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spk08: Good day, ladies and gentlemen, and thank you for standing by. Welcome to the Sangamo fourth quarter 2022 earnings conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 1-1 on your telephone keypad. At this time, I would like to turn the conference over to Ms. Louise Wilkie. Ma'am, please begin.
spk01: Thank you. Good afternoon. I'm Louise Wilkie, Sangamo's Vice President of Investor Relations and Corporate Communications. Thank you for joining us on the call today. On this call are several members of the Sangamo Executive Leadership Team, including Sandy McRae, Chief Executive Officer, Mark McClung, Chief Operating Officer, Farshisha Durrababu, Chief Financial Officer, Jason Fontenot, Chief Scientific Officer, Natalie Dubastring-Fellow, Chief Development Officer, Athena Cockcroft, Chief Medical Officer, and Andy Ramamur, Head of Technical Operations. Slides from our corporate presentation can be found at our website, sangamo.com, under the Investors and Media section of the 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 candidates, the anticipated plans and timelines of Sangamo and our collaborators for initiating and conducting clinical trials, screening and dosing patients, and presenting clinical data. Advancement of our product candidates. Advancement of preclinical programs for the clinic. Our investment focus and the sufficiency of our resources. Our 2023 financial guidance, upcoming catalysts and 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 of the SEC. 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.
spk00: Thank you, Louise, and good afternoon to everyone joining the call. I'm pleased to share today the significant process we have made over the last year in bringing potentially transformative medicines closer to patients that need them most and to convey our outlook for the coming 12 months. 2022 was a year of important clinical and non-clinical milestones for Sangamo. We believe we became the first company to do as a human with an engineered CAR T reg. We established a leadership position in Fabry disease. We presented promising data in sickle cell disease, And with Pfizer, we announced the resumption of our Phase 3 Haemophilia A trial. I'm thrilled with the updated Fabry data from our Phase 1-2 STAR study that was released today at the 19th Annual World Symposium. In addition to sharing updated biomarker data, we revealed the first kidney biopsy data from the study, along with exciting SF36 general health score findings, which, when taken together, bring to point the potential for ST920 to become a truly compelling Fabry therapy. Based on what we've seen in the competitive landscape, we truly believe we have potential best in class leading gene therapy for this important indication. Natalie will take us through the details of this new data shortly, but I wanted to express how happy I am with the progress of the program, which I believe has a strong potential to bring relief to those suffering the debilitating aspects of Fabry disease. We are well underway in dosing the first full cohort of patients with TX200 in our Phase 1-2 Steadfast Study in HLA-A2 mismatched kidney transplant, and we believe we remain in the lead in clinical progress amongst CAR-T red companies. This study potentially paves the way for current projects in development as a proof of concept and demonstration of safety of CAR T regs in humans. Our focus is advancing this trial with urgency while maintaining patient safety. So the team is actively working with the regulatory authorities to explore options to accelerate the dose escalation protocol. We look forward to sharing more information when available. The team has also made significant headway in advancing our second wave of preclinical programs, progressing our CAR-T reg follow-on indications in multiple sclerosis and inflammatory bowel disease, advancing our four wholly owned CNS epigenetic regulation programs, breaking new ground in delivery through our AAV capsid engineering program, and continuing to advance our zinc finger genomic engineering platform. I'm proud of the progress we've made this year, which is a testament to the hard work and dedication of our talented team members across the organisation. During 2022, we remain dedicated to advancing our pipeline and executing on our corporate strategy. In this regard, we're happy to add two new board members to our board of directors. Heckhorn brings with it over 30 years of leadership experience in the biotechnology industry, having led many important strategic and financing transactions. Courtney Beers has also joined us as bring to Sangamo her long experience in drug development and scientific strategy. Looking to 2023, the leadership team is fully focused on progressing our clinical programs and continuing the transition to Sangamo's second wave pipeline, carefully prioritizing our efforts and our spend on cell therapy with our CAR T reg franchise and on epigenetic regulation in the CNS through both our wholly owned and partnered programs. We believe these are programs that both leverage Sangamo's core sync finger capabilities and deep experience in genomic medicines and have the potential to be differentiated while positively impacting patients with high unmet medical need at scale. As we navigate these current market conditions, we fully understand the importance of using capital wisely. And I want to reiterate the focus and prudence with which we are making decisions, both in terms of capital spending and also implementing thoughtful fundraising strategies with long term shareholder benefit in mind. In this respect, we're pleased to present competitive data from our Phase 1-2 precision study in sickle cell disease at the American Society of Haematology annual meeting in December last year. We've also since made additional manufacturing improvements that we believe could further strengthen potential phase three data and reduce manufacturing costs, so important in the syndication. However, in today's environment, we must make difficult choices. Today we're announcing the strategic decision to halt further material investment in phase three planning for our BIVV003 sickle cell disease program. Importantly, Very importantly, we did not make this decision because of efficacy results or due to any safety concerns. We have simply decided to redeploy our resources away from the asset and towards investment in a potential Phase 3 trial for our Fabry programme and efforts to accelerate our Phase 1-2 TX200 programme. As we stated when the programme unexpectedly transitioned back to us last year, we remain committed to the patients and investigators involved in the Phase 1-2 Precision 1 study and expect to complete the study using funds we have already committed. But we will make no material investments in the programme going forward. We're commencing an active search for a partner who can progress this promising asset to a potential Phase 3 clinical trial. I'd now like to turn the call over to our head of development, Natalie, who will discuss the data from our clinical programs in more detail. Natalie.
spk04: Thank you, Sandy, and good afternoon to everyone on the call. This afternoon, we announced updated data from our Phase 1-2 STAR study evaluating isaralgatine seboparvovac, or ST920, our only-owned gene therapy product candidate for the treatment of Fabry disease, at the 19th Annual Word Symposium. As Sandy outlined in his opening, the data presented today support potential best-in-class product profile for ST920 to treat patients suffering from Fabry disease. As of the November 15, 2022 supplemental cutoff date, 13 patients across the dose escalation and dose expansion phases exhibited supraphysiological alpha-galA activity sustained for over two years for the patient with the longest follow-up. All five patients from the dose escalation phase who began the study on enzyme replacement therapy had been successfully withdrawn from ERT and has not required a resumption of ERT treatment as of today. Importantly, we now have kidney biopsy data demonstrating evidence of substantial GB3 reduction in the kidney at six months in a cohort patient along with reduced urine podocyte loss. We have also observed a statistically and clinically significant improvement in mean general health score as measured by the SF36 general health survey. Based on this collective data point, we truly believe ST920 has the potential to become a leading teen therapy for this important indication, and we are actively preparing for a potential phase three trial which we expect to begin in the second half of 2023. Now, digging into the data in a little more detail, in the dose escalation phase, all nine patients treated in the dose escalation phase across the four doses exhibited elevated alpha-gal A activity, ranging from nearly four-fold to 67-fold of mean normal, sustained for over two years for the longest-treated patient, as of the November 15, 2022 supplemental date. cutoff date. As I outlined earlier, all five patients who started the study on ERT were successfully withdrawn from ERT, continue to demonstrate supraphysiological level of alpha-GAO-A activity following withdrawal, and remain off ERT today. For naive and pseudonaive patients in the dose escalation phase, the cohort for patients exhibited significantly higher levels of alpha-gal A activity compared to those patients in lower dose cohorts. As of the 15 November 2022 supplemental cutoff date, the first three patients dosed in the expansion phase at the 5E13 VG per kg dose exhibited a rapid increase in alpha-gal A activity following dosing sustained for up to 14 weeks as at the last date of measurement. The fourth patient had increased to within normal range at four weeks of dosing. The first female participant dosing the study demonstrated a similar response profile to males as the cut-off date. TB3 is a fatty substance that accumulates in the cells of Fabry disease patients and can result in damage to multiple organs, including the kidney, heart, and central nervous systems. The kidney biopsy for patient 9, who demonstrated a high number of TB3 inclusion and high plasma lyso-TB3 level at baseline, exhibited an impressive 78% clearance in TB3 inclusion per peritubular capillary, or PTC, from an average of 8.7 inclusion per PTC at baseline to 1.9 inclusion per PTC six months after dosing. This assessment was made by two blinded pathologists who independently scored digital images of the sectioned kidney from baseline and six-month biopsy, abdicated by a third independent pathologist. In addition, this patient exhibited a 77% reduction in urinary podocyte loss after six months. The significant decrease in renal TB3 inclusion and the reduction in urine podocyte loss support a favorable impact on progression of Fabry nephropathy and indicates the meaningful nature of this potential therapy. The kidney biopsy for patient eight, we exhibited a lower number of GB3 inclusion and lower level of plasma lyso-GB3 upon baseline, demonstrated staple PCT inclusion six months post-dosing. This patient also exhibited an impressive 97% reduction in urinary podocyte loss after six months, which coupled with the significant increase in alpha-gal A activity along with reduction of lyso-TB3 after dosing, provides evidence of a potentially favorable effect on Fabry nephropathy. In addition, changes in general health score for patients in the dose escalation phase from baseline at week 52 were statistically significant, with a mean increased general health score of 19.6. For context, a 3 to 5 point chance of NESF36 score is a minimally clinically important difference. With regard to lyso-TB3 level for naive and pseudonaive patients where baseline level of lyso-TB3 started high, patients experienced a 46 to 65 percent reduction in levels following treatment and continued to decrease for two patients until the data cut off. For the first time in the study and with the highest dose, a 54 percent reduction in plasma lyso-TB3 level was observed where baseline levels started below 25 nanograms per mil. For patients in the dose escalation phase who began the study on ERT, plasma lysoGP3 levels following ERT withdrawal remain within the range of levels and variability normally observed in patients treated with ERT. In this patient, alpha-GalA activity remained elevated and no patient had experienced symptoms requiring the reception of ERT as of today. As of the October 20th, 2022 cutoff date, ST920 was generally well tolerated in the 13 treated patients with no treatment-related adverse event greater than a grade 2 and no treated related serious adverse event. No prophylactic corticosteroid or other immune-modulating agent have been administered. These data are being presented in more detail by one of our study investigators, Dr. Robert Hopkins is coming Friday, February 24th, during a session from 8 to 9 a.m. Eastern time and doing a poster presentation from 3 to 4 p.m. Eastern time. We would encourage you to listen to the presentation. These data are also available on Sangamo's website in the presentation page. Since the October 20th, 2022 cutoff date, we have dosed an additional four patients in the expansion phase, to achieve a total of 17 patient dose in total. We have also withdrawn an additional two patients from ERT. A total of 20 sites are now active and recruiting. Progress in the study continue with additional male and female patients currently in screening. In December, one patient in the expansion phase experienced a grade three serious adverse event of shoulder antisopathy, which was deemed as possibly related to treatment. The patient has since fully recovered and the safety monitoring committee has determined the study may proceed without modifications. No similar events have been observed in any of the 16 other patient dose in the study today. We continue to plan for a potential phase three trial with our strategy in the U.S. progressing alongside our EU strategy. The trial is anticipated to commence in the second half of 2023. and dosing of the first patient could happen as early as the first part of 2024, depending on regulatory interaction. As a reminder, the expansion phase of the Phase 1-2 study, for which we expect to complete dosing in 2023, is not expected to be a gating factor for the commencement of Phase 3. In the Phase I-II Steadfast Study, our wholly-owned TX200 CAR Treg cell therapy candidate for the prevention of immune-mediated rejection in HLA-A2 mismatched kidney transplantation from a living donor, the first two patient dose continued to do well. The third patient has received their kidney transplant. We have successfully manufactured their personalized TX200 cell therapy, and dosing is expected early in the second quarter of 2023. This will mark the completion of the first full cohort of the study. Preparation for the second cohort is actively progressing. The first patient is expected to receive their kidney transplant shortly, and manufacturing is in progress. Dosing is anticipated this summer. Additional patients are in prescreening and continue to enroll. As Sandy outlined, progressing this study quickly but safely is our top priority. As such, we are discussing with regulators option to accelerate the dose escalation scheme to find the optimal dose for efficacy. Moving on to sickle cell, in December, we presented updated preliminary clinical data from the Phase 1-2 Precision 1 study of BIVV003, a zinc finger nucleus gene editing autologous cell therapy product candidate for the treatment of sickle cell disease at ASHE. The data showed that total hemoglobin and hemoglobin F levels were maintained up to 30 months for the longest treated patient, and that BIVV003 continued to remain generally well-treated across the five patient dose, with no treatment-related adverse events. Importantly, this was the first opportunity to present data from a patient dose with a product candidate manufactured use or improved process. At six months following treatment, Patient 5 exhibited fetal hemoglobin level of 45% and total hemoglobin of 12.4 grams per deciliter, which is significantly greater than the level observed in patient dose with the original manufacturing process. Based on this result, we believe VIBV003 is a competitive potential treatment. As Sandy indicated, we have been working on further improvement to the phase 3 manufacturing process which we believe have the potential to further improve the final product, the learning from which we are carrying across our Treg manufacturing efforts. We have also progressed clinical and manufacturing activity in anticipation of dosing patient 7 in the phase 1-2 study and have agreed the phase 3 trial design, CMC package, and other requirements with the FDA. We are disappointed not to progress this program further ourselves, but are hopeful that we can find a potential collaboration partner who can advance this program into a potential phase three trial, as we believe this therapy has strong potential to help improve patient life. Finally, Dosing progress in the phase 3 assigned trial of Giroctocutine-Petal-Pavovec, our investigational gene therapy we are developing with Pfizer for patients with moderately severe to severe hemophilia A. Pfizer expects dosing to support primary analysis to be complete by the end of the first quarter of 2023. Pfizer recently reiterated that this is one of their most promising assets, and we look forward to a pivotal readout. expected in the first half of 2024, along with a potential BLA submission that Pfizer is anticipating in the second half of 2024. I will now turn the call over to our Chief Financial Officer, Patricia, for an overview of the financial results. Patricia?
spk12: Thank you, Natalie, and good afternoon, everyone. We are really pleased with our accomplishments for the year, including the promising data emerging from our FabRIE program, and the progress of our CAR-T reg and CNS epigenetic regulation programs. We ended the year with approximately $308 million in cash, cash equivalents, and marketable securities, which represents a net decline of $157 million from the prior year. This included $85 million of additional capital raises during 2022 through the issuance of equity under our at-the-market offering program. During 2022, we invested our resources in progressing important clinical and non-clinical milestones while operating a focused and lean organization. In these tough financial markets, we will continue to seek ways to streamline spend while advancing programs and thoughtfully raising capital to create long-term value for our shareholders. Turning to our 2023 full-year guidance, We expect a full year non-GAAP operating expenses to be between approximately $235 million to $295 million. This range excludes estimated non-cash stock-based compensation expense of approximately $35 million. During 2023, we'll continue to focus our resources on programs that we believe will create long-term value for our business. including our clinical assets, ST920 and TX200, and our preclinical CAR Treg and TNS pipelines. Additionally, about 8% of operating expenses are allocated towards partnership programs, which are reimbursed. Our detailed financial results are available in the press release issued today. I will now turn the call back to Sandy for closing remarks.
spk00: Thank you, Prathusha. I'm incredibly proud of what the team has accomplished over the last year, And I want to thank all of them for their continued commitment to our science and our mission. As you heard today, Sangamo is focused and disciplined on advancing near-term clinical programs and achieving additional milestones. In 2023, we expect to complete the dosing of all remaining patients in the expansion phase of the Fabry Phase 1-2 study and to commence a Phase 3 Fabry trial. We expect to complete dosing of the first TX200 cohort early in the second quarter of 2023 and commence dosing in the second quarter this summer. We also expect to complete the Phase 1-2 sickle cell study using funds we've already committed, and we intend to make no further material investment but to seek a potential collaboration partner. And in the first half of 2024, we anticipate Pfizer's pivotal readout in hemophilia A with a BLA submission anticipated in the second half of 2024. As a reminder, this program could generate up to $240 million in remaining milestone payments from Pfizer and could provide us with royalties between 14 and 20% on future potential product sales subject to customer reductions. We're also progressing our preclinical programs with PACE and are excited by the data we've seen to date. By the end of 23, we expect to announce and reveal data from our wholly owned epigenetic regulation programs in the CNS. And by the end of 24, we anticipate submitting two new IND applications from our second wave CAR T reg and CNS programs. We will also continue to advance our AAV capsule delivery capabilities, which are increasingly attracting the interest of potential partners. As always, we're working diligently to bring to patients what we believe to be improved treatment options for disease. The unmet medical needs drive our work home here, and it is our mission to bring cell therapies and epigenetic regulation to people with a range of diseases. So at this point, we'd like to open up for questions. Operator, please open the line for questions.
spk08: Ladies and gentlemen, if you have a question or comment at this time, please press star 1 1 on your telephone keypad. If your question has been answered or you wish to remove yourself from the queue, simply press the pound key. Again, to ask a question, please press star 1 1 on your telephone keypad.
spk07: Please stand by while we compile the Q&A roster. Our first question or comment comes from the line of Ritu Baral from Cowan.
spk08: Mr. Baral, your line is open.
spk03: Hi, everyone. Good afternoon. Thanks for taking the questions. Sandy, I wanted to ask you about your comments around face-free interaction. As usual, my question will have about three different parts. Warren, are you looking for any particular follow-up?
spk00: Can I interrupt you so we don't miss the question? Your line is a little garbled. Is there a way you can be clear?
spk03: Hang on just a second. Let me take it off the AirPods. Sandy, is that better?
spk00: Oh, that's so much better, thank you.
spk03: Okay, apologies. So a couple questions, Sandy, on your phase three plans, and as usual, my question will have three parts. One, can you comment on the podocyturia that you reported with your data today? There's some additional posters here at World on podocyturia, and is that sort of gaining steam as a biomarker of import in the disease. And then further, as we look at the expression curve on slide 15, is there any particular follow-up for expression that you are waiting to achieve before you finalize your phase three design with the agency? And then I have a very quick follow-up.
spk00: A question is, the first one is about podocyturia and what does that mean? What do we think about it? And then there's a second one, which I'm going to pass on to Natalie, about the levels of expression and how long they last and are we waiting for a specific time to declare success? Is that correct?
spk03: And finalize the phase three design with the agency.
spk00: Well, I think I can maybe do and help you with both of them. We're always looking for markers of disease and ways to show the success of our program. Fabry causes a podocytosis, which means that the little cells, there's about 500 of them per capsule, disengage with the capsule and fall into the urine. They're terminally differentiated. So once they're in the urine, there's no going back and there's no new ones created. and you detect them in the urine. Now, this is a technique that has been quoted and referenced in other forms of renal disease. But as you say, I think there's two posters at the World Symposium on this, which just reflect the interest in this as a near-term closer marker of success or not with treating the renal disease. Renal disease is important in Fabry. It's a very debilitating condition. Renal disease causes heart disease when it is at its terminal stage. So we were very pleased that both these patients showed this effect. Now, we're only doing biopsies and podocyte urine assays in patients that are at the top dose. and patients that are naive or pseudonaive because otherwise the results may not be interpretable so there'll be future patients in the expansion cohort that we'll be looking forward to share with you and then i'll answer the second one to just for ease of time you said is there is there some kind of length of treatment that we are waiting to be able to declare success yes no No is the simple answer. We feel the first patients were up to 26 months for the first two patients, 26 and 25 months. There's no sign of any change in them. We're absolutely confident that this is a very stable therapy. And in addition, we're collecting months and months of safety data that give us a chance to go back to the agency and show the new data. We visited the agency last year. I got some really good feedback from them, but that was when we only had a few patients in the study. Now we have many more patients. We're up to 17 now, I believe, is the number that have been treated. We have the biopsy data. We have the SF36, which I think is remarkably positive. And we have the podocytes in the urine, and we have continuous expression. I think the package is so much more compelling for us to have a very productive discussion with the agency.
spk03: Understood. And my very quick follow-up, the grade 3 SAE, could you clarify what shoulder condition that was? I missed it.
spk00: So I'll answer this one quickly and then I promise Natalie you'll get the next Fabry question. Basically, the patient presented 14 days after dosing, so a significant time with a fever and shoulder girdle pain. He found his shoulder girdle, like the shoulder and upper arms, was painful and it was painful to move. He was admitted to hospital. four days of observation in hospital, treatment with a course of steroids. He was seen by rheumatologists and neurologists who never really got to the bottom of what it was, but the condition was resolving. And they called it an enthesopathy. An enthesopathy is where the tendon meets the bone, tendon from a muscle meets the bone. And it's basically there's a whole series of kind of inflammatory muscle joint type things that cause an enthesopathy. But the most important thing is it was 14 days after our treatment, resolved quickly, and the patient went home and is well.
spk03: Thanks for taking all the questions.
spk08: Thank you. Thank you. Our next question or comment comes from the line of Yanin Zhu from Wells Fargo. Mr. Zhu, your line is now open.
spk09: Thanks very much for taking our questions and congrats on the data at World. So a couple of questions on the STAAR study data first. So could you put the kidney biopsy data from the study into context of ERT and also GalaFold. What kind of effect would be seen with those kind of modalities? And also another question on this data is patient eight had a good response on podocyte loss, but no reduction in GB3 inclusions. How do you see this phenomenon? Then I have a question on TX200.
spk00: Thanks. Thank you for the question. I'm going to pass this on to Natalie, our head of development.
spk04: Hi. Thank you for the question. So regarding the GB3 inclusion in the kidney, This has been reported for ERT. Usually there is a reduction of similar percentage in ERT treated patient at six months or a year. Some, not all patients respond to ERT treatment and the TB3 inclusion decrease is not, there's a small percentage of the population that doesn't decrease in Gb3 inclusion, so this is important to note in terms of comparison, but we feel that the data is very encouraging because we have really indication of reduction in loss of protocyte. In terms of patient aid, this is a difficult patient because not only this patient has Fabry disease, but he also has type 2 diabetes. hypertension, which really can impact kidney health. So it is a little bit hard to interpret the GB3 inclusion in this patient, and perhaps further time would show further progress.
spk00: And just to add a little to that, this patient would not be included in our Phase 3 because the lyso-GB3 starts so low. we will have some kind of exclusion criteria that allows us to segment out patients like this. And when we showed this to several of the investigators and renal experts, they were not surprised at all by this. They said, this happens. And it's recognized across the other treatments.
spk09: Very helpful. On TX200, you mentioned you're exploring opportunity to accelerate dose escalation with regulators. I was wondering, whether that is a safety or efficacy-driven decision. And also, could you give us a sense of the dose? Since you mentioned that you want to accelerate the escalation, is it possible to let us know, have a sense of the first dose and the second dose? And also, any clarity, any visibility to timing of data, initial data from this study? Thanks.
spk00: So I'll take this one for you. It's based on safety and practicality and that the dose has been so very well tolerated that the trial is a complex one because it pivots around the patient's transplant. And the desire to complete the trial and get through all the doses We haven't stated the number of cells that we give back, but it really depends on the number of cells we can get from the patient and manufacture, and it's low, medium, and high. And as it's somewhat of an arbitrary low, medium, and high, we feel that getting to the top dose as quickly as possible gives the best chance for us to see a compelling result and also offers the best chance to the patient.
spk09: Got it. And timing of data?
spk00: We will be collecting data throughout the year, and we will show the data as soon as we have a complete data package.
spk09: Got it. Great. Thanks for all the color.
spk00: Thank you, as always.
spk08: Thank you. Our next question or comment comes from the line of Gregory Harrison from Bank of America Merrill Lynch. Mr. Harrison, your line is now open.
spk11: Hi there. This is Mary Kate. I'm for Greg. Thanks for taking our question. Just looking at the Fabry program here. So in the presentation, we see the two expansion phase patients, 11 and 12, still at early stages of follow-up at the cutoff, maybe, and they're also still on ERT. Maybe when could we expect these patients to begin the ERT withdrawal process? And could you talk about what factors go into making that decision?
spk00: Thank you. Natalie, can you take this and press your button?
spk04: Yeah, sure. So those patients 11 and 12 that are in the extension phase have been withdrawn from ERT since the data cut off. So, you know, they're off ERT at this point. I didn't get the end of your question.
spk11: Yes, so what factors go into making the withdrawal process decision?
spk04: Oh, so in the extension phase, the investigator can decide start withdrawing ERT as soon as eight weeks after gene therapy treatment. And we've chosen this because at eight weeks, we feel that we have expression above normal level of alpha-gal in our patient treated thus far. So we want to wait until we have above normal At least normal level or above normal level, which we see in all our patients.
spk00: In the initial phase, it was right for us to leave it to the investigator's discretion because they obviously care a great deal about their patients. And when they saw that, as each one saw someone else taking their patient off, they gained much more confidence. And now that five of them are off and for a significant period of time, the investigators are comfortable with us codifying this and suggesting that we first look to take them off from eight weeks onwards. We have an enormous amount of support from the investigators in this study and the number of patients coming in has increased sharply with the recent data.
spk11: Great. Thank you so much for taking our questions.
spk08: Thank you. Our next question or comment comes from the line of Ben Burnett from Stiefel.
spk07: Mr. Burnett, your line is now open. Great. Can you guys hear me? Yes, sir. Very clearly.
spk06: Excellent. I also had a question about the FABRE program, ST920. You have a few points. few patients with cardiac involvement, I guess, for some of the baseline data. Are you seeing any changes on cardiac parameters? Is that something you're able to monitor? Natalie, can you tell us?
spk04: So we're looking at this. The patients were not selected based on their cardiac involvement. They're selected based on the fact that they're classic male. We have a panel of mild, moderate, and severe patient. and we're monitoring their cardiac involvement as we go. But we haven't really disclosed anything yet on the cardiac data at this point.
spk00: We have anecdotal reports from the investigators in these patients that their cardiac condition is stable and their pedoedema has reduced. But as Natalie said, that part of the study wasn't didn't have the sophisticated setup that you require for an accurate cardiac study, which is part of the reason that we're doing a cardiac cohort in the expansion phase And we are interested by what Freeline said the agency where the FDA was open to when they announced the clinical trial hold for their study. They implied that the FDA was open to talking about cardiac events because it's a significant health risk for Fabry patients. And with our results showing we can have an effect in the kidney, there's no doubt in my mind that we would also have an effect in the heart. And we are open to understanding that route for treatment and registration for Fabry disease.
spk06: Okay, excellent. That's helpful. I appreciate that. I also wanted to ask a question kind of on the heels of the last discussion point on kind of what physicians look at to sort of gain confidence to wean people off of ERTs for the folks that are on it. And really, I guess, once they're off, what variables do they look at when considering kind of the durability of effect and whether or not they need to restart enzyme replacement therapy? And you showed some interesting SF36 clinical score data. Is that like a, like how big of a piece of that is that for physicians assessing durability?
spk00: Natalie, if you take the first bit about how they put patients back on.
spk04: Yes. So, you know, the PI know their patient very well. They have regular visits. And the decision to resume ERT is based really not on biomarker, but how the discussion goes in terms of the health of the patient, how the patient feels. And so, so far, you know, the patient are doing well, as is demonstrated by our SF36 analysis. And there's been no need for resumption of ERT in any of the patients that have been withdrawn thus far.
spk00: And I'm so glad you asked about the SF-36. The SF-36 is a real standard of general patient health, invented first in the 90s or described first in the 90s. And I've been doing drug development for 25 years and putting SF-36s into studies that have got drugs that clearly work, antihypertensives, antidepressants. migraine drugs, and very rarely do you get a budge in the SF36. And therefore, the change in result here is really quite remarkable. And I think it's an important one for us to listen to. I know the investigator that is presenting on Friday was very taken by this result. And I think you're also probably got a very good point that when the investigator asks a patient, how do they feel off ERT? It's the equivalent of the SF36. It's a gestalt of how the patient feels. We are delighted with this trial because it's both. We have the biopsy result. We have the biomarker result. We have the physiology and the podocytes. And now we have the patient seeing they feel better. It's that package that I think is really compelling.
spk06: Awesome. Okay. Yeah, that's super helpful. And just one point of clarification, and apologies if I missed it, is the go-forward dose for the Phase 3 Cohort 4, is that still under consideration?
spk04: So we have chosen 5E13 VT per kg as our final dose, and that's what we're doing in the expansion cohort, and that's what we will do in the Phase 3 study.
spk06: Okay. Okay. Got it.
spk08: Thanks so much.
spk04: You're welcome.
spk08: Thank you. Our next question or comment comes from the line of Gina Wang from Barclays. Ms. Wang, your line is open.
spk14: I wanted to revisit patient eight. When I look back at Avro's data, They had like two biopsy data. The baseline of the PTC-GP3 inclusions also was in the low, like 3.5 to 4 range, but their reduction, of course, that's one year was much higher, 87 to 100%. So here, you know, several questions here. First, you know, should we expect further reduction beyond week 24? And also, second question is, how do you see the PTC-GB3 inclusion, the relationship with part of sites? And then lastly, regarding the phase three trial design, given the current data, do you expect to run an active control study or without an active control?
spk00: So Gina, thank you for your questions. So let me go through each one of them. AvroBio, as I recall, had four patients and they showed biopsy from two. They didn't show what happened with the other two. We're only doing two kidney biopsies, one at baseline and one at 24 weeks. So we'll never know what that patient happens with if they got to one year. I think it's difficult to compare the absolute values between studies. And I have no idea of how they did their assay and how it was reported. So I can only comment on my own study. I believe this is a complicated patient. And I say again, this would not be in our phase three trial if the patient was as described. I'm not claiming that it's the level of GB3 at baseline that is the complication, but it's generally for a patient that is naive to have such a low lyso-GB3 is unusual and is surprising. Now, the You asked about the relationship with podocytes. So the real effect of GB3 is not their deposition in these capillaries, it's their deposition in the podocytes. And the reason that the pathologists, and we got three independent pathologists to read these studies in a very intense, well-controlled manner, is that it's easier to look for inclusions in capillaries than it is within podocytes. But the reality is it's a podocyte that is the thing that goes wrong in Fabry disease. It's the thing that effaces and pulls away from the the Bowman's capsule and then disappears into the urine. If we could measure podocyte GB3 out, I'm sure that would be what people would want to do. But it's a capillary GB3 that is the agency guided to in their original regulatory document.
spk14: Okay. And a phase three child, is it?
spk00: And the phase three, it would be unfair to you to give your plans for phase three now. We spoke to the agency last year, got really good feedback, I mean, really detailed feedback and a sense of where they want this field to go. And now we'll go back to them next quarter with the results of this study. We have a plan. We know where we're going. We've been planning for this phase three for some time. We expect to initiate it at the end of the year. And once we've been to the agency and got confirmation that they're comfortable with that, we'll share that data with you and the rest of the community.
spk14: Okay. Thank you.
spk08: Thank you. Our next question or comment comes from the line of Luca Issy from RBC.
spk07: Issy, your line is open.
spk02: Thank you for taking our questions. This is Lisa for Luca. Just a couple for me on the FAB program. First, on the general health score data, can you comment why the patients at six months did not have a statistically significant improvement But at 52 weeks, they did. I'm just wondering, you know, what changed in that time period. Also, quick one, on Friday, will we also have additional biopsy data available to us? And secondly, or thirdly, rather, the phase three trial design, Is there potential to use the urine podocytes as the primary endpoint, or is it fair to assume that the renal GB3 biopsy will still be used as the primary? Thanks for taking our questions.
spk00: Thank you, Lisa. So let me do the first, the SF36, and I'll pass on to Natalie to do the others. SF36 is an instrument that can only be administered so often, and it's not surprising that for a condition like this where it takes weeks for the substance to be produced from the kidney and then for it to have its effect on the organs, that it will increase and improve with time. If you look at the literature, SF36 declines dramatically over years with Fabry patients, and there's a clear decline over 10 to 15 years, and then when they finally go into renal failure, it gets much worse. So I think it's not significant because the change isn't as as great as it is at 12 months when it's at six months. But it's a really remarkable rise over time. I'm sure you must agree.
spk02: Yes. I mean, grateful to see the health story out of there. But maybe you can comment on whether we'll see more kidney biopsy results at the end of this week.
spk07: Okay.
spk04: So what we're presenting today is the kidney biopsy we have thus far. So the kidney biopsy and the protocol were only done for the patient at the highest dose that we've selected for expansion cohort. So those are the two first biopsies in patient eight and nine, the two first patients at the high dose. And this is what we have at this point. In terms of primary endpoint, podocyte being primary endpoint, Even though, you know, there is more noise about put aside being much more relevant to Fabry disease, this is not a validated endpoint per FDA. So it would be included in our endpoint, but probably not as a primary endpoint.
spk02: Okay. That's helpful. Thanks for taking our questions.
spk08: Thank you. Our next question or comment comes from the line of Nicole Germino from Truist. Ms. Germino, your line is open.
spk13: Thanks for taking my question. Just a couple. So, first off, on February, congrats on all the progress. Given that you have several ERT-withdrawn patients, how much time off ERT And how many patients in the target dose cohort does FDA or clinicians need to feel comfortable with potentially viewing ST920 as a potential ERT replacement, assuming the target dose meets the primary endpoint in a larger Phase III?
spk00: Natalie, can you take that one?
spk04: Yes. So as you can see in the five patients that have been withdrawn in the dose escalation from ERT, we have really sustained superficial surgical level for quite a long time in all of the patients. We haven't had a discussion yet with the FDA on how long they would need to see for, but for ERT patient to be off ERT, but we don't think it's a gating component of starting the phase three.
spk00: And Natalie, you reminded me earlier today that none of these patients that are off ERT are on the 5E13 dose. They're all on the dose escalation phase. We've just withdrawn patients who were on 5E13 to patients, and so we look forward to seeing what happens to their levels in future weeks and months.
spk04: But this is not a gating point to start phase three.
spk13: Got it. And just a quick one for TX200. Can you talk about what potentially might be a good bar for Treg localization for immune tolerance, and should we expect much in the first dose cohort? In other words, of the number of infused CAR Treg cells, how much do you think you need for immune tolerance based on animal data? As in, do you expect 30% of the infused CAR Tregs to be sufficient to be able to recruit natural Tregs? Can you just talk a little bit about that, and as well as the timelines for data presentation after the first dose cohort is completed?
spk00: So we haven't commented on the number of cells, but can I pass you on to Bettina for the clinical question? Bettina?
spk10: Yes, absolutely. So in terms of the cohort one patients, those two patients, and we are expecting to those in early Q2, the third and last patient in cohort one, following which an SNC will evaluate the data. And we're actually in the process of manufacturing the dose for the first patient in cohort two whom we expect to dose this summer. And we have not guided at this stage as to when we might be sharing data. We are making sure that we accumulate the data from these patients in these cohorts to then be able to share that data at an opportune moment.
spk07: Thanks, Bettina.
spk08: Thank you. Again, ladies and gentlemen, if you have a question or comment at this time, please press star 1-1 on your telephone keypad. Our next question or comment comes from the line of Mary Raycroft from Jefferies. Mr. Raycroft, your line is open.
spk05: Great. Thank you, and congrats on the update. I was going to ask a question about FABR2. For the PTC-GB3 inclusion data, when considering the types of patients that you would enroll into a Phase III, can you talk about what you would expect for a Phase III with the proportion of patients who would show a decrease in GB3 inclusions over time versus stable GB3 inclusions? And what would you expect in untreated or controlled patients?
spk00: Murray, thank you for your question. That's why we're looking forward to seeing the other which will form that. We would hope to reduce GB3 in patients similar to patient 9. And we believe that patient 8 is an outlier and an exception.
spk05: Got it. Okay. Okay. And for the sickle cell disease phase 3 CMC and other requirements with FDA, can you talk more about what exactly you've aligned on? And can you clarify if the regulatory minutes will enable a partner to move right into phase three, or is there still some work that needs to be done with regulatory discussions?
spk00: Natalie?
spk04: Yes, thank you. So, you know, we just had a meeting with the FDA where we reviewed our phase three clinical plan and agreed on how to move forward. And we also reviewed our manufacturing strategy, and we agreed on a plan forward. So, we think that You know, if we find a partner, the partner could potentially be in phase three at the beginning of 2023. Four, sorry, 2024. Got it.
spk05: Okay. Thank you very much for taking my questions.
spk04: You're welcome.
spk08: Thank you. I'm sure no additional questions in the queue at this time. I'd like to turn the conference back over to management for any closing remarks.
spk01: Thank you once again for joining us today and for your questions. As a reminder, you can access the earnings release and presentation on the investor relations section of the Sangamai website. We look forward to keeping you updated on our future developments. Thank you.
spk08: Ladies and gentlemen, thank you for participating in today's conference. This concludes the program. You may now disconnect. Everyone, have a wonderful day.
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