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spk01: Good day and thank you for standing by. Welcome to the Sangamo Therapeutics fourth quarter and full year 2021 conference call. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you'll need to press star then one on your telephone keypad. Please be advised, today's conference may be recorded. If you require operator assistance during the call, please press star then zero. I'd now like to hand the conference over to your host today, Erin Feingold, Head of Corporate Communications. Please go ahead.
spk10: Good afternoon, and thank you for joining us today. With me this afternoon on this call are several members of the Sankmo Executive Leadership Team, including Sandy McRae, Chief Executive Officer, Mark McClung, Chief Operating Officer. Pratusha Dharibabu, Chief Financial Officer. Jason Fontenot, Chief Scientific Officer. Rob Schott, Head of Development. And Bettina Cockroft, Chief Medical Officer. Slides from our corporate presentation can be found on our website, sangamo.com, under the Investors and Media Sections Events and Presentations page. This call includes forward-looking statements regarding Sangamo's current expectations. These statements include, but are not limited to, statements relating to the therapeutic and commercial potential of our product candidate, the anticipated plans and timelines of Sangamo and our collaborators for initiating and conducting clinical trials and presenting clinical data, execution of our corporate strategy, advancement of our product candidates, our initial 2022 financial guidance, and other statements that are not historical facts. Actual results may differ materially from what we discussed today. These statements are subject to certain risks and uncertainties that are discussed in our filings with the SEC, specifically our annual report on Form 10-K for the fiscal year ended December 31st The forward-looking statements stated today are made as of this date, and we undertake no duty to update such information except as required by law. On this call, we discuss our non-GAAP operating expenses. Reconciliation of this measure to our GAAP operating expenses can be found in today's press release, which is available on our website. Now, I'd like to turn the call over to our CEO, Sandy McRae.
spk15: Thanks, Erin. And good afternoon to everybody on the call. I'd like to start by saying that 2021 was a significant year for Sangamo as we continue to advance the development of genomic medicines for patients across multiple therapeutic areas using our innovative technologies. We're very pleased with our progress despite the challenges of the second year of the pandemic. We're advancing potentially transformative genomic medicines in the clinic and strategically using our R&D capabilities to pursue indications of unmet need. These efforts are supported by our manufacturing infrastructure, including in-house AAV and cell therapy facilities. Our collaboration partners also help us drive toward our mission to deliver on the promise of genomic medicine. And we believe that this progress positions us as well to generate long-term value for our shareholders. In 2021, we executed upon our strategy with several important achievements. First, we and our partners advanced our three-league programs while presenting compelling clinical data. Starting with our wholly owned Phase 1-2 Fabry disease programme, we presented updated data at the World Symposium earlier this month. We're encouraged by the safety and efficacy data we have seen to date. And most importantly, the patients in the study have reported they are feeling better. Investigators are observing improvement in some of the most challenging symptoms, including ability to sweat in the first three treated patients. With the recent changes in the Fabry competitive landscape, we believe we are in a leading position. In the second half of this year, we plan to present additional updated Phase 1-2 data. We're actively planning for a Phase 3 study, including discussions with health authorities, patient advocacy groups, and investigators. We're also delighted by the emerging Phase 1-2 sickle cell disease data presented at ASH in December, showing no treatment-related adverse events in the four treated patients, improvement across several biomarkers, and most importantly, clinically significant reduction in painful sickling crisis. We anticipate that the next four patients treated in the study will be dosed with a product candidate manufactured using improved methods that have been shown in the internal experiments to increase long-term progenitor cells. We expect to complete dosing of these patients in the third quarter of this year. Transition planning of the program from Sanofi to Sangamo is going well, and we are energized to have this asset back in our hands soon as we assess the best way to move the program forward for patients, be that on our own or with a potential partner. Finally, we're encouraged by the follow-up data presented at ASH last year from our Haemophilia A program partnered with Pfizer. Updated Phase 1-2 results show sustained bleeding control in the highest dose cohort through two years following gene therapy. Regarding the phase three study, Pfizer has announced that it hopes to obtain agreements with the health authorities to resume their final trial in the first half of 2022. The trial was previously paused when some of the patients experienced factor VIII activity greater than 150% following treatment. Pfizer is currently in the process of submitting a protocol amendment to health authorities in the countries where this trial has been conducted and preparing responses to the FDA clinical hold. Over 50% of the patients have been enrolled in the phase three affine trial. Second, we're progressing our preclinical candidates based on our second generation technologies, CAR Tregs for autoimmune disease and zinc finger transcription factors for neurological disorders. We have enrolled and expect to dose soon the first patient in our lead CAR Treg program, where we are evaluating TX200 for the prevention of immune-mediated rejection in HLA-A2 mismatched kidney transplant from a living donor. We believe that this will be the first patient ever to be dosed with a CAR Treg therapy and that we are in a leading position with several companies following us into this very promising area. We believe that our expertise across multiple technology platforms, robust cell therapy infrastructure supported by our manufacturing facilities and genomic engineering capabilities and internal strategic and operational synergies comprise a differentiated CAR T-REG platform from which we can potentially offer patients advanced genomic medicines. In addition to our proof of concept study of TX200, we are progressing our preclinical allogeneic renal transplant rejection study, as well as inflammatory bowel disorder and multiple sclerosis programs, including presenting in the first preclinical data from our allogeneic IL-23R CAR-T reg candidate in IBD last year. And finally, with regard to our zinc finger protein transcription factor technology in treating CNS disorders, In addition to our partner programs with Biogen, Novartis, Takeda, and Pfizer, we're advancing multiple internal programs. Third, we continue to hone our differentiated genome engineering platform, including improving the specificity, precision, and efficiency of our cores and finger proteins. We're also progressing our capabilities from nucleases to repressors, activators, and even base editors, and are excited about our progress. We see Cynomos capabilities as representing a one-stop shop for a range of genomic engineering capabilities that are designed to be applied therapeutically. Fourth, we continue to work diligently with our collaborators, supporting the advancement of our partner programs in the clinic, while driving research efforts for preclinical programs for which we receive reimbursement from our partners. These partnerships have been a key component of our development strategy and continue to drive Maui for Saigon. We believe that the buy-in from Pharma validates our mechanistic approach across a range of advanced modalities and as it enables us to benefit substantially from our partners domain expertise to develop high quality therapeutics for patients. The capital provided by our partnerships helps to advance our internal pipeline of assets. while providing our partner programmes with the resources needed to advance the development of these potentially transformative therapies more quickly. Fifth, we completed and brought online our cell therapy manufacturing facilities in Brisbane and Valbonne, and now have operational AAV and cell therapy facilities in-house. We believe these facilities provide many strategic advantages, including flexibility in control, capacity to support our R&D needs, process expertise, geographic diversification, and that supports supply chain resilience and a deep intellectual property portfolio. Six, we believe that we have a strong financial position to take us through our key upcoming catalysts. Our diverse and accomplished leadership team and our talented employees are passionate about our mission and have enabled our multiple 2021 accomplishments, setting us up for what we expect to be a strong 2022. I am very grateful to my leadership team and all my Samuel colleagues for their dedication and hard work in a second challenging year of the pandemic. And with that, I'd like to turn the call over to our head of development, Rob Schott, who will discuss the data from our clinical programs in more detail.
spk17: Thanks, Andy, and good afternoon to everyone on the call. We are delighted by our clinical execution in 2021. We believe the presentation last year of important proof-of-concept data supports late-stage development for our febre and sickle cell programs. At the World Symposium earlier this month, we presented updated preliminary results from the Phase I-II STAR clinical study evaluating isragalgidine psiloparvovac, or ST920, a wholly-owned gene therapy candidate for the treatment of febre diseases. As of the November 9, 2021 cutoff date, the gene therapy candidate continued to be generally well tolerated across three dose cohorts in the five treated patients with treatment-related adverse events that were assessed as grade 1 or mild. Elevated alpha-galactivity has been maintained for the four patients treated in the first two dose cohorts, ranging from three-fold to 15-fold above mean normal at last measurement. For the two patients on enzyme replacement therapy, alpha-gal activity measured at ERT trough was 15-fold above mean normal at week 52 for the patient in cohort 1 and 10-fold above mean normal at week 25 for the patient in cohort 2. For the two ERT pseudonaive patients, alpha-gal A activity was 3-fold above mean normal at week 52 for the patient in cohort 1 and four-fold above knee normal at week 40 for the patients in cohort two. The two patients in cohort one have now begun the long-term follow-up study, and at the one-year mark, alpha-gal A expression remains robust. Withdrawal from ERT has been completed for one patient and is planned for the second patient on enzyme replacement therapy based on the stability of their alpha-gal A activity following treatment. For the first patient in cohort three, alpha-gal A activity has increased into the mean normal range at week two. As Sandy noted, three of the patients have reported clinical improvement with a greater ability to sweat. This allows for greater exercise tolerance in active individuals. The cardiac magnetic resonance imaging data suggests stabilization of important MRI parameters in two patients. This will be followed at intervals to confirm the cardiac benefits of therapy One patient with a significant elevation in plasma lyso-GB3 pretreatment showed a significant reduction from baseline of approximately 40% in his biomarker after treatment with ST920 within 10 weeks after dosing and maintained through week 36. Patients with lower baseline levels of lyso-GB3 maintained steady levels through the cutoff date. The sixth patient in the study, who is the second patient in cohort three, was recently dosed after the cutoff date. We expect to provide updated results from the STAR study in the second half of 2022 and are currently planning for a Phase III clinical trial. At ASH 2021, we announced updated preliminary proof-of-concept data from the Phase I-II Precision I study of SAR 445136 for the treatment of sickle cell disease. As of the September 22, 2021 cough date, the most recently treated patient in the study has been followed for 26 weeks, and the longest treated patient has been followed for 91 weeks. In all four treated patients, there were increases in total hemoglobin, fetal hemoglobin, and percent F cells. None required blood transfusions post-engraftment. The SAR 445136 investigational drug product had on-target BCL11A gene modification of between 61% to 78% in all four patients. There were no adverse events related to therapy with SAR 445136. One patient had a single sickle cell crisis or vaso-occlusive crisis nine months after treatment. There have been no additional serious adverse events reported. Additional data from this study are expected to be presented at a medical meeting in 2022 and dosing of patients in this study is expected to be completed by the third quarter of 2022. We are currently collaborating with Sanofi on planning for a transfer of its responsibilities under this program back to Sangamal this June. We look forward to keeping you apprised of future updates regarding these exciting clinical studies. With that, I'll turn it over to Patricia for a financial update. Patricia?
spk18: Thank you, Rob, and good afternoon. Our financial results for the fourth quarter and the full year are available in the press release we issued and can also be found on our website. I want to reiterate that 2021 was a significant year for Sangamo with execution on many fronts as we continue to progress the advancement of our lead programs, our pre-clinical research pipeline, and our in-house manufacturing capabilities. With approximately $465 million in cash, cash equivalents, and marketable securities at the end of the year, We believe that our balance sheet remains strong for continued execution across our platform and programs. Turning to our initial 2022 full-year guidance, we expect non-GAAP operating expenses to be between $280 million to $310 million for the year. This range excludes estimated non-cash stock-based compensation expense of approximately $40 million. We expect a significant portion of our operating expenses to be invested in continued progress of our lead programs including February Phase 3 planning activities, Phase 1-2 activities for TX200, and preclinical work in CAR TREG and CNS indications. We also expect to grow our investments in sickle cell in the second half of the year following the transformative program back to Sangamo. I will now turn the call back to Sandy for closing remarks.
spk15: Thank you, Patricia. We are excited by where we stand as a company and believe we have a bright future. We are a fully integrated genomic medicine company building momentum with our novel science, clinical execution, and in-house manufacturing. In 2022, we look forward to providing expected updates on Phase 1-2 Fabry data, selection of a dose for cohort expansion, and Phase 3 planning. Dosing of patients in the CAR-T reg step-fast trial. Phase 1-2 sickle cell data and dosing of patients in the Precision 1 study and the transition of the program from Sanofi to Sangamo. And Pfizer's progress with the pivotal Phase 3 Haemophilia A trial. We will now turn it over to the operator to open the line for questions.
spk01: If you'd like to ask a question at this time, please press the star, then the number one key on your touchtone telephone. To withdraw your question, Press the pound key. Our first question comes from Nicole Germino with Truett Securities.
spk09: Good afternoon, everyone, and thank you for taking my question, and congrats on all the progress. If I could ask a two-part question, the first one is, in the backdrop of other companies experiencing clinical holds with their gene therapy programs, can you address the safety concerns and integration risk around your vector for HEMA and for ST920 for Fabry, and second, for your CAR T-REG platform, how necessary is it for a kill switch for regulatory agencies, or maybe put another way, will give you confidence that you don't need one?
spk15: Thank you for your questions. If I could address the first one and then I'll pass the second one on to Rob. So safety is really important to us, and that's why we is safe for the patients that we serve. Now, the choice of diseases remains important because we always have to balance benefit and risk. And we spend a long time thoughtfully gathering preclinical data, sharing it with the regulators, starting at doses that allow us to be sure that patient safety is maximally protected. And then sharing with the community any concerns we have as the trial progresses. I'm delighted with our progress so far. I think it's unfortunate when others have run into difficulties because it does cloud the whole field. It's the advantage of us having a vector that we've worked with and have gathered a lot of safety data. Bob, can you answer this second one?
spk17: Yes. I'd like some clarification to call on Bob. kill switch, and you're suggesting that we program that into the cell therapy so that we can turn off the Tregs? Is that the animation?
spk09: Yes, that's the question. Yeah, because I think a couple of your competitors have a kill switch. Is it necessary for regulatory agencies to you know, have regulatory agencies had any input on this? And if not, like, is it, do you need a kill switch? Or what gives you confidence that you don't need one?
spk17: Yeah, we've not been asked to engineer in a kill switch. Again, these are T regulatory cells that we're engineering for these programs. So they are responsible for inhibiting the immunologic response and and rejection in the case of renal transplants. So it's a different proposition than engineering other types of T cells, killer T cells or CD8 T cells. But I'd actually like to ask Jason to comment on that, too.
spk05: Jason, can you help us with some thoughts on this?
spk14: Yeah, thanks, Sandy and Rob. Yeah, I think what I can say is that we're very confident about the approach that we're using in the TX200 program. We've evaluated the safety and the efficacy of the cells in a variety of preclinical models, and we've been very happy with what we've seen. We've obviously consulted with our own internal experts, clinical regulatory safety, and we've had conversations with the regulators. And we're moving forward, and we're excited to be dosing our first patient in this quarter And, you know, other companies take different approaches, but we're confident that our approach is one that offers a, you know, is going to offer a benefit for patients. And we'll be keeping a close eye on patients as they're treated. Obviously, this is a phase one study where safety is paramount, and that's what our focus is on.
spk15: Thank you, Jason.
spk01: Thanks so much. Our next question comes from Yanan Zhu with Wells Fargo.
spk11: Hi, thanks for taking my questions. First on Fabry program, so you mentioned you will have additional data in the second half of the year. I'm just wondering what might be the follow-up, and presumably this is going to include all all six patients. So the question is the length of the follow-up and in terms of the endpoints, I think we can assume ERT withdrawal is an important endpoint enzyme level substrate, but would there be any additional clinical endpoints that's also going to be studied to be reported at that stage? Thanks.
spk12: Yes, and thank you so much for the question. So later on this year, we will have accumulated more data, especially from the earlier dose patients. As you may know, the parent study, these patients have been enrolled into the one-year study, and patients that have been treated at the beginning, some of these patients have now rolled over to the long-term follow-up study. which is an additional four years of follow-up in total. And we will be able to present data on accumulation of the alpha-gal A expression over time, as well as other biomarkers, like the GB3. And you point out ERT withdrawal data. In terms of clinical endpoints, we will be collecting, once we dose naively, patients moving forward we will be collecting kidney biopsy data. This will not be available this year at this later update. We can expect that type of clinical data to be presented next year. We will also be presenting an update on patient reported outcomes and so really As we move along, we are also intending to dose more patients, and we have patients currently in screening and in baseline. So patients are going to, we anticipate, be dosed.
spk15: So it will give us a wealth of data.
spk12: Exactly. And some that will be a nice profile that we will be collecting from this wealth of data that
spk15: What we like from the data we've seen so far is up until the one year mark that we have concrete data from, there's been no sense of decline in the four patients that have been treated for the longest. That the alpha about, there are investigators talk about stabilization of the cardiac MRI. And those are all really encouraging data that it's only through time that we'll be able to understand it. However, I want to be absolutely clear, we are full on in our planning for the phase three study and look
spk11: Right. Yes, thank you. I'm looking forward to hearing about the Phase 3 design. I think it may be too early to ask that question. If I may, I'm curious about what you mentioned about base editing programs that you're working on. Obviously, this is going to be based on VinkFingers. My question is, does your base editor retain the nuclease part of the zinc finger nuclease, or does it forego that nuclease part? The reason I'm asking is because I think in the CRISPR-based base editors, actually the nuclease capability, i.e., the ability to cut one strand of the double-stranded DNA is actually very useful in terms of improving the editing efficiency because it prevents the degradation of the edited strand. So under that light, I'm interested in whether your architecture for your base editor, basically. Thanks.
spk15: Thank you for a very interesting question. So we've been working on base what gives us great pleasure is that the zinc finger platform allows a range of technologies to be added to the DNA localizing zinc finger and allows us to choose when double-stranded breaks of the nucleus are important or whether things like repression enhancement or base editors are the right things for the right patient compared to CRISPR where there's a company for each of these. But Jason, can you comment on this specific question?
spk14: Sure. Thank you, Sandy. You know, this is a base editor that will not create double-stranded breaks to change a base in the genome, and we're really excited about the advancements that we made, and we look forward to sharing them very soon at the appropriate scientific conference. I don't think I'm going to go into the details of the architecture of the base editor that we've designed, but it's a novel approach, and we're very excited about discussing it and deploying it therapeutically.
spk05: Great. Thanks for the comment.
spk15: The reason we particularly like it is it uses It benefits from the small size of Syncfingers, which are almost a tenth the size of some of the CRISPR architectures, and therefore will allow it to be packaged in AAV in a way that the standard base editor won't. And it allows us choice, and that's what we like, and that's what our partners like.
spk11: Got it. Yeah, thanks. Thanks for highlighting that advantage. So, yeah, that's a question in my mind as well. Thank you very much for all the color.
spk15: Thank you.
spk01: Our next question comes from Maury Raycroft with Jefferies.
spk03: Hi, thank you for taking my question. This is Jing. I'm with Morris Line. So actually, I have two questions. The first one is, can you talk more about where you are at with this designing Fabry's phase three? And what are the gating factors to get all these studies being started? That's my first question. Second one is, what else can you talk about the first patients enrolled in the CAR Treg program? And can you also say if this patient has already been transplanted, and are you currently processing the CAR Tregs? That's my question.
spk15: Thanks. So let me take the easier one, which is . Can you just talk about where we are with CAR Tregs in general, please? So we haven't shared anything about the phase three study. But as I'm sure you know, planning for a phase three takes a long time. And therefore, we've been looking at the design of this and talking to experts for at least six months and are pleased with the progress we're making and will share it more broadly at the right time. Mark, can you talk about the T-Rex? Because we're very excited about that.
spk13: Yeah, so we're about to do our first patient. two patients by the end of the second half 2022. You know, we're delighted to take this forward because it'll be the first opportunity for us to really establish the biologic effect of these agents and really understand what's going on. And this is critical because our goal is that TX200 establishes the foundation for a portfolio of CAR T regs for major autoimmune indications. And so, This will inform us, you know, using the autologous. In the meantime, we're advancing allogeneic approaches. And as we've disclosed, we've got, you know, preclinical candidates against MOG and multiple sclerosis, as well as IL-23R for inflammatory bowel disease. And so we'll be applying the learnings that we have coming out of this trial as we advance the platform, but also those particular candidates.
spk03: Okay, great. Thank you. Thank you very much.
spk01: Our next question comes from Luca Easy with RBC Capital.
spk16: Oh, great. Thanks so much for taking my question. Congrats on all the progress. Two quick ones. Maybe the first on Fabri. I will not ask you the design of the Phase III, but maybe at high level, can you just talk about what gives you confidence that you can start a Phase III here without actually having seen the kidney biopsy data quite yet? And then maybe second on tickle cell disease, can you just provide any additional color on the new manufacturing process here? What are some of the key parameters that you're optimizing here that gives you confidence that the new manufacturing process will drive better outcome preparation? Thanks so much.
spk15: So let me see how I can split these. Rob, can you talk about SYCL, please? And the other question I think you said was in the absence of. How will we decide on the goal decision and the design of the phase three? As I said, we've been designing this and talking with regulators for some time. And we believe that the data...
spk17: And with respect to the sickle cell program and manufacturing, we have made some process changes. We haven't talked specifically about those process changes, but in internal experiments, we've shown that it increases the number of progenitor cells. So we're optimistic that this will carry through into the clinic with better yields.
spk15: And we're being... very transparent and I hope realistic.
spk16: Got it. Thanks so much.
spk01: Our next question comes from Ben Burnett with Stiefel.
spk08: Hi, this is Kaylee Brazon for Ben. Thanks for taking our questions. I just had one quick one about Fabry. So regarding the Fabry program, can you talk at all about the Lyso-GB3 biomarker specifically? Under what situations would you expect this biomarker to move with the ST920 treatment? And then our second one is about hemophilia, and I was just wondering if Pfizer has already received feedback from the FDA on the necessary steps to remove the clinical hold, or if this is something they have yet to do. Thank you.
spk15: So, Bettina, can you do Fabry and Rob, can you do hemophilia, please?
spk12: Yes, thank you for the question. So, lyso-GB3, you will have seen we presented data on at the World Symposium just a couple of weeks ago in San Diego. And different patients are exhibiting different baseline level to start off with on SISO-GB3. And so the movements that we can expect are going to differ based on this as well. I'd like to point to patient number three, who is the first patient in cohort whose lyso-GB3 started higher than the other patients and for whom we've had a significant more than 40% reduction and that within the first 10 weeks post-infusion. And that reduction has been maintained over time until the latest follow-up. And so what we look forward to is seeing the next patient going to be dosing, seeing how their lyso-GB3 fares over time, depending on their baseline.
spk15: And this phenomenon, Bettina, has been seen in all the programs. It's got to be high to go down.
spk12: It's important to point that out, thank you, Sandy, because we have seen the same in other programs that the lyso-GB3 really does need to be at significantly high levels for us to be able to impact it with a gene therapy approach. And that has been seen across other programs. And so we're confident that we're seeing data that is going to be encouraging as we also look at our next patient's dose at the higher dose.
spk15: And roll hemophilia.
spk17: Hemophilia. First, I'd like to acknowledge the terrific partnership with Pfizer on this program. and remind everyone that the trial was more than 50% enrolled at the time it was paused. Pfizer has guided us in the markets that trial will resume or planning to resume in the first half of 2022. So without getting into the specifics of where we are with responding to regulatory authorities, I can point toward that guidance of resumption of trial in the first half of this year.
spk15: It's going very well, and they're putting all their efforts
spk17: they are aggressively and enthusiastically pursuing this trial. Thank you.
spk01: Thank you. Our next question comes from Aspen Morey with Bank of America.
spk04: Hey, guys. Thanks for the question. Maybe you can just talk through your updated thinking as you transition the sickle cell asset over to you guys. Maybe to talk to your updated thinking on how you see that progressing in terms of taking it alone or maybe partnering it out, and if the priority is partnering, if there's any preference for someone with more of an OUS presence as that was kind of Santa Fe's niche in your prior partner. And then the second question, some of your peers have implied that For the gene therapy space, FDA may be stricter on therapies or indications where there's already approved therapies available, not including gene therapies. Do you think that's a fair assessment, or has that at all been, have you kind of seen that dynamic play out within your interactions with the FDA? Thank you.
spk15: I'm going to ask Mark to talk about the strategy around sickle, and then I'll touch on the general comment that the FDA
spk13: So, Austin, I mean, obviously we heard, you know, December 30th that they had made that strategic decision to transition sickle cell back to us. As Sandy mentioned, you know, the team's been working very hard on the transition. We're very pleased with the engagement we have with Sanofi as we progress to the transition plan, which will culminate around June 28th of this year. Our highest priority right now is to ensure that we can complete the Phase 1-2 precision trial, as Rob just mentioned, utilizing that new manufacturing process, which we hope will come through and demonstrate even better results in those four patients. That totality of that data will inform kind of the way we want to proceed forward. In the meantime, the teams have engaged the authorities both in terms of feedback on manufacturing, as well as preliminary discussions around the approach to Phase 3. So, at the appropriate time, we'll provide an update for that. You know, in terms of the geographies and partnerships, we're not going to comment on that now. It's too early to provide a perspective on that. But I would remind you, right, that in the United States, there are about 100,000 sickle cell patients, of which 30,000 of those patients are severe. Outside of the U.S., there's about 150,000 patients. This is a devastating disease that affects a particular population, and our commitment is to do whatever we can to make sure that patients get access to this medicine if it's a differentiated medicine. And we'll know more as we get the clinical data, and our commitment is to ensure that we take it forward if the data suggests it should get to patients.
spk15: We have a great relationship with the agency and I have an enormous respect for Peter and the FDA and what they do because I think one has to understand the exponential growth in this field that they have to deal with and to train people and to stay ahead of the emerging data and understanding. I think there is a bit of a reality check that we're watching now, which is more medicines are in the clinic. more new vectors are being tested, and some of them will be found to have challenges, and that's inevitable in any new field. Which takes me back to what I said to one of the earlier questions about our vector having had years of testing in many indications of the team at Sangamon having filled many INDs and understanding the preclinical and toxicology data necessary to ensure safety. And about the inherent first and would be the first to have that conversation with the agency if we are ever concerned about what we're seeing. But at the moment, we haven't felt any difference in the agency's approach and are glad to have them as partners in the development of our medicines. Thanks, Andy.
spk01: Our next question comes from Ritu Baral with Cowan.
spk07: Good afternoon, guys. Thanks for taking the question. I had a question on the precision one, well, the sickle cell program in general. You know, I think at a high level, I'd love to know the metrics by which you'll gauge sort of where the program will fit in a landscape that's getting more and more crowded and You know, to drill down on that, I guess what we're looking for is HPF levels, but also percent F cells. I guess, which one do you think will be more important, a more important tell on the ultimate clinical benefit? And especially since you're reaching such high levels of percent F, you know, do you need to show that sort of 90s level of percent F cells in a... certain proportion of treated patients for, for you to say that this is, you know, this is, this is going to be the preferred therapeutic.
spk15: So I'm going to ask Rob to comment on the technical bit and Mark on more of the strategic, but what would remind you that we have, we're in the clinic with clinical data. There are many, the competitive landscape is largely of, uh, newcomers from, um, other editing modalities, putting it into the pipeline and talking about doing this. But, Rob, can you talk about what you'll use as a loop for success?
spk17: What's most important to the patient is the frequency of which they have vaso-occlusive crises. That is the most important parameter, is relief of those terrible, painful, expensive sickle cell crises. And what we have seen in the four patients that we've reported is an enormous effect size. We've had a single VOC, whereas prior to treatment, they were having very frequent vaso-occlusive episodes. So if you look at the magnitude of the effect that this therapy has, it's profound. All of the other factors that you mentioned, percent F cells, fetal hemoglobin, are all important. But what is most important is the durability of that effect and the impact that has on patients' lives. And I think with time, we'll understand that relationship between percent F cells and fetal hemoglobin and that protection, but we really need to keep our eyes on what's most important to the patient.
spk07: Nicely said. Oh, sorry, just a quick follow-up to that. Do you think that that relationship is well enough understood right now, snapshot in time, or will be understood in the next couple of years enough that HBF or some analysis of HBF could be a potential solution accelerated approval pivotal endpoint, or will it really come down to VOCs or some other clinical aspects?
spk17: VOCs are easy to measure. It's not a subtle laboratory-based finding. It's what the patients report. I think that will remain the cornerstone of assessing effective therapies is the benefit that that provides patients, particularly in this disease.
spk07: Got it. And then your picture. Thank you.
spk13: Sorry. Thank you. Sorry. Yeah, so, you know, in terms of that, Richie, if I don't answer this, please clarify it for me. But obviously, the CRISPR vertex guiding that they're going to file sometime towards the end of this year. You know, they've not shown as much of the data set yet, at least as far as I know, in terms of any further updates, in particular of the registration-directed study results, which would be expected. And so, you know, so time will tell in terms of how the discussions go once they file with the agency. In the meantime, we've also seen Bluebird withdraw. And so, you know, it really becomes important for us to better understand the data that's emerged and we've presented to date, but more importantly, as Rob alluded to, the additional four patients with the change in the manufacturing process to see if that has an increased benefit in terms of the HBF levels, percent F cell increases, as well as the clinical outcomes for the patients. And I think it's really whether that profile looks competitive enough that will dictate how we take the program forward.
spk07: Got it.
spk01: Thanks.
spk00: Thank you.
spk01: Our next question comes from Gina Wang with Barclays. Thank you for taking my questions.
spk02: Two very quick ones. The first one I'll also follow regarding the sickle cell program. What kind of clinical profile you will be thinking the possible to keep in-house? Would that be CRISPR-like profile or would that be better? The second question is regarding the base editors. So I assume you use the M&As. What about the IT part? Do you have a proper right to use that?
spk15: Why don't you talk about SYCL, and then Jason can speak to the base editors.
spk13: Yes. Hi, Gina. I hope you're well. I mean, in terms of that data that I just sort of alluded to, I mean, I think it's really going to be important to see the clinical profile in these next four patients, and it will give us a sense, you know, roughly around the time that hopefully we'll see a little bit more of an update from CRISPR-Vertex, whether we've got a comparable product or whether we've got a differentiated product. At the end of the day, these are personalized cell therapies, which means they need to be manufactured for the patient, As I described, there's 100,000 of the patients in the U.S., 30,000 of them are severe. And so even if there's one competitor in the market, it's going to take a long time to service the needs of the sickle cell communities, not only in the United States, but more importantly worldwide. And so if we've got an attractive profile that's the same or differentiated through CRISPR-Vertex, we will do, as I mentioned earlier, what we need to do to either find a partner or look for novel ways that we can get this therapy to patients. Jason, can you help on the base editor question?
spk14: Sure. Thanks, Andy. Yeah, you know, regarding the base editor, this is a program that I'm incredibly excited about. We have a great team of molecular biologists, structural biologists, that are continually innovating around our core zinc finger platform. And they're doing that on both the side of the zinc finger portion of the molecule, where we're refining the specificity and accuracy of the molecules to target specific sequences, but they're also doing it on the functionality side. Moving beyond the core group of functionalities that we already have in our toolkit, nucleases, transcriptional activators, transcriptional regulators, we're now exploring other new functionalities, including base editing, but also recombinases and epigenetic editors. And we've got something in our base editor program that we're really excited about. We wouldn't be moving forward if we didn't think we had freedom to operate. So we're pretty comfortable with the really unique architecture that we've developed. And as Sandy pointed out, we think it offers some real advantages in being able to be deployed in a single viral vector. as well as taking advantage of the great specificity and accuracy aspects of the Syncfinger platform.
spk01: Thank you. Our next question comes from Patrick Truccio with HC Wainwright.
spk05: Hi. Good afternoon, everyone, and congrats on the progress for this quarter. So I just kind of have two questions. I guess the first one to start off is, what are some of the components that can result in the patients having an elevated Lysol GB3 level for fat diseases, and how readily do these patients actually have increased Lysol or GB3?
spk15: Patrick, can I make sure I understand your question? It's what Bettina talked to earlier, that many patients, particularly those on ERT, already have repressed Lysol GB3, and that the A few patients, particularly the naive patients, will have elevated levels, and those are the ones where we can see a benefit of our medicine on the Lysol GP3. And I think that you asked, are we screening for those patients? Is that where you were going?
spk05: Yes, yeah. Will you be screening for high Lysol GP3 patients?
spk15: We're delighted to take all patients. take the naive patients. And we're not rejecting patients if they have low levels of lyso-GB3, and we're delighted when we find a patient that's a high level.
spk05: Okay, great. And then kind of just like a follow-up question, and so like for the baseline of like for patient five and patient six, do you also see these increases in lyso-GB3, or is that something that we will see later on?
spk15: Bettina, have we commented on the levels of patients five and six?
spk12: Yeah, thank you for the question. We have not commented on those levels at this point in time. This is something that is part of that update that we can provide later in the year as we provide our clinical update.
spk05: Okay, great. Thank you for the additional comment.
spk01: I'm showing no further questions in queue at this time. I'd like to turn the call back to Erin Feingold for closing remarks.
spk06: Thank you all once again for joining us today and for your questions. We look forward to keeping you updated on our future developments.
spk01: This concludes today's conference call. Thank you for participating. You may now disconnect.
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