Beam Therapeutics Inc.

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. 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 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, Dr. Gopi Shankar, our Chief Scientific Officer, Shravan Amani, our Chief Financial Officer, and Dr. Kiran Musunuru from the University of Pennsylvania. Our President, Dr. Giuseppe 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 BEAN, 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 one-time, 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 one-time 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 allows us to make precise single-based 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 healthcare 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. Face 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 a 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 fetal alanine 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 two 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 genotecting 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 fee levels that can range from 360 to 1,200 micromolar, with classifications ranging from hyperphenylalanemia to mild, moderate, or classic or severe PKU. Guidelines in the United States recommend patients maintain P 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 P can have serious neurologic and cognitive consequences. In children, very elevated fee can result in impaired brain development, intellectual disability, and seizures, with some of these manifestations being irreversible. In adolescence and adulthood, where adherence decreases dramatically and many patients are lost to follow-up, increased fee 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 C levels of less than 360 micromolar, up until about the age of 12. But this percentage steadily decreases with age, and as adults, 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 V levels and that are less burdensome to patients and their families. V 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 one egg and a slice of bread. Instead, they require medical food without fee, 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 fee levels. However, people living with more moderate to severe disease would require enzyme replacement therapy to decrease their fee to reach target. This type of therapy must be administered as a daily subcutaneous injection, and it often takes at least one to two 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 fee 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 established regulatory precedent 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 fee 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 D 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 one-time 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 PKU. To date, we have already identified two development candidates within our Beam 304 program targeting the two 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 and the delivery mechanism for liver genetic diseases are multiple. They can be dosed in an outpatient setting by an intravenous infusion. They are titratable and redosable 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 two meters. 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 demonstrates the potential of base editing to correct underlying PKU mutations, and rapidly normalized plasma fee levels. On the left, you see results from a mouse model carrying the R4AW 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 fee levels by day seven. In both models, plasma feed 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 feed reduction. As dose increases, Editing in the liver grows in a predictable manner with even relatively low levels of editing sufficient to drive feet 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 R4AW mutation. The study is designed to achieve early clinical proof of concept of plasma feed 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 feed concentrations. 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 one-time 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 GSD1A, 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 the 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, Karen.

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-Nicholas, 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 variants causing classic PKU, that is severe PKU, We found that the majority of patients had at least a single fee measurement above the recommended safety zone indicated here by the dotted line, 360 micromoles per liter. About 30% of patients had lifetime average fee levels above the recommended maximum fee 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-Nicholas 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 P 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-Nicholas 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-Nicholas 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, we'll 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-Nicholas and I have been working, the urea cycle disorders. Variants in the genes encoding any of the six 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 non-toxic 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 seven 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 one or 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-Nicholas and I have been extensively engaging with the FDA over the past couple of years, having interact and pre-IND meetings about gene editing therapies for patients with PKU or any of the seven 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 patient in just six 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 seven 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 seven 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 base 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 Shravan 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 RistaCell, our investigational autogloss 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 RistaCell. The facility includes $100 million funded at close, up to $300 million available upon the achievement of certain regulatory, clinical, and commercial milestones for risk to sell, and an additional $100 million subject to mutual agreement during the seven-year term. Repayment of principal is due in early 2033. This structure strengthens our balance sheet while preserving flexibility and enhancing our ability to both commercialize risk to sell, as well as fund future growth and innovation across our pipeline. With this latest announcement, we've 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 Risk to Sell, 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 Risk to Sell 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, Shravan. 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, one-time 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 lean programs, we are accelerating the paths to approval and look forward to providing updated Phase 1-2 data and next steps for Beam 302 pivotal development in Alpha-1 antitrypsin deficiency this quarter, followed by the anticipated submission of the Ristacel VLA 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 GSD 1A, complete the BEAM 103 Healthy Volunteer Study, and continue advancing our in vivo HSC editing efforts this year. As Shravan 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 RistaCell. 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 one-time, 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.

And as a reminder, if you have a question, press star 1-1 on your telephone and wait for your name to be announced. To remove yourself, press star 1-1 again. One moment while we compile our Q&A roster. Our first question comes from Samantha Semenkol with Citi. Please proceed.

Hi, good morning, and thanks very much for taking the question, and congratulations on all the progress. I just wanted to talk a little bit about the regulatory path forward and addressing multiple mutations. You know, from a beam-specific perspective, how should we think about, you know, the opportunity and the timeline to moving beyond the R408W mutation into other mutations? And then just with the strategic financing for RISC-SL, 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? Thanks very much.

Yeah. Thanks, Samantha. Great question. So maybe to start, I'll ask Gopi and then Amy to talk a little bit about how we see additional mutations rolling in over time, first in research and then in the clinic. And then we'll come back and have Shravan 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 two mutations that I described. And we expect the timelines 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 designs to accelerate development in some of the other mutations that also impact patients with PKU?

And this is Shravan. 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 support, the commercial launch, and subsequent revenue generation for risk to self. 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 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 share them.

Samantha?

Thanks very much. I appreciate the answers.

Our next question comes from the line of Maury Raycroft with Jefferies. Please proceed. Line is open. I'm sorry, I'm going to move to the next question. He comes from the line of Eric Schmidt with Kantor. Please proceed.

Thanks for all the updates. A couple questions on 304 as well. First, it sounded like Dr. Lucinaro's lab may have been first at kind of reducing to practice base editing for some of these mutations. Is there some IP associated with either R4AW 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? Thank you.

Yeah, great questions. I can handle those, too. Yeah, 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 Kieran'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, yeah, so it's broadly the same kinds of L&P approaches that we use with 302, 301. You know, we do have our own ionizable lipids at this point as a company, which we expect to use. But the, you know, 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 Yahan Zhu with Wells Fargo. Please proceed.

Great. Thanks for taking our questions and for the update. A couple 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 have to be to qualify for this new framework? I'm 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, two quick technical questions. For the 304 product name, are there going to be two different guide RNAs targeting the two 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. Thank you.

Great. Thank you, Yanan. Yeah, so I think, you know, 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. Musunoro first to say a bit about yesterday and the plausible mechanism pathway, and then Gopi, maybe you can cover the multiple guides and the bystander editing.

Yeah, 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 control trial, but then if you go to the other end of the spectrum, there are N of 1 and a 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. Hogue, the acting CEDAR 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 she 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 Doctors McCary 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 plasma 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.

Thanks for all the comments.

Thank you. Our next question is from . I just wanted to add one.

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

Yeah, thanks for the question. So, the two 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 that 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 benefactor's profile.

And Amy, did you want to add something to Kieran'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.

Thank you so much. Our next question comes from Corey Kasimov with Evercore ISI. Please proceed.

Hi, this is Addy on for Corey. I wanted to ask a question on single-cell using 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 RistoCell, assuming its differentiated profile continues to hold? Thank you.

Yeah, thank you. Maybe I'll have Pino talk a little bit here about our view for risk-to-sell. Of course, we wouldn't be giving market share or other specifics like that at this stage, but I think we have been watching, obviously, the market evolve and have a lot of perspective on that. So maybe, Pino, do you want to talk a little bit about how the market's coming along and what we think the risk-to-sell?

Yes, thank you, John. Yeah, I guess what we've 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 significant demand for a program such as the risk to sell that we're developing, and that, 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've 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-sided 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 with Canaccord Genuity. Please proceed.

Hi, guys. Thank you for taking your question. This is Angela on for Whitney. Maybe jumping over to the AETD, can you just help us set expectations into the upcoming readouts? 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?

Yeah, 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, you know, pretty comprehensive set of data there. So as a reminder for that trial in Alpha-1, so with three or two, we're dosing additional 60 milligram patients, you know, just given the strength of the data we showed last year, and then continue to explore dose and schedule, looking at 75 milligram dose and a two times 60 dose. So we'll put all of that together. And, you know, as a reminder, what we're looking to see there is, you know, is there any evidence of increases in alpha-1, you know, sort of, you know, versus, you know, how close are we to saturation in the liver already? So that will be sort of part one. We'll also be looking at patients with, this is all sort of part A with lung. We'll be looking at patients in part B who have the sicker livers. We're trying to see if there is um you know similar uh efficacy and safety as in part a uh and then um depending what we see there there's some things we can think about um uh we'll also be of course showing uh durability so we'll have a significant amount of time now with the you know patients who are in the the update from last year out you know 12 plus months and then and then a range of follow-ups uh from there um so i think in terms of your second question um you know we i think we said before we we do expect to have sufficient insight over the course of the beginning part of this year to finalize dose and schedule and anything else to go into the protocol. I expect that the data set will be hopefully helpful there and we'll have it or we'll be able to have it soon. But it's not really 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 that they want to. So that is very much on track for getting started.

Our next question comes from the line of Brian Chang with JP Morgan. Please proceed.

Hey, guys. Thanks for today's question this morning. First, just on responses in TKU, do you have a sense of how well these R408W carriers behave and respond to current options like QVAMS or or 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? Thank you.

Yeah, great question. So, yeah, 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 those patients, you know, responsiveness to current therapies, and then a little bit of how we think about getting to different age ranges over the course of the process.

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 zero. And so from that perspective, these patients would not respond to things like BH4 or cofactors 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 is shown signs of being very collaborative. And typically when we do go into these patient populations, we will stage-gate it 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, you know, are having brain growth and 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 impacts on cognitive and executive function.

Thank you so much. That was very helpful.

Thank you. Our next question comes from Luca EC with RBC Capital Markets. Please proceed.

Oh, hi. Thanks, Tim. Thanks so much for taking our question. A congrats on the progress. This is Cassie Angelouka. A quick one on A1AT. 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 the longer question for A1AT's pivotal, has the FDA discussed with you their minimum requirements for representative U.S. enrollments? Correct me if this is not right, please. We see on cd.gov that Phase 1-2 are ex-U.S. Would this mean that your pivot 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 comments there is much appreciated. Thank you.

Yeah, thanks. I can handle some of those. The first question on RNA editing, I mean, 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, having a one and done for alpha one is going to be a preferable target product profile if you can achieve it, which we believe we can. And And then, you know, obviously, you know, just doing head-to-head on the different data sets that occur and have been disclosed, we continue to believe that VM302 has shown the, you know, the best-in-class data in terms of alpha-1 levels as well as, you know, the composition of those levels as well between M and D production. So in terms of US ratio, I think, you know, it's probably premature to talk about that. I think we are You know, we obviously have an open IND. We will be active in the U.S. That'll 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, you know, anything we need for U.S. approval will be satisfied, which I'm sure it will.

Thanks so much. Our next question comes from the line of Sammy Corwin with William Blair. Please proceed.

Good morning. Thanks for taking my question. Congrats on the progress. I was curious for the clinical development in PKU, if it'll be required that patients have two copies of the same mutation, and if not, how that could impact the range of benefit observed.

Yeah, 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, you're welcome to.

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

Great. Thank you. Thank you. One moment for our next question. We have Maury Craycroft with Jefferies. Your line is open.

Hi, good morning. Thanks for taking my question, and 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 1-2 study and how the Phase 1-2 is going to work from like a dosing standpoint to adding these new variants?

Yeah, I think, I mean, maybe I'll just give the high-level answer, which is, you know, we are, you know, 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, you know, I think the other piece about bringing more mutations in over time, I think, you know, we obviously are going to start with two, 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. as the research team, you know, 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, you know, some of the work that Amy and her team will do in consultation with the FDA. And that's where, you know, we're going to continue to sort of pioneer this. But we feel quite confident, especially with the, you know, 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?

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

Yeah. I mean, I think, again, it depends a lot on what we see in our non-clinical 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, you know, as you saw in the preclinical work, you know, we were able to bring fee levels down to below the therapeutic threshold at relatively low doses of LMP. So we expect to be able to do the, you know, dose finding relatively efficiently.

Got it. Okay. Thanks for taking my questions.

Thank you. Our next question comes from William Pickering with Bernstein. Please proceed.

Hi, thank you for taking my questions. 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? Thank you.

Yeah, good question. Maybe, Gopi, why don't you start with the first question, just about the, you know, low threshold for PRAFTA here. And then, Shravan, do you want to talk about how PKU appears in our, you know, 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, you know, non-functional in order to have PKU. And it's often not required in diseases such as these 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 phenylality 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 and operating expenses, I would say that first, and I think this is 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.

If I could even just underline that last point, I think it's true 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 the second time or the third time than the first time. I think we're already experiencing that to a degree with TKU being 304 coming after 302 and 301. 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 to 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 Alex Tranahan with Bank of America. Please proceed.

Thanks for taking our questions. Just a couple from me. Maybe just to 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. They seem 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? Thank you.

Sure. So maybe on the first point, so I think as Kieran already mentioned, I think You know, the causal mechanism pathways 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, you know, disease, you know, followed presumably by, you know, some kind of confirmatory experiment. So, you know, we don't need an innovative new pathway for that. That's pretty traditional. You know, that said, obviously it shows that what we're doing in Alpha-1 is broadly aligned, I think, with the, you know, the kinds of programs working on the kind of root cause of disease that the FDA is clearly leaning on. And then lipid nanoparticle, I think, I mean, I think, you know, Broadly, I think we think that, you know, 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, you know, we're building on that clearly with the three or four IND, you know, and look forward to updating you over time. Thank you.

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

Good morning, guys. Thanks so much. This is Matt on for Mike Yee. Maybe one of the next-gen sickle cell program. It seems like 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 anything you can say there would be great. Thanks.

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

Yeah, definitely. The consideration here is the fact that with LMP, 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, in 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 LMP 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.

Thank you. One moment for our next question. And this is from the line of Patrick Truccio with HC Wainwright. Please proceed.

Hi, Louise here. Thank you for squeezing in our question. For the go-on-or-go decision for 103 in Healthy Volunteers, how are you thinking about that? comparing to the in vivo editing in HSCs. How are the editing efficiencies compared? Thank you.

Sure. Pinar, do you want to talk a little bit? I think you just were talking about this, about the role of escape, obviously, broadly, but also then within the in vivo context.

Yeah, also the initial question was not clear, but I heard healthy volunteers. Yeah, 103. Yeah, 103. So what we're doing with healthy volunteers, basically we are dosing just the antibody component of that escape technology. This is the anti-CD117 antibody. And what we're doing there is, in addition to obviously confirm the safety of that antibody, we're also developing a PKPD 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, you know, 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 of the two? Yeah, it's very high. So it's comparable.

Great. Thank you so much and congratulations. Thank you.

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 with 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. Aaron Nicholas 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.