CRISPR Therapeutics AG (VRTX) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by, and welcome to the CTX001 Investor Event, sponsored by Vertex and CRISPR Therapeutics. [Operator Instructions] Please be advised that today's conference maybe recorded. I would now like to hand the conference over to your speaker today, Mr. Michael Partridge, Senior Vice President of Investor Relations. Please go ahead, sir.

Good morning. This is Michael Partridge of Vertex. Susan Kim, Vice President of Investor Relations for CRISPR Therapeutics, and I are pleased to introduce today's call which will focus on the groundbreaking clinical data for our investigational gene-editing treatment, CTX001, in the treatment of sickle cell disease and beta thalassemia. Providing prepared remarks on the call today are Dr. Reshma Kewalramani, Vertex's CEO and President; Dr. Haydar Frangoul, Medical Director of Pediatric Hematology and Oncology at Sarah Cannon Research Institute; and Dr. Sam Kulkarni, Chief Executive Officer of CRISPR Therapeutics. Dr. David Altshuler, Vertex's Executive Vice President of Global Research and Chief Scientific Officer, will join us for a Q&A session following their prepared remarks. We recommend that you access the webcast slides as you listen to this call. This call is being recorded. A replay will be available on both the Vertex and CRISPR Therapeutics websites. We will make forward-looking statements on this call that are subject to the risks and uncertainties discussed in our filings and CRISPR's filings with the Securities and Exchange Commission. These statements, including, without limitation, those regarding expectations for the therapeutic value, development and commercial potential of CRISPR-Cas9 gene-editing technologies and therapies, including CTX001, and the anticipated benefits of the collaboration between Vertex and CRISPR are based on management's current assumptions. Actual outcomes and events could differ materially. I will now turn the call over to Dr. Reshma Kewalramani.

Thanks, Michael. In October of this year, 2 pioneering scientists awoke to the news that the gene-editing discovery they published in 2012 had won the world's most distinguished scientific recognition, the Nobel Prize in chemistry. CRISPR-Cas9 gene-editing technology is widely heralded as one of the greatest scientific and medical advances of our time, with the potential to realize the ambition that inherited genetic diseases can be cured with a onetime gene-editing treatment. And today, based on the clinical data for CTX001, the potential to cure inherited diseases with the precise gene-editing therapy is one step closer to becoming a reality. I am pleased to be here with our partner, CRISPR Therapeutics, and with Dr. Frangoul to review with you these data and our recent progress and upcoming milestones to bring CTX001 to people with beta thalassemia and sickle cell disease. The CTX001 clinical data presented as part of the ASH plenary session this past weekend and published simultaneously in the New England Journal of Medicine, represent a medical breakthrough and underscore the transformative potential that gene editing holds in the future treatment of many serious diseases. Perhaps most importantly, these data show that CTX001 has the potential to be a onetime functional cure for people living with sickle cell disease and beta thalassemia in the near term. As a result, we are advancing through clinical development with urgency and with the goal of bringing CTX001 to patients as soon as is possible. Dr. Frangoul will review with you in detail these important data in just a moment, but I'd like to provide my perspective on the various reasons why we believe these data are important for patients, but also for Vertex and CRISPR Therapeutics. First, all 7 patients with beta thalassemia treated with CTX001 remain transfusion independent. And similarly, all 3 patients with sickle cell disease remain free of vaso-occlusive or VOC pain crises. Frequent transfusions or pain crises are highly disruptive and debilitating for patients with these diseases. And the elimination of such events underscores both the medical importance of these data and the potential for CTX001 to significantly improve patients' lives. Second, the clinical response to CTX001 has been both durable and highly consistent across these patients. We see a rapid and substantial increase in total hemoglobin and hemoglobin F. And these increases have been sustained over time, ranging from 3 months to well over a year for some patients. Specifically, a precise and permanent change to the DNA made through gene editing is expected to be durable over time as these cells following successful autologous bone marrow transplant and the clinical data generated to date for CTX001 strongly support this view. We will continue to follow these and additional patients to generate a complete picture of the overall safety and efficacy profile for the program. And finally, this program has been gaining momentum over the recent months in enrolling and dosing patients. A total of 20 patients have been dosed across the 2 studies, including 13 patients with beta thalassemia and 7 with sickle cell disease. A key milestone that enabled increased momentum in enrollment and dosing was the progression of this program to concurrent enrollment and dosing in both studies earlier this year. We also amended the studies to include younger patients and for beta thalassemia to enroll patients with severe beta 0, beta 0 genotype. I would also like to note that we've received multiple important regulatory designations in this program. In the U.S., this includes Regenerative Medicine Advanced Therapy, or RMAT, Fast Track, orphan drug and rare pediatric disease designations. And in Europe, we've received orphan drug designations in both diseases as well as priority medicines designation for sickle cell disease. Collectively, these designations indicate an appreciation of the high unmet need in beta thalassemia and sickle cell disease and the promise of CTX001. These designations also provide us with increased regulatory interaction and input around key areas of interest for this program. While it is too early to outline in detail all the specific regulatory requirements for potential approval of CTX001, we anticipate the key factors that regulators will want to evaluate include: the size and duration of the safety database, the primary efficacy endpoint and the CMC requirements for commercial manufacturing. Concerning commercial manufacturing, we recognize that the processing controls required for the manufacture of CTX001 in clinical development and in commercial are of critical importance. Together with our partner, CRISPR, our focus from the start of this program has been to build and scale a rigorous manufacturing process while reducing CMC complexities that could disrupt our progress towards commercialization of CTX001. With that in mind, our manufacturing materials and processes are designed to remain consistent as we advance from development through commercialization. And our expectation is that all of the data generated from our ongoing studies and the manufacturing process used in clinical development will be used to support our marketing approval applications, including our BLA in the U.S. In summary, we are very pleased with the investment of CTX001 development program and look forward to updating you with more details on our regulatory plans as the program progresses in the coming months. I will conclude with just a few words on what CTX001 represents for Vertex and our continued growth beyond CF. Vertex is a portfolio of first-in-class programs in the clinic across 5 different disease areas. The most advanced of these pipeline programs is CTX001, where together with CRISPR Therapeutics, we've now established proof-of-concept in both beta thalassemia and sickle cell disease. To support development and commercialization of CTX001 and other nucleic acid-based therapies, we are building industry-leading capabilities and expertise across cell and genetic therapies with our Vertex Cell and Genetic Therapies site. Over the past 2 years, we have significantly increased our investments in these areas by acquiring or collaborating with many different companies, CRISPR, Moderna, Semma and others fully aligned with our internal R&D strategy. Our investments in cell and genetic therapies are broad and significant. And we believe the data for CTX001 are the first of many important updates to come from these efforts. Over the coming year, that will further define the future of Vertex's pipeline across multiple serious diseases. With that, I will hand the call over to Dr. Haydar Frangoul, who will review the CTX001 data as presented at ASH over the weekend. Dr. Frangoul?

Thank you so much for having the opportunity to present the data. I'm going to go over the very exciting data we presented at ASH last Sunday in the plenary session on both CLIMB 111 and CLIMB 121. They are both a Phase I/II, international, multicenter open-label trials. The CLIMB 111, it's currently accruing patients ages 12 to 35 with transfusion-dependent beta thalassemia, including beta 0/beta 0 genotype. The primary endpoint of the thalassemia trial is the proportion of patients achieving sustained transfusion reduction of 50% for at least 6 months starting 3 months after CTX001 infusion. For the CLIMB 121 study, for sickle cell patients, it's currently accruing patients 12 to 35 years of age with severe sickle cell disease and a history of at least 2 vaso-occlusive crises per year over the previous 2 years. And the primary endpoint for that clinical trial is the proportion of patients with a fetal hemoglobin of equal or greater to 20%, sustained for at least 3 months starting 6 months after CTX001 infusion. Here, I'm going to present data on the first 10 patients infused with CTX001. The principle here is there is naturally occurring genetic polymorphism in BCL11A, which is associated with elevation in fetal hemoglobin and decreased severity in both patients with transfusion-dependent thalassemia as well as sickle cell disease. BCL11A suppresses the expression of fetal hemoglobin. In preclinical data editing of BCL11A resulted a reactivation of the gamma globin and expression and formation of fetal hemoglobin, and this CTX001 is produced using in vivo editing of the erythroid-enhancer region of BCL11A in CD34 hematopoietic cells and reduces erythroid-specific expression of BCL11A. I'm going to start by presenting data on the 7 patients with beta thalassemia that have been infused and have a minimum of 3-month follow-up. The genotype is listed on the slide here, but I just want to point out the 2 patients with the IVS-110 mutation, which is severe mutation in the beta-globin gene and the 1 patient with beta 0/beta 0, which also a very severe phenotype of the disease. 5 female subjects were dosed and 2 male subjects. The median age was 23 years. And the patients received multiple transfusions per year prior to enrollment. You can see on the slide. The median per year number of packed red blood cells received is 33, ranging from 24 to 61 units per year. All patients collected peripheral blood stem cells in 1 mobilization cycle, and the median cell product infused was 11.6 million CD34 per kilogram, ranging from 4.5 to 16.6. All patients achieved both neutrophil and platelet engraftment at 32 and 37 days, respectively. All adverse events we observed on this clinical trial were generally consistent with myeloablation and autologous stem cell transplants. The majority of AEs occurred within the first 60 days after infusing CTX001. 2 patients experienced combined total 5 serious adverse events related to or possibly related to busulfan, including venoocclusive disease of the liver in 2 patients, febrile neutropenia, there were 2 events in 1 patient and colitis, all of which has resolved. One patient experienced serious adverse events related or possibly related to CTX001, includes headache, hemophagocytic lymphohistiocytosis, acute respiratory distress syndrome, and idiopathic pneumonia syndrome. All SAEs occurred in the context of HLH in that patient and resolved. No CTX001-related serious adverse events were reported in the other 6 patients. Now I would like to present the clinical outcome data for the 7 patients. As you can see from this slide, there was early and sustained increase in total hemoglobin and fetal hemoglobin in all patients. This is individual patient data. And again, I want to point out patient #1 and patient #6, both of which have the severe beta-globin mutation, IVS-110, and both patients at last follow-up had normal hemoglobin. I also want to point out the exciting results we are seeing in the beta 0/beta 0 patient we enrolled. And at the 3-month mark, she had a hemoglobin of 9.7. And because I treated her at my center, I can tell you that when I saw her at the 4-month mark, her hemoglobin was 11.5, and she continues to be transfusion-independent. This slide talk about the duration of transfusion independence. So the elevation in the fetal hemoglobin we observed in our patients actually translated into transfusion independence in all patients. This slide shows the number of transfusions patients received on the left side, the number of transfusions, patients received in the year prior to infusion of CTX001. And on the right hand is the follow-up for all patients. And as you can see, with the follow-up of 1.8 to 20.5 months, all patients remain transfusion independent. Now I want to switch gears and talk about the 3 patients with sickle cell disease that have been infused, and we are reporting on with a 3-month follow-up. They were 2 female subjects and 1 male subject. The median age was 22. And the number of vaso-occlusive crises per year averaged around 7 vaso-occlusive crises per year in the last 2 years prior to enrollment. 2 patients require 2 mobilization cycles to achieve the target cell dose and 1 patient collected in 1 mobilization cycle. The drug product cell dose infused was in range from 3.1 million to 3.9 million per kilogram. All patients achieved both neutrophil and platelet engraftment at 22 and 30 days, respectively. Next slide talks about the adverse events. Again, all adverse events were generally consistent with myeloablation and autologous stem cell transplant. Majority of AEs occurred within the first 60 days after CTX001 infusion. One patient experienced serious adverse events related to plerixafor, including chest pain, neck pain, headache, and abdominal pain, all of which resolved. Post-CTX001 infusion, 1 patient experienced serious adverse events, including sepsis related to busulfan, cholelithiasis and abdominal pain, both are related to any study drug. None of the serious adverse events in the patients were related to CTX001. The next slide, we present the clinical outcome data for the 3 patients. As you can see, there was clinically meaningful elevation in fetal hemoglobin and total hemoglobin that was achieved early and sustained over time. As you can see, patient #1 at last follow-up at 15 months had a hemoglobin of 12 with 43% fetal hemoglobin. Patient 2 at the 6-month mark had a hemoglobin of 11.5 with 48% fetal hemoglobin, just noting that the patient baseline hemoglobin was 6. And the third patient at 3-month follow-up had a hemoglobin of 13.2 with 31% fetal hemoglobin. So as you can see from this slide that the fetal hemoglobin range from 31% to 48% in our dose patients. The elevation of fetal hemoglobin we observed in all 3 patients and the elevation in total hemoglobin was also associated with clinical benefit in all patients. This slide shows the number of vaso-occlusive crises each patient's experienced in the year prior to enrollment prior to dosing of CTX001. For patient one, she had 7 vaso-occlusive crises the year before. And as you can see, with a follow-up of 16.6 months, she has not experienced any serious adverse events or vaso-occlusive crises during that time. None of these 3 patients with a follow-up of 3.8 to 16.6 months experienced any vaso-occlusive crises related to sickle cell disease, which is amazing. All patients had undetectable haptoglobin indicating hemolysis of the red blood cells, and I'm happy to report that all patients now have detectable haptoglobin after infusion and improved LDH, indicating stabilization of the red blood cells and decrease or no evidence of hemolysis in the patients. In conclusion, the 10 patients treated with CTX001 have been followed for 3.8 to 21.5 months and have stopped transfusions in the case of beta-thalassemia patients, and none of the patients with sickle cell disease experienced any vaso-occlusive crises. Overall safety profile is generally consistent with myeloablation conditioning and autologous bone marrow transplantation. Clinically meaningful hemoglobin F and total hemoglobin levels are observed early and maintained across all 10 patients. Clinical proof-of-concept for CTX001 has now been demonstrated for both beta-thalassemia and sickle cell disease. And these data demonstrate that CTX001 is a potential functional cure for treatment of beta thalassemia and sickle cell disease. Thank you.

Thank you, Dr. Frangoul. Less than a decade ago, our scientific founder, Dr. Emmanuelle Charpentier, made her Nobel Prize-winning discovery of CRISPR-Cas9 editing. It was immediately recognized as a revolutionary technology, and there was speculation that it would someday benefit human health. Today, we see more evidence that this promise is becoming a reality. The updated data we shared at ASH are a powerful proof-of-concept for CTX001, which we believe will advance us toward a new class of CRISPR-Cas9-based medicines to treat serious diseases. Beyond CTX001, we, at CRISPR Therapeutics, have built a broad portfolio across 3 additional focus areas: immuno-oncology, regenerative medicine and in vivo therapeutics. Earlier this fall, we released our first data on CTX110, an allogeneic CAR-T therapy for CD19-positive malignancies, showing early signs of efficacy on par with autologous CAR-T. Our regenerative medicine program in Type 1 diabetes is progressing rapidly towards initiating clinical trials next year, and we continue to progress our efforts using in vivo approaches. Taken together, we are building the preeminent gene-editing company with multiple groundbreaking programs having achieved or nearing clinical proof-of-concept and a robust early-stage pipeline. Our vision is to become a fully integrated company, commercializing multiple transformative medicines for serious diseases. But today, we are thrilled with the new data released on CTX001. We believe this therapy has best-in-class potential due to a number of its unique characteristics. As you know, CTX001 works by reawakening fetal hemoglobin, mimicking naturally occurring elevations of fetal hemoglobin that have been shown to reduce or eliminate the symptoms of beta thalassemia and sickle cell disease. A single precise edit to the genome is all that is required to achieve the remarkable results that we have seen to date with CTX001. We believe that the addressable market for best-in-class, potentially curative therapy such as CTX001 can be very significant in the near term and maybe expanded even further with the benefit of improved conditioning regimens. We also recognize that CTX001 may benefit patient populations who have historically been underserved and have had limited choices in terms of therapeutic interventions. We believe that there is strong support from the health system to address these diseases with CTX001, given that it not only brings value to patients but also to the health system by reducing the burden of chronic health care utilization. And lastly, by combining the joint capabilities of CRISPR and Vertex, we are well positioned to scale up our manufacturing and our commercial infrastructure to meet the needs of patients globally and have a broad and transformative impact on these patient populations. We also believe that it can impact a large number of patients from both sickle cell disease and beta thalassemia with CTX001 in the near term. In the U.S. and EU, there are approximately 150,000 patients with sickle cell disease and approximately 16,000 patients with beta thalassemia. And a significant proportion of these patients have severe forms of their disease that require frequent medical intervention and shortened life expectancy. Even assuming current conditioning regimens, we believe that people with severe disease will be the most likely candidates for CTX001. And we estimate that this population to be approximately 25,000 patients with severe sickle cell disease and approximately 7,000 patients with beta-thalassemia across the U.S. and EU. Patients with sickle cell disease, as you know, are predominantly in the U.S., where the disease is more prevalent, whereas the beta thalassemia, more patients are in Europe. Taken together, this population of over 30,000 patients represents a significant market opportunity for CTX001. These estimates assume current conditioning regimens. But progress is being made towards novel regimens that are gentler than those used today. We and others are working on several different approaches in this area, some of which are already in clinical trials. These new targeted approaches could offer better tolerability, shorter hospital stays and accessibility at a broader network of treating facilities, which could enable all symptomatic beta thalassemia or sickle cell patients to seek a potentially curative therapy such as CTX001. On behalf of everyone on the CRISPR and Vertex teams, I'd like to thank all the patients and caregivers for their courage and support in advancing the CTX001 program. This is an exciting time for CRISPR and for Vertex, but most importantly, for all those living with beta thalassemia or sickle cell disease, who now have renewed hope in the future treatment of their disease. Reshma, Dr. Frangoul, David and I are now happy to answer any of your questions.

[Operator Instructions] Our first question comes from Salveen Richter with Goldman Sachs.

Congratulations on the data. 2 questions for me. Dr. Frangoul, how do you see yourself incorporating the gene-editing therapy in your treatment paradigm? And do you envision using it only in severe patients? Or would you be interested into going to the mild-to-moderate patient population? And then for Vertex and CRISPR, I think you just mentioned some novel approaches here with these programs. Could you just help us understand as you look to optimize the program longer term, what you're doing here, specifically around the preconditioning regimen? And also whether there is a next-generation in vivo editing program on the horizon?

Salveen, this is Reshma. Let me take the second part of your question first, and then I'm going to ask Dr. Frangoul to comment on your very good question around the potential eligible patient population that I think Sam outlined, but I think Dr. Frangoul, with his clinical experience, can certainly fill in a little bit more color. Salveen, our intent here is to commercialize the CTX001 program with the conditioning regimen that we used in clinical development. That is to say with busulfan conditioning. It's a single agent, myeloablative regimen. It's commonly used, well understood. And that is indeed the regimen that's led to these really just remarkable results. We are actively working with CRISPR, we, at Vertex, along with partner companies on gentler regimens. And I'm going to ask David to comment on our collaboration with molecular templates. And after David speaks, I'm going to ask Dr. Frangoul to comment on the patients. David, do you want to just say a couple of words about the gentle regimens with molecular templates as an example?

Yes. Thank you, Reshma. As mentioned, both Vertex and CRISPR as well as others in the field are working to find gentler conditioning regimens. We established a collaboration with molecular templates in November of 2019 to discover and develop novel targeted conditioning regimens. That's a program in the discovery phase, and we look forward to updating you as it moves closer to the clinic. We also have internal activities to work towards gentler approaches to delivering this to patients, and we look forward to telling about you those in the future.

Dr. Frangoul, could you make a comment about what you see as the eligible population based on your clinical experience?

Well, thank you for the question. I just want to mention that there are hundreds, if not thousands of patients that can benefit from curative or potentially functionally curative therapies for sickle cell disease. And as you know, more than 80% of those patients lack a potential allogeneic donor in the family, basically a fully matched donor. So I anticipate as the efficacy and safety data is followed over time for CTX001 that it might provide help to a lot of patients with sickle cell disease that are suffering from their illness and do not have a good option for treatment. So I see this that can expand the use of autologous cells to treat patients with sickle cell disease.

Just to round it up before we get to the next question, Salveen, I think you know this, but I'll just say it for others on the line. The big impediment to bone marrow transplant for sickle cell or beta thal are really 2 big things. One is Dr. Frangoul outlined the lack of a suitable donor. There are only 20% of patients who can find a related match donor. That's one important point. But the second important point, even if you can find a donor, there is a very important graft versus host disease that can develop. And that is really quite limiting. Both of those are obviously overcome by autologous CTX001 BMT.

Our next question comes from Geoff Meacham with Bank of America.

And also congrats on the data. Just have a couple of quick ones. Reshma, I know you mentioned the regulatory path, and this is probably the most common investor question that we get on 001. Is there an efficacy threshold that you've discussed with the FDA that would allow for a filing on a smaller number of patients? Or is the size of the database not as important as the treatment effect? And then the second question is, when you look at the patients with the longest follow-up, are there lessons to be learned as to how durable the benefit could be? And what is your expectation? How does this inform your ultimate pricing decisions down the road?

Yes. Geoff, thanks so much for the congratulatory words. We are really excited about these data. With regard to the regulatory pathway, as I said in my prepared remarks, we have started our conversations with the regulators, but we have not concluded them. We have every designation you could imagine with both the U.S. regulators and the Europeans. And so we have opportunity to have productive and frequent conversations, and we're certainly going to take full advantage of that. You are right to point out that the treatment effect, the benefit risk profile that you see, the safety profile that you see, all influences exactly what the package is that we would be submitting and what the regulators will be accepting and expecting. We just haven't gone through all of those discussions yet. But the data really just are -- I couldn't imagine better data more positive of a benefit risk profile. And so we're going to be working with urgency and with the expectation that we are going to be able to move forward rapidly to bring this to patients. With regard to what did we learn from the first few patients, a few important lessons. As we expected, the impact is significant in both sickle cell and beta thal. The first patients in each program are now out 12 months or greater. And the effect is durable, hemoglobin F levels and total hemoglobin. And we've been really pleased to see the side effect profile. That has just been wonderful to see.

Our next question comes from Gena Wang with Barclays.

Also, I wanted to add my congratulations to the great data. So I have a few questions regarding the data. First, just wondering if you can both beta thal and sickle cell reach almost like 100% F-positive cells. Just wondering what is the definition of a F-positive cells? Any fetal globin threshold to define as F-positive? And the second is regarding the editing efficiency. You've also shown very impressive editing efficiency. Just wondering, was there monolithic editing or are these biolytic editing? And last quick question with regard for Dr. Frangoul. You mentioned the beta thalassemia patient 7 reached -- at the month 4 reached 11.5 total hemoglobin. Just wondering what is the fetal globin level for that patient.

All right, Gena. You have packed in a few different questions in there. Let's parse it out in the following way. I'm going to ask David Altshuler to explain how we measure F cells. And there is obviously a difference between F cell percentages that we talk about and hemoglobin F percent. So I'm going to ask David to tell you about that as well as the editing efficiency. And then certainly, Dr. Frangoul, about the question you have on how our patient is doing. But without stealing thunder from Dr. Frangoul, I'll tell you the patient is doing exceptionally well. David, let's start with you.

Thank you for the question. So there are a couple of questions there. One is about the difference between F cells and the level of hemoglobin and whether or not there's a threshold, and let me say that the 2 measures are F cells are those that you can measure the percentage of cells that express hemoglobin F, and we would like that to be as high as possible, what's called pan cellular because you'd like to have all the cells be corrected in the circulation of patients that have been described, nearly 100% of the cells expressed fetal globin. There's also a measure, which is the percentage of hemoglobin that is the fetal globin, which, in the case of sickle cell, as you can see in the data, is in the range of 30% to 50% and in the patients with TDT nears 100% as expected because in thalassemia, the patients don't make any hemoglobin on their own. And finally, I'd say, and Dr. Frangoul could comment, that the history in the field is that the levels we're seeing in sickle cell are consistent with the levels of hemoglobin seen in people who have hereditary persistence of fetal globin, and that is a safe and successful -- when people have those high levels, those levels of fetal globin, they do very well in natural history. So that -- and then second of all, there are people in the literature who have been described who have up to 100% fetal globin, and they also are healthy and do well. So we believe that the high levels of fetal globin we're seeing are desirable and expected to bring clinical benefit to people. There's no level too high we're aware of. I'll let Dr. Frangoul comment.

Thank you very much for the question. We are very excited about our patient #7 on the trial with beta 0/beta 0. And to answer your question at the 4-month mark, she had 74% fetal and 25% a hemoglobin, reflecting the last transfusion, which happened at the 2-month mark. I'm glad to say that she is doing very well, and she's coming to our center next week for her month 5, and she remains transfusion-independent, which is, in my mind, extremely great results we are seeing in the beta 0/beta 0 patient. Thank you.

Our next question comes from Maury Raycroft with Jefferies.

And much congrats on the updates. So first question is just wondering if you could talk more about the overall product and treatment consistency and how this compares with competitors. And maybe provide some perspective on how doctors and regulators perceive this?

Yes. Thanks so much. I think that the overarching question here is, how do we view the CTX001 results, and can we provide some context when we look at the field in general. And maybe Sam and I will tag team this, and I'll ask Sam to make some comments about the field in general. As I said in my prepared remarks, we couldn't ask for better results. And I mean that not only in terms of efficacy but surely in terms of efficacy, all patients that we presented in the beta-thalassemia cohort are free of transfusions. All patients that we presented in the sickle cell cohort are free of vaso-occlusive crises. These are the key outcomes that you're looking for. This is what determines the health and well-being of the patients. But I'm also really very pleased with the safety profile of the medicine. And I'm really very pleased with the enrollment momentum and the reception that the data has received from physicians. As I said, we haven't had our conversations with the regulators just yet to conclude on exactly what the data package would look like. But whenever you think about filing and the regulatory package, the strength of the data, safety, efficacy and the benefit risk profile are key. And as I said, I just don't think the data could look any better. Sam, do you want to make a few comments about the competitive landscape?

Yes. Thanks, Reshma. And Maury, thanks for the question. I actually look at that word consistency in 2 ways. One, obviously, we're very pleased with the data we're seeing in how consistent the effect is across patients, as Reshma mentioned, and if you look at the pattern of the fetal hemoglobin elevation. The other part, I think that gives us a big competitive advantage is consistency from a manufacturing standpoint as well. Right from the get-go, we've designed our manufacturing process in a way where we can scale up from clinical into commercial in a very consistent fashion. We haven't changed our processes much. While obviously, there are some tweaks we make. Generally, we kept our process consistent, which is going to be an advantage as we move towards registration and ultimately towards commercialization. And as I look at the field, I think it's hard for us to comment on exactly on the competitive data, and that's generally not our practice. But using CRISPR-Cas9, we're making a single precise and permanent edit to the genome is going to be an advantage because the process is more facile, it's simpler, it's easier to scale up, the cells are healthy. And I think compared to other approaches that use lentivirus where there's random integration into the genome, which brings inherent variability in the process, I think we're well positioned to be best-in-class. Obviously, we need to execute on the program. But I think the fundamentals are there with the data we're seeing today and the fact that we have this facile process that sets us up well relative to the field.

Reshma, it's Mike Yee. Can I pop in with a follow-up there?

Mike, it's nice to hear your voice. Of course.

So thanks for the comments on the regulatory part. What can we learn from the regulatory comments that one of the gene therapy companies has obviously publicly commented on? And what can we learn from what they have to do? And when would you be able to come back to the street and tell us what you would have to do?

Yes. Mike, it's a really great question. I anticipate that in the coming months, we're going to be able to come back to you and share what we think the regulatory pathway will look like. In terms of what have we learned, a few things. Great data in areas of high unmet need are something that we are interested in moving forward to patients quickly and something that regulatory agencies around the world are interested in moving forward to patients rapidly. The Ts here are the size and duration of the safety database. We just have to have that discussion. The enrollment and dosing momentum is very important, obviously, because that brings us to the end faster. And one point that Sam touched on, I think, is critically important, which is manufacturing. As Sam said, we've designed our manufacturing from the get-go to be consistent with what we are going to manufacture in the commercial side of this. And I think that's very, very helpful. Lastly, when you look at the field, just open the aperture and look at the field of genetic therapies as a whole, regardless of the disease in question and regardless of the exact nucleic acid therapy being used, what you see is a filing package that measures in the dozens, not in the hundreds and certainly not in the thousands.

Our next question comes from Liisa Bayko with Evercore.

Wanted to offer my congratulations as well, really great data. As we kind of think about the kind of potential size of this opportunity for Vertex and for CRISPR, I wanted to better understand sort of the flow of patients and how -- what is the capacity in the health care system? This is obviously heavy on resources in terms of like number of patients per year that you could really address with CTX001 in terms of the kind of health care resources required. And also, have you done any work on access to therapy in this population? And what does the payer mix look like? Just things to consider as we're trying to understand the size of this really medically meaningful advancement.

Yes. Thank you for that question, Liisa. And I'll start with some remarks, and also see if Reshma has to add anything. I'll start with your second question first on the access. I think as you heard from Dr. Frangoul and Reshma, we have sort of this trifecta here, right? You have a patient population that has -- is severely underserved, and there's a strong unmet need. These are patients that not had a disease-modifying therapy, let alone a potentially lifetime cure. You have a relatively large patient population here, both in the U.S. and Europe. And moreover, I think what you have is a therapy that could ultimately save health systems costs because of all the reduction in the chronic health care burden. You had recent publications even from CMS, showing what the health care burden is from sickle cell disease where patients are going in for a number of hospitalizations and have a number of crises per year. So with that, I think we believe that there will be strong support from the health system from an access standpoint. Obviously, there's a lot of work to do, I think, in the U.S., primarily you're talking about a Medicaid population. And in Europe, obviously, there is different payers based on each country and the payer landscape is different. But I just think that there's going to be strong support, and we started some of that work already as we build towards -- build our commercial capabilities jointly. To your first question on the patient flow, this is a large number of patients that may be eligible for this therapy and may seek this therapy. In the U.S. alone, we said that a large fraction of the 100,000 or so sickle patients, and between the U.S. and Europe, there's 150,000 sickle patients and nearly a 25,000 of them are severe enough that would seek this therapy. And what you have in the health system today is you may ask the question, why are there not more allogeneic transplants? And the reason for that is what Reshma was mentioning before. You don't have mass donors, and you have the risk of graft versus host disease. But otherwise, I think the system will equip itself to be able to do a number of these transplants -- a large number of these transplants. Obviously, we have to support this health system in -- from a company standpoint to make sure there are the resources and necessary and all the training required to be able to deal with a large number of patients. But that's imminently doable, and I think we can scale up our patient experience and our support systems to be able to meet the needs of hundreds of patients, if not thousands.

Sam, I really don't have much data. I think you've covered it really well. I think that clearly, this is a more resource-intensive shift perhaps in where the patients are cared for today to where they may need their care in the future, i.e., in the setting of having to come in-house receive a bone marrow transplant. That is absolutely true. However, what that means is that what we're looking at is potentially a one-and-done functional cure. And that means no frequent ER visits for pain crises or for IV fluids or for transfusions. It means no more visits to the ER for pain medicines, it means no more hospitalizations, and it means people being able to go and live their life. So I agree with Sam very much that changes in the setting of care may be occurring. But I think that in the U.S. and in Western parts of the world that this is going to be something that can be accommodated for the benefits that people receive.

Our next question comes from Paul Matteis with Stifel.

Let me add my congrats on the data. I had one regulatory question and one quick safety question. On the regulatory side, I know you're engaging with the FDA. But can you talk about the work you're doing with release assays and cellular characterization? And what your thinking is on kind of the regulatory hurdle there and what you need to show? And then on the safety side, I don't know, and I'd be curious on Dr. Frangoul's view as well as to whether or not this is relevant. But can you speak a little bit more about what you're seeing with platelets? I saw that you've disclosed some data that's encouraging on engraftment, but the hurdle in that data, if I'm reading this right, is 50,000, which is still in the thrombocytopenia range. So maybe just give any color you can on whether or not this is a concern at all.

Yes. This is Reshma. Maybe I'll just take the second question first. Paul, on all of the data that we see, laboratory as well as patients' visits in follow-up as well as imaging and fundamentally all assessments of patients, we don't see any areas of concern in the data that we have. Everything looks good to date. With regard to the question around regulatory, and I think this is about CMC and exactly how we're thinking about this. I know Sam had some comments that he'd like to make on that front. Sam?

Yes. Thank you, Reshma, and thanks for the question. I think one of the benefits we have here in terms of regulatory interactions is having the RMAT designation and PRIME designations, which have allowed us to have a lot of seamless dialogue with the regulators who have all been very supportive and collaborative. From a CMC standpoint, as I said earlier, one of the advantages we have with the CRISPR platform while it's the most cutting-edge and novel platform, in many ways, it's simpler than some of the older generation platforms. Take, for instance, characterization of the Cas9 protein. This is a simple protein manufacturing, and it's a very consistent process, and we can characterize the starting components. With the assays, obviously, again, we have to make sure that all the assays meet all the requirements, but that's how we've designed it right from the get-go to make sure that we've in the clinical trials, incorporated the assays that ultimately are scalable into commercial realm. So we're confident that we can meet all the needs on thresholds that the regulators set, and that's been a collaborative process with the regulators with frequent discussions, and we'll update you more as we go along in the program.

Our next question comes from Phil Nadeau with Cowen & Company.

Another regulatory question. Just in terms of the following -- appreciating that you haven't completed the discussions with the FDA yet. What do you think will be limiting? Will it be accumulation of a sufficient number of patients with sufficient follow-up? Or is it something like manufacturing scale-up and assay development?

Yes. Yes. That's a great question, Phil. Genuinely, I don't have concerns. I don't see this as a filing where we are in one place and the regulators are in another. This is a high unmet need population. As Sam mentioned, there really aren't any therapies that treat the underlying cause of disease, and there certainly aren't any therapies that cure the disease. And that's kind of what we're looking at here. There is absolutely going to be a need to have the right number of patients and duration of follow-up. That's a very reasonable expectation. There's going to be discussions around exactly what the endpoint needs to be and how long that endpoint needs to be seen for what duration of time and the CMC questions that we've spoken of on this conference. But they are expected, and we're looking forward to going through the regulatory interactions and being able to update you on exactly what our agreements are. We're simply not there yet, but I am looking forward to those interactions, and I'm equally looking forward to updating you.

Our next question comes from Evan Seigerman with Crédit Suisse.

Really congrats on the data. It's really striking and one of the most interesting that I've seen at ASH. So for Dr. Frangoul, looking ahead, you had talked about potentially using different conditioning regimens kind of in -- to make it more applicable or more accessible. I was wondering if you could speak more to that. And how impactful is the current conditioning regimen? And how much -- how better do you need to get the conditioning regimen to maybe expand the kind of the applicability to more than just the most severe patients?

So Evan, thanks for those kind words. This is Reshma. Let me maybe kick it off, and then I'll ask Dr. Frangoul to comment. I want to be sure that we are very clear about the fact that the current regimen, the one that we're using in clinical development is busulfan based. And again, the reason for that is that it's a single agent myeloablative therapy that is well understood and commonly used. It is indeed the conditioning regimen that's led to these remarkable results, and it is the regimen that we intend to file with. The question you ask about how do patients fare with this, Dr. Frangoul has talked to me about this before, and I really appreciate his words about how the patients have tolerated the regimen, the engraftment, and I'm going to turn it over to him for that. But be sure also, Evan, that in a go-forward basis after the initial approval, we're already working, as you heard from Sam and from David, we're already working on gentler regimens, and that is something that we think is important in the longer term to make this therapy really convenient, not only applicable but very convenient for our patients over the long haul. Dr. Frangoul, do you want to speak a little bit about the conditioning regimen, how you've seen the patients do and just round out that question?

Well, thank you for the question. So when we are enrolling patients and explaining to them the preparative regimen with busulfan only, we really have not met significant resistance from the patient to enroll in the study. So that's one point. The second point is when we have given this regimen as a single agent to the patients we have treated, it has been very well tolerated. And the patients have not really developed any significant side effects that gives us red flag that we should not be continuing using this regimen for now until some alternative regimen is tested. So I'm very comfortable with the busulfan single agent for the time being for the patients we are using, and we are seeing great results with it, as you saw.

Operator, this is Michael Partridge. We're coming up on the hour, so we have time for just one more quick question.

Okay. Our last question comes from Matthew Harrison with Morgan Stanley.

I just want to follow-up on CMC [Technical Difficulty].

Matt, unfortunately, your phone is breaking up. I think you have a CMC question. It's very difficult to hear.

This is Reshma. To Matt, I'm sorry, we really just couldn't hear any part of the question, maybe given the time, we'll just take a moment to say thank you for joining us today. Obviously, we're excited about this data. We look forward to updating you in the coming months. And I'll ask Sam to make some closing remarks.

Yes. Thank you, Reshma. We're equally excited here. I think the collaboration between CRISPR and Vertex is going really well. We're operating with a great sense of urgency, given that these patients don't have a therapy, and this could be transformative for these patients, and we look forward to updating you more. But we will certainly look back at this time as a very important time where we disclose proof-of-concept data that's going to change the paradigm of medicine. Thank you, everyone.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect. Everyone, have a great day.