Sangamo Therapeutics Inc (SGMO) 2021 Q4 法說會逐字稿

Good day, and thank you for standing by. Welcome to the Sangamo Therapeutics Fourth Quarter and Full Year 2021 Conference Call. (Operator Instructions) Please be advised today's conference may be recorded. (Operator Instructions) I'd now like to hand the conference over to your host today, Aron Feingold, Head of Corporate Communications. Please go ahead.

Good afternoon, and thank you for joining us today. With me this afternoon on this call are several members of the 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; Rob Schott, Head of Development; and Bettina Cockroft, Chief Medical Officer. Slides from our corporate presentation can be found on our website, sangamo.com, under the Investors & Media section, Events + Presentations page.

This call includes forward-looking statements regarding Sangamo's current expectations. These statements include, but are not limited to, statements relating to the therapeutic and commercial potential of our product candidate, the anticipated plans and time lines of Sangamo and our collaborators for initiating and conducting clinical trials and presenting clinical data, execution of our corporate strategy, advancement of our product candidates, our initial 2022 financial guidance and other statements that are not historical facts.

Actual results may differ materially from what we discuss today. These statements are subject to certain risks and uncertainties that are discussed in our filings with the SEC, specifically our annual report on Form 10-K for the fiscal year ended December 31, 2021. 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.

Thanks, Aron, and good afternoon to everybody on the call. I'd like to start by saying that 2021 was a significant year for Sangamo as we continued to advance the development of genomic medicines for patients across multiple therapeutic areas using our innovative technologies. We are very pleased with our progress despite the challenges of the second year of the pandemic.

We are advancing potentially transformative genomic medicines in the clinic and strategically using our R&D capabilities to pursue indications of unmet need. These efforts are supported by our manufacturing infrastructure, including in-house AAV and cell therapy facilities. Our collaboration partners also help us drive towards our mission to deliver on the promise of genomic medicine, and we believe that this progress positions us as well to generate long-term value for our shareholders.

In 2021, we had executed upon our strategy with several important achievements. First, we and our partners advanced our 3 lead programs while presenting compelling clinical data. Starting with our wholly-owned Phase I/II Fabry disease program, we presented updated data at the WORLDSymposium earlier this month. We're encouraged by the safety and efficacy data we have seen to date. And most importantly, the patients in the study have reported they are feeling better. Investigators are observing improvements in some of the most challenging symptoms, including ability to sweat in the first 3 treated patients.

With the recent changes in the Fabry competitive landscape, we believe we are in a leading position. In the second half of this year, we plan to present additional updated Phase I/II data. We are actively planning for a Phase III study, including discussions with health authorities, patient advocacy groups and investigators. We are also delighted by the emerging Phase I/II sickle cell disease data presented at ASH in December, showing no treatment-related adverse events in the 4 treated patients, improvement across several biomarkers and, most importantly, clinically significant reduction in painful sickling crisis. We anticipate that the next 4 patients treated in this study will be dosed with a product candidate manufactured using improved methods that have been shown in internal experiments to increase long-term progenitor cells. We expect to complete dosing of these patients in the third quarter of this year.

Transition planning of the program from Sanofi to Sangamo is going well, and we are energized to have this asset back in our hands soon as we assess the best way to move the program forward for patients, be that on our own or with a potential partner. Finally, we are encouraged by the follow-up data presented at ASH last year from our hemophilia A program partnered with Pfizer. Updated Phase I/II results show sustained bleeding control in the highest-dose cohort through 2 years following gene therapy.

Regarding the Phase III study, Pfizer has announced that it hopes to obtain agreements with the health authorities to resume their AFFINE trial in the first half of 2022. The trial was previously paused when some of the patients experienced Factor VIII activity greater than 150% following treatment. Pfizer is currently in the process of submitting a protocol amendment to health authorities in the countries where this trial is being conducted and preparing responses to the FDA clinical hold. Over 50% of the patients have been enrolled in the Phase III AFFINE trial.

Second, we're progressing our preclinical candidates based on our second-generation technologies: CAR-Tregs for autoimmune disease and zinc finger transcription factors for neurological disorders. We have enrolled and expect to dose soon the first patient in our lead CAR-Treg program, where we are evaluating TX200 for the prevention of immune-mediated rejection in HLA-A2 mismatched kidney transplant from a living donor. We believe that this will be the first patient ever to be dosed with a CAR-Treg therapy and that we are in a leading position with several companies following us into this very promising area.

We believe that our expertise across multiple technology platforms, robust cell therapy infrastructure, supported by our manufacturing facilities and genomic engineering capabilities and internal strategic and operational synergies comprise a differentiated CAR-Treg platform from which we can potentially offer patients advanced genomic medicines.

In addition to our proof-of-concept study of TX200, we are progressing our preclinical allogeneic renal transplant rejection study as well as inflammatory bowel disorder in multiple sclerosis programs, including presenting in the first preclinical data from our allogeneic IL23R-CAR-Treg candidate in IBD last year. And finally, with regard to our zinc finger protein transcription factor technology in treating CNS disorders, in addition to our partner programs with Biogen, Novartis, Takeda and Pfizer, we're advancing multiple internal programs.

Third, we continue to hone our differentiated genome engineering platform, including improving the specificity, precision and efficiency of our core zinc finger proteins. We're also progressing our capabilities from nucleases to repressors, activators and even base editors and are excited about our progress. We see Sangamo's capabilities representing a one-stop shop for a range of genomic engineering capabilities that are designed to be applied therapeutically.

Fourth, we continue to work diligently with our collaborators, supporting the advancement of our partner programs in the clinic while driving research efforts for preclinical programs for which we receive reimbursement from our partners. These partnerships have been a key component of our development strategy and continue to drive value for Sangamo. We believe that the buy-in from pharma validates our mechanistic approach across a range of advanced modalities and enables us to benefit substantially from our partners' domain expertise to develop high-quality therapeutics for patients. The capital provided by our partnerships helps to advance our internal pipeline of assets while providing our partner programs with the resources needed to advance the development of these potentially transformative therapies more quickly.

Fifth, we completed and brought online our cell therapy manufacturing facilities in Brisbane and Valbonne and now have operational AAV and cell therapy facilities in-house. We believe these facilities provide many strategic advantages, including flexibility and control capacity to support our R&D needs, process expertise, geographic diversification and that supports supply chain resilience and a deep intellectual property portfolio.

Sixth, we believe that we have a strong financial position to take us through our key upcoming catalysts. Our diverse and accomplished leadership team and our talented employees are passionate about our mission and have enabled our multiple 2021 accomplishments, setting us up for what we expect to be a strong 2022. I am very grateful to my leadership team and all my Sangamo colleagues for their dedication and hard work in a second challenging year of the pandemic.

And with that, I'd like to turn the call over to our Head of Development, Rob Schott, who will discuss the data from our clinical programs in more detail.

Thanks, Sandy, and good afternoon to everyone on the call. We are delighted by our clinical execution in 2021. We believe the presentation last year of important proof-of-concept data supports late-stage development for our Fabry and sickle cell programs. At the WORLDSymposium earlier this month, we presented updated preliminary results from the Phase I/II STAAR clinical study evaluating isaralgagene civaparvovec, or ST-920, a wholly-owned gene therapy candidate for the treatment of Fabry disease.

As of the November 9, 2021 cutoff date, the gene therapy candidate continued to be generally well-tolerated across 3 dose cohorts in the 5 treated patients with treatment-related adverse events that were assessed as grade 1 or mild. Elevated alpha-Gal activity has been maintained for the 4 patients treated in the first 2 dose cohorts ranging from threefold to 15-fold above mean normal at last measurement. For the 2 patients on enzyme replacement therapy, alpha-Gal activity measured at ERT trough was 15-fold above mean normal at week 52 for the patient in cohort 1 and tenfold above mean normal at week 25 for the patient in cohort 2.

For the 2 ERT pseudo-naive patients, alpha-Gal A activity was threefold above mean normal at week 52 for the patient in cohort 1 and fourfold above mean normal at week 40 for the patient in cohort 2. The 2 patients in cohort 1 have now begun the long-term follow-up study. And at the 1-year mark, alpha-Gal A expression remains robust. Withdrawal from ERP has been completed for 1 patient and is planned for the second patient on enzyme replacement therapy based on the stability of their alpha-Gal A activity following treatment. For the first patient in cohort 3, alpha-Gal A activity has increased into the mean normal range at week 2.

As Sandy noted, 3 of the patients have reported clinical improvement with a greater ability to sweat. This allows for greater exercise tolerance in active individuals. The cardiac magnetic resonance imaging data suggests stabilization of important MRI parameters in 2 patients. This will be followed at intervals to confirm the cardiac benefits of therapy. One patient with a significant elevation in plasma lyso-Gb3 pretreatment showed a significant reduction from baseline of approximately 40% in this biomarker after treatment with ST-920 within 10 weeks after dosing and maintained through week 36.

Patients with lower baseline levels of lyso-Gb3 maintained steady levels through the cutoff date. The sixth patient in the study, who is the second patient in cohort 3, was recently dosed after the cutoff date. We expect to provide updated results from the STAAR study in the second half of 2022 and are currently planning for a Phase III clinical trial.

At ASH 2021, we announced updated preliminary proof-of-concept data from the Phase I/II PRECIZN-1 study of SAR445136 for the treatment of sickle cell disease. As of the September 22, 2021 cutoff date, the most recently treated patients in this study has been followed for 26 weeks and the longest-treated patients have been followed for 91 weeks. In all 4 treated patients, there were increases in total hemoglobin, fetal hemoglobin and percent F cells. None required blood transfusion post the engraftment. The SAR445136 investigational drug product had on-target BCL11A gene modification of between 61% to 78% in all 4 patients.

There were no adverse events related to therapy with SAR445136. One patient had a single sickle cell crisis or vaso-occlusive crisis 9 months after treatment. There have been no additional serious adverse events reported. Additional data from this study are expected to be presented at a medical meeting in 2022, and dosing of patients in this study is expected to be completed by the third quarter of 2022. We are currently collaborating with Sanofi on planning for a transfer of its responsibilities under this program back to Sangamo this June. We look forward to keeping you apprised of future updates regarding these exciting clinical studies.

With that, I'll turn it over to Prathyusha for a financial update. Prathyusha?

Thank you, Rob, and good afternoon. Our financial results for the fourth quarter and the full year are available in the press release we issued and can also be found on our website. I want to reiterate that 2021 was a significant year for Sangamo with execution on many fronts as we continue to progress the advancement of our lead programs, our preclinical research pipeline and our in-house manufacturing capabilities. With approximately $465 million in cash, cash equivalents and marketable securities at the end of the year, we believe that our balance sheet remains strong for continued execution across our platform and programs.

Turning to our initial 2022 full year guidance. We expect non-GAAP operating expenses to be between $280 million to $310 million for the year. This range excludes estimated noncash stock-based compensation expense of approximately $40 million. We expect a significant portion of our operating expenses to be invested in continued progress of our lead programs, including Fabry Phase III planning activities, Phase I/II activity for TX200 and preclinical work in CAR-Treg and CNS indications. We also expect to grow our investment in sickle cells in the second half of the year, following the transfer of program back to Sangamo.

I will now turn the call back to Sandy for closing remarks.

Thank you, Prathyusha. We are excited by where we stand as a company and believe we have a bright future. We are a fully integrated genomic medicine company, building momentum with our novel science, clinical execution and in-house manufacturing. In 2022, we look forward to providing expected updates on Phase I/II Fabry data, selection of a dose for cohort expansion and Phase III planning; dosing of patients in the CAR-Treg STEADFAST trial; Phase I/II sickle cell data and dosing of patients in the PRECIZN-1 study and the transition of the program from Sanofi to Sangamo; and Pfizer's progress with the pivotal Phase III hemophilia A trial.

We will now turn it over to the operator to open the line for questions.

(Operator Instructions) Our first question comes from Nicole Germino with Truist Securities.

Congrats on all the progress. If I can ask a 2-part question. The first one is in the backdrop of other companies experiencing clinical holds with their gene therapy programs, can you address the safety concerns the integration risk around your vector for heme A and for ST-920 for Fabry?

And second, for your CAR-Treg platform, how necessary is it for a kill-switch for regulatory agencies? Or maybe put another way, what gives you confidence that you don't need one?

So thank you for your questions. If I could address the first one, and then I'll pass the second one to Rob. So safety is really important to us, and that's why we look on safety as the primary end point of all of the studies that we've done with our AAV6 vector. We've been really pleased by the safety throughout all of the programs, the MPS programs, hemophilia A and now with Fabry disease. And we're gathering an increasing body of data that convinces us that this form of delivery is safe for the patients that we serve.

Now the choice of diseases remains important because we always have to balance benefit and risk. And we spent a long time thoughtfully gathering preclinical data, sharing it with the regulators, starting at doses that allow us to be sure that patient safety is maximally protected, and then sharing with the community any concerns we have as the trial progresses. I'm delighted with our progress so far. I think it's unfortunate that others have run into difficulties because it does cloud the whole field. It's the advantage of us having a vector that we've worked with and have gathered a lot of safety data.

Rob, can you answer the second one?

Yes. I'd like some clarification, Nicole, on the kill switch and what -- you're suggesting that we program that into the cell therapy so that we can turn off the Tregs, is that the -- yes?

Yes, that was my question. Yes, because a couple of your competitors have a kill switch. Is it necessary for regulatory agencies -- have regulatory agencies had any input on that? And if not, like is it -- do you need a kill switch or what gives you confidence that you don't need one?

Yes. We've not been asked to engineer in a kill switch. Again, these are T-regulatory cells that were engineered through these programs. So they are responsible for inhibiting the immunologic response and rejection in the case of renal transplant. So it's a different proposition than engineering other types of T cells, killer T cells or CD8 T cells.

But I'd actually like to ask Jason to comment on that, too.

Jason, can you help us with some thoughts on this?

Yes. Thanks, Sandy and Rob. Yes, I think what I can say is that we're very confident of the approach that we're using in the TX200 program. We've evaluated the safety and the efficacy of the cells in a variety of preclinical models. And we've been very happy with what we've seen. We've obviously consulted with our own internal experts, clinical, regulatory, safety, and we've had conversations with the regulators. And we're moving forward and we're excited to be dosing our first patient in this quarter.

And other companies take different approaches, but we're confident that our approach is one that offers a -- is going to offer a benefit for patients and we'll be keeping a close eye on patients as they're treated. Obviously, this is a Phase I study where safety is paramount, and that's what our focus is on.

Our next question comes from Yanan Zhu with Wells Fargo.

First on the Fabry program, so you mentioned you will have additional data in the second half of the year. I was just wondering what might be the follow-up. And presumably, this is going to include all 6 patients. So the question is the length of the follow-up and in terms of the end points. I think we can assume ERT as well is an important end point, enzyme level substrate. But would there be any additional clinical end points that's also going to be studied, to be reported at that stage?

Thank you for your question. So this is about the longer-term data on Fabry and what we'll be able to show. Bettina, you've been following this track very closely.

Yes, so thank you so much for the questions. So later on this year, we will have accumulated more data, especially from the earlier dose patients. As you may know, the parent study, these patients have been enrolled into the 1-year study. And patients that have been treated at the beginning have -- some of these patients have now rolled over to the long-term follow-up study, which is an additional 4 years of follow-up in total.

And we will be able to present data on accumulation of the alpha-Gal A expression over time as well as other biomarkers, lyso-Gb3 and, you point out, ERT withdrawal data. And in terms of clinical end points, we will be collecting -- once we dose naive patients moving forward, we will be collecting kidney biopsy data. This will not be available this year at this later update. We can expect that type of clinical data to be presented next year. We will also be presenting an update on patient-reported outcomes. And so really, we -- as we move along, we are also intending to dose more patients, and we have patients currently in screening and at baseline. So patients are going to, we anticipate, be dosed...

So it will give us a wealth of data.

And -- exactly. And some that will be a nice profile that we will be collecting from this wealth of data that will...

What we like from the data we've seen so far is up until the 1-year mark that we have concrete data from, there has been no sense of decline in the 4 patients that have been treated for the longest, that the alpha-Gal is -- remains elevated, that the lyso-Gb3 remains flat, that the patients remain -- still get a bit -- claim a benefit, talk about symptoms like sweating, talk about -- their investigators talk about stabilization of the cardiac MRI. And those are all really encouraging data that it's only through time that we'll be able to understand it. However, I want to be absolutely clear. We are full-on in our planning for the Phase III study and look forward to initiating that as the data from the current study matures.

Right, yes. And looking forward to hearing about the Phase III design. I think maybe too early to ask that question. So I might -- if I may, I'm curious about what you mentioned about base editing programs that you're working on. Obviously, this is going to be based on zinc fingers. So my question is does your base editor retain the nuclease part of the zinc finger nuclease. Or does it forego that nuclease part? The reason I'm asking is because I think in the CRISPR-based base editors, actually, the nuclease capability, i.e., the ability to cut 1 strand of the double-stranded DNA is actually very useful in terms of improving the editing efficiency because it prevents the degradation of the additive strand. So under that light, so I'm interested in what are your architecture for your base editor basically.

Thank you for a very interesting question. So we've been working on base editors for some time, and I'll get Jason to comment in a minute. What gives us great pleasure is that the zinc finger platform allows a range of technologies to be added to the DNA-localizing zinc finger and allows us to choose when double-stranded breaks and nuclease are important or whether things like repression enhancement or base editors are the right things for the right patient, compared to CRISPR where there's a company for each of these.

But Jason, can you comment on the specific question, please?

Sure. Thank you, Sandy. This is a base editor that will not create double-stranded breaks to change a base in the genome. And we're really excited about the advancements that we made, and we look forward to sharing them very soon at the appropriate scientific conference. I don't think I'm going to go into the details of the architecture of the base editor that we've designed, but it's a novel approach and we're very excited about discussing it and deploying it therapeutically.

The reason we particularly like it is it uses a zinc finger architecture that we've had years of experience with and so understand about how to tune and how to increase the specificity. It benefits from the small size of zinc fingers, which are almost 1/10 the size of some of the CRISPR architectures and, therefore, allow it to be packaged in AAV in a way that the standard base editor won't. And it allows us choice and that's what we like and that's what our partners like.

Our next question comes from Maury Raycroft with Jefferies.

This is [Jean] on Maury's line. So actually, I have 2 questions. The first one is can you talk more about where you are at with this designing Fabry Phase III. And what are the gating factors to get all this study being started? That's my first question.

Second one is what else can you talk about the first patients enrolled in the CAR-Treg program? And can you also say if this patient has already been transplanted? And are you currently processing the CAR-Tregs? That's my question.

So let me take the easier one, which is Fabry. Then Mark, can you just talk about where we are with CAR-Tregs in general, please? So from -- we haven't shared anything about the Phase III study. But as I'm sure you know, planning for a Phase III has to be -- has -- takes a long time. And therefore, we've been looking at the design of this and talking to experts for at least 6 months and are pleased with the progress we're making, and we'll share it more broadly at the right time.

Mark, can you talk about the Tregs? Because we're very excited about that.

Yes. So we're about to dose the first patient with our TX200 candidate, and so we're very excited about that. And as we've talked about, we'll be expecting to dose 2 patients by the end of the second half 2022. We're delighted to take this forward because it will be the first opportunity for us to really establish the biologic effect of these agents and really understand what's going on.

And this is critical because our goal is that TX200 establishes the foundation for a portfolio of CAR-Tregs for major autoimmune indications. And so this will inform us using the autologous. In the meantime, we're advancing allogeneic approaches. And as we've disclosed, we've got preclinical candidates against MOG and multiple sclerosis as well as IL23R for inflammatory bowel disease. And so we'll be applying the learnings that we have coming out of this trial as we advance the platform but also those particular candidates.

Our next question comes from Luca Issi with RBC Capital.

Congrats on the progress. Two quick ones. Maybe the first on Fabry. I will not ask you the design of the Phase III. But maybe at a high level, can you just talk about what gives you confidence that you can start a Phase III here without actually having seen the kidney biopsy data quite yet?

And then maybe second on sickle cell disease. Can you just provide any additional color on the new manufacturing process here? What are some of the key parameters that you're optimizing here that gives you confidence that the new manufacturing process will drive better outcome for patients?

Yes. So let me see how I can split this. Rob, can you talk about sickle, please? And the other question, I think you said, was in the absence of -- if I can just make sure we answer this question correctly, in the absence of kidney biopsy data, which we expect to see in '23, how will we decide on the go decision and the design of the Phase III?

As I said, we've been designing this and talking with regulators for some time. And the -- we believe that the data perhaps from AVROBIO, one of our -- which is one of our competitors, where they showed very small changes in alpha-Gal beget changes in the renal biopsy data for lyso-Gb3. That in itself gives us confidence that the alpha-Gal we are seeing should benefit the tissues when we get to that stage. So we have to plan in advance and we have to look at the different doses and the dose response curve and decide which one we take forward as we accrue data.

And with respect to the sickle cell program manufacturing, we have made some process changes. We haven't talked specifically about those process changes. But in internal experiments, we've shown it increases the number of progenitor cells. So we're optimistic that this will carry through into the clinic with better yields.

And we are being very transparent and, I hope, realistic to say that we believe this will result in clinical benefit but until we do the clinical experiment, we can't have a direct correlation. So that's why we too are very interested in seeing the data from these next 3 or 4 patients that will be dosed over the coming months. And I want to say thank you to our friends at Sanofi, who are continuing to drive forward the study during the transition period.

Our next question comes from Ben Burnett with Stifel.

This is Kailie Briza on for Ben. I just had one quick one about Fabry. So regarding the Fabry program, can you talk at all about the lyso-Gb3 biomarker? Specifically, under what situations would you expect the biomarkers to move with the ST-920 treatment?

And then our second one is about hemophilia, and I was just wondering if their -- if Pfizer has already received feedback from the FDA with the necessary steps to remove the clinical hold or if this is something they have yet to do.

So Bettina, can you do Fabry and, Rob, could you do hemophilia, please?

Yes, thank you for the question. So lyso-Gb3, you will have seen, we presented data on at the WORLDSymposium just a couple of weeks ago in San Diego. And different patients are exhibiting different baseline levels to start off with of lyso-Gb3. And so the movements that we can expect are going to differ based on this as well.

I'd like to point to patient #3, who is the patient -- first patient in cohort to -- whose lyso-Gb3 started higher than the other patients and for whom we've had significant, more than 40%, reduction and that within the first 10 weeks post-infusion. And that reduction has been maintained over time until the latest follow-up. And so I -- what we look forward to is seeing the next patient we're going to be dosing, seeing how their lyso-Gb3 fares over time, depending on that baseline.

And this phenomenon, Bettina, has been seen in other -- in all the programs. It's got to be high to go down.

It's important to point that out. Thank you, Sandy, because we have seen the same in other programs that the lyso-Gb3 really does need to be at significantly high levels for us to be able to impact it with a gene therapy approach. And that has been seen across other programs. And so we're confident that we're seeing data that is going to be encouraging as we also look at our next patients dosed at a higher dose.

And Rob, hemophilia?

Hemophilia. First, I'd like to acknowledge the terrific partnership with Pfizer on this program and remind everyone that the trial was more than 50% enrolled at the time of its pause. Pfizer has guided us and the markets that trial will resume or planning to resume in the first half of 2022. So without getting into the specifics where we are with responding to regulatory authorities, I can point toward that guidance of resumption of the trial in the first half of this year.

It's going very well, and they're putting all their efforts into it.

They are aggressively and enthusiastically pursuing this trial.

Our next question comes from Aspen Mori with Bank of America.

Maybe you can just talk through your updated thinking. As you move -- as you transition the sickle cell asset over to you guys, maybe just talk to your updated thinking on how you see that progressing in terms of taking it alone or maybe partnering it out. And if the priority is partnering, if there's any preference for someone with more of an OUS presence as that was kind of Sanofi's niche in your prior partner.

And then the second question, some of your peers have implied that for the gene therapy space, FDA may be stricter on therapies or indications where there's already approved therapies available, not including gene therapies. Do you think that's a fair assessment? Or has that at all been -- have you kind of seen that dynamic play out within your interactions with the FDA?

So I'm going to ask Mark to talk about our strategy around sickle, and then I'll touch on the general comment on the agency.

So Aspen, I mean, obviously, we've heard December 30 that they had made that strategic decision to transition sickle cell back to us. As Sandy mentioned, the team's been working very hard on the transition. We're very pleased with the engagement we have with Sanofi as we progress to the transition plan, which will culminate around June 28 of this year.

Our highest priority right now is to ensure that we can complete the Phase I/II PRECIZN trial, as Rob just mentioned, utilizing that new manufacturing process, which we hope will come through and demonstrate even better results in those 4 patients. That totality of that data will inform kind of the way we want to proceed for it. In the meantime, the teams have engaged the authorities, both in terms of feedback on manufacturing as well as preliminary discussions around the approach to Phase III. So at the appropriate time, we'll provide an update for that.

In terms of the geographies and partnerships, we're not going to comment on that now. It's too early to provide a perspective on that. But I would remind you, right, that in the United States, there are about 100,000 sickle cell patients, of which 30,000 of those patients are severe. Outside of the U.S., there's about 150,000 patients. This is a devastating disease that affects a particular population, and our commitment is to do whatever we can to make sure that patients get access to this medicine if it's a differentiated medicine and we'll know more as we get the clinical data. And our commitment is to ensure that we take it forward if the data suggests it should get to patients.

And if I could talk to the more general one about the agency. We have a great relationship with the agency, and I have an enormous respect for Peter and the FDA and what they do because I think one has to understand the exponential growth in this field that they have to deal with and to train people and to stay ahead of the emerging data and understanding.

I think there is a bit of a reality check that we're watching now, which is more medicines are in the clinic, more new vectors are being tested and some of them will be firm to have challenges. And that's inevitable in any new field, which takes me back to what I said to one of the earlier questions about our vector having had years of testing in many indications.

So with the team at Sangamo having filled many INDs and understanding that preclinical and toxicology data necessary to ensure safety and about the inherent belief at Sangamo that is -- everything is about the patient and that we put patient safety first and we'd be the first to have that conversation with the agency if we are ever concerned about what we're seeing. But at the moment, we haven't felt any difference in the agency's approach and are glad to have them as partners in the development of our medicines.

Our next question comes from Ritu Baral with Cowen.

I had a question on the PRECIZN-1 -- well, the sickle cell program in general. I think at a high level, I'd love to know the metrics by which you'll gauge sort of where the program will fit in a landscape that's getting more and more crowded. To drill down on that, I guess what we're looking for is HbF levels but also percent F cells. I guess which one do you think will be a more important tell on the ultimate clinical benefit? And especially since you're reaching such high levels of percent F, do you need to show that sort of 90s level of percent F cells in a certain proportion of treated patients for you to say that this is going to be the preferred therapeutic?

So I'm going to ask Rob to comment on the technical bit and Mark on more the strategic. But what I would remind you that we have -- we're in the clinic, we have clinical data. There are many -- the competitive landscape is largely of newcomers from other editing modalities, putting it into the pipeline and talking about doing this.

But Rob, can you talk about what you'll use as you look for success?

What's most important to the patient is the frequency at which they have vaso-occlusive crisis. That is the most important parameter, is relief of this terrible, painful, expensive sickle cell crises. And what we have seen in the 4 patients that we've reported is an enormous success. We've had a single VOC whereas prior to treatment, they were having very frequent vaso-occlusive episodes.

So if you look at the magnitude of the effect this therapy has, it's profound. All of the other factors that you mentioned, percent F cells, fetal hemoglobin are all important, but what is most important is the durability of that effect and the impact that has on patients' lives. And I think with time, we'll understand that relationship between percent F cells and fetal hemoglobin and that protection, but we really need to keep our eyes on what's most important to the patients.

Nicely said. On a different picture...

Do you think that with some -- sorry, just a quick follow-up to that. Do you think that, that relationship is well enough understood right now, snapshot in time, or will be understood in the next couple of years enough that HbF or some analysis of HbF could be a potential approvable or accelerated approval pivotal end point? Or will it really come down to VOCs or some other clinical aspect?

VOCs are easy to measure. You -- it's just not a subtle laboratory-based finding. It's what the patients report. I think that will remain the cornerstone of assessing effective therapies is benefit that, that provide patients, particularly in this disease.

Mark, how would you...

Got it. And then bigger picture -- sorry.

Thank you. Sorry.

Yes, so in terms of that, Ritu, and if I don't answer this, please clarify it for me. But obviously, see CRISPR-Vertex guiding vector going to file sometime towards the end of this year. They've not shown as much of the data set yet, at least as far as I know, in terms of any further updates, in particular, of the registration-directed study results, which would be expected. And so time will tell in terms of how the discussions go once they file with the agency.

In the meantime, we've also seen bluebird withdraw, and so it really becomes important for us to better understand the data that's emerged and we've presented to date. But more importantly, as Rob alluded to, the additional 4 patients with the change in the manufacturing process, to see if that has an increased benefit in terms of the HbF levels, percent F cell increases as well as the clinical outcomes for the patients. And I think it's really whether that profile looks competitive enough that will dictate how we take the program forward.

Our next question comes from Gena Wang with Barclays.

Two very quick ones. The first one also follow regarding the sickle cell program. What kind of clinical profile you will be thinking possible to keep in-house? Would that be CRISPR-like profile or would that be better?

And the second question is regarding the base editors. So I assume you use deaminase. What about the IP part? Do you have the proper right to use that?

So did you want me to maybe...

Why don't you talk about sickle and then Jason can speak to the base editors?

Yes. So the -- Gena, I hope you're well. I mean in terms of that data that you just sort of alluded to, I mean, I think it's really going to be important to see the clinical profile in these next 4 patients. And it will give us a sense roughly around the time that, hopefully, we'll see a little bit more of an update from CRISPR-Vertex, whether we've got a comparable product or whether we've got a differentiated product.

At the end of the day, these are personalized cell therapies, which means they need to be manufactured for the patient. As I described, there's 100,000 of the patients in the U.S., 30,000 of them are severe. And so even if there's one competitor in the market, it's going to take a long time to service the needs of the sickle cell communities, not only in the United States, but more importantly, worldwide. And so if we've got an attractive profile that's the same or differentiated to CRISPR-Vertex, we will do, as I mentioned earlier, what we need to do to either find a partner or look for novel ways that we can get this therapy to patients.

Jason, can you help on the base editor questions?

Sure. Thanks, Sandy. Yes, regarding the base editor, this is a program that I'm incredibly excited about. We have a great team of molecular biologists, structural biologists that are continually innovating around our core zinc finger platform. And they're doing that on both the side of the zinc finger portion of the molecule, where we're refining the specificity and accuracy of the molecules to target specific sequences, but they're also doing it on the functionality side, right?

And so moving beyond the core group of functionalities that we already have in our toolkit, nucleases, transcriptional activators, transcriptional regulators, we're now exploring other new functionalities, including base editing but also recombinases and epigenetic editors. And we've got something in our base editor program that we're really excited about. We wouldn't be moving forward if we didn't think we had freedom to operate. So we're pretty comfortable with the really unique architecture that we've developed. And as Sandy pointed out, we think it will offer some real advantages in being able to be deployed in a single viral vector as well as taking advantage of the great specificity and accuracy aspects of the zinc finger platform.

Our next question comes from Patrick Trucchio with H.C. Wainwright.

Congrats on the progress for this quarter. So I just kind of had 2 questions. I guess the first one, to start off, is what are some of the components that can result in the patients having an elevated lyso-Gb3 level for Fabry diseases. And how readily do these patients actually have increased lyso-Gb3?

So Patrick, if I make sure I understand your question. It's are we -- it's about the elevated -- it's what Bettina talked to earlier that several -- many patients, particularly those on ERT, already have repressed lyso-Gb3. And the rare -- a few patients, which is the naive patients, will have elevated levels and those are the ones where we can see a benefit of our medicine in the lyso-Gb3. And I think that you asked are we screening for those patients. Is that where you were going?

Yes. Are you -- will you be screening for high lyso-Gb3 patients?

We're delighted to take all patients with Fabry and we take 3 categories. We take the patients that are on ERT. We take what were called pseudo-naive, and those are patients who have been for at least 6 months. And we take the naive patients. And we're not rejecting patients if they have low levels of lyso-Gb3 and we're delighted when we find a patient that's a high level.

Okay. Great. And then kind of just like a follow-up question. And so like for the baseline of like patient 5 and patient 6, do you also see increases in lyso-Gb3? Or is that something that we will see later on?

Bettina, have we commented on the levels of patients 5 and 6?

Yes, thank you for the question. We have not commented on those levels at this point in time. This is something that is part of that update that we can provide later in the year as we provide our clinical update.

I'm showing no further questions in queue at this time. I'd like to turn the call back to Aron Feingold for closing remarks.

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

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