Good day, everyone, and thank you for joining us. Welcome to the Sangamo Fourth Quarter 2022 Earnings Conference Call. Currently, all participants are in a listen-only mode. Following the speakers' presentations, we will have a question-and-answer session. I will now hand the conference over to Ms. Louise Wilkie. Please go ahead.

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 Sangamo executive leadership team, including Sandy Macrae, Chief Executive Officer; Mark McClung, Chief Operating Officer; Prathyusha Duraibabu, Chief Financial Officer; Jason Fontenot, Chief Scientific Officer; Nathalie Dubois-Stringfellow, Chief Development Officer; Bettina Cockroft, Chief Medical Officer; and Andy Ramelmeier, Head of Technical Operations. Slides from our corporate presentation can be found at our website, sangamo.com under the Investors & Media section on 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, advancements of our product candidates, advancements of preclinical programs to the clinic, our investment focus and the sufficiency of our resources, our 2022 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 with 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 Macrae.

Thank you, Louise. And good afternoon to everyone joining the call. I'm pleased to share today the significant progress we have made over the last year in bringing potentially transformative medicines closer to patients who need them the most and to convey our outlook for the coming 12 months. 2022 was a year of important clinical and nonclinical milestones for Sangamo. We believe we became the first company to perform a human trial with an engineered CAR-Treg. 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 hemophilia A trial. I'm thrilled with the updated Fabry data from our Phase 1/2 STAAR 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 SF-36 general health care findings, which when taken together, highlight the potential for ST-920 to become a truly compelling Fabry therapy. Based on what we've seen in the competitive landscape, we truly believe we have a potential best-in-class leading gene therapy for this important indication. Nathalie 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 strong potential to bring relief to those suffering from the debilitating aspects of Fabry disease. We are well underway in dosing the first two cohorts 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-Treg companies. This study potentially paves the way for current projects in development as proof of concept and demonstration of safety of CAR-Treg 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-Treg 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 organization. During 2022, we remained dedicated to advancing our pipeline and executing our corporate strategy. In this regard, we're happy to add two new board members to our Board of Directors. Peg Horn brings over 30 years of leadership experience in the biotechnology industry, having led many important strategic and financing transactions. Courtney Beers has also joined us and brings to Sangamo her extensive 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 spending on cell therapy with our CAR-Treg 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 zinc 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 PRECIZN study in sickle cell disease at the American Society of Hematology Annual Meeting in December last year. We've also since made additional manufacturing improvements that we believe could further strengthen potential Phase 3 data and reduce manufacturing costs, which are so important in this indication. However, in today's environment, we must make difficult choices. Today, we're announcing the strategic decision to pause further material investments in Phase 3 planning for the 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 this asset and towards investment in a potential Phase 3 trial for our Fabry program and efforts to accelerate our Phase 1/2 TX200 program. As we stated when the program unexpectedly transitioned back to us last year, we remain committed to the patients and investigators involved in the Phase 1/2 PRECIZN-1 study and expect to complete the study using funds we have already committed, but we'll make no material investments in the program 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, Nathalie, who will discuss the data from our clinical programs in more detail. Nathalie?

Thank you, Sandy, and good afternoon to everyone on the call. This afternoon, we announced updated data from our Phase 1/2 STAAR study evaluating isaralgagene civaparvovec or ST-920, our wholly owned gene therapy product candidate for the treatment of Fabry disease at the 19th Annual World Symposium. As Sandy outlined in his opening, the data presented today supports a potential best-in-class product profile for ST-920 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 supraphysiologic α-Gal A 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 (ERT) have been successfully withdrawn from ERT and have not required the 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 for a cohort of patients 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 SF-36 General Health Survey. Based on this collective data point, we truly believe ST-920 has the potential to become a leading gene therapy for this important indication, and we're actively preparing for a potential Phase 3 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 α-Gal A activity ranging from nearly fourfold to 67 fold of mean normal sustained for over two years for the longest treated patients as of the November 15, 2022 supplemental cutoff date. As I outlined earlier, all five patients who started the study on ERT were successfully withdrawn from ERT, continued to demonstrate supraphysiological levels of α-Gal A activity following withdrawal and remain off ERT today. For naive and pseudo-naive patients in the dose escalation phase, the Cohort 4 patient exhibited significantly higher levels of α-Gal A activity compared to those patients in lower dose cohorts. As of the November 15, 2022 supplemental cut-off date, the first three patients dosed in the extension phase at the 5e13 vg/kg dose exhibited a rapid increase in α-Gal A activity following dosing sustained for up to 14 weeks as of the last date of measurement. The fourth patient had increased to within normal range at four weeks of dosing. The first female participant in the study demonstrated a similar response profile to males as of the cutoff date. Gb3 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 system. The kidney biopsy for patient nine demonstrated a high number of Gb3 inclusions, and high plasma lyso-Gb3 level at baseline exhibited an impressive 78% clearance in Gb3 inclusion per paired tubular capillary (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 section kidney from baseline and six months biopsy, adjudicated 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 Gb3 inclusion and the reduction in urine podocyte loss support a favorable impact on the progression of Fabry nephropathy and indicate the meaningful nature of this potential therapy. The kidney biopsy for patient eight, who exhibited a lower number of Gb3 inclusions and lower levels of plasma lyso-Gb3 upon baseline, demonstrated stable PCT inclusion six months post dosing. This patient also exhibited an impressive 97% reduction in urinary podocyte loss up to six months, which, coupled with the significant increase in α-Gal A activity along with the reduction of lyso-Gb3 after dosing, provides evidence of a potentially favorable effect on Fabry nephropathy. In addition, changes in general health care for patients in the dose escalation phase from baseline at week 52 were statistically significant with a mean increase in general health score of 19.6%. For context, a 3 to 5 point change in any SF-36 score is a minimally clinically important difference. With regard to lyso-Gb3 levels for naive and pseudo-naive patients who have baseline levels of lyso-Gb3 that started high, patients experienced a 46% to 65% reduction in levels following treatment and continued to decrease for two patients until the data cutoff. For the first time in the study, and with the highest dose, a 54% reduction in plasma lyso-Gb3 levels 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 lyso-Gb3 levels following ERT withdrawal remained within the range of levels and variability normally observed in patients treated with ERT. In this patient, α-gal A activity remained elevated, and no patient had experienced symptoms requiring the resumption of ERT as of today. As of the October 20, 2022 cutoff date, ST-920 was generally well-tolerated in the 13 treated patients with no treatment-related adverse events greater than grade two and no treatment-related serious adverse events. No prophylactic corticosteroids or other immune modulating agents have been administered. This data is being presented in more detail by one of our study investigators, Dr. Robert Hopkins this coming Friday, February 24th, during a session from 8 to 9 AM Eastern Time and doing a poster presentation from 3 to 4 PM 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 20, 2022 cutoff date, we have dosed an additional four patients in the expansion phase to achieve a total of 17 patients dosed in total. We have also withdrawn an additional two patients from ERT. A total of 20 sites are now active and recruiting, progressing the study to 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 pain and encephalopathy, which was deemed possibly related to treatment. The patient has since fully recovered, and the Safety Monitoring Committee has determined that the study may proceed without modifications. No similar events have been observed in any of the 16 other patients dosed in the study to date. We continue to plan for a potential Phase 3 trial with our strategy in the US 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 extension 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 1/2 STEADFAST study, our wholly owned TX-200 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 patients dosed continue to do well. The third patient has received their kidney transplant. We have successfully manufactured their personalized TX-200 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 pre-screening and continue to enroll, as Sandy outlined, progressing this study quickly but safely is our top priority. As such, we're discussing with regulators options 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 PRECIZN-1 study of BIVV003, a zinc finger nuclease gene editing autologous cell therapy product candidate for the treatment of sickle cell disease at ASH. The data show that total hemoglobin and hemoglobin-F levels were maintained up to 30 months for the longest treated patients and that BIVV003 continued to remain generally well tolerated across the five patients dosed, with no treatment-related adverse events. Importantly, this was the first opportunity to present data from a patient dosed with a product candidate manufactured using our improved process. At six months following treatment, patient five exhibited a fetal hemoglobin level of 45% and total hemoglobin of 12.4 grams per deciliter, which is significantly greater than the level observed in patients dosed with the original manufacturing process. Based on these results, we believe BIVV003 is a competitive potential treatment. As Sandy indicated, we have been working on further improvements to the Phase 3 manufacturing process, which we believe has the potential to enhance the final product. The learnings from which we are carrying across our Treg manufacturing efforts. We have also progressed clinical and manufacturing activity in anticipation of dosing patient seven in the Phase 1/2 study, and have agreed on 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 3 trial, as we believe this therapy has strong potential to help improve patients' lives. Finally, dosing progress in the Phase 3 AFFINE trial of giroctogene fitelparvovec, 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 anticipated in the second half of 2024. I will now turn the call over to our Chief Financial Officer, Prathyusha, for an overview of the financial results.

Thank you, Nathalie, and good afternoon, everyone. We are really pleased with our accomplishments for the year, including the promising data emerging from our Fabry program and the progress of our CAR-Treg 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 raised during 2022 through the issuance of equity under our aftermarket offering program. During 2022, we invested our resources in progressing important clinical and nonclinical milestones, while operating a focused and lean organization. In these tough financial markets, we'll continue to seek ways to streamline spending while advancing programs and thoughtfully raising capital to create long-term value for our shareholders. Turning to our 2023 full year guidance. We expect our full year non-GAAP operating expenses to be between approximately $275 million to $295 million. This range excludes estimated non-cash stock-based compensation expense of approximately $35 million. During 2023, we will continue to focus our resources on programs that we believe will create long-term value for our business, including our clinical assets ST-920 and TX200 and our preclinical CAR-Treg and CNS pipeline. Additionally, about 8% of our 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.

Thank you, Prathyusha. 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 hear 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 with Fabry Phase 1/2 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 have 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 customary reductions. We are also progressing our preclinical programs with pace and are excited by the data we have 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-Treg and CNS programs. We will also continue to advance our AAV capsid delivery capabilities, which are increasingly attracting the interest of potential partners. As always, we are working diligently to bring to patients what we believe to be improved treatment options for diseases. The unmet medical needs drive our work 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.

Our first question or comment comes from Ritu Baral from Cowen.

Sandy, I wanted to ask you about your comments around Phase 3 interactions and as usual, my question will have about three different parts. One, are you looking for any particular follow up…

Can I interrupt you, since we don't miss the question? Your line is a little garbled. Is there a way you can be clear?

So a couple questions, Sandy, on your Phase 3 plans and as usual, my question will have three parts. One, can you comment on the podocyte turia that you reported with your data today? There's some additional posters here at world on podocyte turia, and is that sort of gaining steam as a biomarker of import in the disease? And then further as we look at the expression curves on Slide 15, is there any particular follow up for expression that you are waiting to achieve before you finalize your Phase 3 design with the agency? And then I have a very quick follow-up.

The first one is about podocyte turia 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 Nathalie about the levels of expression and how long they last, and are we waiting for a specific time to declare success? Is that correct?

And finalize the Phase 3 design with the agency.

Well, I think I can maybe do and help you both on. So as we're always looking for markers of disease and ways to show the success of our program, the podocyte—Fabry causes a podocytosis, which means that the little cells about 500 of Bowman's capsule disengaged from the capsule and fall into the urine; they're terminally differentiated. So once they're in the urine, they're still going back and there's no new ones created and you detect them in the urine. Now this is a technique that is used—it 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, and 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 pseudo-naive, because otherwise the results may not be interpretable. So there'll be future patients in the expansion cohort that will be looking forward to share with you. And then I'll answer the second one just for ease of time. You said is there some length of treatment that we are waiting to declare success? No, is a 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 we are now—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 and 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 who are up to 17 now, I believe is the number that have been treated, we have the biopsy data, we have the SF-36, 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.

And my very quick follow-up, the grade three SAE. Could you clarify what shoulder condition that was? I missed it.

So I'll answer this one quickly, and then I promise Nathalie, 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 shoulder and upper arms was painful, and it was painful to move. He was admitted to hospital four days of treatment—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.

Our next question or comment comes from the line of Yanan Zhu from Wells Fargo.

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 modalities? And also another question on this data is patient eight had a good response on podocyte loss, but no reduction in Gb3 inclusion. How do you see this phenomenon? And then I have a question on TX200.

I'm going to pass this on to Nathalie, our Head of Development.

Regarding the Gb3 inclusion in the kidney, this has been reported for ERT. Usually, there is a reduction of similar percentage in ERT treated patients at six months or a year. Some—not all patients respond to ERT treatment, and the Gb3 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 big and encouraging, because we have really indication of reduction in loss of podocyte. In terms of patient, this is a difficult patient because not only does this patient have Fabry disease, but he also has type two diabetes and 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.

And just to add a little to that, this patient would not be included in our Phase 3 because the lyso-Gb3 starts low. We will have some kind of exclusion criteria that allows us to segment our patients with this. And when we showed this to several investigators and renal experts, they were not surprised at all by this; they said this happened and it was—it's recognized across the other treatments.

TX200, you mentioned you're exploring the 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 visibility to timing of data, initial data from this study?

So I'll take this one for you. It's based on safety and practicality, and the dose has been 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 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 compelling results and also offers the best chance to the patient.

And timing of data?

We will be collecting data throughout the year, and we will show the data as soon as we have a complete data package.

Our next question or comment comes from the line of Gregory Harrison from Bank of America Merrill Lynch.

This is Mary Kay on for Greg. Just looking at the Fabry program here. So in the presentation, we see that two expansion phase patients, 11 and 12 still at early stages of follow-up at the cutoff. Maybe—and they are also still in 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?

Nathalie, can you take this?

So those patients, 11 and 12, that are in the inspection phase have been withdrawn from ERT since the data cutoff. So they are not on ERT at this point. I didn't get the end of your question.

So what factors go into making the withdrawal process decision?

So in the expansion phase, the investigator can 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 the normal level of α-Gal. A patient treated thus far. So we want to wait until we have above—at least normal level or above normal level, which we see in all our patients.

In the initial phase, we had to—it was right for us to leave it to the investigator's discretion, because they obviously care a good deal about their patients. And when they saw that five—as each one saw someone else taking their patient off, they gained much more confidence. And now that the five of them are off 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.

Our next question or comment comes from the line of Ben Burnett from Stifel.

I also had a question about the Fabry program ST-920. You have a few patients with cardiac involvement. I guess first from the baseline data. Are you seeing any changes on cardiac parameters; is that something you're able to monitor?

Nathalie, can you take this?

So we are looking at this. These 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 patients, and we're monitoring the cardiac involvement as we go. But we haven't really disclosed anything yet on the cardiac data at this point.

We have anecdotal reports from the investigators on these patients. So their cardiac condition is stable and their pedoedema has reduced. But as Nathalie said, that part of the study 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 in what Freeline said to 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, but it's a significant health risk for Fabry patients. And with our results showing that we can have an effect in the kidney, there's no doubt 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.

And I also wanted to ask a question kind of on the heels of the last discussion point on kind of—well, physicians look at to sort of gain confidence to wean people off of ERT for the folks that are on it. And really I guess once they're off, what variables do they look at when considering the durability of effect and whether or not they need to restart enzyme replacement therapy? And you showed some interesting SF-36 clinical score data. Is that like—how big of a piece of that is that for physicians assessing durability?

Nathalie, if you take the first bit, how they put patients back on…

So the principal investigators know their patients very well. They have regular visits, and the decision to resume ERT is based really not on biomarkers but how the discussion goes in terms of the health of the patient, how the patient feels. And so far, the patients are doing well, as demonstrated by our SF-36 analysis, and there's been no need for the resumption of ERT in any of the patients that I've been withdrawn thus far.

And I'm so glad you asked about the SF-36. The SF-36 is a real standard of general patient health developed 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, antimigraine drugs. And very rarely do you get a budge in the SF-36. 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 who 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 they feel off ERT, it's the equivalent of the SF-36. It's a general indicator 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 patients seeming to feel better. It's that package that I think is really compelling.

And just one point of clarification, and apologies if I missed it. Is the go-forward dose for the Phase 3 cohort four still being— is that still under consideration?

So we have chosen 5e13 vg/kg as our final dose, and that's what we're doing in the expansion cohort, and that's what we'll do in the Phase 3 study.

Our next question or comment comes from the line of Gena Wang from Barclays.

I wanted to revisit patient eight. When I look back at the previous data, they had like two biopsy data. The baseline of the PTC Gb3 inclusions also was in the low like 3 to 4, 3.5 to 4 range, but they are reductions. Of course, that's one year with much higher 87% to 100%. So here—several questions here. First, should we expect further reduction beyond week '24? And also, second question is how do you see the PTC Gb3 inclusion, the relationship with podocytes? And then lastly regarding the Phase 3 trial design. Given the current data, do you expect to run an active control study or without an active control?

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 are 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 how they did their data and how it was reported. So I can only comment on my own study. I'm not—I believe this is a complicated patient. And I say again, this would not be in our Phase 3 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 relationship—you asked the relationship with podocytes. So the real effect of Gb3 is not their deep position in these capillaries; it's their deep position in the podocytes. And the reason that the pathologists and we got three independent pathologists to read these studies in a very intense and controlled manner is that it's easier to look for inclusions in capillaries than it is within podocytes. But the reality is it's podocyte that is the thing that goes wrong in Fabry disease. It's the thing that faces and pulls away from Bowman's capsule and then disappears into the urine. If we could measure podocyte Gb3, 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.

And the Phase 3 trial design?

And the Phase 3, I would be—it would be unfair to you to give you our plans for Phase 3 now. We spoke to the agency last year and got really good feedback—I mean, really deep 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 are going. We have been planning for this Phase 3 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 are comfortable with that, we will share that data with you and the rest of the community.

Our next question or comment comes from the line of Luca Issi from RBC.

This is Lisa on for Luca. Just a couple from me on the Fabry 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? And just wondering 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 3 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?

So let me do the first, the SF-36, and I'll pass on to Nathalie to do the others. SF-36 is an instrument that would be administered so often. And it's not surprising but for a condition like this where it takes weeks for the substance we produce 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, SF-36 declines dramatically over years with Fabry patients, and there is 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 changes, 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.

Yes, I mean, grateful to see the health scores out of there. But maybe you can comment on whether we'll see more kidney biopsy results at the end of this week?

So what we're presenting today is the kidney biopsy we have thus far. So the kidney biopsy in the protocol were only done for the patients at the highest dose that we've selected for the expansion cohort. So we have—those are the two first biopsies in patients 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 a primary endpoint. Even though there is more noise about podocyte being much more relevant to Fabry disease, this is not a validated endpoint for the FDA. So it would be included in our endpoint, but probably not as a primary endpoint.

Our next question or comment comes from the line of Nicole Germino from Truist.

Just a couple. So first off on Fabry, 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 the FDA or clinicians need to feel comfortable with potentially viewing SF-920 as a potential ERT replacement, assuming the target dose meets the primary endpoint in a larger Phase 3?

Nathalie, can you take that one?

So as you can see in the five patients that have been withdrawn in the dose escalation from ERT, we have really sustained supraphysiological levels 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 the ERT patients to be off ERT. But we don't think it's a gating component for starting the Phase 3.

And Nathalie, you reminded me earlier today that none of these patients are off ERT and are on the 5e13 dose. They're all on the dose escalation phase. We've just dosed—we've just withdrawn patients who were on 5e13, two patients, and so we look forward to seeing what happens to their levels in future weeks and months.

This is not a gating point to start Phase 3.

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? And of the—in other words, like 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 like 30% of the infused CAR-Tregs to be sufficient to be able to recruit natural TReg? 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?

So we haven't commented on the number of cells, but can I pass you on to Bettina for the clinical question. Bettina?

So in terms of the cohort one patient, we’ve dosed two patients, and we are expecting to dose in early Q2 the third and last patient in cohort one, following which an SNP we’ll 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.

Our next question or comment comes from Maury Raycroft from Jefferies.

I was going to ask a question about Fabry too, for the PTC Gb3 inclusion data. When considering the types of patients that you would enroll into a Phase 3, can you talk about what you would expect for a Phase 3 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?

Maury, thank you for your question. That's why we're looking forward to seeing the other renal biopsies, which will form that. We would hope to reduce Gb3 in patients similar to patient nine, and we believe that patient eight is an outlier and an exception.

And for the sickle cell disease, Phase 3 CMC and other requirements with the 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 3, or is there still some work that needs to be done with regulatory discussions?

So we just had a meeting with the FDA where we reviewed our Phase 3 clinical plan and have agreed on moving — how to move forward. And we also reviewed our manufacturing strategy and we agreed on the plan forward. So we think that if we find a partner, the partner could potentially be in Phase 3 at the beginning of 2023—2024.

Thank you. I'm showing no additional questions in the queue at this time. I'd like to turn the conference back over to management for any closing remarks.

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 Sangamo website. We look forward to keeping you updated on our future developments. Thank you.

Ladies and gentlemen, thank you for participating in today's conference. This concludes the program; you may now disconnect. Everyone, have a wonderful day.