Sangamo Therapeutics, Inc.

this year through our European colleagues.

Got it. And then my quick follow-up is, just beyond renal transplant, will conditioning be required for CAR-T reg therapies and other chronic disease indications in either autologous or allogeneic settings?

Well, depending on the cell therapy, preconditioning is required for, I think, everything that's been required preparation of the bone marrow for the engraftment. I don't know of any examples where preconditioning has not been used. There are a number of preconditioning protocols, so there's constant work to reduce the patient burden with respect to that preconditioning. But in order to ensure adequate engraftment, typically these are being used.

Great. Thanks so much. Awesome.

The next question comes from the line of Luca Isi from RBC Capital.

Oh, great. Thanks so much for taking my question. Congrats on the progress. I have two quick ones. Maybe on Fabry, obviously very impressive serum biochemical response here, but wondering what's the plan on actual kidney biopsy. Would you look at kidney biopsy directly in Phase III, or would you look at them in the expansion cohort or trial? Any call there would be great. And then maybe circling back on hemophilia A, just to be clear, Was the event of deep vein thrombosis reported before or after the clinical hold was lifted? In other words, did the FDA lift the clinical hold fully aware of this event, or was that not the case? Thanks so much.

Thank you for your question. So Bettina's taking the questions for Fabry disease. So Bettina, please.

Yes, so thank you for the question. So as far as kidney biopsies are concerned, We have now started doing kidney biopsies in the cohort four patients, the two cohort four patients that we have enrolled and dosed. These are two naive patients, and as such, kidney biopsies are a good setting for these patients, and we will continue to do so in naive or pseudonaive patients going forward, regardless of which part of the study that is in.

Thank you, Bettina. Rob, can you help us with the timing of the clinical hold and the DVT patient?

Yes. So just to set the timeline, the Pfizer instituted a voluntary hold, and then this was followed shortly thereafter by a clinical hold by the FDA. Then the DVT occurred, and there was no additional regulatory response after the DVT. We've disclosed that the patient had been enrolled in the trial despite a history of prior DVT, which would be exclusionary normally. But the clinical hold was lifted with that knowledge of a DVT. And Pfizer, as we've announced, has planned to resume the trial likely in the third quarter of 2022. Super helpful.

And if I may, why was that patient enrolled in the first place? It looked like That was a patient that was supposed to be excluded, so I'm wondering if you have any color in that. Thank you so much.

I don't have insight into that particular protocol violation, but the patient was indeed enrolled with knowledge of a prior DVT. My understanding, our understanding of this came after all the events were

And you can be certain that the investigators are now reminded that they shouldn't enroll patients with previous history of DVTs. And I'm sure the label will reflect this once the drug is available on the market.

Got it. Thanks so much, guys. Super helpful.

The next question comes from the line of Ben Burnett from Stiefel.

Hi, this is Kelly Breeze on for Ben Burnett. Thanks for taking our questions. I guess really fast, maybe following up a little bit on prior question, but regarding the Fabry disease program, can you give us a sense of the range of follow-up time that the patients in the trial currently have, including both the ones previously on ERT and the ones who were naive, and then maybe how much follow-up time we could expect to see at the update that's expected in the second half of 2022? Thank you.

Certainly, we're happy to do that. Bettina, can you give some color to that?

Yes, absolutely. So we presented our Fabry data for the first few patients at World this year. And the first patients were enrolled approximately, definitely more than a year ago. The first two or three patients are now in the follow-up study, which means they are beyond one year of follow-up, so up to around 15 or 18 months of follow-up for the first patient. And the last two patients are the patients enrolled in cohort four. So for cohort four, the last patient had approximately four weeks, I would say, of follow-up, and we anticipate that data for these nine patients, in particular for the cohort four patients, to be reviewed at an upcoming safety monitoring committee meeting. And we plan to then share data at an upcoming meeting likely in early or later in this year.

And the thing that's been most impressive, Bettina, has been how sustained the levels of alpha-gal have been in both patients on ERT and patients that are not on ERT.

Exactly. We're very pleased with the, especially with the alpha-gal enzyme activity levels for these patients. And in fact, the safety and tolerability as we've gone through with this thoughtful dose escalation process has been very, very comforting. And so we look forward to sharing all of that data later this year.

Okay, thank you so much. If you could also, just a quick question on the sickle cell disease program. I know you dose the fifth patient with an improved manufacturing method. I was wondering if you could elaborate a little bit exactly what those improved methods were at all. Thank you.

We haven't been talking about that. We're very pleased that our friends at Sanofi had been working on that for some period of time now. And so this new patient is the new manufacturing method. So we're very careful that it's not a sufficient change to make it a new product. But it's all... it maximizes the chance of long-term progenitors, which we think are essential for the engraftment and the production of hemoglobin F and the prevention of sickling events.

Awesome. Thank you so much for that question.

Next question comes from the line of Greg Harrison from Bank of America.

Hey, good afternoon. Thanks for taking our question. On sickle cell program, what factors are driving your decision process on the future of this asset as you move forward, either on your own or with a new partner? Where do you see the points of differentiation for your product? Mark, can you take this one?

Sure. Yeah, so obviously our first priority right now is to complete the Phase 1-2 precision trial to try to get a sense of whether the new manufacturing process indeed has an effect on the clinical results. Obviously, we're cognizant that the competitors, including CRISPR-Vertex, are guiding in terms of when they're planning on filing. We will basically take a look at the program if we feel it's competitive. then we will either advance that ourselves or look for someone to advance the program with if we feel that that increases the likelihood that we would be able to get that to patients earlier. I think one thing to keep in mind, you know, with sickle cell disease is that there's about 100,000 patients in the United States of which 20 to 30,000 are severe. If you take a look at the ability to service patients with these personalized cell therapies, effectively, you're limited in terms of your ability to reach patients based on your manufacturing capacity. And so we believe if we've got a competitive profile or if the data suggests we've got an improved profile, then there's an opportunity to service that important disease area. And we'll provide the appropriate updates on our plans when we get there. Great. That's helpful. Thanks.

The next question comes from the line of Gina Wang from Barclays.

Hi. Good afternoon. This is Hershida on for Gina. Thank you so much for taking our questions. I had two on ASGCT. So the first one, again, on the zinc finger architecture for high-efficiency-based editing. I think in your abstracts you noted exploring deaminase domains from other bacterial toxins to improve performance, and you know that one domain led to 60% editing in human T cells. I was curious as to if you could disclose at this point how many deaminase domains you explored and what was the general range of editing you observed. And the second is a quick clarification. For the CAR Treg program, On Steadfast, there was a poster that you'll be presenting at ASGCT. Is this on trial design, or are we going to see data from the first patient? From your prepared remarks, I'm guessing not, but just wanted to confirm. Thank you so much.

Okay. Jason, just before we go to that, Louise, can you say about the –

Yeah, so the Steadfast poster that we'll be presenting at ASGCT is a trial-in-progress poster. We will not be sharing any clinical data coming from that trial at ASGCT.

Jason, can you say something about base estrogen, please?

Yeah, so on the question of the different domains that we explored, we explored, you know, a number of domains, I would say probably over 20. I'm not going to get into the details on that right now, but the team did an incredible job of mining the known proteome for potential deaminases, and we've identified one that is particularly active and effective as a therapeutic. So that's the one that we've moved forward and we believe it has all of the qualities necessary to deliver therapeutic grade base editing in the context of our zinc finger architecture, which as we went over earlier, allows us to design a base editor that is highly compact and capable of being delivered by a single AAV. and also obviously useful for ex vivo engineering or any other delivery platform.

Great. Thank you so much.

Thank you for your questions.

The next question comes from the line of Mari Raycroft from Jefferies.

Hi, this is Kevin on for more. Just a quick couple of questions. First, on the TX200 patient, Could you say how that patient's doing and potentially whether you're getting any Treg persistence or expansion? And then could you talk more about how often you're assessing blood biomarkers and what will drive your decision-making process to reduce immune suppressants?

There's very little I can say at the moment. The patient is doing well. We haven't given any indication yet when we're going to talk about any biopsy data or any biomarker data. So it's early days in this study, and we look forward to sharing that later in this year, probably more likely at the beginning of next year.

Okay, great. Thanks. That was actually my follow-up, if we could potentially see data by the end of this year and what might be included in that data update. And then if you could talk about what's guiding your higher or alternative dosing strategies.

So I think you should expect beginning of next year for the data. And if it comes sooner, that would be a bonus. We've already planned the number of cells for low, medium, and high doses. And we'll be looking to see the from the very first dose, because these cells, when they go to the, when they find the antigen and are activated, our hope is they expand, so any one of the doses could have a therapeutic effect. So this is a trial we will be watching and learning as we go.

Great, thanks.

The next question comes from the line of Reedu Baral from Cohen.

Good afternoon, guys. Thanks for taking the question. Sandy, have you confirmed that cohort four in the FABRI trial is going to be the expansion cohort? And I guess if that's still TBD, how much follow up do you need from cohort three and cohort four? And do you need biopsy data from cohort four to make that final determination of what is going into the expansion cohort.

Bettina, can you take that one, please?

Absolutely. Thank you, Sandy. So cohort four is our final cohort for the dose escalation phase. We have dose cohort four at 5E13. The protocol allowed for us to reach this dose. And that was based on the safety and tolerability profile. As I mentioned earlier, we will be holding a safety monitoring committee meeting. This will be held by Q3. And at that point in time, all of the data that we have up until that point will be used to assess our next steps into the best way forward for our expansion phase. And we intend to those patients in the expansion phase as soon as we help, as we gather the safety monitoring committee and make that decision to move forward. So there won't be any biopsy data. We only have baseline biopsy data at this point in time for cohort four. And the data will be based on safety tolerability and biomarker data. Absolutely. Any other time points?

We've been very lucky to have efficacy from the first dose in this and across each one of the doses. So it's an important decision to make. It will be based on understanding the tolerability and maximizing the chance of efficacy.

What time points for the biopsies are you going to look at?

We look at baseline in six months. And so you can expect that we won't have any biopsy data this year. We'll have biopsy data likely towards the, to share towards the beginning of next year.

Got it. And when do you plan on taking CMC all the way up to commercial product? Do you expect to enter the expansion cohort with commercial grade product or will that be for separate pivotal?

So we are in plans to transition to the commercial manufacturing, but we're not guiding on which we're going to use for the expansion cohort right now. But obviously, you know, where it becomes very important for us is to make sure that we've got the commercial, you know, production facility ready for enrolling the phase three program. And that way we've got a consistent phase three with our commercialization lot.

Got it. And flipping that to precision and the sickle cell program, the CMC, you did mention that phase three readiness activities are in progress and you've got the, I guess, the tech transfer from Santa Fe occurring with their optimized program. When all that is said and done, will you be at commercial grade product for the SED program or will there be further work to be done?

So we expect to do the tech transfer and be Phase 3 ready as part of the preparation for the Phase 3 plan.

And Phase 3 would be run with commercial product, correct?

Correct.

Great.

Thanks for taking all the questions.

Thank you.

The next question comes from the line of Patrick Truccio from HB Wainwright.

Thanks. Good afternoon. I just have a few follow-up questions actually on the CAR Treg platform. So first, I'm wondering if you can discuss the status of the preclinical CAR Treg cell therapy program, specifically in IBD and MS, and what the timeline to an IND or CTA filing could look like for those programs. And then separately, what learnings, if any, have emerged so far from the TX200 program that could impact the IBD and MS programs?

So I'm going to ask Jason to tell you about his passion for Tregs and the work that is done by our colleagues in Valbonne. We've only just dosed the first Treg patient, so there is no learnings yet that we can apply to the other programs, and we haven't guided on the IND timing. So, Jason, can you give some indication of the progress that you're seeing on the Treg programs?

Yes, thanks, Andy. Yeah, so we have very active preclinical programs for developing CAR T regs for both IBD and multiple sclerosis. We've disclosed that one of the CAR targets for the IBD programs is IL-23 receptor, and I believe that there was a poster presented on that topic at a conference in Europe recently, so I would point you to that poster for details on the program. For the multiple sclerosis program, we have disclosed a CAR-targeting MOG, a protein that's restricted to the CNS, and work is proceeding on both of those, preclinical work is proceeding on both of those programs. We've built a great kind of engine to evaluate, to generate and evaluate CARs through an in vitro and in vivo screening funnel so that we have the optimal CAR that's designed specifically for working in regulatory T cells. And so that work is well underway. and we're now evaluating our core engineered Tregs in vivo models in both of those indications. We're really excited about the work that we've done and the platform that we've put in place. And it's true that while we haven't learned anything from the patients that have been dosed with TX200, I will point out that the investments that we've made in process development and manufacturing, as well as obviously the biological expertise of the team that's working on this, were all developed during the TX200 preclinical efforts and up to this day. And all of that information is obviously feeding into both of those preclinical programs. So we're very excited about our progress. And then the last thing I'll point out is that the other area that we're really invested in is leveraging our link finger genome engineering platform to develop allogeneic Tregs. And we're doing that by both doing engineering of Tregs derived from healthy donors, so the so-called healthy donor route to autologous cell therapies, but we're also doing a lot of work to derive Tregs from IPSCs such that we can engineer induced pluripotent stem cells to be allogeneic and have a kind of continuous perpetual source of Tregs for an off-the-shelf therapy. So we've got a really active Treg program, platform program at the company and tremendous advance in getting the first patient dose, and we look forward to telling you more about the latest developments when it's appropriate. That's really helpful.

Thanks so much.

There are no questions at this time. I am now turning to call back to you, Louis Wilkie.

Thank you once again for joining us today and for your questions. We look forward to keeping you updated on our future developments.

This concludes today's conference call. Thank you for participating. You may now disconnect.