Good morning, and welcome to Beam Therapeutics' conference call. At this time, all participants are in a listen-only mode. There will be a question- and- answer session at the end. 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 investor 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 one-time 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 healthcare 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.
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 three 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.
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 GSD1a must take carefully timed doses of cornstarch throughout the day and night to maintain blood sugar levels. 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 GSD1a patient told me she hasn't slept through the night once since her child was born because like so many GSD1a 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 produce 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 Simon will share some of the promising data from the BEAM-301 clinical trial in patients with GSD1a later in this presentation. For 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, two 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 two 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 one-time 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 let 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 one-time 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 GSD1a, 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 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.
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 two examples of what that looks like in practice. In GSD1a, we are developing our base editing candidate, BEAM-301, for a severe mutation found in approximately 300 patients in the U.S. The 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. 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 two 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 GSD1a and the initial clinical data for BEAM-301. With that, I'll turn the call over to Amy.
Thanks, John. GSD1a 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. GSD1a 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. GSD1a patients with the R83C mutation cannot effectively maintain normal blood glucose during periods of fasting and can become severely hypoglycemic within just 2-3 hours without food or cornstarch. 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 base editor and a guide RNA encapsulated in a lipid nanoparticle, or LNP, that directs it to 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 one episode of hypoglycemia in the last two 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 17, 2026 data cutoff, six patients have received a single intravenous infusion of BEAM-301, including three patients treated with 20 mg and three patients treated with 40 mg, 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 six cornstarch doses in a 24-hour period, meaning approximately every four 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 pre-medication, which is typical in this patient population, may have contributed to the Grade 3 IRRs observed, and the steroid pre-medication 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 GSD1a 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 mg cohort and from 2.5 hours- 15 hours in the 40 mg cohort. Importantly, two of three patients treated with 40 mg 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 hypothesize 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 heterozygote carrying the R83C mutation.
We expect to learn more as we advance to the next cohort at the 60 mg dose level. The improvements in glucose control with 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. Two of the three patients in the 40 mg cohort were able to eliminate starch supplementation entirely. For patients and families living with GSD1a, this removed 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 pre-measured 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 GSD1a with a one-time 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 mg 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 GSD1a 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 GSD1a, 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 provide 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. BEAM-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 in advance the BEAM-304 candidates. 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 U.S., 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 two development candidates earlier this year, emphasizing how this flywheel is able to move faster and faster. Together, the editors in the BEAM-304 program have the potential to treat up to half of PKU patients in the U.S., 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 BEAM-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, physicochemical 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 three variants demonstrate the remarkable consistency of base editing technology and support this approach. In mouse models corresponding to three 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 singular 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 dosage 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 two 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 pre-clinical 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.
Thank you. Ladies and gentlemen, to ask a question at this time, you will need to press star 1 1 on your telephone and wait for your name to be announced. To withdraw your question, simply press star 1 1 again. Please stand by while we compile a Q&A roster. Now first question coming from the line of Alec Stranahan with Bank of America. Your line is open .
Hey, guys. Thanks for taking our questions, and congrats on the updates here. Two from me, one on the GSD program and then one on the broader platform. 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? Is there a capability to expand to maybe an 80 mg cohort as well? When will we see data from the 60 mg? 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 two years and one 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 timelines and just overall sentiment from your conversations with the FDA would be great. Thank you.
Yeah, thanks. Maybe I'll take this in a couple parts. Let's start with GSD1a and BEAM-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? Then Pino, if you want to expand at all on our thoughts about path to market here, and then I'll cover the BEAM-302 question after that.
Sure. At 40 mg, we're seeing, as you can see, dramatic effects. We are now having two patients at the 40 mg dose completely weaned off cornstarch, keeping in mind they've been on six doses throughout the day. In addition, they are now fasting for over 15 hours or 15 hours, which is the maximum time point. From that, you can see that we have restored G6Pase's 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. 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 pathway, such as hypertriglyceridemia, hyperuricemia, and increased lactate. While we have very promising results for that right now as well, sometimes that takes a little longer to see.
We would like to be able, during this important dose escalation phase, to make sure we understand the safety and efficacy of our choices for our optimal biologic dose. To date, we have also seen acceptable safety at the 40 mg cohort, and we would like to examine that as well. Once we see the totality of data from both the 60 mg and 40 mg cohorts, we will make the decision of what is the optimal biologic dose to take forward.
Pino?
Yeah, 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. We are 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 two.
That's right. 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. This is a moment where you sort of say, "We're pretty sure this is a potential drug. We want to get this to patients as quickly as we can. We have to then finish off the experiment here to identify the dose work with the FDA." I think we will be working to make this an accelerated pathway. To your other question about BEAM-302, yeah, we've seen that report. I think, obviously Alpha-1 is going to have a lot of different competitors in it. Everybody's going to try to sort of figure out their path. I think until we see more details on protocol design, it's really to say.
That said, BEAM-302 is obviously setting a precedent here where that's sort of the benefit of being in the lead. We get to sort of lay down tracks that the field can use. As you know, we are already in our pivotal cohort, which will be a one-year follow-up for accelerated approval, and then follow other outcomes for the longer term. We look forward to learning more about others while we stay focused on just accelerating our BEAM-302 path as quickly as we can.
Makes sense. Thanks again for taking our questions and congrats on the progress.
Thank you. Our next question in queue coming from the line of Samantha Semenkow, from Citi, your line is now open.
Hi, good morning. Thanks very much for taking the question and congrats on the 301 data and all the progress. I also have two questions. Just first on 301, I am wondering if you could just share a little bit more detail around some of the safety events 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 am 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? Thanks very much.
Yeah, thanks. Great. I will take the second question after, but let's start with Amy on the safety and talking through the steroid experience and the IRRs and then also rhabdomyolysis.
Sure. In general, I think what we are 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 was, let's say, more intensity or longer duration of symptoms which were typical and seen in our other studies. 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.
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 have 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. 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. In that case, we would think it's more elevated muscle enzymes or elevated creatine phosphokinase.
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. Really not concerning and not by the investigators thought to be related to BEAM-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 are 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.
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.
Yeah. Thanks, Amy. 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 BEAM-302 and BEAM-301, but any programs we bring forward from here. Shifting back to your platform question, yeah, that's sort of what we're so excited about here. 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.
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 kills 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. The timeline 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.
In terms of cadence, I think we can't guide there. We're more likely to keep things a little closer to our vest 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.
Thanks very much.
Thank you. Our next question coming from the line of Brian Cheng with JP Morgan. Your line is now open .
Hey, guys. Thanks for taking our questions this morning. Maybe just two 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. In the 40 mg, it seems that there is a pretty wide spread of triglyceride excursions. Maybe perhaps it's due to N of 3. Just curious if you can talk a little bit more about what you expected, and then we have a follow-up. Thank you.
Yeah. Amy, do you want to talk about triglycerides?
Sure. Yeah. I think, when you think about what is 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. For example, you expect then with the block that there is increased triglycerides, increased lactic acid, increased uric acid. 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 is a lot of counter pathways that have been upregulated over time. There is hyperinsulinemia and other things because these patients are often over-consuming starch to keep their sugars in the euglycemic range. There is a lot of different pathways that are intersecting, being upregulated.
Once you relieve the block, it does take some time for these things to then have their throughput. I would argue the first thing that you can see benefit from is this ability to fast, which is quite striking. 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 do not even have normal lactate levels when they are not fasting before treatment. This is quite amazing and suggests that some of these other pathways that have dysfunction are now being actually impacted positively.
I think it is going to take us a little time to definitively know what is going on with triglycerides as more glycogen, et cetera, gets then taken out and then converted to glucose. Because keep in mind, they have had tons of glycogen accumulation over a lifetime. 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. Given that there is a lot going on, that there is dietary adjustments also going on, I think it is going to take a little time until we see how their triglycerides actually settle out.
Okay. 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 are implementing in the study going forward? Meaning, are you enforcing a cutoff for BMI? Are you continuing recruiting patients with compound heterozygosity? I am just curious if you have any thoughts about that, and if that is the case, whether this has any potential to the addressable population. Thank you.
Yeah. 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 are being made?
Yeah. So, in general, our hypotheses are exactly what you said, which 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 mid-20s. 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 heterozygote for the R83C mutation. And so is it possible that you had adenine that was more robust at, you know, one of these mutations that they had, etc
I think going against that is the fact that we had a compound heterozygote 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. From that perspective, looking at our 20 mg data, we don't see a difference in the 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 that's something for us to think about.
Unfortunately, this patient population can have obesity because they're taking so much corn starch that they're trying to keep their blood sugars up, and this can lead to kind of almost overweight because of this high-caloric corn starch. 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. I would say stay tuned on that. We'll learn a lot more as we dose the next cohort.
Great. Thank you for the color.
Thank you. Our next question coming from the line of Yanan Zhu with Wells Fargo. Yanan, your line is now open.
Oh, great. Thanks for taking our question and 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? 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 IRR in a 60 mg cohort. Was wondering with this updated steroid regimen, what is the comfort level, and have you happened to have dosed any patient there yet, and what is the initial takeaway there? Lastly, on PKU, was wondering, it sounds like the initial cohort or study will be on mutation A.
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? Thanks.
Yep. Great questions, Yanan. Maybe we'll go to Pino first for the first and the third. Pino, any comments on how we think about editing efficiency in GSD1a and can we draw conclusions from other programs to this one? Then maybe if you also want to talk about how we will be introducing some of these newer PKU editors over time.
Yeah. Hi, Yanan. Thanks for the question. Yeah, obviously, 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 two responders responded extremely well, so clearly reestablishing the full functionality of that system. In terms of translatability, this is basically a different guide first and foremost, and obviously different guides have got different potency. It is potentially a different editor. So really, the one important thing and 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.
What we do know is that what is translatable is that the preclinical to clinical translation is proving to be very robust and solid. Until now, we have very good ways of predicting starting doses, levels of efficacy that we are expecting to see. So that gives us confidence for the future programs as we develop new combination of guides and editors.
Excellent. Then, Amy, do you want to talk a little bit about just any thoughts about as we go to a 60 mg dose, do we think the IRR issue is solved at this point with the adjusted regimen or anything we're watching out for? Go ahead.
Yeah, I definitely think that the optimization of both potency and duration of steroid coverage has definitely helped. 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 mg cohort. I think that it's something that, obviously, we take safety 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 we've mentioned, very manageable for these sites. So stay tuned on the 60 mg cohort, both in the safety and efficacy profile.
Yep. Well said. I think it's just a general 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 one-time dose that gets you potentially transformative durable efficacy like we're seeing here. It's a pretty good delivery vehicle, and we're quite happy with it.
Thank you. As a reminder, ladies and gentlemen, in the consideration of time, we ask that you please limit yourself to one question per person. Now, next question in queue coming from the line of Michael Yee with UBS. Your line is now open.
Thank you. I'm going to ask one question, two 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 corn starch 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 is 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 are thinking about and how we should be modeling things? Thank you.
Yeah, maybe I will just jump in on this one. I think 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 have signaled in the past about a willingness to look at small data sets and going quickly for very severe rare populations. Several of our other programs, we are also, of course, going to be seeking approval based on our initial trial, and I think we expect this would be potentially no different. Even as we have the 60 mg cohort, we will be working out a couple of these questions. We will also be looking to enroll pediatric patients. I am sure that we might be eligible for a 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. I think that we should see that. I have actually already forgotten your second question. What was the second one?
Yep. Given a potential fast approval, which we would be excited on-
Oh, yes. Commercial.
I completely agree. Commercial framework given the 300 patients and modeling. Thank you.
This is 300 real patients. I think the epidemiology might have suggested it is 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 diagnosed patients, all of whom need treatment. This is a severe mutation uniformly. We think that is quite important and exciting. With a relatively efficient clinical path, we think there is 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. I think I will just leave it there, but I think clearly the value here for patients is quite significant. And we are quite eager to see this reach everyone with this mutation disease.
Thank you. Our next question in queue coming from the line of Maury Raycroft with Jefferies. Your line is now open.
Hi, good morning. This is James on for Maury. Congrats on the results and thanks for taking our question. Just a two-part question. How many patients have you enrolled so far in the 60 mg cohort? Also, do you plan to dose more patients at the 40 mg so you have a sufficient data set to compare against? When do you expect to have enough 60 mg follow-up to meet with the FDA on the path forward? Separately for PKU, the IND cleared in mid-June, but there isn't trial posts 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? Thanks.
Yeah. So maybe, Amy, do you want to cover the first one, and I can talk about the timeline on 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 ask a really good question. Most of our cohorts are N= 3, but we have the option to go up to N= 6 per cohort. So we probably, as you indicated, will dose a minimum of the N= 3 in the 60 mg cohort and then decide what our next step is, which could include getting more information at 40 mg. As John indicated, could mean opening the pediatric cohort.
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 as 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 needs.
Yep. For PKU, I think as we said at the time of the filing, this is one where we actually think this will be a pretty fast path program overall, with the exception of opening the first site. We are going to be in the U.S., we are going to be in big academic centers, so this is not 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 is where to focus. Everything is very much on track. But I think at the time we always said it would be, this is not a 3, 4 months to start the trial. It is a 6- 9 months to get those first sites open.
We are looking at sort of end of year, first part of 2027, most likely, but all on track. From there, it is pretty fast. As I said, we think there will be a dose escalation. As you can see, we think we are getting better and better at this LNP understanding, so we are looking forward to that. Of course, at the same time, we are 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. From there is some kind of expansion where, again, in PKU, all you have to do is show phenylalanine lowering, and some amount of diet normalization, and those are full approval endpoints. So I think it sets itself up for another fast path push like we have done elsewhere.
Thank you. Our next question coming from the line of Adhi Sikand with Evercore ISI. Your line is now open.
Hi. Good morning. Thanks for taking our question. It is 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? Thank you.
Yeah. Pino?
Yeah. We see no bystander editing, and the off-target profile is completely acceptable for moving forward. The AATD situation is quite different given the density of A and Ts in the particular editing window, but it is not the case for GSD1a.
Thank you. Our next question in queue coming from the line of Myles Minter with William Blair. Your line is now open.
Hey, thanks for taking the question. Congrats on the data. I know you have not done liver 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 are getting across 20 mg, 40 mg, and 60 mg BEAM-301 doses? I think previously you have said from preclinical studies that 11% enzymatic activity is required for metabolic restoration. Just trying to understand, where 20 mg, 40 mg, and 60 mg is predicted to get you. Thanks very much.
Yeah. Pino?
Yeah, you are right. There are various models that predict that basically, something around 10% is enough to restore the activities. As you have seen in the 40 mg, we are excited to be above that meaningfully. We will see, obviously, with the 60 mg whether we can also see responses in additional compound heterozygous, which as Amy explained, we have already seen some positive response in our 20 mg patients. We will see how it goes. But we are meaningfully above the 10% for sure.
Thank you. Our next question in queue coming from the line of Patrick Trucchio with H.C. Wainwright. Your line is now open.
Hi. Good morning, and thank you for taking our questions. This is Luis in for Patrick. I was thinking about the addressable population here. The R83C mutation, about 300- 900 patients, but there is also other mutations. Q347X is a common one as well. I was thinking, how are you thinking about BEAM-301 future developments? 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? How do you expect to develop that? What is the cadence of development for those additional mutations? Thanks.
Yeah. It's a great question because it comes back to the addressable market here. I think absolutely correct that the same platform rules may apply. 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 the level of applicability of what we can bring. Then obviously the regulatory frameworks are there, we believe. 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. That's the big breakthrough here in the new paradigm shift that we're seeing in how the FDA is treating these platforms. For sure, with GSD1a, that'll be something that we will consider in the future as we work with this community.
Thank you. Our last question in queue coming from the line of Luca Issi with RBC Capital Markets. Your line is now open.
Oh, great. Good morning, team. Thanks so much for taking our question. This is Cassie for Luca, and we have a quick one for BEAM-301. For the team, given what you have observed pre-clinically across the programs in terms of translatability of PK/PD from animal models to patients, would you expect that those response curves 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 may be a smarter step-up. Or would it be more like what we saw with the top two doses in AATD, that some kind of ceiling effect already achieved with the 40 mg dose from, back in the 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 left on the table. Just want to pick your brain on that. Any color much appreciated. Thank you.
Yeah, I think a simple way to think about this, invite others to comment if they have anything to say is, we've just about maxed out efficacy that we can see in terms of the two 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 the 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 two of the three patients at 40 mg, 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, or we just have to learn that. I mean, most of those hypotheses suggest that more exposure would probably help. 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. 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.
No, 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. 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 opened, 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.
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 possible mutations to increasingly common disorders. 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.