Good morning, ladies and gentlemen, and welcome to the Sarepta Therapeutics Limb Girdle Muscular Dystrophy Type 2e Data Conference Call. As a reminder, today's program is being recorded. I'll now turn the call over to Doug Ingram, President and CEO of Sarepta Therapeutics. Please go ahead.
Thank you very much. This is Doug Ingram. I'm the Chief Executive Officer for Sarepta. Thank you for joining our webcast this morning to report the results of our first cohort of patients in our Limb Girdle 2E program. Please understand that we will be making forward looking statements, and I would refer you to our public filings for obviously the various risks and uncertainties that come with making forecasts about the future.
We're excited to be reporting results today. This is an extremely important milestone for Sarepta. Our collaborator, Doctor. Jerry Mendell wishes he could be with us today and he sends his well wishes, but he is in Columbus, Ohio and he's continuing to dose patients in our DMD microdystrophin placebo controlled trial. So this is certainly a good excuse for Doctor.
Mendel. Presenting the results for us today will be the inventor and the designer of all 5 of the microdystrophin gene therapy constructs, Doctor. Luis Rodino Klapac. Luis Rodino Klapac also happens to be today Sarepta's Senior Vice President and Head of Gene Therapy. So with no further delay, let me turn this over to Doctor.
Louise Rodino Klapac.
Thank you, Doug. So I'm really pleased to be here today to present the results from our first cohort of our LGMD2E clinical trial. LGMDs are a group of devastating muscular These diseases are progressive. They're debilitating muscle wasting diseases and there are no therapies for any of these diseases. There's approximately 30 different subtypes.
Most of these are autosomal recessive. Unlike DMD, LGMD affects males and females equally. They all affect skeletal muscle and in many cases they also affect cardiac and respiratory muscle. The symptoms often are presented with elevated CK and in many of the severe forms, the symptoms develop before the age of 10. Severe forms like LGMD2E, which we'll talk about today, have significant cardiac respiratory involvement that often leads to premature death over the age of 30.
When we look at LGMD as a whole, there is some heterogeneity amongst the subtypes in progression, but when we look within each LGMD subtype, the progression is relatively predictable. Now each of the 5 Myonexus LGMD programs are caused by a single gene defect. So in a sense, we have a very simple procedure. We're simply restoring the missing protein. And in all of these cases, we're restoring the full length protein.
We've not modified the gene in any way. This is the native protein that we're delivering back. So each of these proteins is associated with the dystrophin associated protein complex. So 3 of our programs of the Myonexus programs are caused by mutations in the sarcoglycan complex. The sarcoglycan complex is an important complex embedded in the muscle membrane.
It binds to beta dystroglycan and it binds to dystrophin. So as we've previously mentioned, this dystrophin associated protein complex works in concert. And when you lose one of these proteins, you can lose function of the entire complex. So the sarcoglycan complex is an important binding complex for dystrophin at the C terminus or the end of the protein. The other important binding site for dystrophin to the membrane is at the end terminus or the beginning of the protein through spectrum repeats 1, 23.
And as you can see, this is why it was so critical that we included these domains within our micro dystrophin constructs. So again, all of these proteins work in concert. And when you lose one of the sarcoglycans, you lose assembly of that complex and you also have a secondary reduction in dystrophin. So by simply redelivering one of these normal proteins back, you can restore the complex and restore function. Now the other 2 programs that NOIEXIS is focused on are Dysferlin and enoximab5 and both of these proteins are important proteins involved in the process of membrane repair.
When you have failed muscle membrane repair, this leads to chronic muscle damage and degeneration over time. For the purposes of today, we're focusing on beta sarcoglycan deficiency, which results in LGMD2E. Beta sarcoglycan is critical because it forms the core of the sarcoglycan complex. It's the 1st protein to start assembling this complex and it binds to beta dystroglycan. This again is one of the more severe forms of LGMD with significant cardiac and respiratory involvement.
So now I'll describe the outline for the study. Today we're presenting the first cohort results. Now the LGMD Cohort 1 was an open label trial design. The entire trial was designed for 9 subjects with LGMD between the ages of 4 to 15. These first three subjects received a low dose of 5x1013 vector genomes per kilogram of AAVrh74 MHCK7 beta sarcoglycan.
We were very thoughtful in the design of this construct. Again, we used rh74, which we previously shown to transduce muscle, both cardiac and skeletal muscle very well. And also the MHCK7 promoter, which clearly robustly expresses in muscle as well as the heart. So this is critical for impotent effects within these patients to treat all aspects of the disease. The inclusion criteria included 2 confirmed beta sarcoglycam patients, patients have to be negative for rh74 antibodies and also have greater than 40% of normal on the 100 meter walk time Patients received a pre biopsy prior to gene transfer and then a predefined 60 day post muscle biopsy.
Now unlike DMD, LGMD subjects are not on steroids as a standard of care. So there's not been any clinical benefit showed conclusively within the literature of using steroids to treat LGMD. So these patients were not on 3 subjects were not on steroids prior to gene transfer. We did give the patients prednisone one day prior to gene transfer at 1 milligram per kilogram. They were continued for 30 days and then tapered.
The endpoints for this study, primary endpoints included safety as well as expression. And we predefined the threshold for success as 20% of beta sarcoglycan positive fibers, and I'll talk to you about why in subsequent slides. There was also secondary endpoints, which included a decrease in creatine kinase. Creatine kinase is an enzyme that leaks into the serum when there's muscle damage. And so LGMD subjects like DMD have significantly elevated levels of creatine kinase without any treatment.
We also have various functional endpoints in the study. So we've been designing this program for many, many years and we're very thoughtful about how we design the construct and the doses that we chose. And so we always want to make sure that we're delivering effective dose to patients. And so in early studies, we used vascular delivery in preclinical models. This is the beta sarcoglycan mouse.
And we delivered a dose of 5x1012 vector genomes per kilogram. So this is a low dose, which led to approximately 20% of muscle fibers expressing beta sarcoglycan. Importantly, this expression of beta sarcoglycan led to a functional improvement in the muscle. So if you look at the purple bar in the right hand graph, we saw significant improvement in function as compared to the knockout mouse. So this really defined our threshold for success.
We knew if we could at least get 20%, we would have functional improvement in patients. So now I'll present the preliminary results of this study. So this is cohort 1 of 3 patients. Looking at the subjects demographics at baseline, our 3 subjects range between the ages of 4 13. We also saw a range in weight.
The patients ranged from 17 to 55 kilograms in the study. CK levels of baseline are shown on the right, which were relatively consistent between 10000,000 and 12,000 units. So now looking at the biopsy data. So at 60 days post gene transfer, we are seeing significant levels of beta sarcoglycan in all 3 subjects at the below dose of 5 times 1013 vector genomes per kilogram. The beta sarcoglycan expression was robust.
It was localized to the muscle membrane in all three subjects. So if we look at mean expression, we see 51% of muscle fibers are expressing beta sarcoglycan. We also see that the intensity is 47%. So if we look at the amount of beta sarcoglycan localized at the membrane and compare that to normal, we see it's 47% of normal. Now looking at the patient level data, we see consistency among all three subjects.
We're ranging from 42% to 63% of positive fibers for a mean of 51%. We also see consistency in mean intensity amongst the subjects. So in summary, this data greatly surpasses our predefined threshold of 20% expression in the number of positive fibers. So we are 31% greater than this predefined threshold. We also quantified the amount of total proteins in the biopsies.
So importantly, remember, we are delivering the full length proteins and we are seeing a mean of 36.1% of expression by western blot in these subjects. And it's important to note that when we're looking at the amounts of protein amongst the 3 subjects, we see very consistent results between the 3. So again, very robust, high levels of expression at the slow dose of 5x1013 vector genomes per kilogram. This is a summary slide of the data, but what is important to note is that we are seeing vector copies in the amount of 8.4x10x10x4 vector genomes per microgram of DNA equivalent to 0.6 copies per nucleus. So this is the amount of vector copies that were delivered to the muscle.
And these are relatively low numbers, but this really speaks to the potency of our construct. We've over many, many years, we're very thoughtful about the serotype that we chose, the promoter that we chose and the manufacturing construct. And so at this relatively low copy number, we are seeing robust expression that really speaks to the power of our construct. So we're again seeing 51% beta sarcoglycan positive fibers and 36.1% of normal on Western blot. Now these high levels of expression are also correlating to functional assembly of the complex.
As I mentioned previously, we see reduction of the other sarcoglycans without LGMD2E. So we look at the top panels, we see that we have very low levels of alpha sarcoglycan pre gene transfer. But in the post gene transfer biopsies, you can see significant upregulation of alpha sarcoglycan at the membrane that's consistent among all subjects. So we are not only restoring the protein, we are restoring a functional complex. And this functional complex is protecting the membrane.
And we can further see that by a very dramatic reduction in creatine kinase post gene transfer. Again, we're showing these baseline levels of CK between 10,012,000. At the baseline, after 90 days, we are seeing a dramatic reduction in CK with a mean of 90% reduction, very significant levels of reduction in the following gene therapy. Now this reduction is specific to the gene therapy. And this is evidenced by work that we did previously in another form of LGMD, at a much lower dose.
This is a study that was done just to look at gene therapy in isolated limbs, so not systemic. These patients were given the same steroid protocol that we gave in LGMD2E trial. And what's important to note is that in this trial looking at the same concourse, we saw no drop using the same steroid protocol. The drop that we're seeing is specific to LGMD2E gene therapy in this patient population. Now in terms of safety, all the patients are doing very well.
Patients 1 and 2 have 90 days of follow-up, patient 3 have 60 days of follow-up. In the trial, 2 patients had elevated liver enzyme elevations. 1 of these was designated as serious adverse event. This patient presented with mild jaundice and elevated bilirubin. Out of abundance of caution, the patient was admitted and given fluids as well as readministering steroids.
It's important to note that both of these events occurred when the patients were tapered off of oral steroids. When steroids were readministered, the symptoms resolved within days and now these patients have been tapered off of steroids and completely back to baseline in terms of their liver enzyme elevations. Because of this, we've modified the protocol that patients will now be on steroids for 60 days before being tapered to eliminate liver enzyme elevations in the future. It's important to note that the evidence of liver enzymes is seen in other gene therapy trials. We've seen it in micro dystrophin, others like AveXis have seen it too.
So it's not unexpected, but we will proactively extend the steroids to avoid this in the future. There were no other clinically significant findings. This included no decreases in platelet counts. 2 patients in the study had transient mild nausea that occurred within the 1st week when steroids were administered. This didn't correlate with liver enzyme elevations or any other abnormalities.
So just to summarize, I feel very gratified to present this data to you today. This is after many, many years of work developing this construct and trying to find a meaningful treatment for these patients that we're working so hard for. So I'd just like to thank everyone. I'd like to thank Doctor. Mendell for a great collaboration.
Very gratifying to see a therapy that has the potential to really change these LGMD patients' lives. So now I will turn it back over to Doug Ingram.
Thank you very much, Luis. And Luis, let me give you a little self indulgent here for people in the room. Can we thank Luis for getting a playback and in his absence Doctor. Mendell for extraordinary. So let me contextualize, if I might, the importance of what is a very significant milestone and what we see as very remarkable but preliminary results for this program.
We have been saying for some time that we have a strategy of building an enduring gene therapy engine, a gene therapy platform that really founded on a couple of premises. The first premise is that the era of gene therapy as a transformative modality is upon us now. It's not something in the future and we needed to move fast. And we also have believed that if we design well, if we choose constructs well, if we choose therapeutic areas well, that we can create a portfolio of therapies that have 2 very important features. First, that they will individually and in the aggregate have a greater probability of success than one might see in traditional research and development.
And second of all, that we can have faster time lines than one might see in traditional development. And one of the very encouraging aspects of not only these results, but the results that we saw last year is that we are validating the Savaria approach to building a gene therapy engine. So let's just quickly preview what we're talking about. We've now seen unprecedented results preliminary though they may be in 2 programs in a very short period of time. To remind us, in the summer of last year and then in October, in Mendoza, we saw the preliminary results from our micro dystrophin gene therapy program.
And I would remind again that Doctor. Luis Rodino Klapac was the designer of that construct as well. And we saw what were at the time remarkable results for our 1st neuromuscular gene therapy program. At 2xE14, we had on protein positive fibers 81%, we had intensity of 96%. On western blot quantification, we had 96% across the 4 patients.
And we saw what no one had ever seen before at the time, which was this remarkable drop in creatine kinase or CK levels of 78%. And I think we all understand that CK is closely associated with muscle damage. And I think there was a lot of excitement around that. And we believe at the time that there would be read through from our micro dystrophin program into our first Limb Girdle 2E program for a host of reasons, including the fact it's the same capsid, it's the same promoter, it's the same inventor. And indeed, that is we believe what we are seeing right now.
I would remind you that this dose is 5 times E to the 13. So the results we're seeing right now are at a dose of R874 that is a quarter of the dose that we had with our micro dystrophin program. And yet here we're seeing 51% beta sarcoglycan positive fibers where the study design would have said 20% was a significant functional improvement and success. We're seeing 47% as you know on intensity. On Western blot measurement, I don't think anyone's ever, but for Duchenne muscular dystrophy program, seen quantification on Western blot of the neuromuscular protein at the sarcolemma like this, 36%.
And once again, we're seeing striking reductions and very encouraging reductions in CK of 90%. So it is becoming clear to us that there is something going on here that is much more for instance than just dose. There is something in the elegance of the design of these constructs, the particular promoter that Doctor. Luis Rodino has chosen, which appears to be very productive, the way that the capsid is being used and the like, that's explaining to some large extent the early remarkable results we're getting. So we saw this read through from micro dystrophin to Limb girdle 2E.
And then when we consider these preliminary results, it has implications far beyond 2E. It really does, we believe, have potential read through to all 5 of the limb girdle programs we have. Remember, we are using the same capsid not only in the rest of these programs versus 2E, but also in our Duchenne muscular dystrophy and micro dystrophin program. In 3 of the 5 limb girdle programs where it is important to have robust expression in the heart. We're using the same very powerful promoter MHCK7 and of course as I've said many times already today, we have a common inventor across these programs.
These 5 programs together, while the epidemiology on this is still evolving are very likely in the United States about the same size of epidemiology and patient population as Duchenne muscular dystrophy and perhaps even larger around the world outside the United States given some of the founder effects. So the opportunity to do good here is frankly potentially extraordinary. Good news is that's not that has nothing to do with the fire at Sarepta, so there should be no sell off. Apologies for that distraction. This very next slide is a busy one and it explains all of the various reasons why we have decided to exercise early our option to acquire Myonexus.
But and you've seen that presumably earlier today in the press release given the results that we've just announced, I sincerely doubt that there's anyone on this call that needs to be convinced of the wisdom of a decision to exercise this option early. And so I don't think we need to go through all of these slides. We now have full control over these programs. And in classic Sarepta fashion, we intend to move with rapidity. And so I will move on.
So let's talk a bit about the next steps. We have broadly a couple of things that we've got to get done very soon and we've got to report back to you on. All the first thing we need to do is to meet as soon as possible with our FDA colleagues and chart a path forward for all 5 of these limb girdle programs. To remind us, all 5 of these programs aim to replace the exact native protein that is missing in the patients that live with these 5 diseases. And these are all very well characterized monogenic diseases.
So there may very well be an efficient path forward for these 5, but we need to meet with the agency and talk that through and get their insight before we report back. We also interestingly enough have to analyze what the next cohort in the clinical supply might be. This is going to be a very interesting one. The protocol itself provides for the opportunity to dose escalate beyond the dose that we have right now, which is 5 times E to the 13th. But we have some work and some thinking to do on that, as you can imagine why.
On the one hand, as you've just seen and hopefully would agree with me, we have seen at 5xE13 very significant and robust expression both on the protein itself as quantified in a number of different ways, but also on related biomarkers. But at the same time, interestingly enough, this is actually a dose that is only 1 quarter of the dose and the same capsid as for instance we've used with our microdystrophin gene therapy program. So we do believe there is an opportunity if we choose to do it to go higher. So we need to do that analysis and then we'll come back to you and provide you with an update on it. The good news on that analysis just so we know is that there's nothing in the decision about whether or not to do a higher dose at a different cohort that has any impact on the long term timelines for any of these programs for a simple reason, which is we can do that with clinical supply as we build out commercial is exactly what we did with respect to Duchenne muscular dystrophy, is exactly what we did with respect to Duchenne muscular dystrophy and that timeline needs to be built down.
So what we need to do here, if you look to the right here, we need to do exactly what we've done with micro dystrophin. We need to now that we have complete control over Myonexus, we need to have the INDs for these programs transferred from Nationwide Children's Hospital to Sarepta and we need to transfer them out of the Nationwide facility into our partner of choice in this instance. It's Paragon. And then we need to do exactly what we've done with micro dystrophin, which is we need to evolve from the clinical supply program, which is a mammalian adherent process, but a hyperstack process to a very similar process, which is a mammalian adherent process, but that's a more scalable three-dimensional ISELUS process and we will start that process and that's taken soon and we'll report back. So we've talked about the read through from Duchenne muscular dystrophy to the next five therapies that are under this umbrella of Limb Girdle and it will continue beyond that.
As you know, we have a very significant portfolio of an gene therapy engine and I suspect it will continue to grow over the next 24 months. So moving forward, as you know, we will be dosing first patients by the Q3 of this year And Charcot Marie Tooth that is with we're very proud that it's with Doctor. Zarife Stehank over at Nationwide Children's Hospital. And to remind us, sarcomaritooth or CMT is the largest inherited neuromuscular disease in the world. So we are very excited about the opportunity to do good there.
We have MPS IIIA or Sanfilippo disease, a very serious neurological disorder and we have already with our partner Lysogene begun dosing patients in what might very well be a pivotal trial with MPS IIIA. And then with our Pompe program, we're working with none other than Doctor. Barry Byrne at University of Florida, Lacerta, doing the preclinical work for that right now. And our goal is to start dosing in the Pompe program in 2020. So in short, to use upon based on our concept of a gene therapy engine, it is full steam ahead for us.
We are building out this engine to serve patients. These 2E results and our decision to acquire Myonexus and exercise our option only strengthen our resolve and validate our approach, and we'll continue to execute across 2019 19 and provide updates. And with that, I would open the call up for questions.
Thank you. And our first question comes from Salveen Richter of Goldman Sachs. Your line is now open.
Good morning. Congratulations on the data. So at these levels of expression, why did you dose escalate why would you dose escalate as you go into Cohort 2 and beyond and what goes into that decision? And also I recognize it's early days, but did you see anything in terms of functional benefit?
So let me answer the broad stroke about just sort of this analytics Doctor, which we do have a clinic and provide more granular. I'll add and also I think some of the qualitative information on function. I mean the short answer is we've just got to do some analysis. The concept of ensuring that you pick the absolutely most robust dose particularly in something like gene therapy, which is itself very unforgiving as it stands right now, you get one opportunity to provide a benefit to patients is an important one. And you can envision in advance why we can't simply give an easy answer right now.
On the one hand, we have what appear to be striking results and great expression. And on the other hand, it does appear that we have headroom to safely look at even higher doses. And we can do all of that if we choose to do another cohort. It actually has absolutely no impact on the timeline to get to the community with the therapy. So we've just got to put some thought into it and reflect on what the right answer is and probably also take some insight from the FDA as well.
And with that, I'll turn it over to Doctor. Udine McClaypad.
Thank you. I would just echo that we'll be thoughtful about dose escalation. It was pre contemplated within the protocol. And we've discussed this with the DSMB and they're comfortable in terms of dose escalating if that's the route that we choose to go after careful thought amongst ourselves as well as with the FDA. In terms of functional improvement, it's early days.
We're not providing the quantified data, but we are seeing early signs of functional improvement. We've been talking to the patients that are doing activities that they weren't able to do before. And so we're looking forward to these results. And so far, the early signals look good.
Thank you. And our next question comes from Ritu Baral of Cowen. Your line is now open.
Hey guys, thanks for taking the question. Congratulations on the expression levels. My question is on the adverse event. Can you talk about or the SAE rather, can you talk about the timing of that event versus when you took the biopsy, when you took the CK levels in this patient, the patient has completely normalized and whether we should be worried about roll off of expression or roll off of function after the transaminitis?
So the bilirubin liver enzyme elevation occurred when the after the patient had been tapered off of steroids. As I said, it quickly resolved within days. The biopsy was taken after this event, after the patient had normalized. So there was no impact on expression. CK level was taken over time and we consistently saw this drop in CK.
Thank you. And our next question comes from Alethia Young of Cantor Fitzgerald. Your line is now open.
Hey, guys. Thanks for taking my question and congrats on the very solid data you've shown here. Just maybe 1 and maybe 1.5. Can you maybe frame or help us think about kind of what would be reasonable time period to see a functional improvement? How might that manifest itself?
And then just on the liver enzyme increase, do you think that there was something about this one patient that might have led them to be more predisposed? Is there anything you can talk about there, I think?
Okay, sorry. So actually, this
is Gil Marni here. What I'll
do is I'll take the question on the liver enzymes. And I think the key thing about that is that we don't believe we haven't we don't have evidence that this patient was different from others. I think the key point is that the bump occurred during a taper in steroids. I think the critical point is that with a re escalation of steroids, that bump resolved within days. And I think very importantly, the patient remains at normal levels or at baseline levels off steroids and has been off steroids now for approximately 20 days, 30 days.
And so I think that's very good, particularly in the context of a therapy that is given once. We're not talking about chronic dosing here. We're talking about one dose here. And again, a full resolution and then the patient is actually now off steroids and remains well and laboratory is normal. With regard to the functional data, I think Doctor.
Louise Rodino Klapac has disclosed that we have we are measuring this in the protocol, but we have basically just focused on the expression and by distribution data. Our understanding is that the data, the clinical data are good. However, it is very early days yet, and we feel that it will be later in the time line of the protocol that we will actually be confident in describing.
This is Doug. Just not to I don't want to minimize ease, but just to remind us, in the concept of elevated liver enzymes is what we see with these infusion based therapies. 3 of the 4 DMD children had elevated liver enzymes in the AveXis program. There were significant number of kids saw elevated liver red bloods. And in all of those cases, as well as the MD and then currently as well as this program, it seems to be very manageable with the steroids.
So it looks like a very manageable issue. And then with respect to the functional data, just so we're clear, if Doctor. Mendell was here today, I believe he would tell you that the early reads on function are looking very good, but it is, I think, fairly risky to after 60 days of a patient that has a degenerative disease to be drawing sweeping conclusions on function, we really need to follow these patients longer and frame it better. So then we know that when we're talking, we're not potentially misleading and accidentally.
I think the key point is that I think the key message here is that we are seeing robust expression of a full length protein that is known to be missing in these patients. And it's actually associated with reconstitution of dystrophin associated protein complex. So the biology is certainly very compelling.
Thank you. And our next question comes from Brian Abrahams of RBC Capital Markets. Your line is now open.
Hi, thanks for taking my question and my congrats as well on the data. On the expression data, can you clarify, did you adjust for on the Western for fat content or make any adjustments relative to baseline expression levels? And then maybe if you could clarify whether there's any additional clinical data that you have, for instance, data on carriers that might help you further benchmark what your target levels might be and whether you might consider dose escalating or going forward at this level? Thanks.
So I'll take the second question, Shailz. So in terms of the amount of we're really relying on our preclinical data to guide us in terms of dose escalation, being thoughtful about it. And I think we know that 20% is our threshold for success, but certainly there's an opportunity to go beyond that. We do know that carriers have a reduction in protein. And so I think there's a lot of strong rationale there as well, to be able know that less than 100% of protein expression will lead to significant functional improvement.
And I'm sorry, could you remind me of the first Whether
you made any adjustments for fat content on Western or any adjustments relative to baseline expression levels, if that differed among the patients? Thanks. Right.
So the westerns were normalized for fat fibrosis and then compared as a percentage of normal.
Thank you. And our next question comes from Marty Oster of Credit Suisse. Your line is now open.
Hey, guys. Congratulations on the data this morning. Thanks for hosting the call.
Had a question for
you on the limb girdle natural history study you're conducting. I was wondering if you could provide an update and maybe if you have an idea of when findings might be discussed or presented in the future? Thanks.
Apologies, I distracted. The question was about the clinicaltrials dot a natural history study for Limb girdle. The question was what's the timing of that?
Right. Yes. So the natural history study that's in clinicaltrials dot gov was used to identify patients really as an enrollment study for this as well. So that's continuing on for LGMD2E as well as other subtypes in our portfolio.
Thank you. And your next question comes from Anupam Rama of JPMorgan. Your line is now open.
Hey guys, congrats on the data and thanks so much for taking the question. What are the plans for publication or presentation to the physician scientific community for these initial LGMD2E data? Any specific conferences you're targeting? And how much follow-up could we be thinking about, I guess, dependent on which conference you select? Thanks so much.
In terms of the presentation, we'll be presenting these results at the MDA meeting this year. And we'll be certainly looking for future scientific conferences to extended follow-up data as well.
Thank you. And our next question comes from Debjit Chattopadhyay of H. C. Wainwright. Your line is now open.
Hey, good morning and thank you for taking my questions. Just one here. So would you expect similar outcomes in older patients? And where do you think COGS will line up if you go with the current dose versus if you have to scale up higher? Thank you.
This is Doug. I mean the short answer is we have older patients. So just to remind everyone, one of the interesting things about this program is that we have child that's 4 and 2 teenagers with 2 13 year olds. So with much heavier. So this is additional confirmation both on the safety and the ability to get very consistent expression, at least in the first three children across a very large age and weight range.
And the COGS are not an issue I mean, the COGS are always an issue at some level, but let us remember this is 5 times E13. This is a quarter of the dose of our micro dystrophin program. We are already in the process of working through Duchenne muscular dystrophy program and the rh74 manufacturing. We're very confident about where our COGS are going to come out and our gross margins eventually will come out. And so within any reasonable range, if we stay where we are, obviously, it would be a lower COGS, but still very comfortable.
And if we went higher, it wouldn't stress the system as a slide.
Thank you. And our next question comes from Tazeen Ahmad of Bank of America. Your line is now open.
Hey, good morning. Just to follow-up on the question around age. So it seems like we saw relatively similar reduction in patient number 2, who is the younger patient relative to the teenagers. Is that something that you had expected? Or did you potentially think that the earlier you're starting, the more pronounced effect you would see?
I think we're seeing very consistent results amongst the ages. And I think based on the expression, we see a similar reduction in CK and really based on similar levels of expression. And so I don't think we thought prior to this that we would see a difference between
ages. And certainly one of the hopes that we always have is that as we intervene earlier in a patient's life, the opportunity to catch damage before it occurs and sort of correct in advance is helpful. But of course, the mechanism of action is the same across all of these patients and it's similar across all of the limb girdles and it's similar with respect to this monogenic disease that Duchenne muscular dystrophy. These patients the reason for the patients' degeneration is very well understood. They are missing a particular protein that is you're a 20 year old or a 25 year old.
So we're very this is 3 patients. I want to be very clear. We need to be thoughtful. This is 3 patients. So these are preliminary results.
But certainly, it's gratifying to us that these results are very consistent across all of these 3 patients and that the patients themselves have some validating aspects, once 4, once 2 are 13, the weights are different among these patients and yet we're getting very good expression even at 5 times E13.
Thank you. And our next question comes from Danielle Brill of Piper Jaffray. Your line is now open.
Hi, guys. Good morning and congrats on the data. I'm just curious, was the steroid regimen employed in these patients different from the micro dystrophin program? And then looking at age from a safety perspective, could the LFT effects be more pronounced in older patients? The steroid regimen was the same for the micro dystrophin trial, but it's important to note that the DMD patients were already on steroids as a standard of care, whereas in LGMD, they're not on steroids.
And so when you're tapering them off, they're going to 0 steroids versus DMD where they're still on a maintenance dose of steroids. That's the difference. But the steroid regimen for the trials were exactly the same.
It should also be noted, I know Doctor. Rodino Klapac said this before, but there's reminding that with respect to these patients, because standard of care historically is not to have long term maintenance of steroids, That's one issue on them coming into the trial and getting on steroids, but also know that 2 of the 3 patients have already gotten to the point where they're fully off of steroids, they've gone back. So they are not their liver enzymes are back to normal and they're not on steroids at all. So this looks like so these issues look very, very easily not I shouldn't say that, that overstates it, that they're very manageable with with a good steroid protocol in connection with infusion.
Thank you. And our next
I have 2 very quick parts. First question is, any differences in baseline Western blot and any differences in vector genome copy per nucleus, particularly in the young patient versus the 2 older patients? And then also another related question is, did you check a dystrophin expression on the membrane?
So the baseline levels were relatively low consistently across the three patients. In terms of vector copies, we saw no trend or with age and they were relatively consistent amongst the patients. And as far as dystrophin, we haven't done a quantitative look at increases in dystrophin yet.
Thank you. And our next question comes from Christopher Marai of Nomura. Your line is now open.
Congratulations on the data. I was wondering if maybe you could walk us through thoughts on potentially how you may move to a higher dose and specifically what you've been seeing in non human primate models. I mean, did this dose sort of scale linearly, if you had looked at it in those models? And then secondarily, just could you comment on the self complementary constructs and the potential for durability there versus the other constructs? Thank you.
Sure. So in primate models, we certainly have safety at much higher doses up to 2 to the 14 vector genome copies. I think we'll just be thoughtful about it. We have dosing studies in preclinical models that suggest that we can move up, but we just have to look at the entire picture, discuss it with, the SMB and FDA and decide whether we're going to go up, where these results are spectacular. So we're in a conundrum.
I mean, we have fantastic reduction in CK and do we need to go up. So that's just a discussion that we have to have. In terms of the self complementary construct, that is enabled you don't have to wait for the 2nd strength to this system self complementary vector. So that just allows you to get expression earlier. So we start seeing expression within the 1st week.
But presumably, that doesn't lead to the any increase in expression over time. It's just a more efficient process because you don't have to wait for that 2nd strand synthesis. So really in terms of durability, it has no difference versus a single stranded construct.
Thank you. And our next question comes from Brian Skorney of Baird. Your line is now open.
Hey, good morning guys. Thanks for taking my question. I guess maybe just kind of get a little more color on your thoughts around regulatory strategy here. Obviously, you have EXONDYS 51 approved as a neuromuscular disorder drug based on low levels of protein expression that's similar to a wild type protein. And we sort of discussed the FDA strategy in terms of microdystrophin gene therapy and regulatory, not concerns, but considerations around using an engineered protein that's distinctly different from the wild type protein.
Here you have a wild type protein. So just what are your high level thoughts given that you just went to the FDA to discuss microdystrophin gene therapy in regards to the potential for this to be approved on just expression alone? Do you think that you're going to be pushed to show functional endpoints in a randomized controlled manner? And then just thoughts on how the regulatory agencies are looking towards monitoring durability of this? Will you look at additional biopsies down the line?
Is CK a good measure? And just stemming from that, have you looked at continued CK levels on the micro dystrophin treated patients? And do they remain suppressed below 10,000 units per liter? Thanks.
So yes, thanks for this question. So I'll give you the most direct answer on that, which is we really have to sit down with the agency and talk to them. And anything that we say right now about the pathway forward with the Limb Girdle programs is until we speak to the agency speculation on our part. Now it is your points are very well taken, which is we know that Cedar's perspective on the pathway for truncated dystrophin. We also know the agency's perspective on the importance of showing the functional correlate of micro dystrophin when you've engineered the protein.
This is neither of those. This is the native protein to your very good point. And certainly the agency has made some public comments recently about the pathways for potentially curative gene therapies, particularly when you're dealing with the actual correction of the underlying disease like we would theoretically be doing with all of these 5 programs. So one could envision a world in which the agency may see accelerated approval as the appropriate pathway for these rare diseases where you're getting robust expression of the native protein. But I really do want to caution all of us that the good answer to that question comes only after we have a we sit down, we have a thoughtful discussion with the agency, we take their insight and then we'll come back and talk about it.
And when we do and we will do that by the way, and we will come back and talk about it. And then we'll be able to give you a much better view on the pathway forward and the value of various biomarkers as well. And we'll line that up as well with essentially a form of Gantt chart on the commercial process to get to commercial supply because as will be the case of these limb girdles, I think the gating item is going to be tech transfer over to Paragon, process development and commercial supply for commercial supply dosing as well for all these five trials, just as it is over at Brammer with micro dystrophin. So these are really interesting questions. I think that there are differences between an engineered gene and these genes, but we need to take some advice from the agency and come back thoughtfully after we've done that.
Thank you. And our next question comes from Tim Chiang of BTIG. Your line is now open.
Hi, thanks. I think you guys mentioned that you'll most likely present the data at the upcoming NDA meeting in April. Is it possible that you could show some additional functional data at that meeting?
Well, we don't have any current plans. We just want to be look, I'll just be very direct. I'm sure Doctor. I can tell you because I don't think I'm misspeaking when Doctor. Mendell would say that he has some functional results and he has a clinician's view on how the patients are doing.
And I'm quite confident that all those answers would be very positive right now. But we all must remember that we have these are 2 month biopsies and we just don't want to be we don't want to inadvertently oversell the data until we have more information. And April isn't very far away from where we are today. So I would suspect that the information that we're going to have at MDA is going to be the expression level data, biomarker data and related information. And we'll await a time when we have more confidence on the functional data before we start really discussing it.
Thank you. And our next question comes from Vincent Chen of Bernstein. Your line is now open.
Congratulations on the data. One quick one. In the patients who were treated thus far, could you provide a bit more color on the types of mutations that they had? I'm particularly curious whether these patients be primarily missense mutations who would be likely to have some minimal level of sarcoglycan baseline or these would include patients with, for example, frameshift mutations who might be expected essentially no detectable sarcoglycan? And are there specific mutation types which are being included in the trial?
The patients in this trial are missense mutations.
It's worth pointing out that the in this disease, the great majority are missense mutations that are described in this disorder. It's a different, you say, it's a different span of mutations that we see in this disorder than for example, in dystrophin from whence I think you're taking the frame shift question.
Thank you. And our next question comes from Joel Beatty of Citi. Your line is now open.
Good morning. Thank you for taking my questions. This is Sean Egan calling in for Joel. Maybe just two quick housekeeping questions and then maybe just your thoughts on high level thoughts. You maybe comment whether this modified steroid regimen, the 60 day regimen has been kind of transferred to the micro dystrophin program?
And also could you comment whether all patients in this trial were from the same drug batch? And then maybe also could you provide kind of your high level comments, just kind of the second indication and second construct where you've kind of exceeded your preliminary and preclinical expectations regarding expression. Can you comment how you tease that through and maybe what could be driving that?
First one I'm sorry, there were 3 questions there. I'm so sorry. So the first question, I believe, was the steroid protocol for what we're calling what I call Study 2. Or micro dystrophin. Yes, on micro dystrophin.
And I believe the answer to that is that the investigator, Doctor. Mendel, has the flexibility to do 30 or 60 days. So he has the ability to adapt to steroid use as he seeks to fit over the course of 30 or 60 days. And then I'm really sorry about this. Can you repeat your other two questions?
I think the second question was expression levels. Are these expression levels we're seeing predicted by the non clinical?
Yes. These were predicted by the nonclinical data in both this program and our other programs with rh74 at this dose. And I think you also asked about the vector lot and this was a single vector lot used in all three patients. So it's consistent among the patients.
Perfect. Thank you so much. Thank
you. Thank you. And our next question comes from Liisa Bayko of JMP Securities. Your line is now open.
Hi. Just thinking a little blue sky, and by the way, congratulations on all of this. It's great. Can you maybe comment on where else beyond DMD and limb girdle muscular dystrophy, where else this kind of a construct vector promoter could make sense. And what you're thinking, I guess, for the rest of the limb girdle portfolio?
I know you're going to speak with FDA, but sort of how close are you to maybe starting some initiatives there?
Thanks. Thank you. Well, the short answer is we want to start initiatives across all of these 5 constructs as rapidly as is possible. We've got a lot going on at the same time, but we really want to get to it because the read through from this 2E program to these other programs is, on the face of it, enormous. As I've said many times, this is the same caps.
These are 3 of the 5 of the same promoter. These are all monogenic diseases. They're all neuromuscular. They all are associated with the dystrophin associated protein complex. So the opportunity to do a lot of good across these constructs is enormous.
Beyond that, I don't want to overpromise right now, but Louise and her team have a center of excellence that we were building out in Columbus, Ohio. We have an 85,000 square foot facility that we have. And we're looking at exactly the kinds of questions you're asking, which is with the opportunity to do so much good with 7,000 rare diseases, 80% of which are monogenic and one approved in vivo gene therapy, where do we go with this engine and what other should we be looking at? And we'll have additional targets, at least aspirationally, internally identified by the end of this year. And then of course, we continue to look externally as well to see if there are external opportunities that align with our thesis around gene therapy that are that have the same clever concept and design and approach.
And again, we favor monogenic diseases that have the greatest opportunity for those speed and probability of success. Without over promising, I would say at the end of this year, it will not surprise us and it probably doesn't surprise external folks either that we may have additional opportunities to bolster our gene therapy approach.
Thank you. And our next question comes from Yun Zhong of Janney. Your line is now open.
Hi, thank you for taking the question and congratulations on the data. So are you able to provide a little more details on the clinicaltrials dotgov, looks like 3 patients are to receive placebo in the high dose cohort. So if you do decide to dose escalate, would there be any patient receiving placebo? Or would that be dependent on your discussion with the FDA? Thank you.
We adapted our thinking. So the original design of the study had envisioned maybe you have a placebo patient in some of these cohorts. We look carefully at it, there's really very little additional insight one way to get from that. So for instance, with this cohort, this original cohort had initially been designed to do 2 actives and 1 placebo. And as we took a careful look at it, there was just there was no good reason not to get more of that into 3 patients.
So until we get to the point where we're designing something for to ensure that this is for approval. We're going to adapt ourselves so that we're moving as fast as is possible. And the short answer on the liver enzymes is we had elevated liver enzymes. They very rapidly responded to reinitiation of steroids and resolved. And as it stands right now, 2 of the 3 patients the 2 earlier of the 3 patients have fully cycled all the way off of steroids and their liver enzymes are staying stable.
And we haven't talked about this, but I'm sure it's that people, everybody, I think, is well aware of this. But for the avoidance of any doubt, both in this program and our micro dystrophin program, we have never seen any drops in platelet counts. We've said that in the slides and no one's asked about it, so I think everybody understands that, but in case there was a concern. There's never been a platelet count drop in any of our trials.
Thank you. And our next question comes from Tim Lugo of William Blair. Your line is now open.
Hi, it's Myles on for Tim. Thanks for taking the questions and congrats on the data. It's great to see. My question is just on the is the 25% of the dose that you've given in the micro dystrophin program, yet you're getting this very robust expression. And it's very consistent across the border, it looks like Western blot here.
And I know that we saw some variability in between the 4 patients on the micro dystrophin program. Differences we're seeing in expression between the programs are a differences we're seeing in expression between the programs are a function of expressing full length versus the truncated protein? Or are we getting better at infusion sites? So Doctor. Mantel stood up a lot of patients now.
Or is it still just inherent unexplained variability? I'd love to hear your thoughts around that as we move forward in a potential dose escalation.
Well, in the micro dystrophin program, we had, as you recall, we had 3 patients that were very high expression and similar and then we had one super responder and we have some thoughts on that super responder, which we're excited about, but we're not ready to disclose right now. As it relates to this dose, we do see we're seeing very robust expression. There has been there is a general dose response. But I think the one thing that we see out of this, that's interesting is it's not all dose, That there is something in the design, the construct and for the capsid reps and maybe even significantly the promoter that shows us that even at a quarter of the dose, we're getting very robust expression. I think that is meaningful for the future.
Thank you. And your next question comes from Gil Blum of Needham and Company. Your line is now open.
This is Gil on for Chad. And again, congratulations for your results.
We can't hear you very. Could you speak up? Sorry, we were
having difficulty hearing you. You're very faint.
Sorry, can you hear me now?
That's better. Thank you.
All right. Could you perhaps discuss some preclinical data assessing the stability of expression over time with these constructs?
Sure. So we have preclinical data in the beta sarcoglycan knockout mouse, out from 27 months with this construct and saw no diminishment in expression. So far, preclinical data is very suggestive of a long durable effect.
And also remember with our micro dystrophin program also, the sarcolemma replacement of a protein, same capsid, promoter, across a number of animals, non human primates and with our other partner, the golden retriever Duchenne muscular dystrophy animal as well as the mice, we're seeing very robust durability. For as long as we've been able to watch these animals, which gets out to sort of 7 years and 8 years. So far at least the preclinical models, we're seeing very significant durability.
Thank you. And our final question comes from the line of Ritu Baral of Cowen. Your line is now open.
Thanks for taking the follow-up guys. Going back to your comment Doug on manufacturing, the fact that you're in hyper stacks now and you want to move back up to iCELLis. Why not think of suspension for limb hurdle? How much could that improve your COGS or would it just be offset by complicating scale up? Can you address that a little bit?
Yes. So it's very interesting. There's a number of different approaches one can take to scale up the manufacturing to your very good point. We could do iCELLis, we could do suspension. People talk about baculovirus is an even more efficient approach.
The short answer for us is that we've got to do 2 things at the same time. We've got well, 3 things. Number 1, we've got to be able to have a process that scales. It can scale up and can fully serve the community and that's what we're doing with micro dystrophin 1st of all. The second one is speed.
We need to get to the community. When you see results like this, it does place upon us a feeling of enormous obligation to move as fast as possible. So while people talk about suspension and the like, the truth is that we can scale up with Icellus and we can do it at a cost of goods that is very compelling. And so we would much rather scale as fast as possible on something that's as similar as is possible to what we've already seen. So the nice thing about iCELLis versus suspension is we're moving from hyper stacks by adhering to mammalian to iCELLIS, which is a three-dimensional process, but adhering to mammalian.
And so we can move with much more rapidity. We can lean heavily on what we've already done with micro dystrophin to help inform what we're doing here. The similarities are obviously more than a little striking. And then the final thing, of course, is probability of success. Our goal is to frankly, at every stage, people internally are tired of hearing me talk about this all the time, but essentially shave risk wherever there is the ability to shave off risk.
And so we can choosing iCellis, I think, is a much higher probability of getting to the right place at the right time than suspension. And as I've said, I think before, the very idea of what we're doing in manufacturing is itself a moonshot. We are going from clinical supply to if we are successful in an unprecedented amount of commercial supply to serve very large communities. And so taking it a path, it has the best speed with the highest probability of success, and we can inform ourselves across each program explains why we're so focused on doing the same thing with limb girdle, at least that we're doing with micro dystrophin. That is not to suggest at all that with respect to other programs, we might not look at other manufacturing opportunities, suspension, baculovirus or otherwise.
And with our program with Lacerta and University of Florida, they actually have a very interesting thing that they call the 1DAC system, which is an even improved version of macular virus. But I think given where we are with limb girdle and microdystrophin, this isn't time to experiment with those approaches yet.
Thank you. And that concludes our question and answer session today. I'd like to turn the conference back over to Doug Ingram for closing remarks.
All I will say is thank you very much for your time this morning. We appreciate it. Hopefully everyone appreciated that we've divided into 2 this webcast that we could spend some time really talking about these early results and that we believe frankly are significant milestones for the company and then we will talk to those who are interested in participating later today on our Q4 earnings as well as corporate updates. So appreciate it and thank you very much.
Ladies and gentlemen, thank you for participating in today's conference. This does conclude the program and you may all disconnect. Everyone have a great day.