Beam Therapeutics Inc
NASDAQ:BEAM
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Beam Therapeutics Inc
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Good morning, and welcome to the Beam Therapeutics Conference Call. [Operator Instructions] Please be advised that this call is being recorded at Beam's request. I would now like to turn the call over to Holly Manning, Vice President of Investor Relations and External Communications.
Thank you, operator. Good morning, everyone, and welcome to Beam's conference call to review third quarter 2024 business updates, including abstracts accepted for presentation at the American Society of Hematology Annual Meeting. You can access slides for today's call by going to the Investors section of our website, beamtx.com. With me on the call today with prepared remarks are John Evans, our Chief Executive Officer; Dr. Giuseppe Ciaramella, our President; and Dr. Amy Simon, our Chief Medical Officer.
Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995.
Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties and other factors, including those set forth in the Risk Factors section of our most recent annual report on Form 10-K as updated by our quarterly reports on Form 10-Q and any other filings that we may make with the SEC. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. Except as required by law, Beam specifically disclaims any obligation to update or revise any forward-looking statements even if our views change.
With that, I will turn the call over to John.
Thanks, Holly.
Good morning, everyone, and thank you for joining us for this exciting moment for Beam, for our employees and for the patients we aim to serve. At Beam, our vision is to provide lifelong cures for patients suffering from serious diseases. This vision has never felt more tangible than it does today as we report the first clinical data from our portfolio of onetime treatments.
From the beginning of Beam, we saw an opportunity to advance the gene editing field. CRISPR nucleases are able to precisely target a location in the DNA, but they lack the ability to precisely edit genes. With our innovative next-generation technology called base editing, we can now make more precise single-base changes at specific locations in genes, resulting in predictable edits in all cells without needing to damage or make double-stranded breaks in the DNA.
The central hypothesis behind Beam is that this breakthrough could provide a superior way to modify genes and could open up entirely new applications in gene editing for a wide range of severe diseases. Given the incredible breadth of potential applications for base editing, it was critical to sharpen our focus and execution on areas where we can have the greatest impact in the near term. This led to our 2 core franchises in hematology and liver genetic diseases. In both cases, we are advancing highly differentiated and potentially best-in-class lead programs. With BEAM-101 in sickle cell disease and BEAM-302 in alpha-1 antitrypsin deficiency or AATD, each of which have increased probability of technical success based on strong preclinical validation as well as recent advances in the field.
In sickle cell disease, we have a validated regulatory pathway available for BEAM-101, which the BEACON trial is designed to pursue. We also have a next-generation program using our ESCAPE technology designed to expand the addressable patient population by eliminating chemotherapy from transplants. Beginning today and continuing at ASH, we're reporting the first clinical data from our hematology franchise. Initial data from our BEACON Phase I/II trial support the potential for meaningful clinical differentiation of BEAM-101 compared to currently available treatments for sickle cell disease.
We will also be reporting nonhuman primate data for our ESCAPE technology that validate our vision of enabling gene editing and stem cell transplant using only antibody-based conditioning avoiding hemo therapy altogether. In our liver franchise, BEAM-302 also has the potential for rapid proof of concept in the clinic and represents the first program with potential to be a onetime treatment with benefits for both lung and liver manifestations of the disease.
We expect to report the first clinical data from our ongoing Phase I/II trial of BEAM-302 in patients with AATD in 2025, marking another potentially transformative event for the company, our platform and for patients. I'd like to highlight several important updates from our third quarter financial results press release. To date, we have exceeded enrollment expectations in the BEACON trial with 35 sickle cell patients enrolled. Of these, 8 patients have been treated with BEAM-101, with the remainder going through pre-transplant stages, including cell collection and drug product manufacturing.
We are also excited to share that we have nominated development candidates for our ESCAPE technology, which Pino will detail shortly. For in vivo therapies, this summer, we dosed the first patient with BEAM-302 in AATD and have continued to enroll and treat patients while opening new sites globally. As of last month, we have completed dosing in the first cohort of the study. And as I noted, we expect to share initial data for multiple cohorts in 2025. In addition, in June, we received U.S. IND clearance for our second in vivo program, BEAM-301 for the treatment of glycogen storage disease 1a or GSD1a. Since then, our team has been preparing to advance BEAM-301 into the clinic with fight activation underway and patient dosing expected to commence in early 2025.
And importantly, we continue to be in a strong financial position. Turning now to ASH. We are honored to have 4 abstracts accepted for presentation at the meeting in December. These include 2 oral presentations, 1 featuring initial clinical data from the BEACON trial and 1 with our nonhuman primate data for our ESCAPE technology as well as poster presentations showcasing exploratory biomarker data for BEAM-101 and preliminary clinical data for BEAM-201, our quad-edited CAR T cells for T cell malignancies. Abstracts will be available on the ASH website at 9:00 a.m. Eastern Day.
I'll now turn to sickle cell disease. At the JPMorgan conference in January, I asked the question what if we could develop better onetime therapies for people living with sickle cell disease. I'm pleased today to report that, yes, we believe we are on the road to do just that. For sickle cell disease, we are pursuing a long-term stage development strategy that envisions 3 waves of innovation to progressively reach broader subsets of patients over time. Our Wave 1 approach is BEAM-101, a genetically modified, investigational cell therapy administered via hematopoietic stem cell transplantation with busulfan conditioning.
We believe BEAM-101 has the potential to be a best-in-class option for the roughly 10% of sickle cell patients who have severe disease despite receiving standard of care treatments and are considered appropriate for a chemotherapy-based transplant. Though the market for autologous genetic therapies in sickle cell disease is just getting started, it is important to note that allogeneic transplants for patients with severe sickle cell disease are already a reality with several hundred conducted annually in the U.S.
And that number only represents those patients who could find a suitable match donor, which we know represents a small minority of total eligible patients. And finally, we know that autologous transplants are expected to have real advantages over allogeneic transplants, including a lack of graft versus host disease and no need to coordinate the procedure with a donor. Wave 2 takes the same BEAM-101 platform and now incorporates our ESCAPE technology to enable nongenotoxic conditioning.
If successful, ESCAPE would eliminate chemotherapy, which we believe is one of the main hurdles for patients considering a transplant-based therapy and thus meaningfully expand the patient population for ex vivo gene editing by three to fourfold. A little further out is Wave 3, where we are using our leading capabilities in lipid nano articles to explore the potential for in vivo base editing for sickle cell disease, which would eliminate the need for transplantation, thus enabling even broader patient access around the world.
Now let's start by reviewing BEAM-101. Sickle cell disease is a genetic disorder that affects hemoglobin, which delivers oxygen to cells throughout the body. People with this disease make abnormal hemoglobin molecules called hemoglobin S or HbS. This abnormal HbS can form stiff polymers, which distort red blood cells into a sickle or crescent-shape blocking the flow of blood and oxygen throughout the body. Sickle cell disease begins in early childhood and leads to anemia, infections and episodes of severe pain, which can manifest as vaso-occlusive crisis, or VOCs.
Patients also can experience life-threatening complications such as stroke and significant organ damage resulting in decreased life expectancy. While recently approved gene therapies have been shown to significantly reduce VOCs, patients are still generally left with HbS of more than 50%, suggesting there are opportunities for further improvement. Elevating a protective form of hemoglobin called fetal hemoglobin or HbF is a clinically validated strategy to prevent the consequences of sickle cell disease by preventing HbS from polymerizing thereby preventing red blood cell destruction and organ damage.
BEAM-101 was designed to induce a more efficient editing, leading to greater and more uniform induction of HbF, a deeper reduction of [ HbS ] and normalization of hemoglobin and red blood cell function. What would an ideal outcome from genetic correction look like? As shown on Slide 13, total hemoglobin for a person with sickle cell disease has 100% HbS in circulation, which causes sickling and results in decreased red blood cell lifespan, anemia, pain crises and organ damage. The disease threshold is exemplified by people with sickle cell trait, or carriers with only 1 mutation and are typically asymptomatic. These people generally have about 60% normal hemoglobin and only 40% HBS. The recently approved gene therapies for sickle cell disease, though clearly providing significant benefit to patients do not achieve this threshold.
With base editing, we are aiming for a deeper correction of the hemoglobin profile that is at least on par with or even better than that of a typical person with sickle cell trait. HbF also has the additional biochemical benefit of being anti-sickling, which may provide additional protection. In preclinical models, BEAM-101 achieved these goals, potently inducing HBF to more than 60% and proportionately reducing sickle HBS to less than 40% without the need to make double-stranded DNA breaks.
Today, we are reporting the first data from our ongoing clinical trial of BEAM-101 in patients with sickle cell disease that validate our preclinical findings and support our goals for this program. Let me now turn the call over to Amy to review the BEACON trial and the initial clinical data in our ASH abstract.
Thanks, John. Starting with the trial design, BEACON is a single-arm, open-label study evaluating the safety and efficacy of a single dose of BEAM-101 in patients with sickle cell disease and severe VOCs. The trial is enrolling adult patients 18 to 35 years old with sickle cell disease who have experienced 4-or-more severe VOCs in the 2 years prior to screening.
Patients are mobilized using plerixafor after which autologous CD34 positive hematopoietic stem and progenitor cells are collected by leukapheresis and genetically modified with our adenine based editor. Patients then receive myeloablative conditioning with busulfan, followed by a single infusion of BEAM-101, Key endpoints are outlined here on Slide 16.
As John highlighted, to date, we've exceeded enrollment projections with 35 patients having cleared screening and enrolled in the study. The data will review today are as of July 2, 2024 data cut and includes 6 patients in the safety analyses and 4 patients in the efficacy analysis. In our presentation at ASH, we'll share additional data with more patients and longer follow-up. Baseline demographics are shown on Slide 17 and were as follows: 5 of the 6 patients were beta S/beta S genotype and 1 patient with beta s, beta 0 genotype. All were self-reported as Black African-American, 50% were female and ages range from 19 to 27 years.
The BEAM-101 manufacturing process allows for efficient dose production with all 6 patients requiring just 1 or 2 cycles of mobilization to achieve a dose with a mean of 1.5 cycles. As a reminder, minimizing the number of cycles and mobilization is a key goal for both patients and providers to reduce days in hospital and the overall time required to manufacture a dose. Safety data were captured for all 6 patients. BEAM-101 was considered generally well tolerated and demonstrated a safety profile consistent with myeloablative conditioning with busulfan and autologous hematopoietic stem cell transplant.
Of note, 1 patient died due to respiratory failure 4 months after their BEAM-101 infusion, which was determined by the investigator to be likely related to busulfan conditioning. Busulfan is a cytotoxic drug used in a transplant setting and is known to be associated with significant side effects, including lung injury and death. This is a complex case and the unfortunate outcome while rare has been reported previously with stem cell transplant. The event was determined to be unrelated to BEAM-101 by the investigator.
The case is reviewed by both the Data Safety and Monitoring Committee and the FDA. In all patients dosed, there was no grade 3 or higher adverse events or serious adverse events related to BEAM-101. As shown on Slide 19, time to engraftment is for the 4 patients with a follow-up period of 1 month or more. Rapid neutrophil engraftment was observed for all patients after BEAM-101 treatment with a median of 17 days and a range of 15 to 19 days. Platelet engraftment was achieved at a median of 20 days with a range of 11 to 34 days. These data are similar to what is seen in patients undergoing allogeneic stem cell transplantation with unedited stem cells. Neutrophil engraftment is particularly important. And this is one of the key factors that determine the length of hospital stay in patients after undergoing the transplant. Minimizing time to neutrophil engraftment is another important goal of transplant therapy in sickle cell disease because not only can it result in reduced hospital stays, but also to potentially decrease risk of developing opportunistic infections.
On Slide 20, we detailed total hemoglobin for the 4 patients included in the efficacy analysis where patients had 6-, 5-, 2- and 1-month of follow-up, respectively. After treatment with BEAM-101, we observed an early and marked induction of HbF and a significant increase in total hemoglobin. The patient's total hemoglobin increased with a new baseline of 9.3 grams per deciliter to 17.9, 18.2, 11 and 11.8 grams per deciliter at the last time point. No symptoms or interventions were undertaken for the patients with mild elevated total hemoglobin.
Notably, all 4 patients achieved greater than 60% HbF of non-transfused hemoglobin at month 1 and sustained this elevation at the last time point. The percent of HbF in non-transfused blood dropped to less than 40% in all 4 patients, which again was sustained through the last time point as of the data cutoff. Importantly, these data are consistent with our preclinical results and was in individuals with sickle cell trait, whereas John mentioned, patients generally have 60% normal hemoglobin and 40% sickle globin.
In addition, markers of hemolysis, including lactate dehydrogenase, indirect bilirubin, haptoglobin and reticulocyte counts were seen to normalize or improved in all 4 patients. No VOCs were reported by investigators following BEAM-101 treatment. Collectively, these findings represent a deep correction of the hemoglobin profile of the blood after BEAM-101 treatment. In addition to our primary BEACON clinical abstract, we have an additional abstract detailing exploratory biomarker assessment of red blood cell hemoglobin expression, health and function.
As shown on Slide 22, when the first 2 patients included in the analysis, 98% of red blood cells expressed HbF as early as month 1, with near complete elimination of red blood cells expressing solely HbS post treatment with BEAM-101. These HbS only cells are the cells which would be most likely to sickle and cause pain crises and organ damage over time. Bio marker data also show that treatment with BEAM-101 restored red blood cell function across a range of parameters.
As shown on Slide 23, maximum sickling was significantly reduced for the first 2 patients treated with BEAM-101, below the levels associated with sickle trait samples. Other improvements in blood function include increased dense red blood cells, decreased hemolysis and decreased red blood cell adhesion, all of which are associated with disease severity.
In summary, we're encouraged by this emerging BEAM-101 clinical data, which we believe are consistent with our preclinical findings and demonstrate the potential for differentiation from other cell and gene therapies and outlined in the key takeaways on Slide 24. BEAM cell collection and manufacturing process were efficient resulting in just 1 to 2 mobilization cycles. BEAM-101 was generally well tolerated with a safety profile consistent with the known effects of myeloablative conditioning and stem cell transplant.
Neutrophil engraftment is rapid with all patients engrafting in under 20 days, both engraftment timing and cell collection efficiency contribute to shorter hospital stays and a faster path for treatment for patients. BEAM-101 effectively induced HbF to greater than 60% with HbS meaningfully reduced to less than 40%, consistent with the profile of individuals with sickle cell trait. And finally, multiple biomarkers showed the near elimination of HbS only cells and improved red blood cell health and function following BEAM-101 treatment. Taken together, we believe this initial data set demonstrates BEAM-101 has the potential to be best-in-class onetime treatment for people living with sickle cell disease. We look forward to reporting data from a more recent data cut from our BEACON trial in oral presentation at ASH on December 8, which will feature additional patients and longer follow-up.
I'll now pass the call over to Pino to go through our initial ESCAPE data.
Thank you, Amy. Returning to our overall vision to bringing new options to patients with sickle cell disease, ESCAPE forms the foundation of our Wave 2 sickle cell disease strategy, which aims to provide the same transformative efficacy potential seen in Wave 1, but with an alternative to genotoxic conditioning during the transplant process. This approach offers significant upside, including the potential to improve patient safety and overall treatment experience and become a compelling option, not only for severe patients, but also for more moderate disease patients. As a result, we believe that such a product would expand the eligible patient population for gene editing therapies by up to fourfold. So why is conditioning so important?
Conditioning is a critical component of the transplant. It is necessary to make [indiscernible] patient body to receive the ex vivo edited cells that need to engraft in patient's bone marrow in order to be effective. The field of stem cell transplant has generated dramatic outcomes from many hematology patients with upwards of 22,000 transplants now occurring in the U.S. annually. However, all such transplants still rely on chemotherapy, most commonly on busulfan to enable the replacement of the blood cells. Busulfan was first approved in the 1950s. And as Amy mentioned, is associated with both acute and chronic toxicity that include infertility with the potential for increased rates of malignancy and in rare instances can be fatal. Improving upon that option represents the next frontier in hematology and could bring the transformative impact of transplant to many more patients with many more diseases.
ESCAPE technology has potential to finally enable the vision of a non-genotoxic conditioning approach, thus bringing about the paradigm shift in transplant medicine for the first time in nearly 70 years. Our ESCAPE program consists of 2 investigational therapies, which we named BEAM-103 BEAM-104 as part of our development candidate nomination announced today. BEAM-103 is our conditioning antibody designed to bind unedited hematopoietic cells in the marrow and eliminate them. BEAM-104 is a multiplex-based editing cell product that includes 2 edits. The first is the same therapeutic edit as in BEAM-101 to elevate fetal hemoglobin.
The second is an additional edits to introduce a missense mutation in the extracellular domain of CD117, a receptor expressed by hemopoietic stem and progenitor cells that regulates survival, proliferation and differentiation of these cells. The CD117 edit does not alter CD117 biology but only disrupts the binding of BEAM-103 to the receptor. This allows edit itself to escape the antibody with the goal of enabling engraftment and growth of edited cells and clearance of disease cells. In data shown on the right, you can see that in the presence of a mixed population of [ unedited ] and edited cells, increasing levels of the antibody caused the cell population to shift to become completely edit itself. We have evaluated this system extensively in mice, but to establish proof of concept, we wanted to conduct a comprehensive study in nonhuman primates. We are collaborating with multiple leading experts in the field, and this initial study was conducted by John Tisdale of the NIH, a preeminent leader in autologous transplant in nonhuman primate models of transplant.
The data to be presented by Dr. Tisdale at ASH seek to answer 2 key fundamental questions. Can engraftment of hematopoietic stem cells be achieved without chemotherapy and can a therapeutic level of fetal hemoglobin being achieved.
As detailed on the right side of Slide 30, the monkey autologous transplant process being conducted here is comparable to an ex-vivo gene editing product in humans with the caveat that by necessity various steps of the process have not been optimized to the same degree that we have done for humans. We mobilized CD34 cells from 2 rhesus macaque monkeys nd edited them ex vivo, incorporating both the HbF edit and CD117 ESCAPE edit. The animals were conditioned with BEAM-101 CD117 antibody and then infused with BEAM-104 edited cell product.
Subsequently, these animals received monthly antibody treatments after transplantation to maximize the competitive advantage of edited cells and continued suppression of unedited cells. The BEAM-103 antibody was well tolerated at both doses and no supportive care was necessary for the antibody conditioned animals. Importantly, they did not go through a period of myeloablation as is [ fairly ] seen in chemotherapy conditioning. Remarkably, we observed a significant induction of HbF at early time points post transplant. [indiscernible] levels rose to 61% in periphery as early 8 weeks post transplant in one of the animals and stabilized at approximately 85% at Week 35 for both animals.
Early induction of HbF was also observed with levels surpassing 50% in both animals. These unprecedented results established preclinical proof of concept for conditioning with a CD117 antibody and no chemotherapy, leading to robust long-term engraftment and high levels of HbF expression for ex vivo edited CD34 cells. If replicated in humans, these results will achieve our Wave 2 vision of nongenotoxic conditioning for gene editing in hematology. Intriguingly, the lack of myeloablation also suggests the possibility that the transplant [indiscernible] ESCAPE edited CD34 cells could eventually become an outpatient procedure, further enhancing the access and scalability of these products for patients.
On the back of this strong preclinical results, we are now accelerating the development of our ESCAPE technology towards the clinic. We are currently conducting additional NHP studies to explore antibody dosing regimens, dose response [ antagonism ], and we're on track to initiate Phase I enabling studies by the end of the year. Once complete, we plan to conduct a Phase I healthy volunteer study of the BEAM-103 antibody before moving into studies of both BEAM-103 and BEAM-104 in sickle cell disease and beta thalassemia patients.
As we now look forward to the development of this promising technology, I want to highlight the strong synergies between BEAM-101 and ESCAPE. With an identical edit and underlying base editing technology, today's BEAM-101 clinical data are also [indiscernible] for ESCAPE. And each investment and advancement we make to manufacturing, clinical, regulatory and commercial preparedness for BEAM-101 has direct applicability to accelerating and derisking the future success of ESCAPE.
The 2 programs, therefore, form a single integrated franchises, which we believe can deliver successful improvements to patients with sickle cell disease. I'll now turn the call back over to John to wrap up.
Thanks, Dino. As you can see, we are very encouraged by these emerging data sets. First, for BEAM-101 in patients with sickle cell disease, we are so far achieving a potentially differentiated clinical profile using base editing, consistent with our preclinical data and comparable to sickle cell trait while also potentially requiring fewer days in the hospital for both mobilization and engraftment. Second, with ESCAPE achieving robust preclinical proof of concept and now moving rapidly towards the clinic, we are opening up the potential for nongenotoxic conditioning in transplant, which would expand the initial BEAM-101 market to reach a broader group of patients with a less myeloablative profile that even has the potential to become an outpatient procedure for conditioning and transplant.
And finally, these data sets support that base editing does appear to have significant advantages in predictability, efficiency and lack of double-strand breaks with strong translation from preclinical to clinical data, minimal impact on cell viability and promising efficacy outcomes. Before I close, I'll provide a brief review of the clinical data on BEAM-201, which will be in a poster at ASH. Initial clinical data for BEAM-201, which is the first quadraplex edited allogeneic CAR-T cell therapy candidate in clinical development, establishes clinical proof of concept for a high level of multiplex base editing. The safety profile of BEAM-201 was consistent with these patients' advanced underlying disease as well as with lymphodepletion and CAR-T therapy.
We also observed early evidence of clinical efficacy with 2 of 3 patients treated with BEAM-201, achieving a complete response, allowing them to pursue transplant, which is potentially curative. While not a priority program given our decision to focus on hematology and liver genetic diseases, we continue to seek a path forward for BEAM-201 with a partner and look forward to supporting its future advancement as well as other potential applications of multiplex space editing in cell therapy. Wrapping up, as you've heard, 2024 has been an incredibly fruitful time as BEAM with broad-based execution and validating data across our portfolio of base editing programs. We have a number of meaningful catalysts on the horizon, starting with updated data at ASH in December.
Again, I'd like to thank the Beam team for their continued hard work and dedication to our shared vision, the patients and physicians who participated in our clinical trials and to each of you for your continued support of Beam. With that, operator, please open the line for Q&A.
[Operator Instructions] Our first question comes from Gena Wang with Barclays.
Really impressive update. I have so many questions since I can only ask 1 question. Maybe I'll ask less exciting question. That's the safety. One patient death, just a little bit puzzling why after 4 months and that patient died and then why that will could be due to the busulfan. If you can give a little bit more color there.
Sure. Maybe I'll start and then I'll have Amy Andy a little color on the time course and what we know about busulfan. So thanks, Gena. So it's a very sad outcome, of course. I think what it shows maybe at a high level, is the very real risk of transplant and chemotherapy. We're using busulfan in this case, we use the same protocol and dosing regimen of busulfan as others do in the field, obviously, informed by world experts on our trial. But we know that chemotherapy and transplant do have significant toxicity and in rare cases can have mortality, something that the field continues to optimize, but it's a real choice that patients have to think about.
At the same time, I'd like to say that I think this also underscores the severity of severe sickle cell disease. We've seen sickle cell survival rates improve to about 50 years on median here in the U.S. But that's median. The most severe 10% are much sicker than that. And so the severity of the disease really is what makes that transplant potentially compelling option despite the risks. So importantly, as Amy will outline, the case is consistent with our prior experience with busulfan and with transplant. So we don't see any change in the risk benefit profile of our agent or of the field based on this.
Our goal with BEAM-101 is ultimately to give a better option to patients and transplanters who are seeking transplant. That begins with a shift from allo to auto, which is happening now. And of course, with the data we're showing today, we believe that BEAM-101 is a potentially best-in-class profile out of the autologous therapies. So maybe with that preamble, I'll Amy to say just a little bit about what we know about busulfan and the time course of this kind of toxicity.
Sure. So it turned out busulfan is as John mentioned, a chemotherapeutic and cytotoxic agent, and it is known to be associated with dose-dependent pulmonary toxicity, so as you go up in higher doses, more toxicity and in some cases, can actually be fatal. In general, myeloablative conditioning with agents such as busulfan can cause something that we refer to as the idiopathic pneumonia syndrome. This can occur in up to 6% of patients who have autologous transplant. And this idiopathic pneumonia symptom really represents a spectrum of pulmonary diseases, including lung injury, respiratory failure that tend to start around day 20 or 30 post-transplant and kind of manifest through about day 100. The rates, as I mentioned, are up to 6%. And these can often wind up with multi kind of [indiscernible] a long respiratory failure and in some cases, as I mentioned, be fatal. I think that the team at the site did an extensive workup.
And usually, what you'll do is rule out other potential contributing causes, which they did such as infection or other types of etiologies for pulmonary dysfunction. And in the end, the timing of this dysfunction as well as the extensive clinical workup really point to the fact that this is consistent with what has been seen previously in busulfan, both in what is reported in the label as well as the literature about stem cell transplantation complications with busulfan and other literature. Notably, the patient's blood was corrected and normalizing in line with what was seen in other patients.
So while it's an unfortunate case, it is a known complication that myeloablative conditioning can have really kind of profound effects even though it is required for a successful transplantation. And I think investigators take this into account when thinking about selecting patients who are appropriate from a risk benefit profile as well as talking with their patients so that it's clear that the patients understand the risk benefit and that they're signing up for something that they understand what they're getting into.
Our next question comes from Yanan Zhu.
Great. Thanks for taking our questions and congrats on the data. Again, a very impressive HbF induction. I was wondering how would the higher HBF induction translate into additional clinical benefit compared with approved products and also other upcoming products in the pipeline? If you can shed some light? Because I guess, VOC has been pretty strong for the approved product. So wondering where could we see additional clinical benefit?
Sure. I'd like Pino to cover this one.
Yes. Yanan, thank you very much for the question. As you can see, really, we do believe that this higher hemoglobin F is also associated with the concomitant decline of hemoglobin S to levels less than 40%. That 60 to 40 ratio is really the ratio that you typically see in sickle trait individuals who obviously do not have symptoms unless in very sort of severe conditions. So we do feel that, that combination of 60 to 40 can be like a sickle trait and potentially even better since hemoglobin F is antisickling as opposed to hemoglobin A. So that should lead to a variety of deeper resolution. We share some biomarkers they show that blood function is normalized to the extent that we can measure it.
We also show that we have almost completely eliminated cells that express hemoglobin S on its own. These are really the cells that potentially can go sickling under some severe conditions. And so even though it is great to see a strong resolution of VOCs in the launched products so far, I think we have also potentially the opportunity to improve even upon that. And so the overall combination of the parameters that we have really for the first time reproduce the sickle trait that others have not yet done.
Our next question comes from Dae Gon Ha with Stifel.
I'll add my congrats on the initial data as well. Look forward to 302 update next year. Circling back on the efficacy side, a question for either John or Amy. Patients 3 and 4, the female patients. Just wondering if you can comment on the progress you're seeing there specifically on the fetal hemoglobin induction. And when you look at both -- across the board, it seems like Month 2 seems to be sort of the start of a plateau, if you will, on the total hemoglobin. So just wondering how we should think about sort of the longer-term efficacy for these 2 patients and specifically on the patient 4 side?
Yes. Thanks, Ian. So I think it's -- I think there's not much to see between the patients. There's going to be some variability. All of these patients have what I would consider to be a robust early induction of F. In Patients 3 and 4, it's also worth noting they received their last transfusion closer to the month 1 time point, which means you have more transfused blood around. That has to clear before the marrow is going to turn on it's endogenous production quite as strongly. So that's a subtle variable. I think ultimately, we'll just wait for a longer follow-up and we should be able to compare these data sets.
Our next question comes from Eric Joseph with JPMorgan.
Just digging into the first 2 patients, 1 and 2, the total hemoglobin count is fairly high at least months 5 and 6. So I'm just wondering how we -- whether there's any concern about the total hemoglobin counts being sort of where they are, whether you expect those to sort of normalize or come back down with time. Any sort of concern, I guess, with long-term follow-up with persisting hemoglobin around that level?
Yes. Thanks, Eric. Amy?
Yes. 2 patients, as you noted, have experienced mild elevations in hemoglobin. And importantly, there have been no clinical signs or symptoms from those patients or medical interventions required. These are really considered laboratory abnormalities at this point by the investigators and have not even been considered as adverse events. Importantly, as Pino alluded to recently, with the elevated hemoglobin F to S ratio of 60 to 40, we feel that these patients are no longer patients who have sickle cell disease, but in fact, with editing their blood health and function have improved to what would be similar to that of a trait or a healthy person. And those include, as I already mentioned, the hemoglobin F-S ratio, the improvements or normalization in hemolysis, the decreased RBC sickling, RBC density and RBC adhesion.
And for all those reasons, there has been really no concern by the investigators of these mild elevations seen to date. And as you mentioned, we'll continue to follow these. But at this point in time, this reflects really just a lab abnormality.
Got it. Appreciate it. Maybe just 1 quick follow-up, if I could, on the safety front. Any changes to either screening criteria or modifications to the conditioning regimen as a result of the unfortunate death attributed to busulfan?
Yes. Great question. There's been no change to our eligibility criteria. It was determined by the DMC and concur with the FDA that the safety profile of the study had not changed after this event. However, we already had in place what's called therapeutic drug monitoring for busulfan. And that type of therapeutic monitoring is often done when there's a narrow therapeutic window for a drug typically done by all the various studies in gene editing as well as investigators who use busulfan for conditioning. And just to note that the patients busulfan level was within the target range that we were basically trying to obtain to try to ensure both conditioning was appropriately done, but at the same time, trying to guarantee safety.
Our next question comes from Kostas Biliouris with BMO Capital Markets.
Congrats on the progress and the data here. One clarification and 1 question from us, please. I think you already kind of described that, but can you clarify whether you have observed any off-target editing or [indiscernible] edited in the patient who die. I know there is no clinical evidence for that, but this is a question that comes up from investors. And then the second question on commercialization of 101 and scale, how are you thinking about the sequencing of commercializing these 2 products and potential cannibalization of 101 from ESCAPE.
Great. Thanks, Kostas. So I'll let Pino answer the first question, then I'll do the second.
Thanks for the question. Yes, we have not noted any off target biology of concern in any of the studies that we've done Specifically, we do not do off-target biology on every single drug product. But as part of our preclinical package, you do extensive offtarget biology on several donors, including the adjustment in silico of looking at different genomic background, which was the context of the CASGEVY Advisory Board conversation that added. And through none of that activity, there was any off-target biology of concern emerged.
Great. Yes. And then on the market perspective, I think our plan has always been -- we consider this a life cycle strategy across this franchise. So beginning with BEAM-101 then leading to Escape, now BEAM-103 and 104 and ultimately thinking about in vivo as well. So we see this as a progression. I think if ESCAPE fully achieve its profile, which would be the efficacy comparable to 101 or other gene therapies in the field, but without chemotherapy. I would expect that to overtake and replace 101 of the market. But of course, we'll have to see the profiles and consider that at the time.
In terms of the market progression, I think we've talked about this as well, and I had it in my slides, but we continue to believe that the market for these sort of Wave 1 therapies, as we call them, is about 1 in 10 patients, really those patients who are severe enough to consider a transplant. And there, our goal is to give transplanters a better option. It's quite clear that autologous will be preferred over allogeneic. There's already several hundred allogeneic transplants that occur every year in the U.S. for sickle cell patients with severe disease, and that's after including the fact that most of these patients who might seek a transplant can't find a match, okay? So I think that implies a certain market size that we expect will be there. And we believe with today's data, assuming it holds up over time, will show that BEAM-101 is the best-in-class option for patients in this first market. Once we can bring ESCAPE forward, of course, that really changes the game because now you have, of course, eliminated a lot of the risks of transplant and chemotherapy. You've also expanded the addressable patient population. So there are many more patients who might not have been a good fit for transplant before now can come in and as Pino said, we think that leads to an addressable population that's up to 4x larger. So the final point to make in terms of the staging of the programs is the one that Pino highlighted as well, which is the ESCAPE program is almost identical to be 101 plus one single guide RNA to get to the CD117 edit and of course, the antibody.
So from a regulatory preclinical package, the clinical trial sites and design, regulatory strategy and end points and ultimately even commercial infrastructure, all of that is shared between the 2 programs, which will make for a much more efficient development program. And I think ultimately, we'll accelerate what we can do with Escape.
The next question comes from Samantha Semenkow with Citi.
Heard of expanding on the last question, the NHP data that you shared today for ESCAPE, they look pretty encouraging on both engraftment and HBF injection. Given the safety advantage with avoiding chemotherapy, I'm just curious on your thoughts on the potential trade-off for a slightly less efficacious profile on the trade-off for the better safety profile? And then relatedly, for BEAM-103, the CD117 antibody, are there any safety concerns for targeting CD117 that we should be aware of?
Yes. Maybe I'll have Pino answer the second question. I'll just highlight on the first question. I think, of course, if you have safety advantage, but lose some efficacy then there's more of a debate to be had. I think what you see from the data that Pino shared is we're achieving fairly full efficacy with ESCAPE and then we get that safety advantage. So so far, that looks quite compelling. Obviously, as I noted, it will take some time to evolve the full product profile. But maybe I'll hand over to pino to expand on that.
Sorry, could you repeat the second question just for a moment?
Yes, of course. I was just thinking about, as you move BEAM-103 into the Phase I healthy volunteer study next year, are there any safety concerns of targeting 117 that we should be aware of?
Yes. Thanks for repeating the question. So there have been actually several studies already conducted with antibodies against CD117. Actually, Celldex was the latest company to reveal some of the data they use in anti-CD117 for the treatment of urticaria. And basically, what you see in those individuals is that you see a transient but mild neutropenia been the major sort of outcome that you'll see. And so really, these antibodies do not lead to myoblation, as you would see with chemotherapy. And that's why, as John mentioned earlier, it opens the possibility actually that this kind of treatment may even become the future outpatient treatment paradigm because they obviously do not run the risk of opportunistic infections due to neutropenia.
So we think that really the healthy volunteer is a very expeditious and efficient way of quickly getting to a PK/PD understanding of the antibody. And that gives us a more assured essentially dosing regimen for us to go into the sickle cell and beta thalassemia patient without having to have extensive sort of treatment options tested during those trials.
Our next question comes from Sami Corwin with William Blair.
Congrats on the data. Pino, you just mentioned this, and I noticed on the slide that you plan on exploring the ESCAPE technology in beta thalassemia in addition to sickle cell disease. I guess I was curious what kind of prompted that expansion. And then as you're thinking about the clinical trials for the Escape platform, are you thinking about running those in the U.S.? Or would those likely be conducted ex U.S.?
So a couple of things on there. Just -- so in terms of the beta-thalassemia consideration, it's really a fact that we think that ESCAPE essentially alters the risk-benefit profile, and in particular, reduces the risk to the point that even in the beta-thalassemia patients, a transplant might be justified, particularly in the broader beta thalassemia patient, which goes beyond the transfusion-dependent thalassemia patients, which, as you know, is a relatively small number of patients, obviously, very sick. But we think that ESCAPE opens up the opportunity to treat even beyond TDT. And so that's fundamentally the main reason to consider that. And then in terms of the various places where we'll go, the healthy volunteers we have not yet decided exactly whether it's in U.S. or ex U.S. We will just be really efficiency and rapid exploration of that Phase 1 is really what's going to guide us in the choice that we make.
Our next question comes from Luca Issi with RBC Capital.
Maybe, John, big picture, just to me that ESCAPE is becoming increasingly order now, especially in the context of the [indiscernible] today kind of reminding us the risk associated with busulfan. In a scenario where ESCAPE is actually not game changing, are you still committed to commercialize BEAM-101 solo? Or would you be open to partner BEAM-101 or out-license it, similar to what Editas has recently communicated. Any color there is much appreciated.
Thanks, Luca. It's a great question. I think as you noted, we are playing the long game here in hematology, and we see a very exciting progression of technology that takes advantage of base editing not to mention our now significant capabilities in CD34 manufacturing and these sorts of blood therapies to create a lot of impact for patients over time. And it is a progression that begins with 101 as a potentially best-in-class product for this Wave 1 market, leading to escape, which is no question, incredibly exciting and would be a really revolutionary product in the conditioning field, expanding us from sickle cells also include beta thalassemia, et cetera. And as I have noted before, I think a lot of the capabilities we build along the way there now adding the ability to change your blood system potentially without chemotherapy could lead to a lot of other places, right?
So we see a lot of growth opportunity here in hematology over the long term. That's why it's 1 of our core pillars. So I think when it comes to partnering, I think we've always said that we have the luxury here of we don't have to partner for financial reasons. We would only partner strategically. And so the partnership would be considered if a party could help us reach more patients more quickly than we could do ourselves. And then it would be something that we would consider.
To your hypothetical, I think if some of the elements of that pillar were to start to change, if we didn't have the Escape technology, for instance, or it didn't work in some fundamental way. I do think that would change the long-term outlook in hematology. That might change the balance of our strategic thinking. But in the near term, I don't think it would change the value we have with BEAM-101 to potentially help a lot of patients who need help. So I think the calculus would basically be the same. It would be -- these are products that I think can make a big impact for patients and generate sustainable revenue and market value. If there's a party out there who can help us do any of this better without getting in the way of what we need to build, that's a conversation that we'll entertain. Otherwise, we're prepared and well financed to do this ourselves.
Our next question comes from Michael Yee with Jefferies. if
I may, since this is an earnings call as well, right? There are some other pipeline developments. You did announce that you had completed dose in the first cohort in AATD, which I think is a big achievement. Can you just remind us to what extent you believe that there would be material enough information to disclose at what time point given my understanding is the AAT levels should be rising pretty quickly. And certainly, based on today's data, I'm sure you have more confidence in the editing here in vivo. So at what point would there be enough proof of concept for you to disclose and given you've already dosed 3 patients already?
Thank you, Mike. Yes, great to hear from you. So you're absolutely right. We have a lot going on in the portfolio. We're very excited about the progress on the liver side as well, as I noted in the Q results. with alpha 1, obviously, first cohort completed and now moving forward with that dose escalation. And it is true as a reminder to everybody, we're dose escalating beginning at a low dose, but a low dose that is nonetheless expected to have biological activity, that's important ethically. And then we will seek to understand the optimal biological range as we go. So we've guided to a 2025 data release on that program. I feel confident in that guidance. I think when we will narrow that as we can, obviously. I think what we've always said is we would look to bring out data when there is a clear profile of the drug. And I think that -- I think clearly means at least multiple cohorts, exactly how we define that will be TBD. But we'll be watching it closely.
And as you know, this is a program that does have the potential for early clinical proof of concept based on levels of alpha-1 normal M alpha 1 going up. based on Z protein hopefully going down. And then, of course, we'll be looking at safety in a Phase I study. So stay tuned, but that's certainly an update that we'll be looking forward to 2025.
Our next question comes from Rick Bienkowski with Cantor Fitzgerald.
Congrats for the update. I was just Hoping to get a little more color on the expected pace of dosing in BEACON. I believe you said there was 35 patients enrolled in the study and 8 patients dosed to date. So if we can just get a little more detail on where we are with cell collection of the 27 patients who weren't dosed yet and the potential time line for all of these patients to be dosed
Yes. Thanks, Rick. So I think as you rightly noted, that we're quite pleased with the enrollment. It's actually exceeded expectations at this point. 35 patients now fully enrolled. That does not include additional patients who are in screening and consenting. So it's a pretty robust pipeline and moving quite quickly now. as we had hoped. I think when we set up the clinical program that we did and thanks, Amy and her team for driving it. Dosing is now, basically, as you know, it takes a long time to create the dose. At this point, we have doses rolling off the the line fairly regularly. So there is going to be a big uptick in doses in the near future as that trial commences. As a reminder, the overall trial, we're looking for 45 total patients who will be dosed here. So clearly, we're well on our way to that. Also interestingly, we've always designed this trial as a potential to be a registration trial. And our best understanding of that package based on the benchmark set by the Exa-cel program was 30 patients followed for about 15 months to get their endpoint assessed.
And so clearly, in the 35 patients, we've already got those patients moving. So the clock has started at this point as we execute on these doses and look to enable what could be a potential filing package for one-on-one.
Our next question comes from Debjit Chattopadhyay with Guggenheim.
This is [indiscernible] Force on for Debjit. What are your human translational expectations from the NHP ESCAPE data? Do you expect performance or underperformance relative to 101. And does having BEAM-101 clinical data help bolster your confidence in ESCAPE'S clinical performance.
Yes, no? Yes. Thank you very much for the question. We expect, frankly, equivalent, if not better performance in human. And that's driven by the sequence of the guide that we use is in the antibody being cross-reacted actually between nonhuman primates and humans. So we -- obviously, we are refining a little bit the treatment paradigm of the antibody so that we can optimize it even further. But I think this non-human primate data gives us tremendous confidence that we can move forward to the clinical studies.
Our final question comes from Mani Foroohar with Leerink Partners.
A quick follow-up on Mike's question on AATD. As we think about the market opportunity in this indication, this is obviously a fairly heterogeneous population. How should we think about the path forward, both in terms of enrollment and clinical data and then ultimate sort of commercial opportunity between patients with a predominantly lung phenotype and those with a liver phenotype? And how will your enrollment strategy reflect the opportunity set across both.
Yes. Great question, Mani, thank you, and thanks to everybody for your engagement today. So alpha-1, it is a somewhat heterogeneous population. You have, of course, the majority of patients are primarily lung involved, a minority have primary liver involvement. And of course, there's a spectrum of patients who share both. The beauty of BEAM-302 is that it addresses both sides of that equation. So for every allele, we edit, we are going to start secreting normal protein which should benefit the lungs and be under normal regulation, and we're going to decrease the production of this toxic protein that is causing so much trouble to liver. So I think at the end of the day, we don't need to choose. Now on the trial itself, we're initially studying this in patients who are primarily [indiscernible] just to make sure we have a clean profile given this is a liver delivered therapy then we will treat patients who have much more liver involvement.
But our expectation based on preclinical data and our goal would be to deliver a single dose that is usable across the entire population and develop the drug across the entire population. So I think by the time we get to considering market potential, ultimately, all patients are in view here, both currently diagnosed and then continuing to identify additional patients who have that ZZ phenotype and are in really severe need of new therapeutic options.
Can I get in a quick follow-up here. it makes a lot of sense to me that the technology can address the underlying genetic cause of disease and therefore, address the molecular genetics to drive all of thse phenotypes. That makes a lot of sense to me the biologically and clinically. But from a regulatory perspective, the time horizon approval endpoints for these 2 phenotypes aren't necessarily aligned. So if you give us a little bit of color on how you think about how to get approved for treatment for liver mixed lung, et cetera. And what that looks like for regulatory practical perspective?
Yes, understood. And I mean, look, I think our first job here is to deliver a hopefully compelling Phase I data set, right, which shows the kind of fundamental correction of the gene in the body for the first time. So that's step one. And that, of course, that data opens the door to the conversation with the regulators for a lot of the different options here. You're right that formally a lung endpoint may have a certain set of requirements and characteristics that may be different than a liver endpoint. Of course, the RNAi knockdown therapies have been exploring the liver pathway. We can learn from that. And so certainly, for the different kinds of patients, we may explore both. At the same time, across both of them, there's the opportunity to consider the use of just the biomarkers themselves and the protein deficiency, which defines this disease as endpoints and markers of benefit that we would be exploring as well. And that, of course, would be universal across patients. So I definitely, grant your point, I think it's early days. There's a lot to work through. I think our first step is generate a compelling data set. That will then drive the conversation with regulators and investigators on how to develop the drug.
This concludes the question-and-answer session. Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.