to deliver to the liver, that's reusable. If it works once, it's going to work again and again. That's going to mean consistent preclinical and clinical outcomes.

Manufacturing is highly scalable. And the more we do it, especially at Beam, where we're doing it internally in our own team, our own facility in North Carolina, the better we are at it.

And finally, as I said, the flexible regulatory frameworks that are emerging. So this flywheel is now spinning faster and faster and the confidence that we're generating is only going to go up from here.

So I think the evidence for this vision is already clear. At Beam, we have multiple growing high-value franchises in view. Because of the success of these early programs, we are eager to now double down and expand the pipeline, bringing more programs in that can take advantage of the derisking and validation we've already established. And this platform is going to generate excess value beyond even what we can capitalize on ourselves, and that's going to be a substrate for some really exciting and creative platform partnerships.

So of course, none of that can be done without a foundation of financial strength, and we have that at Beam. So Beam has $1.25 billion in cash at the end of the year. That gives us runway now into 2029, which will carry us through the launch of Ristacel, our sickle cell disease product as well as full execution of the pivotal development plan for BEAM-302.

We remain focused on our spend strategy, managing expenses over the long term. The commercialization of Ristacel and sickle cell is actually quite efficient. And as I said, I'm going to go into this in more detail, the development pathway for 302 is also efficient as well.

All of this gives us a very clear path to value creation with a wholly owned pipeline addressing significant markets and behind that, a sustainable growth engine based on this platform.

So 2025, I think, was the year that all of this became visible. This has been our vision and dream for the 8 years since we founded the company, but I think 2025 was really the proof.

So as I said, first human proof of concept ever for an in vivo correction of a gene in alpha-1 with 302, continued differentiation of Ristacel and sickle cell disease, now FDA regulatory alignment on the path to market for both of those programs, as I will describe; exceeding our clinical enrollment, advancing our next wave programs, a very significant financing early in the year and as I said, now runway into 2029. So we're very excited leaving the year and couldn't be more eager to see what comes next.

So let me dive in now to some specifics, and I'll talk a little bit first about our liver programs and then turn to hematology.

So in liver, the lead program here, as I think everyone knows, is our alpha-1 program, BEAM-302. This is a potential best-in-class and first-in-class program disease-modifying for alpha-1 antitrypsin deficiency. Because of its success, we're very excited now to expand the pipeline and bring more assets forward. We will be announcing another liver program soon.

All this is built on our industry-leading LNP capabilities, enabling delivery to the liver. And so far, LNPs have been well tolerated clinically. Finally, this entire area has platform synergies that make it perfect for the kinds of novel regulatory pathways that the FDA is flashing the green light on, so we can go faster and faster and reach more and more patients.

So now let me dive into alpha-1. So alpha-1 antitrypsin deficiency is a severe genetic disease, characterized in almost all patients by a single letter misspelling in the SERPINA1 gene, which makes the protein alpha-1 antitrypsin. So that [ GA ] point mutation, we call it the Z mutation. And patients who have 2 copies of that mutation called the ZZ genotype, have the disease.

So when you have this disease, you get two problems. First, you have a progressive lung disease. That's caused by low levels in your body of the alpha-1 protein, which is designed to protect your lungs when you're infected. And in addition, what little alpha-1 protein you have is the Z form of the protein. It's a mutant form, and it is not as effective. It actually causes problems, it can cause inflammation and aggregation.

In addition, there's a progressive liver disease, and that is caused by the fact that, that Z protein is actually building up in the liver in a toxic way. It's causing aggregation and accumulation. And that causes a progressive liver disease and gradual liver failure. There are very few therapeutic options for patients. They are generally unsatisfactory. We clearly need to do better and nothing addresses the full spectrum of the disease.

So that's what BEAM-302 is designed to do. So with BEAM-302, we're going to use base editing to correct the single letter misspelling in this gene and turn it back to normal. That will address the root cause of the disease and restore physiologic control of alpha-1.

So what would success look like? We would see the liver producing the normal form of this protein for the first time. We call that the M form. If we're doing that, we would, of course, significantly reduce the amount of Z in the body, which is the bad actor. We would see total alpha-1 levels rise above the 11 micromolar protective threshold. It would rise because the M form is so much better secreted from the liver than the Z form.

And we know 11 micromolar is protective because clinical genetics tells us that patients with this disease where you have 2 copies of Z have alpha-1 levels in the 4 to 6 range. No one has 11 or above. If you're in the teens, 10 to 20, you're generally a carrier. You might have only one copy of Z and you have no progressive disease, you're safe.

We would also, of course, want to know that the AAT we produce is functional. And finally, this is an inducible gene. So when you get sick, you create a lot more, and we'd want to see that the AAT increases with inflammation. All of this would be in a durable single-course treatment, one time for life, addressing both lung and liver.

So it sounds very exciting, and it turns out that's exactly what we've shown with BEAM-302 so far. So here, this is the data that we showed in March. This is the 60-milligram cohort. And you see on the left-hand side, total AAT levels indeed rising above 11, here reaching 12.4 micromolar, and that's at day 28 after a single dose on day 0.

We also then show significant reduction of the Z protein because we're literally converting Z genes into M genes. Here showing almost 80% reduction again at day 28. Finally, the composition of the AAT in the body has shifted. You see here going from 0% at baseline to 91% in circulation again at day 28.

So all of this is truly indicative that we've achieved those therapeutic goals that we've converted these patients from disease to carrier where they shouldn't have any progression anymore. We really believe this could be a functional cure.

So what have we been doing since then? The trial is very active. So we're hard at work dose exploring. We're treating more patients at 60. We've gone up to 75 milligrams. We're going to try 2 60-milligram doses, all just to explore different variations of dosing schedule.

We're also running a Part B in patients who have very sick livers. This is a minority of the population. But given that our program is liver directed, we want to make sure there's no change in safety and efficacy in that population.

And all of this is to identify the optimal dosing schedule for a pivotal study. So we look forward to giving updated clinical data across all of these cohorts, and that is expected by the end of the first quarter of this year.

So clearly, we believe this is the most advanced genetic and disease-modifying program for alpha-1 in the clinic. We've actually treated over 25 patients at this point and still going, and there is quite significant patient and physician enthusiasm.

Excitingly, I can now add FDA alignment to the list for BEAM-302. So the timeline goes like this. So in March, we showed the clinical proof of concept, that 60-milligram data, got the IND open in the U.S. shortly thereafter. And that data was submitted to the FDA for RMAT designation.

So RMAT may be less familiar, but it's basically the breakthrough designation for gene and cell therapies. And to get that, the FDA will review your data and has to decide that, yes, this is worthy of trying to work with you to accelerate the program to get to patients faster because RMAT allows you to have multiple meetings with the FDA in a sort of continuous manner. And so they said yes, they invited us in.

So we've been working with them ever since. And I'm happy to say that in Q4, we did indeed reach alignment with the FDA on a potential accelerated approval pathway for this drug in alpha-1.

What does that look like? The primary endpoint is expected to be based on AAT biomarker, so levels of alpha-1, functional alpha-1, M level, Z levels, all the things that we've already shown, measured over 12 months. So clearly, we want to be able to show we've changed AAT physiology and that it's durable.

We anticipate enrolling approximately 50 additional patients in an expansion of the existing Phase I/II trial. So that's going to be a very efficient approach. We're already open in many countries and sites around the world, and we think this will be easy to implement.

We are also accepted into the FDA's CDRP program, which is basically designed to give CMC consulting advice to companies and programs that are on expedited pathways with the FDA. So great progress. We're so excited to bring BEAM-302 to patients with alpha-1 who really desperately need new options as quickly as we can.

So one quick update on our next program in the liver. This is BEAM-301 for glycogen storage disease 1a, patients with the R83C mutation. So this is a very orphan disease. Patients have to continuously take in cornstarch every few hours, including overnight, or they can potentially die of hypoglycemia. So this is much slower to enroll because it's much more rare, but we're actually making good progress here. And now we do plan to report our initial clinical data from this program by year-end.

Third, in the liver, as I said before, we look forward to sharing an additional liver program that will be added into this portfolio, and that will come out in the first half of this year. So we look forward to that as well.

But now let me turn our attention over to the hematology franchise. So here, as you may know, our major focus is sickle cell disease. And we now see an opportunity for really a pair of complementary approaches, one, near-term ex vivo approach that is a near-term commercial opportunity; and then longer term, an in vivo delivery approach to achieve maximum scalability and reach all patients.

So for ex vivo, we're focused on the severe sickle cell market. This is about 10,000 patients in the U.S. We believe it's really poised for growth at this point going forward. And we see very clear clinical differentiation for Ristacel based both on the mechanism of base editing and on our very advanced manufacturing process.

For next-gen technology, we do still have the ESCAPE program that is very exciting and can be used in a wide variety of places. But at this point, in vivo delivery to hematopoietic stem cells has made enough progress that we're moving that into our preferred position as the platform for our next sickle cell program after Ristacel.

So on Ristacel itself, as I said, we see three major areas of differentiation. So first, we're achieving deeper resolution of this disease. So we're trying to raise field hemoglobin to higher levels to protect these cells. We're achieving over 60% F that's higher than anyone else is achieving in the field. And at the same time, we're driving sickle protein down below 40%.

So those numbers are comparable to sickle trait, a carrier, okay? And that tells us that we're finally achieving a normalization of the biology for these patients. We're also fully resolving anemia and markers of hemolysis and oxygen delivery are normalized or improved.

Second, patients are spending less time in the hospital after the transplant. We think because the base editing doesn't make that double-stranded break, the cells may be a little more viable, a little more ready to turn on more quickly.

And we're seeing rapid neutrophil and platelet engraftment, okay? When you get the transplant, you have to wait until those cells appear again from your new graft before you can go home. And so this could mean an overall safer transplant journey and, of course, a faster time to return to life.

Finally, predictability is about not just editing or delivery. It's also about things like manufacturing. and we're seeing that. So we have a very advanced process. At this point, patients are seeing a median of one collection cycle for mobilizing those cells that we can make a dose out of. We're seeing consistently high yields and viability.

And we really think that's a function of both the base editing mechanism as well as the fact that we have our own facility in North Carolina, allowing us to have our internal team do all of the manufacturing and release in a seamless way.

So we get a lot of questions about the market for this drug and sort of where is it? And haven't -- have the launches gone as expected from some of the other players in the field? So our perspective is there's actually a lot to like about what we've seen so far.

So first, there's patient interest. There are waiting lists in most of the major centers. Patients are eager to participate. Treatment centers. There are 70-plus centers where whole teams of people have trained themselves to get ready to do this work. So they are motivated.

On the other end of the spectrum, patient outcomes have been positive. And payer, we believe that there have been no payment rejections to date as far as we have heard. It's still very bespoke, but that's going to get more systematized over time.

The major issue, we believe, has been in that cell collection and manufacturing process. These are challenging processes. So we hear reports of inefficient or unpredictable processes, patients facing multiple cell collection cycles with a lot of uncertainty and then manufacturing slot limitations as they try to work through that.

So we expect some of these things can be improved, but they're clearly holding back the market as of today. So that creates an opportunity for Ristacel. And in fact, the data we're already seeing in BEACON shows that we actually address these problems quite directly.

So if you focus in on the collection and manufacturing steps of this process, as I said, 1 cycle per patient median, we're actually running -- if you start from the beginning of mobilization to when we release the drug, it's about 3 months.

From the beginning of mobilization to when the patient receives the drug, that sort of vein-to-vein time, that's 4.5 months, okay, with high predictability, and that's for the majority of patients. At that point, you benefit now from the faster time to engraftment, okay, under 20 days for neutrophil and platelets to turn on and get you home. So in total, we're looking at 4 to 6 months for the entire journey to potentially cure yourself of sickle cell disease.

So clearly, we believe this would be very attractive and bode well for Ristacel's uptake within the market. But in fact, we think we can actually grow the market because you can use an existing amount of clinical infrastructure and potentially with numbers like these, treat more patients. So we're very excited about the potential of the program and its differentiation.

So what have we been doing with this? So we've actually been engaging with regulators continuously also on this program through 2025. We do have clarity on that BLA package now, and it's very consistent with what we had been expecting. We've actually completed manufacturing of all doses on the trial. Dosing of the final patients will sort of occur through the beginning of this year. And so at this point, we are able to guide that we plan to submit the Ristacel BLA package as early as the end of this year.

In parallel, we'll be initiating our commercial build. And as I said before, it will be a very efficient build. Again, there are 70-plus centers we need to focus on. We're already doing the manufacturing out of North Carolina. That facility can go commercial, it was always designed to. So this is not a big lift. This is an upgrade and a scale-up of the things that we're already doing quite well.

So I couldn't be more excited about the potential of Ristacel for sickle cell disease, and that's for that 10,000 sickest patients for whom a transplant makes sense. Let me turn our attention now to what are we going to do for the rest of this population.

We're not satisfied only treating 10%. And so here, we're looking at this next wave, and we are prioritizing in vivo delivery using lipid nanoparticles. So this is really building on breakthroughs that have been made recently on how to make these sort of particles reach these cells in the marrow. We do still have the ESCAPE technology, which we've talked a lot about. It's a powerful approach. BEAM-103, the antibody is in the clinic and advancing.

We can always do it ex vivo and pursue a sort of nongenotoxic transplant. But at this point, we think the in vivo approach is going to go faster and is ready to accelerate. And we have the optionality, of course, to use ESCAPE with it if we choose.

So why now? At this point, we believe Beam actually now has all of the capabilities needed to do this. That includes the LNP, of course, as you saw from our liver portfolio, we have many potent lipids in hand and proprietary LNP processes. But importantly, now we can do extrahepatic delivery. That takes two things. So one is you make modifications to the LNP to de-target the liver, which is where LNPs usually want to go. And then you add targeting binders that can enable cell-specific delivery in vivo.

So in addition to that, of course, we have the efficiency and potency of the base editing payload, and as I said, the option to use ESCAPE as well.

So the proof points for why we think this is ready now, we've actually worked on this for several years. A company that we helped start called Orbital has been using beam reagents to do this exact approach to deliver LNPs to T cells in the body for autoimmune disease. They showed really beautiful NHP proof of concept last year. That program is now progressing to clinical studies and was actually acquired by BMS for $1.5 [ billion ].

In parallel to that work, we have been working on the HSC delivery side. HSCs are going to be a little harder than T cells, but not a very different concept. And at this point, we have multiple HSC targeting LNPs in hand and identified. The development scale-up for that program already largely in place, and we are in lead optimization. So stay tuned. We look forward to updating you on this exciting program as it advances as well.

So let me spend one moment now on our partnerships. So this has been a strategy we've taken to really drive both value creation for the company as well as therapeutic impact. So at this point, our partnerships have resulted in over $900 million in nondilutive funding for Beam over the course of our 8 years in existence and by the way, gained rights to both innovative and complementary technologies for us to use.

In addition, it's allowed us to move some of our science, be it delivery technology, editing technology or otherwise; towards patients in areas that we were not going to be able to get to ourselves. So it's been a big success. We couldn't be more happy with this. And I think you should expect this to be a big part of our business model going forward, and we expect to continue with this track record.

So I'll now close just by talking a little bit about what we expect for 2026. So as we noted, the headline here is we're going to be pursuing a path to approval for both of our lead programs. For BEAM-302 in alpha-1 antitrypsin deficiency, we'll be reporting updated Phase I/II data and giving a little more clarity on the timing for our pivotal development program by the end of Q1 this year. And then for Ristacel and sickle cell disease, we plan to submit that BLA as early as year-end this year.

So building on the success of those programs, we're now also quite eager to take advantage of that, right? If this technology is as predictable and reproducible as I think it is, then we're very excited to do more for patients. So we'll be disclosing along those lines another liver-targeted genetic disease program in the first half of this year, and we'll be reporting the initial data for BEAM-301 in GSDIa by year-end.

On the hematology side, we'll be completing the BEAM-103 healthy volunteer study in the first half of this year and then advancing that in vivo editing program, all while maintaining financial strength with $1.25 billion in cash. And as I said, runway through into '29, including the anticipated launch of Ristacel and the execution of the 302 pivotal development plan.

So really, we're at the point where we have the funding we need to get to that commercial transition and begin generating sales as a company. So it's a remarkable place to have gotten to, and we couldn't be more excited about it.

So I'll close by saying thank you for your time, but also thanking the patients and families, who have partnered with us on this journey. They are on our minds all the time, they are waiting for better and curative potentially therapeutic options. And in addition to helping them, we want to get to more patients and more diseases. The impact we can have, I think, with these technologies is quite profound, and we look forward to working with you all to move this forward.

So with that, thank you, and we'll take some questions.

Great. Well, let's start with the Q&A. [Operator Instructions] I want to start off with on what happened. I think the news really caught us by surprise in a really good way, right? What a great surprise to kick off the week.

Can you walk me through the interactions that you have had with the agency? How do we get to the accelerated approval path now in place? I think I also get this question of, have they seen data from the higher dose? Have they seen the double dose cohort? Can you just kind of walk me through what they have, what kind of interactions you have had with the agency?

Yes. I think, in many ways, I think this is a classic accelerated approval program, right? FDA likes it when you have -- you're on mechanism, right? We know the problem here, it's the mutation. We have a mechanism that directly fixes what's wrong. And then they want to see that the science they're showing is consistent with that, right?

And all of the biomarkers I just described are going in the right direction, consistent with that functional cure. So I actually think that the FDA has been thinking about an accelerated approval pathway themselves for some time.

To answer your second question, they have seen -- the only things that they saw to make these decisions and put us on this pathway was the same things that we've shown today, okay? So it's the same data set that we shared back in March. They haven't seen some of those newer, more recent things, and those will come out at the end of Q1.

The timeline I described, I think, is really descriptive, right? That data came out in March. We had RMAT designation with the FDA by April, I think it was. And again, RMAT is explicitly about we want to work with you to find a way to go faster to get to patients. I think everything else was really just working with them on the details, okay?

I don't think it was a big picture disagreement. It was more, okay, what does this cohort look like? What's the follow-up? How do we manage variability, all the classic development questions that come up.

Great. And then maybe just turning to the primary endpoint of the trial. We noticed that the press release sets biomarkers, plural. How should we think about the selected biomarkers? Are these known biomarkers to those of us who have been trafficking in alpha-1? How should we think about just the selection of it?

On PMS and cycle?

Yes. Maybe I'll take it. First of all, my name is Pino Ciaramella. I'm President of Beam, and it's great to -- for your interest and participation today.

So a couple of things maybe just to complete the prior conversation. I think actually, it was really pleasant for us to see that we could come to this agreement with the FDA, but it wasn't completely a surprise. In fact, in the pre-IND conversation that we had, they did open the door to an accelerated approval on the basis of biomarkers.

And the biomarkers fundamentally are essentially exactly what you've seen. As John mentioned, the data package that you've seen has been disclosed is exactly the same that the FDA has seen. And essentially will be obviously total AAT, but will also be functional AAT. We'll obviously be interested in the levels of [ M ] relative to Z, and all of those will be the kind of biomarkers we'll do.

There's nothing new that we need to develop or novel assays that the FDA has requested on that. So it's really just a confirmation of what we've seen, but in an extended data set.

Great. Any questions from the audience?

Thank you for being here today and sharing your perspective. As you think about base editing technology scaling, what do you think the biggest bottleneck is going to be? Is it capital? Is it talent? Is it operational know-how, something else?

That's a great question. I think -- so the question was how are we going to scale base set in technology. Just from a pure manufacturing perspective, it is highly scalable. These are synthetic, easily manufactured intermediates. We're doing it ourselves in North Carolina.

I think that it really just takes the time to develop the science and the evidence base that we can do this safely, that we can do it with efficacy, that we understand how to deliver to a certain organ. And then once you've done that, doing it the next time is going to be much more predictable and more repeatable.

So I think we're just building that track record now. And you can hear from my presentation that we do feel like we're kind of at that inflection point where now we have enough of that evidence and the foundation built that we can start to shift it into higher gear and do more things in parallel.

Yes. I would say, certainly from a manufacturing point of view, we deliver the base editor as a messenger RNA and enveloped into an LNP. It's exactly the same technology to some extent as what has been developed with vaccines for mRNA. And you have seen there have been literally billions of doses have been able to manufacture a very managed cost. So I think the scalability from a manufacturing point of view is not an issue.

Really, then it depends on how many tissue you can successfully deliver. And I still believe that delivery is somewhat of a rate-limiting step in how many tissues you can actually afford that.

The good news is that the LNP technology actually is making progress in going to other tissues and other cell types, particularly with now the ability to target different cell types by coating the LNP with different [ moidays ].

So I think the field is moving along and the strength of the base editing is the predictability that we just said. We know that if we can deliver to the cell that we want, we know what the outcome is going to be.

Just turning to the first quarter update by the end of this first quarter, what is expectation? And what do you ultimately want to see, especially among the new cohorts, the 75 mg, the double dose cohort? And we're also going to see liver plus/minus lung disease patients. So ultimately, what do you want to see so that you have the best view going into the expansion part of the study?

Yes. Great question. So I think as we've tried to communicate, we're very confident we have a potential drug here at the 60-milligram data, and I think the FDA agrees, as far as we can tell. So really, what we want to do in addition to moving it forward is do a few last checks to make sure we have the right path going forward.

So one of those is to make sure we've optimized dosing schedule, right? So we've clearly edited a substantial portion of the liver here with the 90% M that you see, the 80% reduction in Z. At the same time, we haven't edited all of the liver because there's still some Z there. So we want to make sure we don't leave efficacy on the table, okay?

And so the 75-milligram cohort, the 2x 60, we're actually adding more 60s. All of this is just designed to test for, is there additional efficacy to be gained, higher levels that could be achieved without compromising safety, we wouldn't want to do that. And so that's sort of one set of data that we're going to get. And that will inform sort of a final recommended dosing schedule, is it 60 or is it one of these other flavors? But importantly, all of them we expect to be therapeutic and plausible.

And then in the liver cohort, the sort of Part B of the trial, we're asking a different question, which is, as we know, alpha-1 patients are on a spectrum from liver and lung involvement. So in Part A, we excluded patients with really sick livers because this is a liver-delivered therapy. So just to be conservative, we wanted to first target patients who didn't have sick livers. And then in Part B, we're testing in those patients.

And so we want to see there is does the safety and efficacy look similar in those patients as in the Part A. If it does, we will collapse the back together and just treat everybody as one group. If for some reason, it looked different, then we would have a different modified approach to treating those patients. So that's the second big question we want to ask. And I think we'll have plenty of data, I think, to have a conversation about both of those questions at the end of Q1.

Great. I want to touch on a relatively frequently asked question, which is, is 20 micromolar the new bar? We have been hearing 11 micromolar is the protective threshold for a long time. And if you look at some of the older agents, that's where it should be, right? What's your take on that? There seems to be a bit of a debate on where it should be to get a meaningful benefit in the clinic.

Yes. Maybe I'll start and then, I don't know if you want to expand. But remember, the disease is in that 4 to 6 range. A carrier is in the 10 to 20 range. and carriers don't have the disease. So I think the difference between 11 and 20 is -- would be undetectable from a clinical perspective.

So I think at the end of the day, the reason 11 is the number that people focus on is that's the breakpoint where you would stop seeing symptoms. I think that's what ultimately matters. Of course, if you can go higher, you would.

Yes. Yes. Of course, 20 is the sort of -- typically 20 and above is where normal MM sort of phenotype lives. But as John says, basically, as long as you are out of the disease and you are in the 10 and above, you essentially you do not show any progression of the disease.

So really, what our technology and the data that we have already shared already does is to set these individuals as essentially heterozygous. And as a consequence of that, they're not expected to have a progressive disease. And not only that, we've demonstrated with the -- all the biomarkers that we have disclosed is that the functionality of the gene has now been restored. So you essentially eliminated the cause of the progression of the disease from the body.

So we think that, that 11 micromolar is really the threshold to be worried about. And then, of course, you try and generate as much as possible, but the reality being able to demonstrate clinically the benefit of a difference will be very challenged.

Let me add one other point because people sometimes are comparing us with augmentation, which is a very different paradigm. The numbers we're sharing, so the 12.5 micromolar at 60 milligrams, that's a floor, not a ceiling, right? And so because this is an inducible gene, we would expect when you get sick, the gene will turn on and you actually go -- you go up from there, right?

Whereas augmentation, exogenous protein that you put in is basically washing out and it's not regulated. So you're not ever going to get more until you get another dose. So I think it's important also to keep track of the very different sort of profile of the AAT levels in the body based on these mechanisms.

Well, in the last 2 minutes we have, one quick one on GSDIa. I don't think we touched on that quite a lot. We're going to get some data, first class of data this year. Where should we focus?

I think GSDIa is really an important disease with very strong unmet medical need. And the R83C mutation in particular, we're targeting is the most severe form of that disease.

What we're hoping to demonstrate is that a proof of concept that we've essentially restored the glucostasis in these individuals and also rectified many of the negative biomarkers that are associated with the disease like, for instance, enlargement of the liver, high levels of triglyceride, cholesterol and so on.

And this is obviously an ultra-rare disease, and therefore, there are fewer patients, but it will -- we expect demand the opportunity for, obviously, high prices, but also the ability with very small number of patient data set to hopefully achieve a licensure very relatively quickly as part of that.

So we think it is a program that has benefit both from -- certainly from an unmet medical need, but also potentially from a small commercial opportunity that will be a meaningful one. So that's what we're hoping to be able to show you that progress.

Looking forward to it. Thank you so much for your time, and that's all we have for today.

Thank you.

Thank you.