Good day, and welcome to the Soripita Therapeutics Conference Call and Webcast for the SRP-nine 9,001 Microdystrophin R and D Day. At this time, all participants are in a listen only mode. After the speakers' presentation, there will be a question and answer session. As a reminder, today's program is being recorded. Now, I'd like to turn the call over to Doug Ingram, President and CEO, for opening remarks.
Thank you, Catherine, and good morning, everyone, and thank you for joining us today for what we are calling throughout this microdystrophin day. First, remember, we will make a number of forward looking statements today. Please refer to our various public filings for a list and discussion of the risks and uncertainties that come with making predictions about what may occur in the future. Now in a moment, Doctor. Luis Rodino Klapac will walk us through recent updates from our 3 ongoing studies, the Study 101, Study 102 and Study 103, And then we'll provide information on the protocol for our pivotal trial study, 3 zero one, a study that we call EMBARK.
SRP-nine thousand and one represents the most advanced and significant opportunity in gene therapy today. The goal of this meeting is to share additional data from what is indisputably the most comprehensive evidence set for any Duchenne gene therapy to convey to you the basis for our deep conviction in the transformative potential of SRP-nine thousand and one for those living with Duchenne muscular dystrophy and to detail the thoughtful design of IMbark, our Phase 3 trial, which we recently announced has already initiated. We are indeed proud of how far we have come with SRP-nine thousand and one with 77 patients dosed thus far. We have the largest database to inform us on the performance of SRP-nine thousand and one and to inform our program and enhance its probability of success. We have become leaders in the manufacture and release of gene therapy.
We are the 1st Duchenne gene therapy sponsor to have been green lighted in the U. S. To commence a genuinely global pivotal trial with sites eventually in the United States, Europe and Asia. And with the wealth of patient data so far, some of it stretching beyond 3 years, it is beyond genuine debate that as of now we have a highly differentiated gene therapy construct in terms of safety, in terms of tropism, in terms of expression and in terms of functional signals. And yet we advance forward with the humility of a patient driven team that never forgets that the patients we serve and for whom we exist are in a daily fight against a brutally degenerative disease, where time is of the essence.
So while SRP-nine thousand and one may stand alone today, nevertheless, we know that we are indeed in a race. We are in a race against the disease that daily wobs children of their muscle and their function and invariably their lives. Hopefully, by the end of our discussion, you will agree that we have kept that race in mind and have built a program with the greatest probability of rapidly advancing to the community a potentially life altering therapy. And with that, let me turn the presentation over to Doctor. Louise Rodino Klapac.
Louise?
Thank you, Doug, and good morning, everyone. It's a pleasure to be here today to really describe the breadth and depth of our data with SRP-nine thousand and one. And just to quickly review the agenda for today, as Doug mentioned, we'll be reviewing data from our 3 trials, 101, 102 and 03. In terms of new analyses for the 101 study, we'll be showing new pre year functional data in comparison to natural history. And then we'll also be sharing additional analysis for Part 1, where we've also compared to natural history as well.
And finally, in our 103 study using our commercial process material, we'll be sharing functional results from the Cohort 1 first 11 patients. And this is all leading up to the study design for our 301 in BARK study. So if we go to the next slide, this slide really needs no introduction. As Doug mentioned, DMD is a devastating disease and children need urgent treatment. SRP-nine thousand and one was designed specifically to target all aspects of DMD, which includes skeletal muscle weakness, cardiac manifestations and respiratory manifestations.
And it is truly a race to be able to get to these patients. On the next slide, just to review the 3 components of gene therapy that are essential really and that just includes the vector, the promoter and the transgene. The vector, which really drives how you get to your target, in this case, muscle, skeletal muscle and cardiac tissue, and then really defines the safety or immunogenicity profile of your construct. Next, the promoter, which turns it on and off in the tissues that you like or desire and then also the transgene. So the next slide just to talk specifically about the components of SRP-nine thousand and one.
As you know, we have selected the AAVrh74 vector. We selected it specifically for several reasons. 1, in comparison to all of the vectors, we saw the transaction profile, specifically in muscle, which had a broad distribution across all the muscle cells, also in cardiac tissue. It also has a low level of pre existing immunity. We see approximately 15% of patients with antibodies to rh74.
Next is the promoter. We are using the MHCK7 promoter, which expresses nicely in skeletal muscle and cardiac tissue, which is critically important to any therapy for Duchenne. And then lastly, our transgene, which I'll talk about in a few slides, which was designed specifically to maintain all of the critical components of the dystrophin gene and protein. On the next slide, just to highlight rh74, as I mentioned, it has broad uniform distribution, and we currently have it in gene transfer trials for both Duchenne and Limb girdle muscular dystrophy, and it remains to have a differentiated safety profile. We've now dosed over 80 patients in both CMD and LGMD trials combined.
Also, specifically just the MHCK7 promoter to specifically target cardiac muscle as well as high levels of skeletal muscle transduction. Next slide. Now microdystrophin is a shortened functional form of dystrophin. If you look at the left in normal muscle, dystrophin is a shock absorber that has critical links inside the cell to outside the cell. So when muscle contracts, it's open and absorbs that shock.
It's too large, as you know, to fit into adeno associated virus or AAV. And about 30 years ago, a patient was identified by Doctor. Kay Davies, who is a 61 year old ambulatory vector muscular dystrophy patient. Vector muscular dystrophy is a form of hysteroclonalpathy in which patients have shortened versions of dystrophin, so it's a much milder course of disease than Duchenne. So this particular patient retained critical components of dystrophin and was still ambulating until an older age of 61.
And so when we designed our micro dystrophin construct, we took lessons from that patient
and made sure that we
were maintaining these critical regions. Specifically, if you'll note, spectrum repeats 1, 2 and 3 directly bind to those muscle membrane and really are important for maintaining force and resistance to contraction. Also, we've reinstalled the critical components to restore the dystrophin associated protein complex. So all of this design and iteration over many years has led to the development of FRP-nine thousand and one and it shouldn't be forgotten in terms of the differentiation of our construct. So now turning to NSAA.
Apologies. Just wanted to highlight the key considerations for evaluating gene transfer therapies. 1st and foremost, we always highlight safety. It's critically important for each of the trials, we'll go through the safety profile. Next, in terms of biopsies, it's important to know is the transgene getting into the cell, we did this by measuring vector genome copies of the nucleus.
Is it making protein? And this is measured by measuring the total amount of protein. And then is it getting to the right place in order to do its function? So is it getting to the muscle membrane? We measure this by percent positive fibers and intensity.
And then finally, is all of this leading to functional improvement? And our primary functional outcomes across these studies is NSAA, which I'll talk more about, and then various time function tests and secondary outcomes. So now specifically, we'd like to highlight the understanding of the NFPA. This is such a critical outcome. It's a 34 point scale of 17 different activities.
And these represent daily life. And each patient could have 0, 1 or 2 for each of these activities. 0, you're unable to do the function. 1, you can do it with assistance. And 2, you can perform it without any difficulty.
And each of these measures is, as you can see on the left, goes from most difficult, and these are lost early on in the course of disease to least difficult or last week. So some of the more difficult activities are things like coughing on one leg and rising from the floor. It's important to note that these tasks are administered by professionals and this whole scale was developed by investigators to really mimic clinically meaningfulness. So now thinking about one of the more difficult activities rising from the floor, what
we'd like to do on
the next slide is really show you what this means, because I think seeing it in action really makes the point and how different one point can mean on this scale. Now we're going to see the first video, if you'll direct your attention to the video screen on the first video on the left, the boy rising from the floor. And this is a 2 point on the scale. Are you able to play it? Is it playing?
Sorry, I'm not able to see it. Okay. He's unable he's able to get up from the floor without any difficulty at all. Next is, one point on the scale, and you can see that this child has significant difficulty getting off the floor. He needs to use his arms to be able to push himself off the floor and has significant difficulty.
And now a 0 on the right. This is a hard video to watch and it has is unable to get off the floor. And this really speaks to the impact of the disease and how it impacts not only a child having difficulty getting off the floor, needing assistance to get to a sitting position, then also the family, because he becomes completely dependent. And so this just speaks to the significant impact of a one point change on the scale. And so as we go through the NFA data for each of the components, sort of keep us in mind on the impact of these changes.
Okay. Now turning to Study 101. Just to remind you on the next slide of the study design. This was a single center study of 4 boys, open label with baseline biopsy biopsy at 12 weeks and then the boys will be followed for a total of 5 years. Patients had to have confirmed DMD mutations between 1858 and B negative for the antibody.
So we'll review the results that we've previously shown. On the next slide, I'd just like to point out the baseline characteristics for the first four patients. As you can see at our treatment, there was a mean age of 4.8 and the baseline NFAA, you see a mean of 20.5. Now first, just to review the biopsy data, this is their expression at 12 weeks. And you can see all 4 boys post gene therapy had robust expression with a mean intensity of 96 percent and percentage of dystrophin positive fibers of 81.2%.
On the next slide, it was also important to show that this micro dystrophin expression led to right, this is beta cycloglycan, one of the components of the DAP C, was off regulated correctly, localized to the sarcolemma post treatment. And next just to summarize the expression results, we see by Western blot, we had 74.3%, When it was adjusted for fat and fibrosis, it was 95.8 percent. Our intensity, 96%, 81.2% of positive fibers. And when we looked at VectorGM copies for Nucleus, there were 3.3 copies. So next now turning to the functional time test results.
What we want to point out is that NSAA will show you that data consistently improved over time, but the planned function tests have also been supportive and improved over the course of 3 years. You can see on all time function tests, each of the patients has improved. So for time function tests, you're looking for a reduction in the amount of time that takes to do the activities. So the negative that you've seen are actually a positive response with the exception of the 100 year percent predicted where you are looking for a positive response. So this is where you want to see a rise in the amount of prediction it takes to do the activity.
And so next train to the NSAA. And so here, this is each of the 4 boys individually showing their NFA scores over time from 1 to 3 years. And on the right, you see we saw a mean of 7.5. Improvement from baseline in the 4 boys. And what's important to note is I showed you previously that the boys were 4 to 6 as treatment, but now as per year, they're at 79 in terms of age.
And so at this point, we would be expecting a downward trajectory for these patients, but yet they're stable or improving. And so what we did in the next slide is did a comparison to natural history. And so we used a model to predict where these boys would be over the course of 3 years. And we developed the trajectory model from approximately 300 patients across 3 data sets and then modeled the trajectory over the course of 3 years using an MRN model to fit. As you can see, we see a highly significant difference between the treated patients and natural history comparator arm.
So it's a highly significant p value, less than 0.0001. And so what's really important about this, as you can see from the graph, is that the treated voice continued to improve over the course of 3 years, whereas the natural history comparisons are declining over that. So you really see an increased separation over time. And this is leads to about an 8.6 difference when treated compared to natural history. So really strong and this just speaks to the point that the effect will grow over time and that we're really looking for a difference from natural history over the course of time and this will become apparent in our next trials as well.
So if we now turn to Study 102, Safety summary. In terms of safety on 1 100 and 1, we now have 3 years of follow-up and no additional safety signals. We had treatment related FAUs that were mild or moderate that all resolved and these all occurred within the 1st 90 days of treatment. We had no additional safety within the 2nd or 3rd years of follow-up. The 3 patients had 3 patients that we did see safety signals were elevated, damaged UTs in the 1st 3 months and they all resolved with steroid treatment.
And then the most common treatment related AE was vomiting. We had no AEs that were associated with clinical complement activation. So to summarize, we've seen no additional safety signals since our last report. It was all within the first 90 days. Now turning to Study 102.
To remind you of the study design, the study was designed with one stratification factor and that was age. And so this is a study of 41 boys, stratified by age, where half were 4 to 5, generally half and the others were 6 to 7. This was a randomization factor. The Part 1 of the study, half of children received SRT-nine thousand and one, the other half received placebo. The primary endpoint was NSAA at 1 year and then the boys crossed over to the other treatment.
We did have a weight based dosing at 1.23x1014 petrogemes per kilogram that's using our linear TPCR standard. As you recall, we started off Study 102 with a different tidying method using supercoiled QPCR. And then it was later identified when we developed our validated CPCR method with the linear standard that 60% of those patients had a did not receive the target dose. And so we'll talk about that later on. We did convert to 1.33x1014th of linear QPCR and not all children receive that dose moving forward.
Next slide. These are the baseline demographics. As you can see, half received placebo, half received 9,001. Approximately 8 children per group were in the 4 to 5 year old group. The rest majority were 6 to 7 year old.
Next slide. So these are the baseline demographics in the intensive sleep group. And what we'd like to highlight here is that in all cases, this is going in all patients. The placebo group is better in all parameters relative to the SRP-nine thousand and one group. So all of the time function tests in addition to the NSIA, the placebo group was better at baseline.
This is all patients. When you look at just the 6 to 7 year olds, it's even more profound. The next slide. These are the micro dystrophin biopsy endpoints. This is just a summary slide.
So at 12 weeks, we saw a mean of 28.1% by Western blot. As far as immunofluorescence, we had 63.7% intensity, 32.9% distrochem positive fibers and a mean of 1.6 carbides per nucleus. This is Part 1 of the study. And so now translating into function, as we mentioned, the primary endpoint was NSAA, and this is looking at all patients in the study. As you can see, we saw an improvement at every single time point in the treated group was a baseline the change from baseline of 1.7 points compared to 0.9 points in the placebo group.
This is not statistically significant. And the reason for this becomes so clear on the next few slides. So if we go to the next slide, as you recall, we had a pre specified analysis with the 4 to 5 year olds. We did see a statistically significant improvement in NSAA versus placebo group at week 48. As you can see, the baselines were very well balanced with 20.1 and 20.4 and in just 8 children per group, we did see a significant difference at 48 weeks.
Now if you look in the next slide of the 6 to 7 year olds, you see a much different picture where the baseline MSA scores for the 2 groups placebo versus treated were significantly different from one another, 19.6 versus 24 is highly significant actually with a P of 0.0046. Now what's important to note is that when we look at the placebo group here, as a validation for our natural history model, we use that prediction model to model out where the placebo patients would be in the 6 to 7 year old group. And in fact, it was highly concordant with only a 0.3 point difference between what was observed at 48 weeks versus what our model would have predicted, where P was equal to 0.0013. So this really validates our natural history model that we've used for the additional studies. Now on the previous slide, what we noted was that the treated patients
Let me
go back.
Sorry. Yes, what I'd like to highlight here is out of the bottom, the purple graph, the treated patients, although they were significantly affected, and in fact many of these patients had a rise time of greater than 5 seconds, they remained stable over the course of the 48 weeks. And so when we compare those on the next slide to the natural history arm, where we've matched for both baseline age and MSLA, we do see a significant difference from what natural history would predict with a 0.3 change in FRP-nine thousand and one group versus 3.2 change in the natural history comparison, so an approximately 3 point difference in previous versus natural history. All right. So now turning to safety.
In terms of safety for 102, we've seen no additional safety signals. So let me just summarize. So approximately 85% of the patients had treatment related SAEs, but these were primarily mild with most common being vomiting or that there was no clinically relevant complement activation observed. There was a total of 4 patients with 5 treatment related SAEs. 4 of those were in the treated group and 1 in the placebo group, 3 were rhabdomyolysis, 2 in treatment group, 1 in placebo, these resolved.
And we had increased transaminases in another patient that resolves with increased steroids. No other clinically significant laboratory findings, no complement activation clinically relevant complement activation. So in terms of safety, no new safety signals since the last report. And so now turning to Study 1,103. Again, this is our commercially representative process material and we'll be looking at 6 month functional data.
We previously showed expression data for the first 11 patients. So we go to the next slide and talk through the study design. And this is a multicenter open label study, looking to evaluate the commercial processing material. In total, 32 boys have been treated, 20 in Cohort 1, this is between the ages of 4 to 7, 6 in Cohort 2, this is older ambulatory between the ages of 8 to 17 and in Cohort 3, this is 6 patients who are non ambulatory. In this study, we did expand the patient population to study all mutations.
As I mentioned in the previous studies, we studied 18 to 58. This is again a linear QPCR dose of 1.33x1014. This we will be showing results of the first 11 of 20 ambulatory boys in Cohort 1. On the next slide, this is the first 11 patients of Cohort 1. We just wanted to point out that the majority of these patients, 9 of the 11 are aged 6 to 7, the other are aged 4 to 5.
You can see the various demographics here. So the next slide just reminds you of the expression profile that we saw. We saw robust expression correctly localized to the membrane, again with our commercial processing cereal at 12 weeks. We saw a mean expression of 55.4 percent for Westrom Lot, 70.5% by dystrophin positive fibers and 117% in terms of mean intensity. And so now on the next slide, we'll show the 6 month functional data for the MSAA.
And what you can see is that we saw a 3 point improvement on MSAA at 6 months in the first 11 patients. And if you look at just the 67 year old, who are 9 of those patients based on improvement approximately 2.9 points from baseline. So it's virtually identical to the total cohort. So very pleased to see this improving across 6 months. When we look at natural history, we would predict approximately 0.5 point decline in natural history if we were to look at this age group.
So that would be a delta of approximately 3.5 over the course of 6 months. And now turning to safety. In general, safety was similar to what we've seen in our previous studies with the most common AAE being vomiting. We also saw increases in severe enzymes that were responsive to steroids as we've seen previously and no clinically relevant complement activation was observed. We did have one new SAE in Cohort 2, which was immune mediated myositis.
This patient experienced muscle weakness post infusion. He did have a cellular immune response that was detected to his mutation, and I'll talk more about that. There was no associated myocarditis. He did receive plasmapheresis and at discharge sacrolinus and he has now returned to his pre event function and is doing well. As you recall, an immune response to the transgene was a theoretical risk that Doctor.
Mandel and I had previously identified. And as you remember, our first two trials, we exclude certain new patients for this reason. So then in Study 103, based on the safety profile, we've expanded the mutation in 103. And in total, we had dosed a total of 9 of the 32 patients with mutations in the N terminus. Only one of those patients had difficulty and that was the FAE I just described.
This patient had a particular mutation in the N terminus that was large and different from the others. We've taken the conservative approach to exclude these mutations in 301 study, but we'll be studying this group separately. So in addition to the 8 additional patients that we've already treated in this area of the gene, we'll be studying to understand exactly what patients or what mutations are at risk. Ultimately, based on the data in hand, we believe that the number of mutations at risk is quite small and we'll do this in collaboration with external consultants to determine the final number, but it would be well below 3% in terms of the final number that would potentially be affected. But we'll confirm that over time with data and in consultation with experts.
So now turning to the just to summarize so far what we've described across FRP-nine thousand and one. What I hope you can appreciate is now we have a wealth of data across 77 patients with SRT-nine thousand and one in 3 ongoing studies. 45 have been dosed with the clinical process material and 32 have been dosed with commercially represented material. 59 were ambulatory boys and 12 between agents of 4 to 8, 12 ambulatory boys greater than 8 and 6 are non ambulatory boys. We have a wide age range of 4 to 19 and then also a very wide weight range between 13.7 kilograms 80 kilograms.
So we've successfully dosed older and non ambulatory boys, boys up to 80.1 kilograms, which speaks to the graph of our data. We see durable clinical activity with sustained functional improvements compared to Natural History now having data after 3 years in Study 101 with consistent positive expression results and all patients are at least 6 weeks post follow-up. And as I mentioned, the first one on one boys are now in year 4 follow-up. We also have a consistent safety profile. Now turning to the 301 design.
As you know, we will we've taken in all the learnings from our 101 and 102 study and then apply them to the 301 study. And so it highlighted the key features here of 301. We have an end of 120 patients. And we've now included 2 stratification factors, which include age and baseline NSAA. In addition, to ensure our homogeneous trajectory, we will also have an exclusion criteria for time to rise with patients having a rise time of less than 5 seconds.
We'll have a balance between the age cohorts with at least 50% of the patients, 4 to 5. This is a one to 1 randomization between the 2 groups. And in terms of the study design, it's similar to the 102 study where you have patients after patients receiving treatment, while the other is placebo. The primary endpoint is at 52 weeks for NSAA. Patients are then crossed over to the other treatment and then followed in a long term extension study.
This is a global study with 43 sites in approximately 10 countries. And in terms of the dose, it's again the 1.33x1014 using linear standard. As I mentioned, the inclusion criteria include the rise time less than 5 seconds, stable dose of corticosteroids, this is the same regimen we used previously in 102, and antibody titers less than 1 to 400. We are excluding mutations between the exons 1 to 17, as I mentioned previously, and also mutations within exon 45 because of the malts force of disease. The primary endpoints are NSAA, it could be 2 weeks, but with various secondary endpoints of expression and time to function.
So this study is very well powered to seek the benefit in the NFDA at 1 year.
Next
slide. So just to summarize, 9,001 is the only candidate development with results from a randomized placebo controlled trial. This construct has been very carefully designed and studied over time. We've developed a robust and reproducible manufacturing process and improved assay matrix acceptable to FDA and other regulatory agencies for disease. We've now demonstrated robust micro dystrophin in Duchenne patients with this commercially processed commercially represented process material.
And the totality of the clinical data that was demonstrated and showed you today shows you that the micro dystrophin construct conserves clinically meaningful benefits to Duchenne patients. This benefit is sustained and is now showing up to 3 years of follow-up in terms of function. Our broad 80 plus patient experience, including those of limb girdle, including patients over 70 kilograms has to date observed the safety profile is consistent and manageable. We continue to use only a single drug CRA regimen. So now where are we going next?
We have several upcoming milestones, which include announcing expression of functional data for FRP-nine thousand and one 102 Part 2 and that will be in early 2022. And then as far as our 103 study are commercially representative material, We'll have Cohort 1 full expression and function coming up as well as Cohort 2 expression and function and as well as Cohort 3. And so this will say the breadth of data in both our younger patients, 4 to 7 older ambulatory patients and older non ambulatory patients really addressing the full spectrum of this disease in Duchenne. And so with that, I'm going to turn it back to Doug for question and answers.
Thank you, Luis. Catherine, let's open the line for questions.
Thank you. Our first question comes from Tazeen Ahmad with Bank of America. Your line is open.
Hi, good morning. Can you hear me? Yes.
Okay, great. Thanks guys. How are you? Just wanted to get a sense about Study 103. So based on the data that you've presented today and based on your understanding with FDA about what needed to be shown and by when, Doug, can you give us an update on where you stand today?
With just what the path forward?
Whether or not you had to agree to show a certain level of efficacy or equivalence between the commercial grade supply and your previous data and how today's data would potentially address that?
Okay. Yes. So just so we're clear, that is not an issue at all today. So just to remind us, there was a period of time when we were considering some bridging issues between the clinical supply and the commercial supply. As we stand here today, just so we're absolutely clear, we've had very productive discussions with OCAT and FDA.
OCAT, as everyone hopefully knows, is the division within CBER and FDA that is responsible for cell and gene therapy. They have blessed the commencement of our next trial, which is Study 301 and all of the assays associated with that trial. So we are in good shape. We don't have any additional work to do or bridging to do as well. And so as we announced very recently within the last 2 weeks, we have already initiated Study 301 with the blessing of the FDA and obviously with regulatory authorities around the world and we're getting going as fast as we can for Study 301.
Thank you. Our next question comes from Gena Wang with Barclays. Your line is open.
Thank you for taking my questions. So Doug, maybe wanted to ask you now with the new evolving data, the study 103 data you showed today and then beginning of next year, you also show Study 102, 2 year data. So what kind of data package will make you reconsider the potential accelerated approval path? And then very quickly just on Study 301, is the study powered to detect significant differences in group 4 to 5 and also 6 to 7?
Yes. So let me ask you the second question first. Yes, You'll notice we have at an end of 120, this is a robustly powered study. And I think kind of going to the point that I made at the inception of the meeting, we have prioritized probability of success. It is the from our perspective, the wisest way to ensure that children around the world will get this therapy and that's why we didn't cut any corners.
We've been very, very specific with respect to the protocol. We've got floors, we've got ceilings, we've got we're eliminating or limiting kids to being under 5 seconds in rise time, not because obviously the therapy is to limit that, but just so that we reduce any heterogeneity and we see it. And of course, the NM120 answered that same question. And we did that not only for the pooled analysis, but for the separate pre specified analysis as well. And just to remind everybody, so there is no misunderstanding, we are stratifying on the basis of not only age, but baseline characteristics that we will not have the issue that we had in Part Study 1 Part 1 of Study 102 nor will we have any of the titer issues that we had in Part 1 of 102 because we use our linear approach.
Now let's go to the first part of your question, the question about the path forward. I want to be very clear about the discussions that we've had with the agency to date. So our goal this summer was to get our pivotal trial study 301 going, get them to bless all of the assays, get them to bless the protocol and we've done all of that to the satisfaction of the FDA and obviously we're doing the same thing with regulatory bodies around the world. And I'll repeat what I've said many times, which is the base assumption that everyone should have is that Study 301 in BARK, which is probably start using the name of the study now, BARK, That is the pathway to our approval in the United States and around the world. It is also true, Gina, that the data that has evolved is becoming significant in the breadth of the data and in the signals.
I mean, in almost every single way you look at this, the potential for a profound effect comes off, not just the expression levels, the safety profile, the functional signals, the restoration of the dystrophin associated protein complex. We're not showing some of this stuff today, but we have an independent study of muscle MRI, it's clear. So we will see what happens early next year. As everyone knows, we're going to have very informative information early next year. Part 2 of 102, we'll have that completed right at around the end of this year.
And we'll QC that and have that data available in the Q1 of 2022. And there's going to be a wealth of information, that's 41 patients. Half of the approximately half of those kids who have been on that therapy for 2 years against specified, not post hoc, it's the number, this is still blinded, a pre specified natural history cohort and then the other group will have been tracked for a year off therapy and tracked for a year on therapy again, against the natural history cohort. We can look at their trajectories. If that data is additionally compelling with everything else we're seeing, then we will of course consider whether given the wealth of the information that we have and the data set that we have, whether the totality of evidence justifies us beginning to have conversations with divisions, agencies around the world about a more accelerated approach to bringing this therapy to patients who do not have the benefit of time.
But I want to be very clear from my perspective, the base case assumption and I would argue for investors, the investing assumption ought to be that Study 301 as it stands today will be the pathway for approval for SRP-nine thousand and one in the United States and around the world.
Thank you. And our next question comes from Brian Abrahams with RBC Capital Markets. Your line is open.
Hey, good morning. Thanks so much for taking my question and really appreciate the comprehensive overview and contextualization of the data. I was wondering if you could maybe expand a little bit more on the immune SAE that you observed in terms of the which mutation, whether there was any overlap with what any other companies have observed with their transgene or might you expect some differences there and any kind of monitoring that you'll incorporate into the ongoing studies? And then I'm also just curious on that front, the natural history data that you showed as comparison for studies 102 101, 102 and 103, to what degree does that represent all the different mutations matched by age and then SAA versus just the ones that are being included in these studies? Thanks.
Yes. I'll turn those two questions over to Doctor. Rodino Klapac.
Yes. In terms of the FAE, this was the mutation in the N terminus and it was large, significantly larger than the others. We do note that other sponsors have seen cases of immune mediated myositis, and we do think it's related to the cost effect of certain new patients, certainly not related to anything with the capsid. So in terms of monitoring this, this is something we're already monitoring for and that we will continue to be monitoring for it closely. We're being conservative by excluding all these mutations, as I mentioned, in the next trial that we will be sure to identify the exact mutation at risk, because ultimately, we believe that it's a very small number that would be at risk specifically.
The size of the mutation does appear to matter, but ultimately over time between the data and then consultation with expert will just determine the exact amount. And so it is specific to each program in terms of constructs, you may see different exclusions in other trials, not just based on the what's included in individual constructs. And so the second question was around the natural history. And so this is a comprehensive data set that was derived from 300 patients. So it does represent our population.
You develop a model and then in certain cases where we can these are then matched for both age and SAA. So it does take in count to consideration the characteristics of our patients in comparison.
One final thing, just to bring us back a bit on this mutation related issue. I know we note for instance that Pfizer has had 3 of these, I think 2 of them actually were associated with a myocarditis, ours was not. But I want to be clear that we feel pretty confident that this is the mutation related issue that just may very well be the case that Pfizer just got unlucky with their 3. And if you look back, actually, we're the data that we've developed has been very informative for our ability to bring this therapy to the greatest number of patients possible. In Study 101102, because of this theoretical risk that if you have a mutation in these ranges, you might have an immune response to the gene itself.
We were very conservative. Then in 103, the ranges were extended. In fact, they were those issues were eliminated. And while we're very we wish we had had none, it was actually quite informative. In that 1 through 17 range of exons, we dosed 9 children with mutations in that range that would have historically would have worried about theoretically.
In fact, 8 of the 9 had no issue. And the 9s that had an issue, it isn't just random. That mutation is qualitatively different than the others in a very significant way. So there's sort of 2 issues there. There's this enormously large mutation deletion and it's in 1 through 17.
Now we're taking a conservative approach for Study 301, of course. And while we have limited the exclusions from 101102, we are going to maintain this idea of excluding exons 1 through 17 during Study 301, but we are separately and frankly, we're going to do as rapidly as possible. We're going to start other development and studies so that we can really frame out what is this combination of where the mutation exists and the enormity of the deletion that would be at genuine risk. So that's pretty confident given all the data we have right now and given what we've done in 103 that by the time that SRP-nine thousand and one is approved, it will be a fleetingly small group of children who would have to be excluded. And that's of course extremely important work because if we remain with this conservative approach that we're taking for 301, 8 of the 9 kids that are today have been treated and are doing very well wouldn't have been treated and that's not right for the community.
So we are going to do the work so that when we launch this therapy, we're going to be in a place where a fleetingly small number we suspect of children would be at any risk of this issue.
Thank you. Our next question comes from Salveen Richter with Goldman Sachs. Your line is open. Good morning. Thanks for taking my question.
Could you just comment on your confidence level here that when you've gone back and looked at the previous studies that these 2, stratification methodologies and the tittering aspect are really the only trial design changes that need to be made here?
Well, we've tweaked a number of things in the protocols, but there is no doubt that in Study 102, the therapy performed brilliantly, the study did not for the top line because of the changes that we've mentioned. The first is, of course, as we went back and used our linear titering method and retested the lots that were released through the supercoiled method from Nationwide Children's Hospital concluded that 60% of the kids were dosed at substantially less than the 1.3pE14, which was our target dose. That is 100% solved. So we're very clear it was solved at the crossover for 102 and of course it's solved in 103 and it will be solved in Embark of course because we're using this method going forward. And it is also clear, you see it jump off the page for us that the problem with the 6 7 year olds is that the baseline characteristics were so wildly different that it was comparing the long groups.
There was just no way that intelligently compared to actually use this very sophisticated natural history modeling that we use, we would have seen a strong statistical significance if we had had the right group against the 6 and 7. That is also fully solved in Study 301. We are stratifying on the basis both baseline characteristics as well as gain. So we will not have a repeat of that issue. And then of course, if you look at Study 102.1 and you look at the 4s and 5s, even with the titering methods, when you get the baselines right in a short 48 week period, you see a strong statistically significant benefit of this therapy in the 4 to 5.
So that's in 16 patients And yet our study 301 is 120 patients across those age ranges with those tight entrance criteria. So we have an enormous amount of conviction in the design of the study and frankly in the probability of success at this study.
Thank you. Our next question comes from Alethia Young with Cantor. Your line is open.
Hey, guys. Thank you for taking my questions. Maybe just 2. One, can you talk about kind of how you're thinking about enrollment timelines for the next commercial study, in light of everything going on in the space? And the next one is just kind of a big picture question.
Are you I mean, there's a lot of obviously some concerns, not exactly in gene therapy, but around safety. So I wanted to get your perspective on how you're thinking about kind of safety and the FDA is thinking about safety overall with cell and gene therapies.
Okay. So on the first one, the enrollment, so we're going to take obviously, we had started much earlier in the year, I think I had talked before about given certain timelines, we're now obviously initiating this trial and we'll have kids enrolled and dosed this month. So it will first things first, it will enroll robustly. Some sites come online and we'll have eventually over 40 sites up and running, we'll be serving in the U. S, which I'm very excited about, And then we'll be moving in Europe and Asia and the like.
The study will robustly enroll. Just to give you anecdote, one of the reasons we're being a little circumspect about exactly which sites exist because we have heard stories anecdotally of patients trying to move countries just to get the chance of being in a study and that we would not recommend that and so we'll be careful about that. The study will robustly enroll. I'm going to say that conservatively, we will have this enrollment complete and dosed by the first by the end of the first half or in the first half of next year. So but it will enroll very robust.
There is extraordinary demand for potentially transformative therapies such as this one. On the safety side of things, the FDA has reviewed, I mean, let me focus specifically on our therapy. I don't want to be overly competitive, so I won't talk to others. We've seen but we have and you saw it in the advisory board that occurred in September. There have been issues that have been discussed with respect to other AAVs, things like effects on dorsal root ganglion, neurological effects, integration related issues and of course this concern that people have regarding complement mediated aHUS and kidney failures and the need to use SOLIRIS and the need to use dialysis on kidney failures.
We see none of that. We have had none of that in our program. The FDA has looked across all of our safety database, including obviously all of the information that we provided today and on that basis has blessed our ability to move to our pivotal trial. That's why we've been able to initiate it. So we feel very good about where we are as an organization from a safety perspective and expression perspective, a functional signal perspective and a performance perspective.
Thank you. And as a reminder, we ask that you please limit yourself to one question. Our next question comes from Anupam Rama with JPMorgan. Your line is open.
Hey, guys. Thanks so much for taking the question. On Study 301, just thinking about your inclusion exclusion criteria based on time to rise, what portion of 4 and 5 year olds and 6 and 7 year olds will be excluded from this? And then logistically, how many attempts do the kids get to meet the criteria? Thanks so much.
We appreciate it.
Luis? In terms of the 4 to 5 year olds, it would be a low percentage that would screen out for that very small 6 to 7. I can't give a specific number, but obviously, the goal of doing this is to create a study that has a high probability of success. And we have successfully treated patients with price time above 5 seconds. And so our and we've proven that within Study 102.
And so I think that's an important thing to keep in mind. The sorry, was there a second part to the question?
How many times did I think the question that Anupam asked is, how many attempts does the child get to rise before you decide that they are definitively over 5 seconds?
The physiotherapists will do the test once officially.
One final thing we should say. Look, the exclusion criteria, just so we're very clear, and I'm sure everyone understands this, the goal of the majority of these exclusions for purpose of the trial is to simply reduce heterogeneity so we see an effect. Obviously, I think I'm telling people what they don't need to know. But one should not imagine that commercially this therapy wouldn't be available to children who had rise times over 5 seconds. That's not the goal.
We just in a controlled experiment, you have to reduce this. Now, there is one significant exclusion criteria that is meaningful commercially. And so ensuring that, that exclusion percentage is low is unbelievably important and that is exclusion for pre existing binding or neutralizing antibodies because we're not excluding that for heterogeneity issues, we're excluding that because as it currently stands in gene therapy, if one has a previous experience with something that looks like the capsid and then therefore has neutralizing or binding antibodies related to that capsid, it isn't currently safe to dose those children. The good news about our construct right now and it's stayed very stable over a long period of time is that we're in the mid teens around 15% or so excluded. We don't like 15%.
We want we'd like it to be 0. And Louise and team are doing an enormous amount of work to eventually someday have a pathway through the use of other therapies or other treatment paradigms to knock down pre existing neutralizing antibodies to bring these children back in the frame. But the good news is the vast percentage of children will not have a pre existing neutralizing antibody. And the second good thing at least so far remember is that we're a little different than other companies. We're not simply working with rh74 for Duchenne.
We also use rh74, which is our capsid for limb girdles and limb girdles affect adults as well as children. So we've had an opportunity to look at screen out rates over ages. And interestingly enough, it does not get significantly different as one gets older. So even looking up at full adults with limb girdles, the screen out rates we're seeing from an rh74 perspective, but the seroprevalence looks about 15% stably. So that is a really important issue to ensure that we can reach the maximum number of patients possible.
Thank you. Our next question comes from Collin Bristow with UBS. Your line is open.
Hey, good morning and thanks for this presentation. Just a little bit more on the controlling for baseline characteristics and specifically trajectory. I think if you look at the mean Toni data, certainly at the younger ages like around 4, 4, 5, the different classes can have very similar baseline NFAA scores. And so how well does the time to rise control for this? And did you at any point consider just doing serial NSA to just try and at least plot trajectory on a shorter term basis?
And then just second quick question, what's the longest duration data you have for expression? And any commentary you could give on just what you are seeing in terms of trends over time would be helpful? Thanks.
On the latter, I'm going to turn the first part of the question over to Louise. On the latter part of the question, obviously, we have 3 year data from the children from a functional perspective. From an animal model perspective, one of the things we've often said is that in one sense, muscle is a very difficult place to go for gene therapy because getting the tropism and getting the gene to the right place can be very challenging. Obviously, we've solved for that. We're now seeing with respect to our expression in our commercially representative material, some 3.8 genome copies per nucleus.
The good thing about muscle is that once you get there, you don't get significant turnover, so you see very good long term durability. So we've been we've seen solids, consistent durability for as long as we've been able to look across models for microdystrophin generally, mouse models, non human primate models, with our partner Golden Retriever models. So we will see we predict very good long term durability with this therapy and we're certainly seeing it functionally of course in the first three kids, of course 4 kids. But with that, I would turn over the first part of the question to Louise.
Sure. So characterizing the baseline characteristics by both age and baseline MSA is highly predictive. And in terms of the rise time, it's been shown that a rise time less than 5 seconds is predictive loss of ambulation within 1 year and that's been demonstrated by experts in the field. I would just add that as far as the predictability of that, you can just look to the model work that we did. So using the model that we generated, we then applied that to the 102 placebo patients.
And using those baseline characteristics, we were able to see very highly concordant data between what was predicted and what we actually observed. So there was less than there was about 0.3 points difference between the 2. In terms of the predictability of applying the, NFCA and age criteria using our model, it's highly predictive of what we would expect. And so that would kind of lead to our overall confidence in the 301 study that is very well adequately powered based on those criteria.
And I would just add finally just to keep reminding us, I mean, this is an end of 1 and 20. So we have robustly powered this study so that we're we should be in good shape.
Thank you. Our next question comes from Brian Skorney with Baird. Your line is open.
Hey, good morning everyone. Thank you for taking the question. I was hoping you can maybe help us sort of understand the key differences between Part 1 and Part 2 of Study 102. It seems like the Part 2 analysis that we'll see early next year is becoming increasingly important. So when we sort of look at that Part 2 data, what should we really be looking for as the proper comp here to determine the effect size here?
Are we looking at something like the 2.9 point benefit, which I think is what you're saying you saw in the 6 to 7 year olds in the 103 cohort at 6 months. Just help us think through what would really be the expected difference here between sort of the better baseline controlled Part 2, 102 and the Part 1?
Sure. Well, the first thing to know, Brian, is that this will all be pre specified. There'll be nothing post talk about it. We'll have a pre specified natural history cohort, both against the kids that have been on therapy for 2 years as well as the kids that have been on therapy for 1 year plus a trajectory analysis plus a pooled analysis, I believe as well. And so the broadest strokes, our goal is to see a significant difference between the natural history, what a kid would do with these trajectories versus what they're doing on therapy.
But beyond that, I will turn it over to Louise on that.
Yes. I would just point out some of these 7 or several pieces of data from 102 in comparison. We'll have the 2 year data of the treated patients that were treated in the first Part 1, we'll have the comparison of the patients treating Part 2 compared to natural history as well as the initial placebo. And so there'll be several pieces of data coming from that that will be critically important and also the trajectory data from the patients that were placebo in and crossover. So taking together those 3 pieces of data will
be highly supportive. And as Doug mentioned, it's all pretty specified.
And then remember the 2 confounding issues in Part 1 of Study 102 was the titering method that was previously used as well as a mismatch in the baseline characteristics of the 6 7 year olds. I think the use of the natural history set, because we won't be able to use the placebos, no kid will be on placebo by then, But the use of the pre specified rigorous match natural history set can correct for that issue, of course, in Part 2. And then as you know, in the Part 2 crossover kids, half of the kids that were crossed over, that tighter issue was resolved. We used the linear titering method. So we should be in a good shape to get very informative information out of Part 2 of Study 102 early next year.
We're very excited to share it with everybody in early 2022.
Thank you. Our next question comes from Joseph Swartz with SVB Leerink. Your line is open.
Hi, thanks very much. I was wondering, how many sites will you use to enroll the 120 patients in Embark? And
how will
you ensure that you don't sacrifice any rigor when you go from I think there were just 1 or 2 sites for Study 102 and 3. And so you don't try to power up the trial, but potentially dilute it by having more variability across many different clinicians evaluating patients within SAA?
Yes. So we'll ultimately have about 41 sites or so around the world. And the second point is a really good one. It's something we obsess over. I would say the way we're going to ensure that we don't increase standard deviation as we move to sites around the world is through sort of our quintessential, obsessive, detail oriented worldview.
We are going to stay very, very close. We've got great monitoring. We've got a great clinical operations team. We've got the insight of people like Doctor. Mendell, who knows how to do this, who's helping inform all of the other sites precisely how to do this.
And then we are going to obsessively focus on the rigor of the exclusion and inclusion criteria, the performance of the functional tests, the way the infusions are performed to ensure that we don't increase standard deviation across sites as we move across the world. So that second one is a real straightforward issue. It's just obsessive operational excellence and execution. And I would hope people would see, particularly with the work that we've done this year, that we're an organization across tech ops, commercial, medical affairs, development, clinical operations were obsessively detail oriented and executing organization. That's the best way.
And then finally, of course, I keep saying it over and over again, we've got a net of 120. So we're taking a conservative approach even with respect to that. We are not cutting corners with respect to Study 301.
Thank you. Our next question comes from Yoon Jung with BTIG. Your line is open.
Hi, thanks very much for taking the question. So just a follow-up on the enrollment criteria. I wonder, are there any external natural history data besides what you have seen from the subgroup analysis from the Study 102 that suggests that in addition to making sure that the baseline condition is similar, you have to look at the 4 to 5 years old, that's a pretty narrow range to make sure. I understand that it increases data homogeneity, but just wondering if any additional evidence?
Doctor. Vedino Klantoff?
Yes. I mean, the short answer is that we certainly took into account all natural history data sets and designing this trial and informing our model. There are external data sets, which support our model in terms of the prediction of our natural history. So I would just say, certainly, we took into account all the available data and that was informed our model and consistent with our model in terms of probability of success and powering our study.
I should also say, I won't name them because it's premature, but there is an independent modeling approach that is unrelated to us that have applied this to our data, it is almost identical. This is the 3 year data, so really the long term now, almost identical to the information that we have. We're not at liberty to share it yet. That will be published early next year and then we'll see the additional confirmation of the validity of our models. So we feel very good about where we are.
And I will just finally say, and I don't think this comes as a surprise to anyone, no one in this at least in the sponsor world has more access and more patient level data to inform their programs than Sarepta does given the amount of work we've done with Duchenne muscular dystrophy.
Thank you. Our next question comes from Tim Lugo with William Blair. Your line is open.
Hey, this is Lachlan on for Tim. Thanks for taking the questions. I was just wanted to clarify, Doug, when you were talking about the regulatory path forward in your base case, are you assuming that you could file after the first cohort of IMbark? Or would you be expecting to wait the 2nd cohort and have a cohort with 1 year and a cohort with 2 years' worth of data before you went to the agency?
Yes. Thank you. Thanks for asking that question. So I can make sure that people know this. It's the first cohort, unquestionably the first cohort.
That is our goal. That is our primary. Thank you for that.
Thank you. And our next question comes from Ritu Baral with Cowen. Your line is open.
Hi, this is Sandakao on for Ritu. Just two quick questions from us, please. First, in Study 101, do you think there's a slight roll off of effect in patient 1 at year 3? Any thoughts on why that might be? And then Study 103, how many 12 to 19 year olds have you dosed?
And how many would you say were heavier weight across the cohort? Thank you.
I think I missed the first part of the question. If I'm not mistaken, you were asking about whether there was a dip in the first patient and whether that was meaningful. If I'm right about that, the answer is no, it's not meaningful, just within the variability that the child has done. If you look across the study, look across the 3 years, it's done just brilliantly and far better than natural history would have assumed. So of course, you're going get moment to moment variability.
These are function tests. Sometimes kids can be tired, etcetera, and it creates some variability. But those kids are all doing brilliantly. And then I'm trying to remember what was the second question. Louise, did you capture it?
Thank you. Our next question comes from Shaichang Hsu with Berenberg. Your line is open.
Great. Thank you. Good morning. Thanks for taking my questions. So I'm wondering if you can comment on how many patients in your Phase III INBARQ trial will be eligible for your 3 approved drugs?
I guess, do you think you are running into a situation where patients might receive those drugs in the trial and potentially confound your results? Thank you.
Yes. Lucy, correct me if I'm wrong, but they would not be permitted to take another Duchenne related therapy while they're in the trial. Am I correct about that, Louise?
Yes. Correct.
There are no other questions in the queue. I'd like to turn the call back to Doug Ingram for closing remarks.
All right. Well, thank you everybody for spending time with us this morning. As you can well imagine, we're very excited about where we're going with 9,001. We've done I think the organization has done a brilliant job moving this therapy forward as fast as possible from a bank, everybody involved, our technical operations folks, our process development analytical folks have just done a brilliant job with respect to our commercial process materials so that we're in a place where we are starting our Phase III trial in the United States and in Europe and Asia. I want to thank our development team for the great work they did in developing what is a very sophisticated protocol and of course our research and translational group as well.
This is the entire regulatory group did just a wonderful job of representing us with regulatory bodies around the world. Everyone has just done a fantastic job getting us to where we are. And I also want to thank our investigators, of course, who have done just been enormous enormously valuable and Doctor. Mendel, who deserves just more credit than one could give a single human being for what he's done for Duchenne and SMA and gene therapy generally. Obviously, I want to thank Luis, who was the one of the co designers of SRP-nine thousand and one.
We stand in a wonderful place right now. We're very excited about where we've come. We have an enormous amount of conviction to the transformative potential of SRP-nine thousand and one, but I will end with what I said at the beginning, which is, it is always dangerous with success to get complacent or arrogant. We stand alone, SRP-nine thousand and one is a unique construct with unique qualities and it is undoubtedly to anyone whose objective quantitatively, safety, tropism function, a therapy that stands alone. But we have an enormous mission in front of us every single day.
Patients and their families are not simply suffering from Duchenne muscular dystrophy, but are degenerating and having their muscles stolen from them. So we are going to execute aggressively to enroll Study 301 to get 301 moving as fast as possible and to be fully enrolled. We are then as we look forward to the rest of the year and into early next year, we're very excited to come back and talk to you early next year about the results of Study 102, Part 2, which we'll have. And along with our just wonderful partner, Roche, who's just been a fabulous partner with us as we develop this therapy, We're really excited about moving this program forward as fast as possible, exploring the art of the possible once Study 102 Part 2 comes out and getting this therapy once confirmed to patients living with Duchenne muscular dystrophy around the world. I look forward to updating everyone on this call and the community as we do that.
And with that, please have a great rest of the week.