Sangamo Therapeutics, Inc. (SGMO) Earnings Call Transcript & Summary

Good morning, everyone. My name is Gena Wang. I'm SMID cap biotech analyst at Barclays. Welcome to our fifth Gene Editing and Gene Therapy Summit. It is my great pleasure to introduce our next speaker, Sandy Macrae, President and Chief Executive Officer from Sangamo Therapeutics. Sandy, I hand over to you for introduction.

Good morning, Gena. It's always a pleasure to be here with you. And thank you to the team for putting together and running these slides for me. So can we go to the next slide, please. As always, we guide you to our forward-looking statements. Next slide, please. And I want to describe a genomic medicine company. I want to describe Sangamo and its unique and novel science that we have driven forward and delivered on clinical stage programs. And underpinning that, we have our own manufacturing that allows us to be in control of our product and our fate. Next slide, please. And this has resulted in what I think is a remarkable pipeline. We have one product in Phase III, 2 others that are moving forward towards late phase development; and the first-in-class first effort, we believe, the TX200 program, which is a first ever CAR-Treg program. But behind that is a platform and a pipeline that is both allogeneic and CAR-Treg, and zinc finger suppressors for our own internal urology pipeline, and then a set of partnership programs that help fund the company. Next slide, please. And 2021 has been the year of delivery for us. We realize as a clinical stage company that our analysts and investors are looking for progress in our clinical programs. For Fabry, we have shared Phase I/II data and the fifth patient has been dosed, and we're planning to move into Phase III. For sickle cell disease, we showed initial data on the abstract, and Sanofi will show more data at ASH next month. For renal transplant, we have enrolled the first patient in our Phase I/II study. For hemophilia, Pfizer has shown data -- we have shown data, sorry, in our Phase I/II study, and Pfizer will show more data at ASH and talk about their Phase III program. And finally, we have completed manufacturing both in Brisbane and by the end of the year in Valbonne. Next slide, please. And as I say, we are very proud of our partnerships, which in my time at Sangamo raised $815 million in cash. But it's more than the cash. I think the 2 other important things is they bring expertise in biology and clinical medicine that allow us to get to patients quicker. But there's a further one, which is a form of validation. Six times large companies have commented on deep diligence on Sangamo. We haven't relied on our corporate presentation, but then deep diligence of the science. And each time we have chosen zinc fingers as a way to create genomic medicines for their company. Next slide, please. So I want to take time and then split this presentation to our proprietary programs and then our partnership programs and give you an idea of what's coming next at Sangamo. Next slide, please. And at our quarterly call, we showed the first data for isaralgagene civaparvovec, ST-920 in Fabry disease. And this is a study that we're very pleased with the results of. So it includes enrolled patients with either naive to ERT, on ERT or pseudo-naive where they haven't had ERT in the past 6 months. Of course for a study like this, it's all about safety. But we also assess alpha-Gal, the impact on ERT administration and many other clinical milestones. We describe data on 4 patients in the first 2 cohorts. And the fifth patient has been dosed at 3e13. And we have line of sight for the sixth patient who will be dosed soon. We see these results as very compelling and have initiated Phase III planning based on the preliminary data that we've seen. And what we think this offers patients is a onetime infusion without need for preconditioning, to deliver long-lasting improvement. And our first patients are a year out with very clear maintenance effect. And hopefully, we will eliminate the need for biweekly ERT infusions, which end up dominating the patient's life. Next slide, please. As I've said, in these early studies, safety is the most important thing. I'm very pleased with the treatment-related adverse events that we have not seen in this study is generally well tolerated. There have been no liver enzyme elevations and no treatment-related serious adverse events. And all adverse events have been grade 1, which in common parlance is mild. This is important because these patients are making important decision when they take our medicine. I think there's a further layer, which is this hasn't required any preconditioning. And none of these patients have required steroid prophylaxis or steroids for liver elevations. Next slide, please. And then the second part is about efficacy. So I'm going to take a moment to describe this graph here. So the gray bar along the -- that goes horizontally describes the normal range of alpha-Gal. We took a lot of effort to validate an alpha-Gal range based on patients and on -- sorry, normal people in this study. The 2 columns I want you to pay first attention to are patients 2 and patients 3. These are patients who didn't take ERT. And I'm very pleased with the level of expression that they have shown, which is absent any complication from the ERT. So they are two- to threefold the normal level. And patient 2 is now out at 48 weeks without any sign of diminution effect. This seems to be a very stable gene therapy. In patients 1 and patient 4, we take great care to measure their alpha-Gal level 14 days after the last ERT, which should be the way beyond the trough level because alpha-Gal ERT has a very, very short half life. Despite that, their levels are much higher, 14- to 15-fold. And this dichotomy has been seen in other gene therapies. But together looking at these results, there seems to be some significant clinically important efficacy in these patients. Why do I say that? We're already receiving reports from the investigators who tell us how pleased the patients are, because they're now able to exercise because they're now able to sweat. In addition, one patient talks about stabilization of his pedal edema, and the investigator comments on stabilization of cardiac imaging. Now these are very early results, and one always needs to be cautious. But it gave us confidence to move to the next cohort, which is 3e13, and feel that this is -- this offers great hope for these patients. The next test in this experiment is to withdraw ERT. Patient 4 has recently withdrawn, and we are working with the investigator for patient 1 to plan the withdrawal. And we look forward to sharing you these results over the course of the coming year. Next slide, please. Sangamo's very pleased to be driving forward in the CAR-Tregs. Next slide, please. We feel these are the important next step after CAR-T and oncology. And our first trial based from our French outfit where we acquired a company called TxCell, who are real deep experts in both the biology of T-regs and also the manufacturing, looks at HLA-A2 mismatched renal transplant. Put simply, a patient who is HLA-A2 negative receives a kidney for a patient who's HLA-A2 positive. Before they receive the transplant, we [ freeze] and purify their Tregs. And then we engineer them to express a CAR-T that will only recognize HLA-A2. After the patient has had their transplant and have time for that transplant to heal, we then infuse the engineered CAR-Treg cells. And we'll hopefully show benefit both to the patient and to our understanding of Tregs. Next slide, please. The first patient has been enrolled, and we're guiding that we expect to dose 2 patients by middle of next year. Obviously, with renal transplant and surgeons to be coordinated, this -- the dosing of these patients will take some time and has to be done carefully because of the preciousness of the renal transplant. The patients are very normal renal transplant patients waiting for a new kidney from an identified living donor that has an HLA-A2 mismatch. While as always safety and tolerability is our first and foremost driver in these studies, we will be able to assess acute -- we'll be able to assess the Treg biology, as renal transplants are often biopsied. And we'll get a unique understanding of -- that the Tregs go to the kidney, that they're activated and that they survive for a long time. In addition, we hope that these patients will get great benefit. And in the polyclonal Treg studies, the patients have been able to withdraw from many of their immunosuppressions. And we hope to be able to replicate that in this first study, an exciting first step in an important field. But it takes us beyond that, and we have CAR-Tregs being built at the moment for multiple sclerosis and inflammatory bowel disease. That could open up a whole gamut of allogeneic autoimmune indications. That could be an exciting new future for Sangamo. Next slide, please. In our partner programs, next slide, I would like to update you on hemophilia, which is partnered with Pfizer. Next slide. We are in that strange time between abstract for ASH and the data, that we have to be careful in what we say to respect the embargoes that ASH brings in. So as of our cutoff date, there have been 4 patients who have been treated for up to 104 weeks and whose factor VIII activity is 30.9%. What's more important to the patient, though, is annualized bleeding rate, which was 0 for the first year and 0.9 throughout the total duration of follow-up. These patients are well. Next slide. These patients are well. And we've only had occasional ALT elevations have been treated with courses of steroids. Next slide, please. Now Pfizer has already driven ahead and treated half of the patients in the Phase III study. And at that point, they decided to pause the study. Because what they found, unusually, was that some of the patients had factor VIII levels that exceeded 150%. And they decided, out of abundance of caution, that they pause this study and understand this. It's important to say that none of these patients have experienced thrombotic events, although some have been treated with direct oral anticoagulants. The patients are well. Pfizer is doing this because they feel that patient's safety is the most important thing in any clinical trial. We applaud them for their decision. Now they plan to move ahead with this and have -- are putting together amendment that will codify how to treat and how to manage patients if they can't go to these very high levels. Understandably, the FDA put this under clinical hold. So Pfizer will put together the amendment, share with health authorities, and respond to their clinical hold, after which they expect to move forward and update the trial. Next slide, please. Our second partner program that I want to update you, that is also between abstract and ASH, is about sickle cell disease. Next slide. As I'm sure many of you know, our approach to sickle cell uses our zinc finger cell therapy nuclease technology to edit the BCL11A locus, which results in a rise in fetal hemoglobin, which compensates for the defect of sickle hemoglobin to these patients have in their blood. And if you look in the bottom left box, of the 4 patients that are in this study that Sanofi is running, the Precision study, you can see the burden of the illness that they had with pain crisis and chest syndrome and regular transfusions. This is an awful disease, and it's wonderful that this -- our industry is now waking up to it. Next slide, please. And Sanofi has shown initial efficacy data showing the patients are producing and sustaining hemoglobin F, that F cell percentages has increased, and that the patients are no longer being transfused. And we look forward to showing you more data on these 4 patients on December 12 at ASH. Next slide. We and Sanofi are continuing to advance this program with a great passion and drive. And the company has recently talked to the FDA about manufacturing and understanding for the clinical studies. However, we did decide that for a business decision, we would cease development of the beta-thalassemia program and focus on sickle. Next slide, please. So what are the key points in our story? Next slide. We are executing our a clinical stage pipeline with hemophilia A, Fabry and sickle cell moving forward are in late-stage studies. And the first-ever CAR-Treg program enrolled the patient. Next slide. We have completed our promised manufacturing with AAV in Brisbane. AAV completed -- sorry, cell therapy completed in Brisbane. And cell therapy in France on track for completion by the end of this year. And we have dedicated capacity at Thermo Fisher. Next slide. We know what we need to do in the coming year. We will enroll the sixth patient and update you in Fabry. We will dose 2 patients in the renal transplant study. We will present full data on sickle and hemophilia at ASH. Pfizer will restart the Phase III study for hemophilia. And Sanofi will continue to drive forward with the sickle program. Last slide, please. In summary, we have 3 programs progressing towards late-stage clinical development. We have a broad portfolio primoritized in both rage -- rare and large indications. We have technology validated by our partners, a strong balance sheet and in-house manufacturing. So Gena, thank you. And I'm happy to answer any of your questions.

Thank you, Sandy. That's very helpful overview. Maybe I would just start with Fabry disease. We just presented the very encouraging initial data. So regarding the alpha-Gal A activity. Since you measured activity pre-ERT dose, so -- and the ERT level therefore should be at the lowest, why do you think that we still saw the super physiological level? What could be the contribution to that?

I don't think anyone knows. What I can tell you is that if you look at the literature, the half life of ERT is very short. And when we measure it, as we did originally almost like every few days, you can see a big peak from the ERT, that then comes down. And then when you look at it at 14 days, there shouldn't be ERT in the plasma. But there's clearly some effect from having been on ERT that we won't fully understand until we withdraw the patients. But again as I said in the presentation, look at the patients who are on ERT. It's clear that the gene therapy is working, and it's having an effect. It's just in the patients on ERT, we will need to understand what is the background of the previous ERT therapy on obviously gene therapy. But the patients without ERT are noting benefit and have got super physiological evidence.

Okay. And regarding the lyso-Gb3, we did see some with a low baseline. Any differences in terms of disease progression or disease type for patient with a low baseline? Like a Gb3 versus a high baseline?

I think that's a very fair question. But unfortunately with only 4 patients, it's really hard to categorize them. But it's clear, both from our trials and from others, that the only way to make -- sorry. In patients who have got very low lyso-Gb3, it doesn't change, but in -- and the dramatic decreases others have quoted have been from patients with very high lyso-Gb3 on entry. I'm fascinated about the work that AVROBIO has done where they showed very low alpha-Gal levels in the classroom, much lower than we've shown. But we're able to show changes in lyso-Gb3 in the kidney. So I think we are all learning from what is cutting-edge clinical science or what's the level of alpha-Gal you need to achieve. And what does the lyso-Gb3 in the plasma and the tissue mean. So we're very pleased that our levels are higher and that we still have at least another dose cohort to go. And at 3be13, we should see an even greater effect.

Okay. For the update in 2022, what are the factors to trigger the data presentation?

Well, we will -- we have dosed the fifth patient, and we will dose the sixth patient soon. That data takes time to mature. We have taken one patient off of ERT. That takes time to re-equilibrate. And so we will -- we're very excited. We're going to want to talk to you about this because it is an exciting and important program for Sangamo. So throughout the year, as this data matures, we will share it with the community. What I can tell you is that investigators are excited by this. And we're now -- we've also shared it with the patient support groups because I think it's important and will help with recruitment and also help with patients' decisions on which form of gene therapy or medicine they want to be treated with.

Okay. And for the Phase III, planning has been initiated. So do you need to see cohort 3 data in order to make a final decision? And what are the data points you are looking for to decide Phase III trial design?

I know you know this, but I don't think many people understand how long it takes to do the planning and finding the right sites and CROs and all these kind of things for Phase III. So we have initiated that planning. That is fully underway. I have a great clinical operations group. We will decide the final dose that we go into Phase III based on cohort 3. So we need to see that data to set the final dose. But it doesn't affect the manufacturing or the planning. It simply affects which tools we use.

Okay. And what kind of data sets will tell you this is the right dose, and we are ready for the Phase III?

Oh, we're ready for the Phase III. This is a medicine. I'm certain that this is a medicine. It's just which dose balances maximum efficacy against potential safety. We have -- it's been extremely well tolerated even in the first patient at the higher dose. And we at Sangamo have dosed many patients at 3e13. So we know it is a well-tolerated dose. And so it's a balance that we will take advice from our data monitoring committee and from investigators and from KOLs, on how to balance that efficacy versus safety.

Okay. Quickly moving to your partner programs, hemophilia A. When you say 150% factor VIII level, was that measured by 1-stage assay or chromogenic assay?

That's by chromogenic. And Pfizer are very clear. This is an ongoing Phase III study, so they want to be extremely careful about releasing too much data, because it -- we want the Phase III data to be intact and regulatory approvable. So they're being very careful. But I also think Mikhail and his team at Pfizer are doing absolutely the right thing. If I've been in their shoes, I would have done exactly the right thing. Pause, take a moment, and understand what it is you need to do to meet -- protect patients. Increased efficacy is a very unusual challenge to pass through. Now it's also unusual in a gene therapy trial and that the patients are still -- we're still acquiring safety data from all of those patients have been dosed. The medicine remains within them and it remains producing effect within them. And so we're gaining important long-term safety data in the first half of the trial that has already been dosed. We look forward to dosing the other half of the trial as soon as possible.

Okay. For the sickle side, so I think I -- did I hear correct, for the full data presentation, there will still be 4 patients...

Yes.

for the full data. Okay. So it will be just a longer follow-up on the 4 patients?

It's longer follow-up. And Sanofi continue to recruit and prepare and dose patients. But we're going to present on the 4.

Okay. And regarding -- if we take one step back looking at the competitive landscape. And this is a disease I did see, like the pretty high bar set by a few different approaches out there and already showing the data. And we saw like over maybe 40%, right, the feroglobin level. So anything you have in your mind that with the Sanofi, what could be the -- a viable product moving forward? What kind of clinical profile you'll be looking for?

So we and Sanofi have made a very deliberate public declaration that we'll move -- continue to move forward, which I think speaks to our confidence in what we've seen. We feel that this is an important product for patients with sickle cell. I find it always difficult to comment on the first 4 patients because it's so little data to be able to properly describe the profile. And we look forward to talking about more patients in the future.

Okay. Great. Maybe just one quick last question, I know we are running out of time. Going back to the factor hemophilia A, like do you think that Pfizer being overcautious given that we saw, say, BioMarin factor VIII level was much higher and they continue. And yes, it's a very precaution, but on the other hand, you delayed the clinical, like the trial enrollment. So would that -- do you think it's overcautious regarding what they put in place? Or maybe I put in a way, is there something else that we should be worried about, that the higher level was not similar to what we've seen from the other programs?

So I get great reassurance from seeing the BioMarin data and the patients didn't come to harm. I wonder that I would have react to that data differently if I had been a primary. I note, having been a Chief Medical Officer of a large company previously, that what Pfizer did was absolutely correct. And it is what I would have done if I've been solely in charge of that trial. Once you dose patients, you can't undose them in gene therapy. And therefore, just take a moment, pause and codify how to deal with them is the right thing to do. And I would even argue that it will make the final data package more uniform and more interpretable for the agency. So this is not just a good thing to do, it's absolutely the right thing to do, and I'm proud of what Pfizer have done.

Thank you very much, Sandy, for the insight, for discussion. Thank you.

Always a pleasure, Gena.