Sarepta Therapeutics, Inc. (SRPT) CEO Doug Ingram Presents at Credit Suisse 29th Annual Virtual Healthcare Conference (Transcript)
Sarepta Therapeutics, Inc. (NASDAQ:SRPT) Credit Suisse 29th Annual Virtual Healthcare Conference November 9, 2020 3:30 PM ET
Company Participants
Doug Ingram - Chief Executive Officer
Conference Call Participants
Martin Auster - Credit Suisse
Martin Auster
This is Martin Auster. I am the lead Smid cap Biotech Analyst at Credit Suisse. Thanks for joining us at the 29th Annual Credit Suisse Healthcare Conference. I’ve got Doug Ingram, CEO, along with some members of the Sarepta Therapeutics team.
Very happy to have here today, Doug. Just for the folks listening in, having done one yet but I think this one might be different. If anybody has any questions they like me to work into this fireside chat, please send me an email, it’s martin.auster@credit-suisse.com and I am happy to try to work in some questions as they come in.
But with that, I would like to turn it over to Doug. Thanks again for joining us and I guess, I would just open with most of the questions we get on Sarepta over the last year or so has been around 9001, the micro-dystrophin gene therapy, but there is obviously a lot more going on in Sarepta and there is a bigger vision beyond just a single gene therapy program. So, maybe, give you a chance to kind of intro of the company and kind of talk about that big picture.
Doug Ingram
So, thanks a lot for that. I 9001 is extraordinarily important to the company, of course, and it’s important to patients with Duchenne muscular dystrophy or waiting for a transformative therapy, micro gene therapy and something like. I wanted to bring a point, we have a broad strategy to bring therapies to and transform the lives of patients with the disease across Duchenne muscular dystrophy which is nearly the area everything we do.
But beyond that, other rare diseases, I mean, internal muscular dystrophies and a host of other diseases that we are working on. So from a gene therapy perspective and currently RNA that we’ll move RNA either into other areas besides DMD as well. We have over 40 programs between RNA and gene therapy. We are doing two things at the same time and our RNA therapy, right now we are focused on Duchenne muscular dystrophy.
We’ve got both our base technology, the PMO technology that induces exon skipping and creates a truncated form of dystrophin that benefits kids. We have two approved therapies there. If all goes well by early next year, will be a third therapy there and we can keep doing that. I think we have a next-generation version of that which is a peptide conjugated version of the same therapy.
So, somebody call the PVMO and the goal of that is to improve the penetration of this therapy into the cell, greater tissue exposure, greater dystrophin and if all that works well and works safely it would be transformative to next DMD and potentially beyond DMD and other therapies. And then we’ve got this gene therapy engine now we are building with a number of different pillars that, first of which is of course pipeline.
We’ve got - this SRP-9001 for DMD without limb-girdle, gene therapy six of those and then we have a host of other ones behind that well over 20 and 27 now focused on gene therapy. We have manufactured and if you are going to be serious about gene therapy, you’ve got to be serious about manufacturing. We have spent enormous amount of energy and capital and focus still the expertise around manufacturing and doing what will be ultimately one of the most significant capacities for gene therapy that exists.
And of course, we are gathering both the expertise that we can bring in the company and tools that can advance gene therapy when we are doing lots of interesting things there. We’ve done 22 transactions this year, 20 of which were done during the pandemic. So, our goal is to be an enduring global leader in genetic medicine focused on rare disease, both in RNA and in gene therapy, advancing our PMOs and next-generation version and then building out this very significant gene therapy engine that’s taken up a lot of our energy and service over the last few years.
Martin Auster
Great. Okay. I am going to expose my hypocrisy and then spend the rest of the time talking about 9001, which is what – well, I want to do a couple of things. I wanted – I mean, obviously, you said in your earnings call last Thursday and I think that there was – I think I recall, things got a little circular in terms of explaining.
So I want to try to like walk through and get a kind of a clear picture of the development path. I thought, why don’t we start – let’s talk about the body of evidence that kind of supports the basis for kind of optimism around that program just from a clinical, from an efficacy and safety perspective and then, let’s shift it more towards the development path and the regulatory path and those first. So, I was just talking about, yes go ahead.
Doug Ingram
And when we get to that latter part, I am willing to sort of walk through the timeline explains it how we got, where we are right now and why we think this is a really good result for now. And the short answer on the evidence set is, remember, first we – SRP-9001 has been in development and designed for a very long time, really with Dr. Louise Rodino-Klapac claims that Nationwide Children's Hospital building a very elegant approach to treating children with Duchenne muscular dystrophy through the use of this form of form of dystrophin called micro-dystrophin, which in many animal models shows that it’s not only potentially safe, but transformative that then you could see that across a number of different animal models.
And they all was based on our national history set that came out of the 80s. And then, from there, when we got that optimized and by the way over that period of time, Louise went from Dr. Rodino-Klapac went from being at Nationwide Children’s Hospital along with Dr. Jerry Mendell to coming over to being our Head of Gene Therapy and running our Gene Therapy Center of Excellence in Columbus Ohio with anyone to patients.
And we dosed a small, but a very important proof-of-concept trial with something we call Study 101 in four patients and the first thing we saw was, the biggest question with gene therapy, particularly full body infusion gene therapy was, number one, can you do it safely? I presume the amount of therapy, let me be clear.
It’s just truly enzymes, truly viral capsid. Can you do it safely and equally challenging, can you get the genes in the right place and stay there and have it actually make our sufficient in approach gene to make a meaningful difference. Because you are asking a lot this is not like an injection in the eye or something. This is a full body infusion and it has to go to cardiac muscle, Dreifuss muscles skeletal muscles.
And the short answer to these first four cases, it was really they had expression levels that were approaching normal levels of the dystrophin, but in this case micro-dystrophin. Genome copies made that point, can you get it to the right place? We had 3.3 genome copies for nucleus it was well-tolerated and we were seeing some of the issues that some other programs had been in place with – have been functionally.
We worked out those at a year and at two years and the short answer on these children all the way up to two years is that they are all improving on all functional endpoints in significant ways versus baseline and significantly greater than what you would have expected from natural history giving us a lot of excitement and forcing us frankly to the same – aggressively but how we bring this therapy forward as kids are awaiting and frankly degenerating every day while they went in.
So we started this next trial 102. 102 is a blinded, placebo-controlled trial using clinical material from Nationwide Children’s Hospital and it’s a 41 patient trial with that last patient last visit in December. It’s proceeding very well even in the phase of this pandemic in large measure because the children were all – it’ where the pandemic arose.
So they made announces and we’ll have results from that study both efficacy, is the therapy efficacious? Is it transformative? Like we have answering this and is it safe like we have - and we’ll have that early next year, right. And that – and so that’s where we are with that. And then, as we sort of lean over on what we need to do next which kind of gets to some of the updates we made recently I can do that if that makes sense for you.
Martin Auster
Yes. So, maybe to start that conversation and play out the timeline maybe, talk about from your perspective, from an update perspective, but what is the agency looking for to support registration of a gene therapy for DMD boys?
Doug Ingram
Well, I will say, the short answer to that one is, that we haven’t had that dialogue with the agency. So, really want to be careful that people don’t misread into anything I’d say, some task at understanding with the agency and this is in development or regulatory pathway for the therapy indeed. We have explicitly not had that dialogue and then we’ve – I think our recent – this is our view.
But we don’t want to have the dialogue, because I think that’s a better discussion to have with that attached in and but I think it will be a much more – it will be a much more tangible real conversation we are trying to have a theoretical discussion with the agency. But I think where we were and where we are, so we are – so remember…
Martin Auster
And also address conceptually, what you are trying to put together to bring to agency when you have that conversation?
Doug Ingram
So, understand what we are doing. Number one, we are into summer of 2020. So think about where we are. We’ve seen really exciting results from Study 101 first forecasts and very, very excited and giving us a lot of confidence. And then giving us confidence is Study 102, that’s our placebo-controlled trial. And that trial will be the track to functional results and safety results and expression results, early next year.
Now, the thing that we definitely have to do is dose cases with commercial material. So, for the first two studies evolving doses with clinical material at the Nationwide Children’s Hospital is very similar to if you look back at times as we sort of access both Gems in that approach. So Gems manufactures starting it nationwide its clinical material of all which are very similar for us, but scalable for us as using the same kind of material as a medium approach by using its three dimensional structure of – make more material we are doing the same thing.
And we need to dose kids with that commercial material and we need to prove to the commercial material it operates in a similar way on expression and safety perspective to what one would see with the clinical material. So we are seeing in the summer of 2020 and we have proposed several larger study, about a 70 patient or so study, a global study, because we have global aspirations of course with our partner Roche and a placebo-controlled trial with the same age range of children by using commercial material.
It still have lot of different things in this study was going to be for our global purposes of approvals. We also realize we need to fairly rapidly validate the commercial material from an expression and safety perspective. So we will do an interim kind of that material on about ten patients early next year. And we started in the summer of this year and we realize we are in the middle of a pandemic.
And there is a real chance that right as we are going to start study 301, this pandemic is going to go through a second wave and there is two problems with that is, one is we are putting lots of kids at risk and putting even placebo kids potentially at risk, right as there is economics of the integrity of the study could be risk if it turns out real margin right at the wrong time.
And then, we realized, we should do – we should split these ideas up. We should do 301, so just want to clear, I think there has been some misunderstanding that somehow we are walking away from 301. 301 we are going to start up 301. 301 is going to happen. That’s placebo-controlled global study. But let’s pull out the commercial material validation study, the – let’s what looking at expression and safety.
Let’s pull it away and have a separate study, Study 103. So we probably trapped into our September meeting with the agency, we had a Type-C meeting with the agency. It was a time we are on the papers. So there wasn’t any live dialogue with this meeting. We had a proposal. We have this 301 proposal. We have some other things doing, but we have 103 the commercial material, which is really important that we see this as soon as possible next year.
And of course, I think that everyone knows what happened in early September the agency questioned the approach that we were taking to our potency release assay, which means we couldn’t start any study until we had that resolved, certainly not with the commercial material that we have builds with our iCELLis in our hybrid manufacturing model.
Now, what technically you could take, many months to resolve that issue and others have had much more replacement time to resolve some of these potency related – potency assay release related issues with the agency and first that would be an unacceptable result. We all know, children are waiting for this therapy and we need to get that material validated to see the performance of the commercial material and see if it acts the way we envisioned get well with clinical.
And we have lots of good reasons to believe that. We’ve got lots of CMC that tells us they should at present. So we are able to get and I really wanted to kudos to the division as well. I know they are very stressed. We were able to get an actual live meeting with the division which has been somewhat difficult recently.
Literally, only two weeks after this setback that we had and we made a decision at that time that we need to go into this meeting and all possible to come out of that meeting with a solution, because in the absence of a solution who knows when we might get yet another meeting where we could explore these issues. And so, we made the call going ahead as number one issue w need to understand that at what the division’s perspective is on the approach to potency assays and solve that issue in the meeting.
And number two, we need to make sure that we can start our commercial material validation study and that we pull the site, which we call 103 and when we went to the meeting I am proud to say that we held that with short meeting, we were able to get to both of those in answers. We understood better what the agency’s perspective was on the potency assay approach. We proposed a solution that they accepted.
We’ve built the data for that already. So that should be good to go and we suggested that we would like to start 103 – start 301 after we get a data readout on 103 and they concurred in that result. And so that’s where we are right now, which means that by relatively early next year, depending on how fast we can recruit and dose patients in 103, we will have the readout 102.
So we’ll have functional results of 102, if all goes well and assignments cooperates showing that this therapy is transformative to children with Duchenne muscular dystrophy while safety results from 102 and we’ll have the material validation results of Study 103 both from a expression perspective and from a safety perspective.
And then, we’ll do a couple of things at the same time. We’ll obviously start Study 301. So this does affect maybe a five months delay or so on the start of study 301. But we’ll also sit down with the agency with data in hand and talk to them about what the development in regulatory pathway is.
Martin Auster
So, a couple things. Well, you started the second answer, but I am going to start, is the potency assay question, is that completed within the timing of 103 versus 301? I guess, what I want to start with though is, could 301 start today and if so, why are you choosing to do it sequentially and because that study is after the kind of the answers come out of 103 and the second part of that is, I think you said on the earnings call that 301 would likely be required for European approval.
So, there has been more guidance from Europe about specifically what will be required for approval. And so, I just want to make sure I understood that, was your partner then involved in kind of the step-wise process of 103 or 301?
Doug Ingram
Yes. Our partner is involved. So obviously, communicate closely with rest of them and what we are doing understanding concurrent to the approach that we are taking. Yes, and we’ve taken advice outside the U.S. and there are a number of places around the world where the – we would need 301 completion as a predicate to an approval.
So, we – and we have lots of other good reasons why 301 needs to start. So, let’s just be very clear we are going to start 301. And 103, the short answer is one couldn’t start another trial right now without getting the concurrence of the agency which would obviously require an additional – depending on our meetings that probably would be able to happen even this year or even if we wanted it.
And in any event, it turns out in a month that we are overly pressured about this. But our concerns are about the same. They were not unfounded right now, it’s as hard as right now in the U.S. but obviously in Europe, as well. So, our goal right now is to get Study 103 up and running as soon as possible to get kids dosed on that and then, by – as really as possible next year we have those functional results from construct, safety results from the clinical material, safety and expression results from the commercial material and then we’ll sit up with these and talk about next steps.
Martin Auster
So, is that FDA would like to – I am trying to understand that the Study 301 start would have required agency input sign off and you need that commercial validation data from 103 to kind of facilitate that pathway or it would sort of taken longer to start 301 than 103, so make more sense to do the 103 pathway?
Doug Ingram
It would start – it would take longer to start 301 to 103 would create more risk and the problem and the patients. Any study in there we would start requires the concurrence of the agency obviously the start and we went into this – we resolved as a result of the minutes from the September, early September meeting and we went into the later meeting realizing that we need to get – we need to be surgical in what we ask for.
So we get the information most valuable to the program and the patients now and from our perspective while 301 is very important and I don’t want to see just for a second it’s not. We will indeed start this as soon as reasonably possible to do that with the concurrence of the agency.
It is absolutely necessary that we dose children on the commercial material and that we get the – we see the performance of the commercial material to see if as we – as our CMC permits, it performs in the same way one would have anticipated from the clinical material.
Martin Auster
Okay. And so, it sounds like there has been European guidance to Sarepta and to your partner around, say, 301 completion in events of filing approval. In the U.S., it sounds like, you haven’t had those specific conversations and so your interpretation is, FDA is maybe flexible around a little more flexible on their view.
They are going to look the data drive their review as opposed to having a fixed kind of outlook in mind before you started the clinical program. Is that a fair way to think about it?
Doug Ingram
Yes. I wouldn’t – I don’t want to create the impression that we have fantastic understanding with them that we don’t have. I just say…
Martin Auster
So, Sarepta’s view is that the approval path could be data-driven in the U.S. it’s where that’s kind of more protocol-driven in Europe?
Doug Ingram
I think that is a – so much fair way to say that.
Martin Auster
Okay. And so, I guess, can I ask you to kind of frame what you – what is that robust dataset? And what – like, if you had to imagine some parameters around that, what does that sort of look like? And then, I guess, you referred to the ZOLGENSMA approval and that was a somewhat accelerated approval. There is similarities and there is differences between these diseases and these programs. I am curious how you’ve kind of thought about so much of a comp ZOLGENSMA if it’s in to 9001?
Doug Ingram
So ZOLGENSMA has been a large measure, a significant blueprint. And because remember, we are in a nascent field of course with gene therapy. There aren’t that many examples one can use and certainly ZOLGENSMA – there are differences between the disease states certainly and between the therapies themselves. But the programs are strikingly similar and not by accident.
They both came out of Nationwide Children’s Hospital. They both started with HYPERStack and both of all to commercial iCELLis units. That’s not by accident. I mean, we thought it was a very intelligent concept of ABACUS Stroke chose iCELLis for the reason that, that is a commercially scalable approach to manufacturing.
It doesn’t get too far away from – technically from using HYPERStack. So you are taking less risk. There are less reasons why you would envision the commercial process and the commercial material to act in anyway different in that clinical material. So in a lot of regards, I think we’ve looked at the ZOLGENSMA approach is something that’s been at least informative to us as we track forward.
Martin Auster
And do you want to take the other part of that question, which was kind of, when you are thinking about or do you want to you can pass on it if you want to.
Doug Ingram
I’ll take it. I think…
Martin Auster
It’s one of these like you know and you see it. But again, if you are going to base – so you are trying to prove it like a dystrophin produces a functional benefit, right. And then, you are trying to demonstrate that commercially validated product, behaves the same the clinical material then you can kind of verge that from biopsy data.
So, can you talk about what those two components in your mind kind of – I know it’s hard to be specific about that. But just in usual terms, one of those components either look like for you to feel like, this is the right thing to do to go to FDA and say we want to pursue a stable decision.
Doug Ingram
I know what we – so let’s think about what we need to prove and then what additional data or information we need will come with additional discussions. But, let’s think about what is fair and what’s necessary. First, that this is an edited form of dystrophin. So, unlike let’s say a program or limb-girdle program where you see neither protein to spend a little so.
It’s fair for someone to say I am not going to rely on this biomarker alone, I need to see that the biomarker actually acts like the shock absorber, the dystrophin does. Tons and tons of preclinical data that says, it well, great early read on cells, well, we should have to prove that in a well-controlled, placebo-controlled trial that’s one.
So the first thing is, I want to see frankly and we see a statistically significant benefit at one year from the kids on access therapy for some placebo kids, I think that would be unbelievably compelling at one year. Obviously, the next big issue is safety.
The therapy is generally safe and well-tolerated. So far, it looks, very good and we have been able and I don’t think it’s serendipity or accident, I think it’s planning by Dr. Louise Rodino-Klapac on his scientific construct we waited some of the significant issues that have played the feel out there in gene therapy programs.
But I think ultimately we have to get that and say look at safety. and then the third thing of course, because a lot of that data is on clinical supply and we need to look at the performance of the commercial material and see that the commercial material acts in a way that one would anticipate with that as we look at CMC.
And then, based on all that, that’s compelling and compelling to me is, statistically significant benefit at one year on function, safe and well-tolerated and the commercial material is performing the way our CMC would predict that as we went through. But I think we need to sit down with the agency and say, what do we need to accelerate this therapy to engagements in the United States and around the world.
Martin Auster
And then, just on the Study 102, obviously the safety side of this is much of the endpoint is going to be meaningful in terms of do we need to see more data not from the regulatory perspective? Do you have insight on a blinded basis some of the issues obviously are common place with kind of high dose AV administration systemically, platelet reductions any sort of kidney injuries, need for kind of comp intervention, can you speak to any of these things from a blinded basis from the Study 103 trial that’s ongoing.
Doug Ingram
I could tell it’s all blinded, I could tell you we have not serious to any complement related to those. So we are not seeing any concern of that would be worried about with respect to 101 or 102. And frankly, we would definitely in pre-clinical models either. So we are just simply not seeing. So that doesn’t seem to be our complement issue that sets you with this construct and perhaps it’s back to AAVrh74, because we haven’t seen it either I will point out in limb-girdles and then limb-girdle at that.
So we clear the high dose of that limb-girdle is the same dose as DMD and those kids are larger kids and where those limb-girdle trials we get kids that were in the 50, 51 kilogram range. And we just simply are not seeing this complement mediated issue, these drop in platelet count, kidney issues and alike, we are just simply not seeing them.
Martin Auster
Okay. Just a few minutes left in this conversation, but I do want to touch, so you mentioned limb-girdle one of the appeal that several of these programs are giving native protein full-length protein and you’ve done it with the I70 forecast which has been shown to be well – reasonably well-tolerated and safe through 50 something exposures or something like that, alright?
So, this program to me is, this is more straightforward, looks at more natural history is a little less developed than DMD maybe. Where are you now with the kind of the regulatory discussions on defining path forward there? When do you think you’ll have something clear in place, because that program does seem reasonably straightforward because of that factor.
Doug Ingram
So, first, so, the focus always been to have a discussion with the agency about exactly what the next trial will look like and we would certainly hope the next trial would be on commercial material and they would be. What we need to have that conversation, and I mean, you’ll hear this repeatedly from me. I don’t want to have just theoretical discussions with an overburdened decision. I really want to add that enhance, so we need all the CMC work to be done – we are in GMP realms right now for SOP 9003 and we are the – that won’t be an issue and the issue is all the analytical work, more analytical work that will be done until next year. Once we have all that in hand, I want to sit down with the agency, go over the CMC and then talk about the development pathway and of course, I would not get shy about the view on this and this is, the most significant difference between the DMD construct and SOP – and SOP 9003 in limb-girdle is that, with micro-dystrophin, you’ve edited the gene and therefore edited the resulting from the gene that is not an unfavorable meaning to say, it show us that we didn’t edited inappropriately, it shows that it still acts the same way inside you that natural liquid dystrophin would do. This one, we don’t have – this has been native – this is the gene, whole gene that codes for the native approaching. So and the real significant question that would seem to me would be that we would have to show that we get the kind of robust expression that would be needing for and we are seeing nearly more and more expression right now and I mentioned genome copies earlier again. Our 874 keeps delivering for us as we had four point to you genome copies per nucleus for the high dose cohort and we had again expression nearly normal. If you take that and then you couple it with something else, which is limb-girdle actually is a ultra-rare disease that I think we are obviously going to at least close to the agency that there should be a very lean practical approach to getting these therapies the way the patients and this is a therapy – it’s not this therapy that there are no – there are no therapies in the background. We need to come out to help these children of when the generation is done. SOP 9003, doesn’t come to these kids not they will get to them. So it’s one of the facts. But we haven’t had those conversations. We’ll have them with our clinical material our commercial material ready to go.
Martin Auster
So, that’s sometime in 2021?
Doug Ingram
Yes.
Martin Auster
And then, maybe just last one. You mentioned the PPMO, the next therapy on those. Just, I know this is something noteworthy kind of the data presentation has been able to go up and explore higher dose cohorts. I just want to confirm again this is still on track for an update before the end of the year. And remind us one last time, what that dose range you might get it on and in the short it is?
Doug Ingram
Sure. So, yes, I mean, just for those - I am sure [Indiscernible] the PPMOs or Peptide-Conjugated PMO is a limitation of PMO which is not usually charged doesn’t get into the cell. It gets into cell only pass if we crucify that in four hours. The peptide will drag the PMO into the cell using the envelopes and I think we are very confident in that mechanism of action.
So, we will have 20 mgs per kg dose range, we’ll have a read out before the end of this year. We’ve already dosed past that dosing to 30 mgs per kg and our goal would be dose as high as we can and we may dose up to 40 mgs per kg or even higher to see what the safety signals will tell us. I mentioned that, because it’s really important for all us to understand that – understand us for a year-and-a-half.
The most important thing to see would be look at the first read out to say, it’s the real question, we aren’t very, very confident mechanistically that the PPMO with the right dose will drag the PMO have much greater tissues or better as such get them in a much greater dystrophin. You are holding questions for us. That will be the really interesting part of it.
Small to mid tissues are [Indiscernible] but I think safety and safety signals is the most interesting one. Obviously, given that we are at 30 mg per kg you could imagine not to be a big swindler but if you kind of look back from a safety signal perspective and 20 mg per kg it’s just great.
Martin Auster
This initial update we’ll have, is it 12 weeks biopsy?
Doug Ingram
Yes.
Martin Auster
And you described it on the highest dose group?
Doug Ingram
I think what – I am just still reviewing what all with that we are going to – we made a decision on that, but simply that people would be interested in the range of the 20 mg per kg.
Martin Auster
Got it. Okay. Super. And thanks so much for joining us today, Doug and the rest of the Sarepta team. It’s great talking to you and have a good rest of the day. Thank you.
Doug Ingram
Thank you very much.
Martin Auster
Okay. Take care. Bye.
Question-And-Answer Session
End of Q&A
