Q4 2025 Beam Therapeutics Inc Earnings Call & Business Update

February 24, 2026

Operator: 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.

Speaker #1: 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.

Speaker #1: Please go ahead.

Speaker #2: 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.

Holly Manning: Thank you, operator. Good morning, everyone. Welcome to Beam's conference call to review updates announced this morning in conjunction with our Q4 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 Shanker, our Chief Scientific Officer, Sravan Emany, 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.

Speaker #2: 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 Musinuru from the University of Pennsylvania.

Speaker #2: Our President, Dr. Joseppe Pino-Caramella, 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.

Speaker #2: 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.

Holly Manning: 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. 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.

Speaker #2: 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.

Speaker #2: 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.

Speaker #3: Thanks, Holly, and good morning, everyone. At Beam, our vision is straightforward but ambitious: to provide lifelong cures for patients suffering from serious diseases. We believe base editing has the potential to deliver on that vision through one-time, durable genetic medicines with predictable and reproducible outcomes.

John Evans: Thanks, Holly, good morning, everyone. At Beam, our vision is straightforward but ambitious: To provide lifelong cures for patients suffering from serious diseases. We believe base editing has the potential to deliver on that vision through 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. 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.

Speaker #3: 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.

Speaker #3: 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.

Speaker #3: Base editing is a next-generation form of CRISPR that allows us to make precise, single-base changes, resulting in predictable edits without the need to make double-stranded breaks in DNA.

John Evans: Base editing is a next-generation form of CRISPR that allows us to make precise single-base changes, resulting in predictable edits without the need to make double-stranded breaks in DNA. With consistent gene sequence outcomes conferring potentially lifelong benefit, base editing enables predictable, reproducible outcomes for patients. This scientific foundation underpins everything we do. Predictability is a theme you'll hear throughout today's discussion. We believe it is a powerful driver of progress, not just for patients, but across the broader 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. Base editing is a highly modular and scalable technology.

Speaker #3: 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.

Speaker #3: 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.

Speaker #3: Base editing is a highly modular and scalable technology. This means that the core elements of our therapies can be reused again and again. And once they are proven to work a first time, we expect to have a higher probability of technical success as we expand to other genes and other diseases over time.

John Evans: This means that the core elements of our therapies can be reused again and again, and once they are proven to work the first time, we expect to have a higher probability of technical success as we expand to other genes and other diseases over time. 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. 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.

Speaker #3: 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.

Speaker #3: 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.

Speaker #3: We have built leading lipid nanoparticle, or LNP, capabilities to enable efficient in vivo delivery to the liver. These capabilities can be leveraged for multiple programs, allowing us to move faster with each successive candidate.

Speaker #3: 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.

John Evans: We're excited to share today that we're expanding this franchise with an innovative new development program for PKU called BEAM-304. BEAM-304 exemplifies how we can leverage base editing to directly correct not just one, but multiple disease-causing mutations over time. PKU represents an important strategic expansion of our portfolio and an ideal application of our platform. To start, we have the technology and expertise that positions us well to address this condition. PKU is often caused by a single point mutation in the phenylalanine hydroxylase, or PAH gene, exactly the type of error base editing is designed to correct. PAH is primarily expressed in hepatocytes, making it highly addressable through LNP delivery, which is an area where we have an industry-leading expertise.

Speaker #3: 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.

Speaker #3: PKU is often caused by a single point mutation in the phenylalanine hydroxylase, or PAH, gene. Exactly the type of error base editing is designed to correct.

Speaker #3: 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 remain significant unmet need despite available therapies in a large population of approximately 20,000 individuals in the US and many more around the world.

John Evans: There also remains significant unmet need, despite available therapies in a large population of approximately 20,000 individuals in the US 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 US 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.

Speaker #3: 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.

Speaker #3: 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.

Speaker #3: Blood phenylalanine, or Phe, reduction has been accepted as an endpoint for full approval in both the US and Europe, providing an attractive opportunity for both early clinical proof of concept and an expedited path to market.

Speaker #3: 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.

John Evans: 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.

Speaker #4: 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.

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

Speaker #4: In the United States, PKU is typically identified at birth through the federally mandated newborn screening program, and genotyping of these patients is increasingly common, as it can guide therapy.

Speaker #4: As shown in a large arrow, the severity of PKU depends on the amount of residual PAH enzyme function an individual has, which determines their pretreatment Phe levels that can range from 360 to 1,200 micromolar, with classifications ranging from hyperphenylalaninemia to mild, moderate, or classic, or severe PKU.

Speaker #4: Guidelines in the United States recommend patients maintain fee levels below 360 micromolar across their lifetime, but as I'll show in the next slide, many patients struggle with uncontrolled disease, particularly as they age.

Amy Simon: As I'll show in the next slide, many patients struggle with uncontrolled disease, particularly as they age. People living with PKU can face a significant impact on their health and quality of life, as very elevated Phe can have serious neurologic and cognitive consequences. In children, very elevated Phe can result in impaired brain development, intellectual disability, and seizures, with some of these manifestations being irreversible. In adolescence and adulthood, where adherence decreases dramatically and many patients are lost to follow-up, increased Phe can also have detrimental health consequences such as cognitive impairment, headaches, anxiety, and depression. As you can see in the chart on the right, the majority of pediatric patients are within the recommended blood Phe levels of less than 360 micromolar up until about the age of 12.

Speaker #4: People living with PKU can face a significant impact on their health and quality of life, as very elevated Phe can have serious neurologic and cognitive consequences.

Speaker #4: In children, very elevated fee can result in impaired brain development, intellectual disability, and seizures, with some of these manifestations being irreversible. In adolescents and adulthood, where adherence decreases dramatically and many patients are lost to follow-up, increased fee can also have detrimental health consequences, such as cognitive impairment, headaches, anxiety, and depression.

Speaker #4: As you can see, in the chart on the right, the majority of pediatric patients are within the recommended blood Fe levels of less than 360 micromolar, up until about the age of 12.

Speaker #4: 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.

Amy Simon: 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 Phe levels and that are less burdensome to patients and their families. Phe exists in most foods, including meat, dairy, grains, vegetables, and fruits. Thus, people living with PKU must follow a severely restricted diet, limiting protein intake from foods to only 5 to 10 grams per day, which, as you can see from the chart on the right, would mean 1 egg and a slice of bread.

Speaker #4: There remains a significant unmet need for new treatment options to address PKU that offer better control of fee levels and that are less burdensome to patients and their families.

Speaker #4: Fee 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.

Speaker #4: 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.

Amy Simon: Instead, they require medical food without Phe, shown in the lower right-hand panel, to get their needed protein. Medical food is often poorly tolerated and very expensive. Patients with more mild disease and some residual PAH enzyme activity are able to take BH4, a cofactor used to stimulate the PAH enzyme to reduce their elevated Phe levels. People living with more moderate to severe disease would require enzyme replacement therapy to decrease their Phe to reach target. This type of therapy must be administered as a daily subcutaneous injection. It often takes at least 1 to 2 years for patients to achieve target levels. Overall, this occurs in only about 60% of the patients. In addition, it requires frequent labs to adjust treatment based on diet and Phe levels, and the discontinuation rate is high due to immune reactions and hypersensitivity.

Speaker #4: 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.

Speaker #4: 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.

Speaker #4: 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.

Speaker #4: 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.

Amy Simon: 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 precedents, the literature, including the updated ACMG clinical guidelines for PKU diagnosis and management, and direct feedback from clinicians treating this disease. Importantly, the regulatory precedent in PKU is well established. Blood Phe reduction has been accepted as a surrogate endpoint for full approval in both the US and EU. Within this context, a successful gene therapy would be expected to achieve significant and sustained Phe reduction below 360 micromolar, be well tolerated, enable normalization of diet, enabling people to get off of medical foods, which really has the potential to meaningfully improve quality of life.

Speaker #4: To guide our development strategy in PKU, we have anchored our target product profile to established regulatory precedents, the literature, including the updated ACMG Clinical Guidelines for PKU Diagnosis and Management, and direct feedback from clinicians treating this disease.

Speaker #4: 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 US and EU.

Speaker #4: Within this context, a successful gene therapy would be expected to achieve significant and sustained Phe reduction below 360 micromolar, be well tolerated, enable normalization of diet, and enable people to get off of medical foods, which really has the potential to meaningfully improve quality of life.

Speaker #4: 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.

Amy Simon: 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.

Speaker #5: 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.

Gopi Shanker: Thank you, Amy. As John said earlier, PKU is an ideal expansion of Beam's genetic medicines pipeline and application of our platform technology. I'm excited to share the incredible rapid progress that has led us to the cusp of clinical development today. In the United States, there are approximately 20,000 people living with PKU. To date, we have already identified 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.

Speaker #5: In the United States, there are approximately 20,000 people living with PKU. To date, we have already identified two development candidates within our Beam 304 program, targeting the two most prevalent PKU mutations.

Speaker #5: 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.

Speaker #5: 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.

Gopi Shanker: With this approach, we believe that Beam has the potential to create a scalable path to get transformative therapies to the majority of patients with PKU as efficiently as possible. BEAM-304 leverages our proprietary and clinically validated base editing technology, together with our internally discovered and optimized LNP delivery system, to precisely target hepatocytes in the liver and directly correct the disease-causing mutations. This technology is adaptable, utilizing a unique guide RNA for each mutation, while the rest of the components of the therapy can stay largely consistent. The advantages of LNPs as a delivery mechanism for liver genetic diseases are multiple. They can be dosed in an outpatient setting by an intravenous infusion. They are titratable and re-dosable 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.

Speaker #5: 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.

Speaker #5: 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.

Speaker #5: The advantages of LNPs as a delivery mechanism for liver genetic diseases are multiple. They can be dosed in an outpatient setting by an intravenous infusion, they are titratable, and redosable if necessary, and benefit from a synthetic and highly scalable manufacturing process.

Speaker #5: 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.

Gopi Shanker: 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 years. We are pleased to have Dr. Musunuru here with us today to discuss this work, as well as his pioneering work on the development of customized genetic medicines for rare diseases.

Speaker #5: 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.

Speaker #5: 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 years.

Speaker #5: We are pleased to have Dr. Musinuru here with us today to discuss this work, as well as his pioneering work on the development of customized genetic medicines for rare diseases.

Speaker #5: This slide highlights the preclinical data supporting Beam 304, which demonstrate the potential of base editing to correct underlying PKU mutations and rapidly normalize plasma fee levels.

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

Speaker #5: On the left, you see results from a mouse model carrying the R408W mutation, and on the right, data from a second prevalent mutation, which we refer to here as mutation B.

Speaker #5: 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 fee levels were reduced below the therapeutic threshold, effectively normalizing levels in animals consuming an unrestricted standard protein-containing diet.

Speaker #5: These reductions were accompanied by robust on-target editing in the liver, consistent with correction of the underlying PAH mutation. Here, we show the dose-response relationship between on-target editing and plasma Phe reduction.

Speaker #5: As dose increases, editing in the liver rose in a predictable manner. With even relatively low levels of editing sufficient to drive fee below the therapeutic threshold.

Gopi Shanker: As dose increases, editing in the liver grows in a predictable manner, with even relatively low levels of editing sufficient to drive Phe below the therapeutic threshold. We are eager to advance BEAM-304 into the clinic and have already completed productive pre-IND interactions with the FDA. Structured similarly to our BEAM-302 and BEAM-301 clinical programs, the planned phase one/two study will be an open-label, single-ascending dose trial, initially in PKU patients with the R408W mutation. The study is designed to achieve early clinical proof of concept of plasma Phe reduction, establishing a potential path to market and laying the foundation for expansion of the program to additional mutations. Key endpoints will include safety, tolerability, and reduction of blood Phe concentration. We expect to file the IND for BEAM-304 in 2026, following completion of pre-IND activities.

Speaker #5: 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 1/2 study will be an open-label, single-ascending dose trial, initially in PKU patients with the R408W mutation.

Speaker #5: The study is designed to achieve early clinical proof-of-concept of plasma fee reduction establishing a potential path to market and laying the foundation for expansion of the program to additional mutations.

Speaker #5: Key endpoints will include safety, tolerability, and reduction of blood fee concentration. We expect to file the IND for Beam 304 in 2026, following completion of pre-IND activities.

Speaker #5: 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.

Gopi Shanker: 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.

Speaker #5: 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.

Speaker #5: With that, I'd like to formally introduce Dr. Kiran Musinuru. Dr. Musinuru is a professor of cardiovascular medicine, genetics, and pediatrics, and the Perelman School of Medicine and the University of Pennsylvania.

Speaker #5: 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.

Gopi Shanker: A practicing cardiologist and geneticist, his research focuses on genetics and genomics of cardiovascular and metabolic diseases, with a particular emphasis on developing gene-editing therapies. Dr. Musunuru is widely recognized as a leader in applying CRISPR and other genome-editing technologies to prevent and treat heart disease. He also played a central role in the development of world's first personalized base editing therapy to treat an infant known as Baby KJ, marking a landmark advance in precision medicine for ultra-rare genetic diseases. Over to you, Kiran.

Speaker #5: 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.

Speaker #5: Over to you, Kiran.

Kiran Musunuru: It's a real pleasure to have the chance to speak to you today. I've been working with my friend and colleague, Dr. Rebecca Ahrens-Nicklas, at the Children's Hospital of Philadelphia, or CHOP, for several years now to develop personalized gene-editing treatments for a variety of inborn errors of metabolism, including PKU. I should start by emphasizing the poor metabolic control achieved in patients with PKU under the current standard of care, even at an academic medical center where patients are receiving specialized care from a team of metabolic physicians. We looked at data from patients with PKU treated at CHOP, specifically all individuals with at least one copy of the PAH R408W variant, which is the most frequent variant causing classic PKU, that is severe PKU.

Speaker #6: 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 Aarons-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.

Speaker #6: 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.

Speaker #6: We looked at data from patients with PKU treated at CHOP, specifically all individuals with at least one copy of the PAH R408W variant, which is the most frequent variant causing classic PKU, that is, severe PKU.

Speaker #6: 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.

Kiran Musunuru: We found that the majority of patients had at least a single Phe measurement above the recommended safety zone, indicated here by the dotted line, 360 micromoles per liter. About 30% of patients had lifetime average Phe levels above the recommended maximum Phe level. There's clearly enormous unmet medical need here. There are more than 1,000 PAH variants cataloged in patients with PKU worldwide. Many are potentially amenable to adenine base editing, meaning that, like the R408W variant, they could, in principle, be corrected by A to G edits, either on the sense strand or the antisense strand. Rather than focus on the top few most frequent PKU variants, Dr. Ahrens-Nicklas and I chose to initially focus on a lower frequency variant, the PAH P281L variant.

Speaker #6: 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.

Speaker #6: Rather than focus on the top few most frequent PKU variants, Dr. Aarons-Nicholas and I chose to initially focus on a lower frequency variant, the PAH P281L variant.

Speaker #6: 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-based editor and a guide RNA specific to the variant caused the elevated fee levels in these mice to be entirely normalized by 48 hours after treatment.

Kiran Musunuru: Early on in our work, using a humanized mouse model with PKU caused by the P281L variant, we found that treatment with an LNP test article with an mRNA encoding an adenine base editor and a Guide RNA specific to the variant, caused the elevated Phe levels in these mice to be entirely normalized by 48 hours after treatment. This got us excited about the prospect of addressing not only the P281L variant, but a broad range of disease-causing variants in the PKU population. Since then, Dr. Ahrens-Nicklas and I have found promising adenine base editing solutions for other variants, which together comprise a majority of PKU patients.

Speaker #6: This got us excited about the prospect of addressing not only the P281L variant, but a broad range of disease-causing variants in the PKU population.

Speaker #6: Since then, Dr. Aarons-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.

Kiran Musunuru: It's not hard to envision using the same LNP formulation, slightly different versions of mRNAs to cover a family of closely related adenine-based editors, and individualized guide RNAs, effectively variations on the same drug product to treat all these patients. That said, Dr. Ahrens-Nicklas and I are very committed to the idea that no patient should be left behind. Our goal is to be able to rapidly develop and validate a corrective editing therapeutic for any PAH variant in any patient with PKU. Solving a small number of variants isn't enough. What about the 1,000 plus other variants that have been cataloged? That actually understates the problem. Here's a figure from the most comprehensive study of PKU variants worldwide, published in 2020.

Speaker #6: Effectively, variations on the same drug product to treat all these patients. That said, Dr. Aarons-Nicholas and I are very committed to the idea that no patient should be left behind.

Speaker #6: 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.

Speaker #6: 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.

Speaker #6: Plenty of data from some parts of the world, like Europe, and then whole stretches of the globe from which there is little data. For example, the entire African continent and large parts of Asia.

Kiran Musunuru: Plenty of data from some parts of the world, like Europe, and then whole stretches of the globe from which there are little data, for example, the entire African continent and large parts of Asia. This highlights that you can't make gene editing therapies for patients if you have no idea what genes and variants are causing their diseases. As gene sequencing becomes more broadly accessible, we can be sure that many more PAH variants will be identified. It won't be feasible to design gene editing therapies for these patients beforehand, for many of these patients will need to be able to make these therapies in real time. The problem is even more acute in another set of diseases on which Dr. Ahrens-Nicklas and I have been working, the urea cycle disorders.

Speaker #6: 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.

Speaker #6: It won't be feasible to design gene editing therapies for these patients beforehand for many of these patients will need to be able to make these therapies in real time.

Speaker #6: The problem is even more acute in another set of diseases on which Dr. Aarons-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.

Kiran Musunuru: Variants in the genes encoding any of the six liver enzymes and the transporters 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. These are ultra-rare diseases, and most of the patients' 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.

Speaker #6: 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 patients' variants are N of 1 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.

Speaker #6: 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.

Kiran Musunuru: It goes without saying that the current regulatory framework was never intended to handle this type of personalized therapy, and that regulatory innovation is needed. Dr. Ahrens-Nicklas and I have been extensively engaging with the FDA over the past couple of years, having interact 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.

Speaker #6: Dr. Aarons-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.

Speaker #6: 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.

Speaker #6: 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.

Kiran Musunuru: 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-based editors, and individualized guide RNAs. They were agreeable to this, opening the door to a so-called umbrella clinical trial. We 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.

Speaker #6: 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.

Speaker #6: Using the same LNP formulation, slightly different adenine-based editors, and individualized guide RNAs, they were agreeable to this—opening the door to a so-called umbrella clinical trial.

Speaker #6: 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.

Speaker #6: 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.

Kiran Musunuru: 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 a 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.

Speaker #6: 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.

Speaker #6: 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.

Speaker #6: In all, we think this is a very positive development for the ultra-rare disease space, and we 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.

Kiran Musunuru: In all, we think this is a very positive development for the ultra-rare disease space and are excited to move forward with this kind of clinical trial for the urea cycle disorders, with funding support from the NIH's Somatic Cell Genome Editing Program.

Speaker #1: Thank you, Dr. Musunoro. 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.

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

Speaker #3: 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 Ristacel.

Sravan Emany: Thanks, John. In addition to PKU, today, we shared another important update that further strengthens our balance sheet and reaffirms our belief in the commercial potential of risto-cel, our investigational autologous cell therapy with potential for best-in-class profile for the treatment of sickle cell disease. This morning, we announced a strategic financing agreement with Sixth Street that provides up to $500 million in long-term, non-dilutive capital to support the anticipated launch of risto-cel. The facility includes $100 million funded at close, up to $300 million available upon the achievement of certain regulatory, clinical, and commercial milestones for risto-cel, and an additional $100 million subject to mutual agreement during the seven-year term. Repayment of the principal is due in early 2033.

Speaker #3: Our investigational, autologous cell therapy with potential for best-in-class profile for the treatment of sickle cell disease. This morning, we announced a strategic financing agreement with 6th Street, that provides up to $500 million in long-term non-dilutive capital to support the anticipated launch of Ristacel.

Speaker #3: The facility includes $100 million funded at close, up to $300 million available upon the achievement of certain regulatory clinical and commercial milestones for Ristacel, and an additional $100 million subject to mutual agreement during the seven-year term.

Speaker #3: Repayment of principal is due in early 2033. This structure strengthens our balance sheet while preserving flexibility and enhancing our ability to both commercialize Ristacel as well as fund future growth and innovation across our pipeline.

Sravan Emany: This structure strengthens our balance sheet while preserving flexibility and enhancing our ability to both commercialize risto-cel as well as fund future growth and innovation across our pipeline. With this latest announcement, we have established a foundation of financial strength for sustainable growth. We ended 2025 with $1.25 billion in cash equivalents, and marketable securities. With the anticipated minimum draw of $200 million from the Sixth Street facility, we now expect our runway to extend into mid-2029. This supports Beam's pipeline execution through key anticipated milestones, including the launch of risto-cel, the BEAM-302 pivotal plan, and clinical proof of concept for BEAM-304.

Speaker #3: 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.

Speaker #3: With the anticipated minimum draw of $200 million from the 6th 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 Ristacel, the Beam 302 pivotal plan, and clinical proof of concept for Beam 304.

Speaker #3: We remain focused on being efficient with our investments, including building focused commercial capabilities ahead of the anticipated Ristacel launch, and positioning Beam 302 for a potentially accelerated path to market.

Sravan Emany: We remain focused on being efficient with our investments, including building focused commercial capabilities ahead of the anticipated risto-cel launch and positioning BEAM-302 for a potentially accelerated path to market. Finally, our pipeline is wholly owned and addresses significant markets. Combined with our platform-enabled approach, we believe this provides a clear path to long-term value creation and sustainable growth. I'll turn the call back to John for closing remarks.

Speaker #3: 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.

Speaker #3: I'll turn the call back to John for closing remarks.

Speaker #1: 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.

John Evans: Thank you, Sravan. We believe our PKU program clearly illustrates the power of Beam's genetic medicines platform. By correcting the genetic cause of the disease, base editing is a potentially ideal 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.

Speaker #1: 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.

Speaker #1: 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.

Speaker #1: As we look ahead to 2026, we believe Beam is well positioned to realize the power of predictability across our growing portfolio. For our lead programs, we are accelerating the paths to approval and look forward to providing updated phase one-two data and next steps for Beam 302 pivotal development in alpha-1 antitrypsin deficiency this quarter.

John Evans: For our lead programs, we are accelerating the paths to approval and look forward to providing updated Phase one/two data and next steps for BEAM-302 pivotal development in alpha-1 antitrypsin deficiency this quarter, followed by the anticipated submission of the risto-cel BLA as early as year-end. In addition, we continue to advance and expand the pipeline. We expect to file the IND for BEAM-304 for PKU, report initial BEAM-301 data in GSD1a, complete the BEAM-103 healthy volunteer study, and continue advancing our in vivo HSC editing efforts this year. As Sravan outlined, we are doing this from a position of increasing financial strength, with a strong cash balance and new long-term, non-dilutive capital from Sixth Street to support risto-cel. At Beam, everything we do is driven by our commitment to patients.

Speaker #1: Followed by the anticipated submission of the Ristacel BLA as early as year-end. In addition, we continue to advance and expand the pipeline. We expect to file the IND for BEAM-304 for PKU, report initial BEAM-301 data in GSD-1A, complete the BEAM-103 healthy volunteer study, and continue advancing our in vivo HSC editing efforts this year.

Speaker #1: 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 6th Street to support Ristacel.

Speaker #1: 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.

John Evans: 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.

Speaker #1: 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.

Speaker #1: 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.

Speaker #1: Operator, please open the line for Q&A.

Kiran Musunuru: As a reminder, if you have a question, press star one one on your telephone and wait for your name to be announced. To remove yourself, press star one one again. One moment while we compile our Q&A roster. Our first question comes from Samantha Semenkow with Citi. Please proceed.

Speaker #4: In as a reminder, if you have a question, press star 11 on your telephone and wait for your name to be announced. To remove yourself, press star 11 again.

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

Speaker #4: One moment, while we compile our Q&A roster. Our first question comes from Samantha Semencol with Citi. Please proceed.

Speaker #5: 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 in addressing multiple mutations.

Samantha Semenkow: 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 in 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? Then just with the strategic financing for risto-cel, does this allow you to reallocate more of your existing capital to additional liver-targeted indications? How should we think about the rollout of those additional programs? Thanks very much.

Speaker #5: From a Beam-specific perspective, how should we think about the opportunity and the timeline to moving beyond the R408W mutation into other mutations? And then just with the strategic financing for Ristacel, 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?

Speaker #5: Thanks very much.

Speaker #1: Yeah, thanks, Samantha. And great questions. So maybe to start, I'll ask Gopi and then Amy to talk a little bit about how we see additional mutations rolling in over time, first in research and then in the clinic.

John Evans: Yeah. Thanks, Samantha, and great question. Maybe to start, I'll ask Gopi and then Amy to talk a little bit about how we see additional mutations rolling out over time, first in research and then in the clinic. We'll come back and have Shraven talk a little bit about, yeah, what this allows us to do financially. Gopi?

Speaker #1: And then we'll come back and have Shravan talk a little bit about what this allows us to do financially. Gopi?

Speaker #6: 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.

Gopi Shanker: 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. 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. Based on our initial interactions with the FDA, we expect to be able to bring multiple mutations forward within one program.

Speaker #6: And we expect the timelines could be fast given that we're 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.

Speaker #6: And based on our initial interactions with the FDA, we expect to be able to bring multiple mutations forward within one program.

Amy Simon: 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. 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.

Speaker #3: 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.

Speaker #3: 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.

Speaker #7: And this is Shravan. I'll tackle the finance question. So I think we're really confident that this financing gives us a lot of flexibility with the long-term non-dilutive capital, support the commercial launch, and subsequent revenue generation for Ristacel.

Sravan Emany: This is Shraven. I'll tackle the finance question. So I think we're really confident this financing gives us a lot of flexibility with the long-term, non-dilutive capital to support the commercial launch and subsequent revenue generation for risto-cel. 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. You know, 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.

Speaker #7: And I think you were kind of hit the point, which is it also enhances our ability to redirect our capital to the growth of our pipeline.

Speaker #7: 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.

Operator: Samantha?

Sravan Emany: Samantha?

Speaker #4: Samantha?

Speaker #5: Thanks very much. Appreciate the answers.

Samantha Semenkow: Thanks very much. Appreciate the answers.

Speaker #4: Our next question comes from the line of Mauri Raycroft, with Jefferies. Please proceed. Line is open. Sir, I'm going to move to the next question.

Operator: Our next question comes from the line of Maury Raycroft with Jefferies. Please proceed. Line is open. Sir, I'm going to move to the next question. It comes from the line of Eric Schmidt with Cantor. Please proceed.

Speaker #4: It comes from the line of Eric Schmidt, with Cantor. Please proceed.

Speaker #1: And thanks for all the updates. A couple of questions on 304 as well. First, it sounded like Dr. Musuneru's lab may have been first at kind of reducing to practice base editing for some of these mutations.

Eric Schmidt: Thanks for all the updates. A couple of questions on BEAM-304 as well. First, it sounded like Dr. Musunuru's lab may have been first at kind of reducing the practice of base editing for some of these mutations. Is there some IP associated with either R408W or others that the company has access to? Second, in terms of the predictability of the platform, that seems to be the theme today. Does BEAM-304 use the same ionizable lipid or even same or similar lipid nanoparticle? What can you say about the delivery there relative to, say, BEAM-302 or BEAM-301? Thank you.

Speaker #1: Is there some IP associated with either R408W or others that the company has access to? And then second, in terms of the predictability of the platform, that seems to be the theme today.

Speaker #1: 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?

Speaker #1: Thank you.

John Evans: Yeah, great questions. I can handle those too. I think we will have access to all of the IP that we need here. Certainly, there is a lot of pioneering work from Kiran's lab to point the way in this mutation. Obviously, a lot of work has happened at Beam in the last few years, as Gopi said, to then, you know, make these industrial and leverage all of the platform capabilities that we have as well. In terms of the LNP, it's broadly the same kinds of LNP approaches that we use with 302, 301.

Speaker #8: Yeah, great questions. I can handle those too. So yeah, so I think we will have access to all of the IP that we need here.

Speaker #8: 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.

Speaker #8: In terms of the LNP, so yeah, it’s broadly the same kinds of LNP approaches that we use with 302, 301. We do have our own ionizable lipids at this point as a company.

John Evans: You know, we do have our own ionizable lipids at this point, as a company, which we expect to use. The, you know, the way we make them, the formulation, the approach, as well as the internal manufacturing, will all be leveraging the work that we've done for 302 and 301 as well.

Speaker #8: Which we expect to use. But the way we make them, the formulation, the approach as well as the internal manufacturing will all be leveraging the work that we've done for 302 and 301 as well.

Speaker #4: One moment for our next question. It comes from Yahanju, with Wells Fargo. Please proceed.

Operator: One moment for our next question. It comes from Yangbo Xu with Wells Fargo. Please proceed.

Yangbo Xu: Great. Thanks for taking our questions and for the update. A couple of questions. 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? Wondering within the PKU range of mutations, are there any that the company, you know, are some or a lot of the mutations would have fall under this new framework? If I may, two quick technical questions.

Speaker #1: Great. Thanks for taking our questions and for the update. A couple of questions. Wanted to take advantage of the presence of not only the company, but also Dr. Musuneru on the line.

Speaker #1: Yesterday, the FDA provided a draft guidance for individualized therapy. One thing that's not quite clear is: how rare does a disease have to be to qualify for this new framework?

Speaker #1: Wondering, within the PKU range of mutations, are there any that—or some or a lot of the mutations—that would have fallen under this new framework?

Speaker #1: 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?

Yangbo Xu: For the BEAM-304 product name, are there going to be 2 different guide RNAs targeting the 2 different mutations or the same guide RNA? If you can also talk about in your preclinical work, the presence of bystander editing, that would be great. Thank you.

Speaker #1: And if you can also talk about in your preclinical work, the presence of bystander editing that would be great. Thank you.

Speaker #8: Great. Thank you, Yannon. Yeah, so I think you're touching on some of the more innovative aspects of what we're doing here, which is quite exciting.

John Evans: Great. Thank you, Yanan. I think that, you know, you're touching on some of the more innovative aspects of what we're doing here, which is quite exciting. Maybe I'll ask Dr. Matsunuru first to say a bit about yesterday and the Plausible Mechanism Pathway. Then, Gopi, maybe you can cover the multiple guides and the bystander editing.

Speaker #8: So maybe I'll ask Dr. Musuneru 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.

Speaker #9: Yeah, thanks, John. So my perspective on the plausible mechanism 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.

Kiran Musunuru: Yeah, thanks, John. My perspective on the Plausible Mechanism that was announced yesterday is that it's primarily talking about potential approvals of platforms. 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. There are a bunch of conditions that are set there as to what particular types of diseases might qualify under the Plausible Mechanism framework. 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 Biologics License Applications. It's not necessarily prescriptive about clinical trial designs per se. What I should say with respect to PKU is that there's some ambiguity there.

Speaker #9: 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.

Speaker #9: 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 Biologics License Applications.

Speaker #9: 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.

Speaker #9: So if you're talking about urea cycle disorders, which I mentioned during the presentation, it's 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.

Kiran Musunuru: If you're talking about urea cycle disorders, which I mentioned during the presentation, those are very clearly ultra-rare diseases. You're talking about perhaps a few dozen patients at most, who are born in any given year, who might be amenable to this type of gene editing approach. What's less clear is with a disease like PKU, where there's a wide spectrum of mutations, there are relatively frequent mutations where potentially you could contemplate doing a standard randomized controlled trial. If you go to the other end of the spectrum, there are N of one and a few type scenarios, would be individually considered ultra-rare. I don't think it's clear. I'm not sure the FDA necessarily has thought about this so much. Dr.

Speaker #9: What's less clear is with the 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, N of few type scenarios that would be individually considered ultra-rare.

Speaker #9: And so I don't think it's clear. I'm not sure the FDA necessarily has thought about this so much. Dr. Hoag, 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.

Kiran Musunuru: Høeg, the acting CDER director, yesterday, during the press conference, when asked about this very issue, demurred to some extent and said that the agency doesn't want to be prescriptive, at least at this point, as to what distinguishes ultra-rare from rare. She expressed openness to the idea that it doesn't necessarily need to be an ultra-rare context in order for the plausible mechanism framework to apply, but she didn't give much specificity. I would point out again that this is a draft guidance, not the actual final guidance. 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. We'll have to see what the final guidance says.

Speaker #9: 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.

Speaker #9: 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.

Speaker #9: 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.

Speaker #9: 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.

Kiran Musunuru: 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 The New England Journal of Medicine article published by Doctors Mauteri and Prasad back in November. Those clinical trial designs, where one can include multiple variants, in the same IND under, you know, a single umbrella clinical trial, those are relevant regardless of whether the disease itself would qualify for the plausible mechanism framework or not. The clinical trial designs will stand on their own. It's very clear that the FDA is open to those types of designs.

Speaker #9: 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.

Speaker #9: And so, those clinical trial designs where one can include multiple variants in the same IND under a single umbrella clinical trial—those are relevant regardless of whether the disease itself would qualify for the plausible mechanism framework or not.

Speaker #9: The clinical trial designs will stand on their own. It's very clear that the FDA is open to those types of designs. Whether they're going to be accelerated approvals under the framework, that was announced yesterday, less clear.

Kiran Musunuru: 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.

Speaker #9: I think that would entail discussions with the agency on a case-by-case basis.

Speaker #1: Thank you for all the color.

John Evans: Thank you for all the color.

Yangbo Xu: Thank you for all the color.

Speaker #10: Thank you. Our next question is from.

Operator: Thank you. Our next question is from Corey-

John Evans: Oh, one.

Speaker #11: I just wanted to add one.

Amy Simon: I just wanted to add one.

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

Speaker #9: One moment. One moment. I think we wanted Gopi to answer the second half of Yannon's question. Gopi, over to you.

Speaker #11: 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.

Gopi Shanker: Yeah, thanks for the question. 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. On the bystander profile, even though we didn't disclose details today, we feel confident about the on-target editing and the benefit-risk profile.

Speaker #11: So the guide RNA will be unique for each mutation, but they'll all be part of a single clinical program. That's how we intend to carry this forward.

Speaker #11: And on the bystander profile, even though we didn't disclose details today, we feel confident about the on-target editing and the benefit risk profile.

Speaker #8: And Amy, did you want to add something to Karen's discussion?

John Evans: Amy, did you want to add something to Kiran's discussion?

Speaker #12: 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.

Amy Simon: I would just indicate that we've had also very good meetings with the FDA. They're supportive of this platform approach, where multiple variants could be treated under one single program or one type of IND. 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.

Speaker #12: 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.

Speaker #8: Yeah.

Speaker #10: Thank you so much. Our next question comes from Corey Kasimov with Evercore ISI. Please proceed.

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

Kiran Musunuru: Hi, this is Adi on for Corey. I wanted to ask a question on sickle cell, given the new financing. The recent increase in update of approved ex vivo therapies, can you help frame your current view of peak penetration or sales for ex vivo modality? Specifically, what market share assumptions do you currently expect for risto-cel, assuming its differentiated profile continues to hold? Thank you.

Adit Jayaraman: Hi, this is Adi on for Corey. I wanted to ask a question on sickle cell, given the new financing. The recent increase in update of approved ex vivo therapies, can you help frame your current view of peak penetration or sales for ex vivo modality? Specifically, what market share assumptions do you currently expect for risto-cel, assuming its differentiated profile continues to hold? Thank you.

Speaker #13: Hi. This is Addy on for Corey. I wanted to ask a question on sickle cell given the new financing. The recent increase in uptake of approved Xvivo therapies can you help frame your current view of peak penetration or sales for Xvivo modality?

Speaker #13: And specifically, what market share assumptions do you currently expect for Risto Cell assuming it's differentiated profile continues to hold? Thank you.

Speaker #8: Yeah. Thank you. So maybe I'll have Pino talk a little bit here about our view for Risto Cell. Of course, we wouldn't be giving market share or other specifics like that at this stage.

John Evans: Yeah, thank you. Maybe I'll have Pinot talk a little bit here about our view for risto-cel. Of course, we, you know, we wouldn't be giving, you know, market share or, you know, other specifics like that at this stage. I think we do have. We have been watching, obviously, the market evolve and have a lot of perspective on that. Maybe, Pinot, do you want to talk a little bit about how the market's coming along and, you know, what we think risk as well?

Speaker #8: But I think we do have we have been watching, obviously, the market evolve and have a lot of perspective on that. So maybe Pino, do you want to talk a little bit about how the market's coming along and what we think Risto Cell?

Speaker #13: 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.

Giuseppe Ciaramella: 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. That is that clearly there is a significant demand for a program such as the risto-cel that we're developing. That's as you can see, there are basically patients waiting in order to do that. Also, other aspects of the market are very positive. Like, for instance, to our knowledge, nobody has been refused the payment despite the fact that these treatments are, you know, north of $2 million.

Speaker #13: And that is that clearly there is a significant demand for a program such as the Risto Cell that we're developing. And that's as you can see, there are basically patients waiting in order to do that.

Speaker #13: 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.

Speaker #13: 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.

Giuseppe Ciaramella: What has been, you know, 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. 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. That causes also limitation on the overall capacity of the system, as well as not making the money essentially on behalf of this company. We have really, from the get-go, optimized our manufacturing process very strongly so that you can see our median mobilization cycle is only one. That's also, like, likely helped by the fact that we don't make double-strand break.

Speaker #13: 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.

Speaker #13: 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.

Speaker #13: We have really, from the get-go, optimized our manufacturing process very strongly so that you can see our median mobilization cycle is only one. And that's also likely helped by the fact that we don't make double-stranded break.

Speaker #13: 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 this product.

Giuseppe Ciaramella: 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.

Speaker #10: One moment for our next question. It comes from the line of Whitney Yam with Canocore Genuity. Please proceed.

Operator: One moment for our next question. It comes from the line of Whitney Ijem with Canaccord Genuity. Please proceed.

Speaker #14: Hi, guys. Thank you for taking our question. This is Angela on for Whitney. Maybe jumping over to the AETD, can you just help us set expectations into the upcoming readout?

[Analyst] (Canaccord Genuity): Hi, guys. Thank you for taking our question. This is Angela on for Whitney. Maybe jumping over to the AATD, can you just help us set expectations into the upcoming readout? How should we all be thinking about what is good in terms of AAT levels from the 75 and the 60 milligrams double dose? 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?

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

Speaker #14: How should we all be thinking about what is good in terms of AET 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?

Speaker #8: 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 pretty comprehensive set of data there.

John Evans: Yeah, great. I'll handle that one. 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. As a reminder, for that trial in alpha-1, with 302, we're dosing additional 60 mg patients, you know, just given the strength of the data we showed last year. Then continue to explore dose and schedule, looking at 75 mg dose and a 2 times 60. We'll put all of that together.

Speaker #8: So, as a reminder, for that trial in Alpha-1, so with 302, we're dosing additional 60-milligram patients, just given the strength of the data.

Speaker #8: We showed last year and then continue to explore dose and schedule, looking at 75 milligram dose and a 2 times 60. So we'll put all of that together and as a reminder, what we're looking to see there is is there any evidence of increases in Alpha 1?

John Evans: 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 out in the liver already? That will be sort of Part 1. We'll also be looking at patients with, this is all sort of Part A with lung. We'll be looking at patients in Part B who have the sicker livers. We're trying to see if there is, you know, similar efficacy and safety as in Part A. Depending on what we see there, that's some things we can think about. We'll also be, of course, showing durability.

Speaker #8: Sort of versus how close are we to saturation editing 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.

Speaker #8: We'll be looking at patients in part B who have the sicker livers. We're trying to see if there is similar efficacy and safety as in part A.

Speaker #8: And then depending on what we see there, there's some things we can think about. We'll also be, of course, showing durability. So we'll have a significant amount of time now with patients who are in the update from last year out, 12-plus months and then a range of follow-ups from there.

John Evans: We'll have a significant amount of time now with the, you know, patients who are in the update from last year out, you know, 12 plus months, and then, and then a range of follow-ups from there. I think in terms of your second question, you know, I think we've said before, 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 that needs to go into the protocol. You know, I expect that the dataset will be, you know, hopefully helpful there and we'll either have it or we'll be able to have it soon. It's not really limiting at this point.

Speaker #8: So I think in terms of your second question, I think we've said before, 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 that needs to go into the protocol.

Speaker #8: I expect the data set will be hopefully helpful there. And we have it or we'll be able to have it soon. But it's not really limiting at this point.

John Evans: We're already operationalizing the Accelerated Approval cohort. That can just take in the input from the rest of the part, the Phase 1/2. That is very much on track for getting started.

Speaker #8: We're already operationalizing the accelerated approval cohort and that can just take in the input from the rest of the phase one, two. So that is very much on track for getting started.

Speaker #10: Our next question comes from the line of Brian Cheng with JPMorgan. Please proceed.

Operator: Our next question comes from the line of Brian Cheng with J.P. Morgan. Please proceed.

Speaker #15: Hey, guys. Thanks for taking our question this morning. First, just on responses in PKU, do you have a sense of how well these are 408W carriers behave?

Brian Cheng: Hey, guys. Thanks for taking our question this morning. First, just on responses in PKU, do you have a sense of how well these R408W carriers behave and respond to current options like Kuvan, Sephience, or Palynziq in the real world? Any thoughts on their uniformity in terms of response to a base editing approach? Second, just on the Phase one/two design, can you talk about the age range you're thinking of recruiting here? How quickly can you get to the newborn at the time of their diagnosis? Thank you.

Speaker #15: And respond to current options like 2 grams of science or pounds seeking the real world? And any thoughts on their uniformity in terms of response to a base editing approach?

Speaker #15: And then second, just on the phase one, two, 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?

Speaker #15: Thank you.

Speaker #8: 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.

John Evans: Yeah, great question. As a reminder, the mutations we're going after are really in the classic kind of severe PKU part of the market. Maybe, Amy, if you could speak a little bit to, for 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 product.

Speaker #8: So maybe, Amy, if you could speak a little bit to those patients' responsiveness to current therapies, and then a little bit about how we think about getting to different age ranges over the course of the trial.

Speaker #15: 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.

Amy Simon: Sure. Thanks, John. 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. 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. 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.

Speaker #15: 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.

Speaker #15: 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.

Speaker #15: 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.

Speaker #15: 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.

Amy Simon: 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. Typically, when we do go into these patient populations, we will stage-gate it a little bit and, you know, typically start either at 18 and above, or, for example, sometimes you can get an indication directly to go to 12 and above. Once you get some data, then working with the regulators to then be able to open up cohorts that are younger and younger. 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.

Speaker #15: 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.

Speaker #15: And some of this also can be done with some obviously PKPD modeling and other kind of things to kind of figure out dosing, etc.

Speaker #15: But we are very confident that we will be able to get to the patient population that frankly would benefit tremendously from this because those are the patients who are having brain growth 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.

Amy Simon: 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.

Speaker #15: And I think it's so much that was very helpful.

John Evans: Got it. Thank you so much. That was very helpful.

Brian Cheng: Got it. Thank you so much. That was very helpful.

Speaker #10: Thank you. Our next question comes from Luca Issi with RBC Capital Markets. Please proceed.

Operator: Thank you. Our next question comes from Luca Issi with RBC Capital Markets. Please proceed.

Speaker #16: Oh, hi. Thanks, Tim. Thanks so much for taking our question. The Congress on the Progress. This is Cassian for Luca. A quick one on A1AT.

[Analyst] (RBC Capital Markets): Hi. Thanks, team. Thanks so much for taking our question, and congrats on the progress. This is Cassie on for Luca. A quick one on A1AT. Appreciate that you are DNA editing, and some of your competitors is RNA. What is your read on GSK returning the rights on A1AT? Maybe a longer question for A1AT's pivotal, has the FDA discussed with you their minimum requirements for representative US enrollments? Correct me if this is not right, please. We see on ClinicalTrials.gov that the phase one/two are ex-US. Would this mean that your pivotal of NL50 will have to be mostly from the US, if the agency does require majority of patients in approval package to be US patients? Any color there is much appreciated. Thank you.

Luca Issi: Hi. Thanks, team. Thanks so much for taking our question, and congrats on the progress. This is Cassie on for Luca. A quick one on A1AT. Appreciate that you are DNA editing, and some of your competitors is RNA. What is your read on GSK returning the rights on A1AT? Maybe a longer question for A1AT's pivotal, has the FDA discussed with you their minimum requirements for representative US enrollments? Correct me if this is not right, please. We see on ClinicalTrials.gov that the phase one/two are ex-US. Would this mean that your pivotal of NL50 will have to be mostly from the US, if the agency does require majority of patients in approval package to be US patients? Any color there is much appreciated. Thank you.

Speaker #16: 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?

Speaker #16: And also maybe the longer question for A1AT's pivotal. Has the FDA discussed with you their minimum requirements for representative US enrollments? Correct me if this is not right, please.

Speaker #16: We see on CDA.gov that the Phase One and Two are ex-US. Would this mean that your pivotal in NL50 will have to be mostly from the US if the agency does require a majority of patients in the approval package to be US patients?

Speaker #16: Any kind of there is much appreciated. Thank you.

Speaker #8: Yeah, thanks. I can handle some of those. So, the first question on RNA editing—I mean, I wouldn't want to comment on another company's situation.

John Evans: 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'd just have to ask them. I think our belief remains that all things equal, the having a one and done for Alpha-1 is going to be a preferable product profile if you can achieve it, which we believe we can.

Speaker #8: I think you just have to ask them I think our belief remains that all things equal, the 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.

Speaker #8: And then obviously, just doing head-to-head on the different data sets that are currently been disclosed, we continue to believe that BM302 has shown the best-in-class data in terms of alpha one levels as well as the composition of that of those.

John Evans: You know, obviously, you know, just doing head-to-head on the different datasets that have currently been disclosed, we continue to believe that NEM-302 has shown the best-in-class data in terms of alpha-1 levels, as well as, you know, the composition of that, of those levels as well between MvL production. 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 US. That'll be a big part of the entire trial going forward, along with the ex US regions that we're in.

Speaker #8: Levels as well between M and Z production. So in terms of US ratio, I think it's probably premature to talk about that. I think we are we have obviously an open IND.

Speaker #8: We will be active in the US—that'll be a big part of the entire trial going forward, along with the ex-US regions that we're in.

Speaker #8: So we'll certainly be keeping an eye on that and make sure that anything we need for US approval will be satisfied, which I'm sure it will.

John Evans: We'll certainly be keeping an eye on that and make sure that, you know, anything we need for US approval will be satisfied, which I'm sure it will.

Speaker #16: Thanks so much.

[Analyst] (RBC Capital Markets): Thanks so much.

Luca Issi: Thanks so much.

Speaker #10: Our next question comes from the line of Sami Corwin with William Blair. Please proceed.

Operator: Our next question comes from the line of Sami Corwin with William Blair. Please proceed.

Speaker #17: 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.

Amy Simon: 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?

Sami Corwin: 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?

Speaker #17: And if not, how could that impact the range of benefit observed?

Speaker #8: Yeah. Great question. Maybe Gobi, 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.

John Evans: Yeah, great question. Maybe Gopi, do you want to talk a little bit about the preclinical work we've done on that subject? Then, Amy, if you want to expand on that, you're welcome to.

Speaker #3: 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.

Gopi Shanker: 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 Phe levels below the therapeutic threshold is relatively modest, and that is, you know, one copy of PAH gene corrected is sufficient. A large number of patients are compound heterozygous. They will have two different mutations on, you know, each of their alleles. It's sufficient to correct one of them. To model such patients, who actually used compound heterozygous mice, meaning mice that have two different mutations, we were only correcting one of the mutations. Then demonstrated that that was sufficient in order to reduce the Phe levels to below the therapeutic threshold.

Speaker #3: And that is one copy of PAH gene corrected is sufficient. A large number of patients do are compound heterozygous, so they will have two different mutations on each of their alleles.

Speaker #3: And it's sufficient to correct one of them. And two, 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 F.E. levels to below the therapeutic threshold.

Speaker #17: Great. Thank you.

Amy Simon: Great. Thank you.

Sami Corwin: Great. Thank you.

Speaker #10: Thank you. One moment for our next question. We have Māori Raycroft with Jefferies. Your line is open.

Operator: Thank you. One moment for our next question. We have, Maury Raycroft with Jefferies. Your line is open.

Speaker #18: 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.

John Evans: Hi, good morning. Thanks for taking my question, 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?

Maury Raycroft: Hi, good morning. Thanks for taking my question, 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?

Speaker #18: 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 one, two study and how the phase one, two is going to work from a dosing standpoint to adding these new variants.

Sravan Emany: ... how much of that you already have? 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 one/two study, and how the phase one/two is gonna work from, like, a dosing standpoint to adding these new variants.

Maury Raycroft: ... how much of that you already have? 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 one/two study, and how the phase one/two is gonna work from, like, a dosing standpoint to adding these new variants.

Speaker #8: Yeah. I think I mean, maybe I'll just give the high-level answer, which is we are quite far at this point through all the preclinical preparations.

John Evans: Yeah, I mean, maybe I'll just give the high-level answer, which is, we are quite far at this point through all the preclinical preparations. We've already had interactions with the FDA, which have been supportive of this approach, which has been very encouraging. I think, as you've seen, we've guided to IND filing this year, so clearly we're in the final steps here. You know, I think the other piece about bringing more mutations in over time, I think, you know, we obviously are gonna 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.

Speaker #8: 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.

Speaker #8: So clearly, we're in the final steps here. And then I think the other piece about bringing more mutations in over time, I think we obviously are going to start with two, but there is an understanding that we can then append additional mutations into the same IND over time.

Speaker #8: That's basically the framework that has been put forward here. And so as the research team brings them along, we can then adaptively put that forward.

John Evans: 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. That's where, you know, we're gonna continue to sort of pioneer this. We feel quite confident, especially with the well-precedented endpoint in this disease, that we will be able to do that.

Speaker #8: Some of the nuances of exactly how we manage the trial over time and mix these different populations together on our approval pathway is obviously some of the work that Amy and her team will do, in consultation with the FDA.

Speaker #8: And that's where we're going to continue to sort of pioneer this. But we feel quite confident, especially with the well-precedented endpoints in this disease, that we will be able to do that.

Speaker #18: 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?

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

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

Speaker #8: Yeah. Either Gopi or Amy want to talk about sort of initial dose selection and escalation?

John Evans: Yeah. Either Gopi or Amy, you wanna talk about sort of initial dose selection and escalation?

Speaker #19: Yeah. I mean, I think again, it depends a lot on what we see in our non-clinical. And we do PKPD modeling. And obviously, it's unique for each kind of LNP and drug product that you make.

Amy Simon: Yeah, I mean, I think, again, it depends a lot on what we see in our non-clinical, and we do PKPD modeling, and obviously, it's unique for each kind of LNP and drug product that you make. I think we're just going to base it on kind of those analyses like we have in the past for 302 and 301.

Speaker #19: 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.

Speaker #8: I think you can expect it to be standard, would be what I would say.

John Evans: I think you can expect it to be standard, would be what I would say.

Speaker #3: And maybe I can just add that, as you saw in the preclinical work, we were able to bring FEE levels down to below the therapeutic threshold at relatively low doses of LNP.

Sravan Emany: Mm-hmm.

Maury Raycroft: Mm-hmm.

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

Speaker #3: So we expect to be able to do the dose finding relatively efficiently.

Speaker #18: Got it. Okay. Thanks for taking my questions.

Sravan Emany: Got it. Okay, thanks for taking my questions.

Maury Raycroft: Got it. Okay, thanks for taking my questions.

Speaker #10: Thank you. Our next question comes from William Pickering with Bernstein. Please proceed.

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

Speaker #8: 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 risks that translating to humans?

William Pickering: 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? 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? How does that scale with the number of unique mutations you take into the clinic? Thank you.

W. William Pickering: 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? 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? How does that scale with the number of unique mutations you take into the clinic? Thank you.

Speaker #8: 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?

Speaker #8: Thank you. Yeah. Good question. Maybe Gopi, why don't you start with the first question just about the low threshold for practice here and then Shrevin, do you want to talk about how PKU appears in our cash planning and runway guidance?

John Evans: Yeah, good question. Maybe, Gopi, why don't you start with the first question just about the, you know, low threshold for here, and then, Sravan, do you want to talk about how PKU appears in our, you know, cash planning and runway guidance?

Speaker #3: Sure. So PKU is caused by what's called recessive loss of function mutations, which means both copies of PAH need to be non-functional in order to have PKU.

Gopi Shanker: Sure. 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. 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. As you saw from the mouse data, it's sufficient to only get modest levels of the enzyme activity restored in the liver for the enzyme to then reduce the phenylalanine levels and to be active. You see this in other diseases in addition to PKU as well.

Speaker #3: 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.

Speaker #3: And as you saw from the mouse data, it's sufficient to only get modest levels of the enzyme activity restored in the liver for the enzyme to then reduce the phenylalanine levels and to be active.

Speaker #3: And you see this in other diseases, in addition to PKU, as well.

Speaker #8: 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.

Sravan Emany: On the question about runway and operating expenses, I would say that first, and I think it's the most important thing, PKU is already baked into the operating runway guidance we provided at the start of the year and updated today. You know, 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. 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 as of taking advantage of that platform as subsequent programs come online.

Speaker #8: An updated today. And that we're just at this point in time, probably not going to disclose the level of detail around costs by program.

Speaker #8: As it's kind of balanced across the entire portfolio. And I think I mentioned all 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 as of taking advantage of that platform as subsequent programs come online.

Speaker #8: Yeah. And if I could even if I could even just underline that last point, I think it's just too generically as the platform gets built that an entirely new program is easier and faster and more efficient and more likely to succeed when we do it at the second time or the third time than the first time.

John Evans: Yeah, if I could even just underline that last point. I think generically, as the platform gets built, that an entirely new program is easier and faster and more efficient, you know, and more likely to succeed when we do it at the second time or the third time than the first time. I think we're already experiencing that to a degree with PKU being BEAM-304 coming after BEAM-302 and BEAM-301. The adding additional mutations within the same program is even more efficient, right? I mean, the flywheel now is simply an additional Guide RNA, you know, some minimal testing, and then you're off to the races.

Speaker #8: And I think we're already experiencing that to a degree, with PKU being 304 coming after 302 and 301. Adding additional mutations within the same program is even more efficient, right?

Speaker #8: 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.

John Evans: You know, 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.

Speaker #10: One moment for our next question. That comes from the line of Alex Tranahan with Bank of America. Please proceed.

Operator: One moment for our next question. That comes from the line of Alec Stranahan with Bank of America. Please proceed.

Speaker #18: 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.

Alec Stranahan: 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 seemed consistent with the biomarker-driven path you're pursuing, but any additional thoughts relating to the applicability to AATD would be great. 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.

Speaker #18: Curious if you have any thoughts on the FDA comments on plausible mechanisms specifically related to AATD? They seemed consistent with the biomarker-driven duration path you're pursuing, but any additional thoughts relating to the applicability to AATD would be great.

Speaker #18: 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?

Speaker #18: Any structural modifications you're making here specifically thinking for optimizing safety and specificity? Thank you.

Speaker #8: Sure. So maybe on the first point, so I think as Karen already mentioned, I think the plausible mechanism pathway is sort of one way that the FDA anticipates getting these sorts of programs to approval, but it's not, of course, the only way.

John Evans: Sure. Maybe on the first point, I think as Kiran already mentioned, I think, you know, the Plausible Mechanism Pathway is sort of one way that the FDA anticipates getting these sorts of programs to approval. But it's not, of course, the only way, once you're in this sort of platform world. I think with alpha-1, we can say that we think we're taking a frankly more traditional path, which is an Accelerated Approval pathway, you know, addressing the root cause of disease, you know, followed presumably by, you know, some kind of confirmatory experiment. You know, we don't need an innovative new pathway for that. That's pretty traditional.

Speaker #8: 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 based on addressing root causes of disease.

Speaker #8: Followed, presumably, by some kind of confirmatory experiment. So, we don't need an innovative new pathway for that—that's pretty traditional. That said, obviously, it shows that what we're doing in Alpha-1 is broadly aligned, I think, with the kinds of programs working on the root cause of disease that the FDA is clearly leaning in on.

John Evans: 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 in on. And then, with the 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 3 or 4 IND, you know, and, you know, look forward to updating you over time.

Speaker #8: And then lipid nanoparticle, I think I mean, I think broadly, I think we think that LNPs are the best available option for the liver in terms of getting there.

Speaker #8: We think we've got a lot of expertise in that area. And I think as I mentioned before, we're building on that clearly with the 304 IND and look forward to updating you over time.

Speaker #8: Thank you.

Alec Stranahan: Thank you.

Speaker #10: Our next question comes from the line of Michael Yee with UBS. Please proceed.

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

Speaker #8: Good morning, guys. Thanks so much. This is Matt on from Mike Yee. Maybe one of the next-gen sickle cell programs, it seems like in vivo is maybe a leapfrog escape in terms of priority.

[Analyst] (UBS): Good morning, guys. Thanks so much. This is Matt on for Mike Yee. Maybe on the next gen sickle cell program, it seems like in vivo has maybe leapfrogged, ESCAPE in terms of priority. Could you just speak to what goes into choosing the right next gen program for sickle cell? What gives you confidence in the in vivo program and, you know, the HSC targeting that you might use there, just anything you can say there would be great. Thanks.

Matthew Weston: Good morning, guys. Thanks so much. This is Matt on for Mike Yee. Maybe on the next gen sickle cell program, it seems like in vivo has maybe leapfrogged, ESCAPE in terms of priority. Could you just speak to what goes into choosing the right next gen program for sickle cell? What gives you confidence in the in vivo program and, you know, the HSC targeting that you might use there, just anything you can say there would be great. Thanks.

Speaker #8: 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 say there would be great.

Speaker #8: Thanks. Sure. Pino, do you want to maybe just talk a bit about our prioritization of in vivo and prospects there?

John Evans: Sure. Pino, do you wanna maybe just talk a bit about our prioritization of in vivo and, you know, prospects there?

Speaker #11: Yeah. Definitely the consideration here is the fact that with LNP, of course, we can deliver a product much more easily than an ex vivo approach.

Giuseppe Ciaramella: Definitely, you know, the consideration here is the fact that with LNP, of course, we can deliver a product much more easily than an ex vivo approach, and therefore it would provide support for a larger number of patients if the efficacy obviously, were proven to be, you know, equal or certainly manageable from a disease point of view. I think, 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 LNP with the use of our ESCAPE-like technology as well.

Speaker #11: And therefore, it would provide support for a large number of patients if the efficacy obviously were proven to be equal or certainly manageable from a disease point of view.

Speaker #11: I think the important aspects of, and because we make, in progress, frankly, in preclinical studies, would suggest that that can also move relatively quickly in clinical studies.

Speaker #11: And therefore, that's what is guiding us to making that choice. We also have opportunities, obviously, to further enhance the engraftment rate, if you will, of an LNP with the use of our escape-like technology as well.

Speaker #11: 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.

Giuseppe Ciaramella: I think that gives us, you know, 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.

Speaker #10: Thank you. One moment for our next question. In views from the line of Patrick Trucio, with HC Wainwright, please proceed.

Operator: Thank you. One moment for our next question. It's from the line of Patrick Trucchio with H.C. Wainwright. Please proceed.

Speaker #8: Hi, Louise here. Thank you for squeezing in our question. For the go-on-of-go decision for 103 in healthy volunteers, how are you thinking about that?

[Analyst] (H.C. Wainwright): Hi, Louise here. Thank you for squeezing in our question. For the go or no-go decision for 103, in healthy volunteers, how are you thinking about that? Comparing to the in vivo editing in HSCs, how are the efficiency, the editing efficiencies compared? Thank you.

Patrick R. Trucchio: Hi, Louise here. Thank you for squeezing in our question. For the go or no-go decision for 103, in healthy volunteers, how are you thinking about that? Comparing to the in vivo editing in HSCs, how are the efficiency, the editing efficiencies compared? Thank you.

Speaker #8: And comparing to the in vivo editing in HSCs, how are the efficiency the editing efficiencies compared? Thank you. Sure. Pino, do you want to talk a little bit?

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

Speaker #8: I think you just sort of were talking about this—about the role of escape, obviously broadly, but also then within the in vivo context.

Speaker #11: Yeah. Also the initial question was not clear, but I heard healthy volunteers. So yeah.

Giuseppe Ciaramella: Yeah. The initial question was not clear, but I heard healthy volunteers.

Speaker #8: Yeah, 103. Yeah.

Speaker #11: Yeah, 103. So what we're doing with the healthy volunteers, basically, we are dosing just the antibody component of the escape technology. This is the anti-CD117 antibody.

John Evans: Yeah, BEAM-103. Yeah.

Giuseppe Ciaramella: Yeah, 103. What we're doing with the healthy volunteers, basically, we are dosing just the antibody component of the ESCAPE technology. This is the anti-CD117 antibody. What we're doing there is, in addition to obviously, confirm the safety of that antibody, we're also developing a PK/PD model that would guide us the dosing in the context of the sickle cell patients that we plan to test in subsequent studies. We do not have any editing in that particular healthy volunteer study.

Speaker #11: 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.

Speaker #11: We do not have any editing in that particular healthy volunteer study. And the other thing to confirm is that by having the additional edit that essentially protects the edit itself from the binding of that antibody, it gives us the opportunity for edit itself to basically survive over the unedited cells, even in the context of an in vivo delivered technology.

Giuseppe Ciaramella: 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.

Speaker #8: And the efficiencies compared to the in vivo program?

[Analyst] (H.C. Wainwright): The efficiencies compared to the in vivo program?

Patrick R. Trucchio: The efficiencies compared to the in vivo program?

Speaker #11: The efficiency, do you mean, of editing in combination with the two?

Giuseppe Ciaramella: The efficiency to mean of editing.

Speaker #8: Editing.

Speaker #11: Yeah. It's very high. So it's comparable.

[Analyst] (H.C. Wainwright): Editing.

Patrick R. Trucchio: Editing.

Giuseppe Ciaramella: of the two? Yeah, it's very high. It's comparable.

Speaker #8: Great. Thank you so much, and congratulations.

[Analyst] (H.C. Wainwright): Great. Thank you so much, and congratulations.

Patrick R. Trucchio: Great. Thank you so much, and congratulations.

Speaker #11: Thank you.

Giuseppe Ciaramella: Thank you.

Speaker #10: 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.

Operator: 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.

Speaker #8: Thank you all. It's obviously a lot of exciting updates. We continue to be really pleased with our momentum here across the board and very excited about what's ahead.

John Evans: Thank you all. It's obviously, you know, a lot, 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 wanna 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. Look forward to continuing the partnership. Thank you all for your time.

Speaker #8: 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.

Speaker #8: 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.

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

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