Sarepta Therapeutics, Inc. (SRPT) Earnings Call Transcript & Summary

Good morning, ladies and gentlemen, and welcome to the Sarepta Therapeutics Clinical Update MOMENTUM Multiple-Ascending Dose Study of SRP-5051 for Duchenne Muscular Dystrophy Conference Call and Webcast. [Operator Instructions] As a reminder, today's program is being recorded. At this time, I'll turn the call over to Doug Ingram, President and CEO, for opening remarks.

Thank you very much for that, and thank you all for joining us this morning. This morning, we are pleased to report our interim results from MOMENTUM, which is our multi-ascending dose study for our second-generation PPMO RNA therapy, SRP-5051, at 20 mgs per kg. Now we will be making some statements and potential predictions about the future this morning, so-called forward-looking statements. So please refer to our public filings for a discussion of the inevitable risks and uncertainties that are attendant when one makes forward-looking statements. And with no further delay, I will turn the call over to Sarepta's Executive Vice President of R&D, Dr. Gilmore O'Neill, who will present the results. Dr. O'Neill?

Thank you very much, Doug. It's a pleasure to be here with all of you today to share these interim results from our lead PPMO program, SRP-5051. Now as many of you know, Duchenne Muscular Dystrophy is a rare, fatal neuromuscular genetic disease, an inherited X-linked condition that almost always affects young boys. Duchenne is caused by the absence of the dystrophin protein, which acts normally as a shock absorber within the muscle. Disease progression follows a predictable trajectory. Muscle weakness becomes increasingly noticeable between the ages of 3 and 5. Boys are often wheelchair-bound by the time they are pre-teen. And then they experience cardiac and respiratory muscle deterioration that typically and sadly lead to death in their mid to late 20s. Sarepta's PMO platform uses a phosphorodiamidate morpholino backbone chemistry and precisely targets a specific sequence of a pre-messenger RNA that enables the transmission of an internally truncated yet functional dystrophin protein. Sarepta is currently serving the Duchenne community with approved products born from our PMO platform, EXONDYS 51 and VYONDYS 53, which are approved for patients amenable to skipping exon 51 and 53, respectively. Assuming approval, we will soon have a third product among this 45 for patients amenable to exon 45 skipping. All 3 drugs have consistently increased exon skipping and dystrophin in patients. Now despite the promising efficacy we have seen from our PMO platform, there is one limitation, the ability of the PMO to get into the cell at high concentration. For this reason, we set out to engineer the next-generation of this technology, which we called PPMO, with the sole purpose of safely delivering more of the peak PMO into cells. To do this, PPMO adds a positively charged cell-penetrating peptide, or CPP, to the PMO backbone. The addition of the peptide should increase cellular uptake. And if we can safely drive more drug into the cells, we will see greater exon skipping and greater dystrophin production. This is no small feat though as we and many others have tried approaches to increase cellular penetration that has been hampered by dose-limiting toxicities. I will present some dense data today, but the key takeaway is simple. Based on our experience with the PMO, we know that if we can safely increase tissue concentration, we can bring forward a major advance for Duchenne patients, one that offers the potential for greater efficacy with more convenient dosing. I will now provide an overview of our preclinical program for SRP-5051 that shows that the PPMO can indeed safely increase cellular uptake and drive higher exon skipping and higher dystrophin production in less time and with fewer doses than the PPA -- PMO -- sorry, than the PMO. Now before I get into the data, I should note that eteplirsen is referenced in the slide today by its investigational program name of AVI-4658, although I will call it eteplirsen throughout this presentation. Now turning your attention or our attention to the graph. The red line shows that the cell-penetrating peptide does indeed enhance cellular uptake of SRP-5051 in Duchenne patients-derived myotube as compared to eteplirsen in blue at the bottom in a concentration-dependent manner. In the images on the bottom of this slide, you can see via immuno fluorescent staining of myotubes at 72 hours how quickly and significantly the cell-penetrating peptide, or CPP, enhances uptake compared to PMO. In the next slide, you will see 2 key takeaways. First, SRP-5051 has a tissue half-life of approximately 8 days; and secondly, exhibit tissue exposures sevenfold greater than that seen with a eteplirsen. Please note that the Y axis is a logarithmic scale, so you may not appreciate visually that sevenfold difference between the red line representing 5051 and the blue line representing eteplirsen. In sum, the tissue half-life and exposure level gave us strong evidence to investigate monthly dosing, which we studied in nonhuman primates. Here, we ran a single dose experiment of SRP-5051 in nonhuman primate. We observed a dose-dependent increase in exon skipping, and importantly, a prolonged pharmacodynamic effect on exon skipping out to at least 28 days, which supports monthly dosing. Now with monthly dosing, our current NOAEL, no observed adverse effect level, is 40 milligrams per kilogram. A moment ago, I mentioned that we determined the half-life of 5051 in the tissue is approximately 8 days. Therefore, with a monthly dosing regime, we would not expect to see a significant accumulation of drug in the tissue. I should also note that we have ongoing toxicology studies at 60 mg per kg in nonhuman primates and 80 mg per kg in juvenile rat and have not seen adverse findings. Now here, you can see that we assessed single ascending doses of SRP-5051 in healthy nonhuman primates and measured exon skipping in muscle biopsies taken 10 days after administration. In the chart on the left, you can see that we observed that greater tissue exposures led to higher exon skipping. And on the right, you can see a steep dose-dependent response. When the dose is increased from 20 to 30 mgs per kg, this 50% increase in dose results in a nearly tenfold increase in exon skipping. So in summary, in our preclinical work, we have observed that the cell-penetrating peptide resulted in greater tissue uptake as compared to PMO alone. The prolonged pharmacodynamic effect for one month -- once-monthly dosing, we have not yet reached our maximum tolerated dose and have no adverse safety findings at 60 mg per kg in nonhuman primates or 80 mg per kg in juvenile rat. And finally, increased tissue exposure with SRP-5051 leads to higher exon skipping with a steep dose and exposure response. Taken together, we are pleased that our preclinical program gave the information we need to support the move into the clinic. Now let me move into the clinical development program for SRP-5051. But before I get into the results, I do want to remind you that exon skipping and dystrophin production increased over time as evidenced by these data from our 96-week PROMOVI study of eteplirsen, which you see here. On the left, you can see exon skipping increasing over time, and on the right, dystrophin expression increasing over time. I should note that the earliest time point for which we have results with our PMO platform is 24 weeks. And as we analyze today's data for SRP-5051, please keep in mind that they are from week 12, supporting the view that PPMO acts faster than PMO. Now the SRP-5051 clinical development plan to date comprises 3 main studies: a single-ascending dose study in healthy human volunteers; a single-ascending dose study in Duchenne patients; and the multiple-ascending dose study in Duchenne patients, which is known as the MOMENTUM study and is ongoing. I want you to note that the patients in the single-ascending dose study can enroll in a long-term extension study as well. Now the healthy human volunteer study included pre dose arms with 6 subjects in each, with doses of 1, 6 and 20 milligrams per kilogram. Each arm specified a muscle biopsy 10 days after dosing and a 6-week safety follow up. In the healthy human volunteer study, a few things became apparent. First, as you can see in the chart, after a single 20-milligram per kilogram dose of SRP-5051, we observed comparable concentration in healthy human volunteers and nonhuman primate. This is important, because, as a result of this observation, Sarepta has adopted a one-to-one body weight scaling method using nonhuman primate data to predict human exposures and calculate safety margins. Second, 5051 drove higher muscle concentrations in a dose-dependent manner in purple on the left as compared to eteplirsen in gold on the right in healthy human subjects after a single dose, thus providing the first proof-of-concept data in humans that conjugating our cell-penetrating peptide to PMO does indeed increase cell penetration. Now our operating hypothesis proposes that increased tissue concentrations of PPMO should increase exon skipping. And indeed, we do see a dose-dependent increase in exon skipping with 20 mgs per kg of SRP-5051 in healthy subjects when compared to eteplirsen. On to our single ascending dose study in Duchenne patients, which has 5 cohorts, each enrolling between 3 and 6 patients. The starting dose was 0.3 milligrams per kilogram and progressed to 6 mgs per kg. This safety study supported our initiation of the MOMENTUM study. Now let me turn to the multi-ascending dose, SRP-5051 201 or MOMENTUM, which has 2 parts. Part A is to evaluate the safety and tolerability of SRP-5051 in patients with Duchenne muscular dystrophy and to determine the maximum tolerated dose or MTD. The dose levels for Part A are 4, 10, 20, 30 and 40 milligrams per kilogram administered once monthly by IV, with each dose cohort enrolling 3 to 6 patients. Part B will evaluate SRP-5051 administered at the maximum tolerated dose and will include patients who complete Part A and an additional cohort of approximately 15 patients. As you can see, Part A of the MOMENTUM study has been designed to evaluate the safety profile of SRP-5051 as the primary outcome. Today, we will report on the 10 and 20 mg per kg doses from the MOMENTUM study, sharing the primary outcome measure of safety plus measurements listed on this slide that include change from baseline at week 12 for muscle concentration of 5051, exon skipping as measured by digital draft PCR and dystrophin expression corrected for muscle content. Here, we show mean baseline demographics for the dose cohorts in the MOMENTUM study. We enrolled both ambulant and nonambulant patients between the ages of 7 and 21 years old. In the left-hand column, you can see that 5051-treated patients were dosed once monthly for 4 doses prior to muscle biopsy at 12 weeks. Now whereas it is important to be cautious comparing between studies, we have nevertheless included for reference purposes a control group of Duchenne patients selected from the PROMOVI study, all of whom received eteplirsen, dosed at 30 mgs per kg once weekly for 25 doses prior to muscle biopsy at 24 weeks. Let me draw your attention to the column on the right, which highlights that patients in the SRP-5051 20 mg per kg arm at 12 weeks received approximately tenfold less total drug dose than patients receiving eteplirsen up to 24 weeks. I do want to point out that this interim analysis of the MOMENTUM study uses muscle biopsies specified to occur 12 weeks after the first dose. This is in contrast to the PROMOVI data set where the earliest muscle biopsy was specified to occur at 24 weeks. In addition, some patients in MOMENTUM did opt for a less invasive needle biopsy at 12 weeks, which we found could deliver enough muscle to evaluate exon skipping, but unfortunately, insufficient material for measures of dystrophin protein and drug concentration. This is why an N of 2 will be seen in our 20 mgs per kg dystrophin slide later. And we have recognized this limitation, and going forward, have amended the protocol to specify open biopsies. Now to the data. Both the 10 milligram per kilogram and 20-milligram per kilogram monthly doses of SRP-5051, in purple on the left, resulted in higher muscle concentrations compared to eteplirsen and were fourfold and twofold higher, respectively. You may be puzzled that the 10 milligram per cohort was apparently higher muscle concentrations than the 20 mg cohort because this does not make mechanistic sense, it does not reflect the nonclinical data, and it does not reflect the tissue concentration dose response seen in healthy subjects that I just shared with you. There is an explanation for this apparent diversion. You will see noted just above the integral graph bars that 10 mgs per kg patients were biopsied on average within 5.6 days of their last dose. In contrast, 20 mgs per kg patients had biopsies a mean of 16.5 days after their last dose. The biopsy delays occurred because of COVID-related disruptions of clinic visits. And as a result of this delay, which are apparently twofold, the 8-day tissue half-life of 5051, it would be reasonable to hypothesize that this apparently lower concentration is an artifact and that we are likely underestimated the true tissue concentrations that we would expect to see at 5 to 6 days. Now if this explanation is correct and the data from the nonclinical and healthy human subjects are correct, then we would expect to see dose-dependent increases in exon skipping and dystrophin expression. And indeed, as expected, we observed a dose-dependent effect on exon skipping. At 12 weeks, the SRP-5051 20 mg per kg dose group saw an increase in exon skipping of 1.6x compared to the eteplirsen group at 24 weeks. Surprisingly, because we were not expecting to see dystrophin at such an early time point, but indeed, in support of what I have earlier said, we are excited to share that SRP-5051 also drove a dose-dependent increase in dystrophin at week 12. While the results are from a small data set in the 20 mg per kg group, we observed a nearly fivefold increase in percent normal dystrophin compared to the eteplirsen group at 24 weeks. And if you recall, back at the beginning of today's presentation, I mentioned the main objective with our PPMO was to deliver more of the PMO into the cells and to do so safely. We have just shown that we're able to get more PMOs to the cells. And I am pleased to report our safety results to-date in MOMENTUM. The incidence of any adverse events is similar across all dose cohorts. No adverse events resulted in discontinuation of the study drug and no renal safety signals were observed. The treatment-emergent adverse events in the 4 mg per kg group was deemed unrelated to study drug. And the incidence of adverse events across the dose cohort does not suggest those dependency. In conclusion, first and foremost, this interim analysis demonstrates that SRP-5051 was well-tolerated, and we have not seen any clinical or laboratory-based safety signals. The results suggest an encouraging safety profile that will allow for continued dose escalation, and I'm pleased to share that all patients in the 30 mgs per kg arm have begun dosing. Additionally, the data provides proof of concept that the cell-penetrant peptide has the ability to increase tissue penetration and lead to higher exon skipping and higher dystrophin production with less frequent dosing. And indeed, in these results, we have seen increased levels of tissue exposure, exon skipping and dystrophin in half the time with fewer doses and 10 times less cumulative drug exposure. Finally, our dose response and nonclinical findings predicts significantly greater expression at higher doses. As for next steps for the program, we continue to dose escalate to find our maximum tolerated dose. Data from the 30 mgs per kg arm are expected in the second quarter of 2021, and we expect to commence dosing in the 40 mgs per kg cohort in the first quarter of 2021. Once we have identified the NTD, we will commence partly the MOMENTUM study. In addition, we have several follow-on PPMOs in our pipeline and will apply learnings from SRP-5051 to inform the development. Finally, and most importantly, on behalf of everyone at Sarepta, I want to thank all of the patients, families and clinicians who participated in these trials and continue to participate in all of our studies. And now I'll turn the call back over to Doug for Q&A. Doug?

Thank you very much, Gilmore. I really appreciate that. At the risk of repeating some of what Dr. O'Neill said, I think, hopefully, you can see why we are very excited about what we're seeing so far. When one considers it, we have with the 20 mgs per kg, 1/10, literally 10% of the aggregate drug exposure, the eteplirsen comparable, we are not yet, at least based on our preclinical models and nonhuman primate models, even at the predicted steep portion of the dose response curve and you will note that it's not linear. There is actually an inflection point. We took biopsies at 12 weeks, which is half the duration of eteplirsen. And of course, COVID, unfortunately, caused biopsies to be taken 2x the half-life of the therapy for the 20 mg per kg. And yet, notwithstanding all of that, we're seeing double the tissue exposure already. We're seeing a significant increase in exon skipping. Those who have had meetings with us will know that we were not confident that at 12 weeks, you would even see dystrophin production yet as dystrophin builds over time, and yet we're seeing a fivefold increase versus the eteplirsen comparator in dystrophin production for the 20 mg for PPMO SRP-5051. And of course, unbelievably important, let us not forget, we are not seeing, as yet, any untoward safety signals and no -- currently, no negative labs for this therapy or this dose. So we're really excited about what this may mean for the program, and as we dose escalate, what we may see as we get to 30 mg per kg, and hopefully, if we can get there also at 40 mgs per kg. This, of course, is a small data set. We must remember that. But notwithstanding all of that, we are very, very pleased with everything that we're seeing so far. And with that, let us turn the question over for questions.

[Operator Instructions] Our first question comes from [ Crystal Beery ] with Goldman Sachs.

This is Salveen Richter from Goldman Sachs. So with regard to the dose escalation plan, could you just help us understand overall what you're doing on the Board with this program and look to understand and how you might then incorporate the other exon skipping programs within Duchenne just to broaden out the program?

Sure. And broadly speaking, I'm going to let Dr. O'Neill talk about this and go beyond into the other programs for the other mutations. Broadly speaking, with respect to this program, we call this portion of the multi-ascending dose trial Part A, where we're going to find the most beneficial dose with the best safety profile and dystrophin expression. And then we'll move to Part B, which will be an extension study, which if -- after conversations with the FDA, we'd like to believe will be our pivotal trial for this program. And then beyond that, we have, of course, plans for the other mutations. And we've already built a significant number of constructs for those mutations. But with that, I'll turn it over to Dr. O'Neill to provide a little more color on that.

Yes. Thanks very much, Doug. As Doug has correctly said, we will be moving into Part B with the MTD. Obviously, we have a sort of a global ambition and desire to support patients around the world. And we'll be engaging with regulators to ensure that we can deliver the data sets that they would require for approval. And then with regard to extending across all the exon skip classes for Duchenne patients, we are going to leverage what we have learned from 5051 to enable the most rapid dose selection and bridgeability across all those exon classes to make sure that we can as rapidly as possible develop for all the Duchenne patients.

Our next question comes from Brian Abrahams with RBC Capital Markets.

This is Steve on for Brian. Congrats on the data. Speaking beyond skeletal muscle, do you have any indication about how PPMOs might work in cardiac or diaphragm? And did today's results affect any of your thinking there?

Yes. That's a great question. I'm going to -- Dr. O'Neill's going to answer this in more -- with more specificity. You raised a very good point. Of course, the value of our therapy, if it's successful, would be, in the skeletal muscle in the diagram, hopefully, in the cardiac muscle. The PMO technology certainly gets into not only skeletal muscle but diaphragm muscle very significantly in diaphragm muscle as well as -- versus skeletal muscle, but struggles in cardiac muscle. And that's one of the potential values of this peptide-conjugated PMO. And then beyond that, of course, we have the opportunity to treat smooth muscle as well. But Dr. O'Neill, you might want to give a little more color on that.

Yes. Thank you. So we are actually -- we have been carrying out, if you call, tissue mapping, for delivery of the PPMO, both at a tissue and cellular level. That is ongoing. But indeed, we do actually have -- or we have seen good delivery in nonclinical species to the heart muscle amongst other organs. Those other organs being important because it helps us think about how we bring our technology beyond Duchenne alone.

Our next question comes from Tazeen Ahmad with Bank of America.

Doug, I just wanted to get your thoughts about how high do you think you would need to dose, because based on what you've shown so far, as you've said, you're already seeing dystrophin expression in the 20 mg per kg arm. You were trying to find the MTD, but do you really need to find that?

It's a really interesting question in one sense. Like -- so first of all, this is a small data set. So there's a real risk that I'm going to say something that is premature. But if this data was confirmed in a larger data set, in a Part B, even at 20 mgs per kg, one would envision that we would have preferable therapy, both on dystrophin production already, we're 5x at this early day, as well as on safety and as well as on convenience of dosing. Remember, the PPMO is a monthly dosing versus weekly dosing, which is, obviously, it's great for Sarepta because of cost of goods. It's better for patients and caregivers because of the burden of weekly dosing versus the -- obviously, more -- much more modest burden of monthly dosing. But with that said, I should point out, our goal is to make a profound benefit, a profound impact in a positive way in the lives of children with Duchenne muscular dystrophy. So we do feel that it is incumbent upon us to -- particularly where we're not yet seeing safety signals with the PPMO to continue to dose escalate and to look at further doses to determine what the optimal dose is for children living with, degenerating from, and unfortunately, inevitably currently succumbing to Duchenne muscular dystrophy. And so we'll have the 30 mgs per kg data in May. The animal models themselves, the nonhuman primate, predict that you'll see a significant inflection point between 20 and something right above 20. And it will be interesting to see if such is the case with our patients. But I do think that continuing to dose and find the optimal benefit for these kids is going to be a real significant benefit. We'll have the 30 mgs per kg certainly next year, and we'll be dosing the 40 mgs per kg, if I'm not mistaken, Dr. O'Neill, you correct me, I think pretty early next year, we'll start dosing the 40 mgs per kg. Did I -- have I missed anything, Dr. O'Neill?

No. That's correct. Just by way of confirmation, we are planning to start dosing 40 mg per kg cohort in the first quarter of next year. And I absolutely agree with Doug that while this small data set suggests we've already differentiated, our objective is not just a difference. Our objective is to deliver a maximum impact on this extraordinarily serious disease. That's why we want to keep pushing to a -- at the highest dose we can to help these boys and young men with serious [Audio Gap]

Our next question comes from Gena Wang with Barclays.

I wanted to just try to understand why the differences between nonhuman primate data versus human data. And I think your early study also showed that 4x weekly IV dosing in nonhuman primates was able to achieve almost like 45% exon skipping efficiency in biceps. And if we're even taking ddPCR consideration, that could still be more than 20%. So would that be because of under-dosing? Do you think that the dosing frequency when you choose once-monthly dosing could lead to the under dosing?

Yes. Thank you for that question, Gena, I really appreciate it. And the short answer is no. You'll see from the earlier slides, and we'll certainly post them, that we've looked very carefully at the dosing schedule. And in the nonhuman primate dose once weekly, then dosed biweekly and then dosed monthly, and what you see is you get -- and with an 8-day half-life, it gives us a really interesting window where you see that you don't get cumulative toxicity. So you have the ability to start pushing this dose up to something that could be really meaningful without getting a cumulative toxicity. And of course, the toxicity that we worry about is renal. But at the same time, you don't get a diminution in any significant way on exon skipping itself. And so it may very well be the case that we're not yet at the steep proportion of inflection curve. Certainly, the nonhuman primate studies would suggest that that happens right after 20 mgs per kg. And you'll see in the nonhuman primate between 20, and I believe, it was 30, we saw a 7x increase. Not to suggest with certainty that it's precisely predicted, but it gives us belief that we're going to see another inflection point. And of course, remember also that with the 20 mgs per kg, we took these biopsy not through choice, but through COVID pandemic, at 60.5 days after the biopsy. That compares to about 6 days for the 10 mgs, compares for about 5 days, I believe, for eteplirsen. So we took these biopsies literally 2x longer than the half-life of this therapy, and we still saw a doubling in tissue exposure. We still saw an increase -- significant increase in exon skipping. We still saw [indiscernible] in dystrophin. So I don't want to predict in advance that we'll see another really significant increase in dystrophin production. But we're -- I'm not going to lie and say we're not hoping for that, notwithstanding the fact that we're already excited at 20 mgs per kg. And one final thing, I think you've noted this already in your question, but I do want to make sure we're clear about this. There is no -- when you talk about looking at eteplirsen versus the 20 mgs per kg, just so we're clear, we're not looking at different methods. We reran the eteplirsen biopsies with the new method. So you really -- there's a certain danger in looking at old data or RT-PCR data and cross-comparing it. This is ddPCR. It is a different approach. The good news about what you'll see in the slides and the studies, it is all internally consistent. You can comfortably compare the eteplirsen to the 20 mg per kg, for instance, on exon skipping and dystrophin production because the methods were run exactly the same way in those instances. Dr. O'Neill, did I miss anything with my harangue?

No. I think you've covered everything. And I just want to highlight the point regarding the frequency of dosing that in the slide deck, I think Slide 12, you can actually see that after a single dose in nonhuman primates, we biopsied at 10 and 28 days. And we actually could see a percent of the exon skipping effects at least 28 days after, and it was actually comparable to the day 10.

Okay. Just wondering, is the human biopsy also from biceps?

We actually -- pardon me? Sorry, sorry. Go ahead, go ahead.

I'm sorry. Go ahead. My apologies. Go ahead.

We actually used biceps, although we had some -- we actually used biceps here, although there was an option if the patients had difficulties to use another muscle.

Our next question comes from Alethia Young with Cantor.

Congrats on the progress here. Can you just talk a little bit about whether you think that having the nonambulatory patients, like you're getting better tissue exposure, is maybe helping drive an increase in dystrophin? I mean I noticed that in the study, you had a few nonambulatory patients with 5051, whereas, obviously, with PROMOVI, you didn't.

Yes. On a whole, we don't believe that to be the case, but Dr. O'Neill can sort of touch on that.

Yes. I agree, Doug. We all know we don't believe that to be the case for 2 reasons. We do not have evidence that PPMO was taken up by fatty tissue. And because of the -- because we had recruited both ambulatory and nonambulatory patients, we were very conscious that there might be differences in the muscle content. And for that reason, we corrected for muscle content to exclude that fatty tissue. I'm glad that we had…

Yes. Apologies, I just jumped on top of your statement.

No. That gives us good confidence that using nonambulatory or muscle from nonambulatory patients is not going to skew the results.

And I was just going to say the side note, of course, we're very pleased that we were able to recruit and include in our trial nonambulatory patients. In a broad sense, that's something very important. For Duchenne muscular dystrophy generally and for Sarepta in particular there have been -- historically, there have been a paucity of opportunities for nonambulatory patients to participate in the clinical trials for new therapies. And we're working hard as an organization in a thoughtful way to correct that without being unable to actually get trials that will show the benefits that we believe our therapies have. And I think this is one opportunity that we've had. And we'll look for other opportunities across our portfolio, including our gene therapy.

Our next question comes from Brian Skorney with Baird.

Congrats on the data. When I go back and I look at the eteplirsen data from Study 201, there was a big difference in 12-week and 24-week dystrophin positive fibers. And I know at the time, there was a big question in terms of kind of duration of treatment to look at biopsies versus dosing. Can you just help us understand your thoughts around the PK/PD with PMO? How this might be different with PPMO? And how you think that translates to PPMO when we start thinking about 24 weeks there versus 12 weeks? I mean if you sort of model out what you saw with PMO, you may not even need higher doses. Once we start looking at biopsies, you could see much, much higher levels of expression. And then can you also remind us, I don't think it was ever reported, but was there any measurable dystrophin above baseline on Western blot at week 12 from Study 201?

Yes. I'll turn this over to you. The broadest strokes, in the first part of your question, and I'll let Gilmore comment on both, is -- you raised a very good point that we know inside, too, that dystrophin builds over time. And in fact, to your very good point, one of the things that we have been saying, significantly saying for many, many months now, is that don't expect to see dystrophin at 12 weeks. It seems, from our history, too soon to even look for dystrophin production. We note that dystrophin builds over time. 24 weeks would certainly on its Phase B build versus 12 and 48 weeks build significantly thereafter. And then frankly, with the -- historically, with eteplirsen, we've looked out 4 years later, and we've seen an increase in dystrophin as we had long-term chronic therapy. One of the reasons we are always saying that it's important for our kids when they get on our therapy to stay consistent in our therapy so that they get the long-term cumulative benefits. Now we won't know exactly what that means until we start taking some biopsies and look maybe in Part B to looking at other time points for biopsies either versus 12, versus 24, maybe 48, although that's a long time for a therapy we're trying to move very fast on. But your points are very well taken, Warren. I mean one of the interesting things -- I'll harken back to what I said before we started. One of the interesting things is that we -- that we set this trial up, to some extent, by necessity, and to some extent, inadvertently, to actually make a tough bar for us. We looked at 12 weeks. But we knew that the biopsies we had for eteplirsen were 24 weeks. We looked at -- we had the -- because of COVID, we had -- we have the biopsies. Again, 16.5 days when the half-life of the therapy is only 8 days, and yet we're seeing 5x almost of dystrophin production versus the eteplirsen group. So it may very well be the case. We don't know yet where the data and the science will lead us. And if you could look out a little further out in time to 24 weeks or beyond, even at 20 mgs per kg, you might see a significant increase even from where we are on dystrophin production, but we don't know that yet. It will be interesting to see what we have at 30 mgs per kg. It's certainly our hope and goal that we're able to take those biopsies in the window that you would expect in the first 6 or 7 days post last dose, similar to eteplirsen and similar to the 10 mg per kg. Dr. O'Neill, you want to comment on that and maybe comment on the second question as well.

Yes. Thank you. So I think the question was an interesting and complex question where you were sort of tying the dose of the drug to the kinetics and pharmacodynamic effects of the drug to the dystrophin kinetics and biology. In asking the question, I think, do you really want or need to go and dose higher? So let me address a couple of the elements that you addressed. First of all, we have used our PROMOVI data set, which actually is a large data set in which we took samples at different time points with and used ddPCR to measure exon skipping. And it's important to remember there was digital drop PCR, which was not the case for the original 201 eteplirsen studies. And I will draw your attention, I think it's slide -- we have 16 subjects in PROMOVI at 24 weeks. I think that's the first piece. I think the second piece is that the plasma kinetics of eteplirsen and PPMO are similar. However, as you can see, as you saw, and again, remind you with the log scale, we're seeing a substantially higher exposure in tissues, both in the nonclinical patients, that was where the log scale would show as well as in human subjects, both healthy and Duchenne patients. Then I think you were sort of concerned about the timing. Do you just need to -- couldn't you just stay at a lower dose because it will accumulate over time? I think the key thing, and this is, of course, the more therapeutic consideration, is that patients with Duchenne don't have time. And what we believe is that if you can get earlier onset of higher expression, and as a bonus, do it with less frequent dosing, which is inconvenient, unpleasant, that is going to accrue into substantial benefits in the immediate and long term. So that's kind of the rationale for why we continue to drive the dose against a background of an optimized chemistry to ensure higher exposure.

Our next question comes from Anupam Rama with JPMorgan.

This is Tessa on the call for Anupam this morning. I know it's early days still here with the program. But curious, can you comment on what you have collected or observed so far with respect to markers of inflammation and fibrosis in the muscles? I think in some of your preclinical mouse model work, you saw effects as early as 10 mg or 20 mg.

I believe it's a little early to look for that. But Dr. O'Neill, you correct me on that one.

No. That is correct. It is too early. And this interim was focusing particularly on those issue concentrations and pharmacodynamic measures of exon skipping and dystrophin expression.

Our next question comes from Matthew Harrison with Morgan Stanley.

I guess there are 2 for me, and I know you've touched on these topics, but I guess I was looking sort of for your clearest answer you can give. So I guess the first one is in terms of dose range, how high do you think you can go? And let's just assume you don't hit an MTD, when will you say we've gone far enough, we're ready to move into Part 2 or move quickly in terms of a regulatory process? And then the second question is just around, I guess, what I would say is -- when we're going to get more information from other tissues and how you think about being able to demonstrate that in humans. I guess what I'm really asking is how broadly do you think you're getting uptake in other muscle tissues? And how do you think you'll be able to prove that in humans?

Thanks a lot. As it relates to the second question, and certainly, Dr. O'Neill can give more data-driven response to that. We have seen -- first of all, we know because we've observed it often that we will get a significant increase in diaphragm consistent with what we see in skeletal muscle. There should be no significant difference. In fact, it's dangerous to overestimate, but in fact, we tend to actually see a modest increase in dystrophin production, even with our PMOs versus skeletal muscles, in the diaphragm. In the cardiac muscle the preclinical models suggest that the PPMO could have a significant impact on the cardiac muscle but has an impact on the skeletal muscle, but Dr. O'Neill can go into that. On the dose ranging, it is all going to be about what we see in risk benefit as we proceed. The NOAEL for this therapy, as we started the study, was 40 mgs per kg based on the nonhuman primate. And as we've talked about, it looks like, based on the data we have today, we're really weight-based dosing between the nonhuman primate and the human -- the patient. However, we've been continuing to dose and look at repeat dosing and look at additional tox. And we're right now in the middle of trials where we're not seeing a dose-limiting toxicity, and we look like we might have a NOAEL already at 60 mgs per kg, although the studies are still in flight right now from a preclinical perspective. What we're going to look -- what we're going to do across this is look at each cohort, and we're going to make a risk-benefit decision. If we see a significant inflection from here at 30 or 40, then we're going to have to -- even if we have not hit a dose-limiting toxicity, we're going to have to sit down in a group and weigh what's the right answer for patients. And there's a lot that goes into that. It's obviously the benefit of the therapy to the patients, the efficacy. It's obviously the risk profile of the therapy. And of course, with respect to Duchenne muscular dystrophy, we can never forget, it's the timing of these issues that time -- as Dr. O'Neill brilliantly said, time is not on the side of these children, so we'll have to make those decisions. But what I would say is we're going to look at the 30. We'll probably look at the 40. And then we're going to make a call. And if there's an opportunity to go to 60, we can make that decision then or we'll pick one of those doses, between 20, 30 or 40, and we'll move into Part B. But it will be really driven by the data and I think a thoughtful risk-benefit analysis at the time. Gilmore, you can correct all of everything I said if I'm wrong.

I agree with what you said. The truth is it's always lovely to speculate that you're going to never find a dose-limiting toxicity. And while we hope that, obviously, the data will speak to the truth, what we want to do is do exactly what Doug said, which is do a look at the data as they come in. And we will make a benefit risk calculation to help us select the dose that we will take forward. With regard to your questions about tissue mapping, that is ongoing. We have, as I said, already evidence that the PPMO delivered well to cardiac muscle in nonclinical species. It would be more challenging and certainly nontrivial to demonstrate that in human subjects. So what we will be doing is continue that mapping. And I hope that we will be able to share that at some point in the future.

Our next question comes from Tyler Van Buren with Piper Sandler.

Just had a follow-up on the inflection and the steep dose increase curve that you guys are referencing with respect to exon skipping. Clearly, you're seeing almost an exponential increase as you go from 20 to 40 to 60. So is it possible to, I guess, relate that to what you saw with eteplirsen in similar study at increased doses in terms of the increase and the rate? Maybe quantify how much more is increasing or at least speak towards it qualitatively.

Yes. You just don't -- you don't see this with eteplirsen. We know -- we love our PMOs for -- because they really are the first therapies that have provided real phenotypic benefit to patients who have Duchenne Muscular Dystrophy there. And the technology there really are amazing technology, both precise in their ability to actually engage in steroid blocking and exon skipping and then creating essentially a reformed pre-messenger RNA, and making dystrophin, and of course, their safety profile is laudable. But there is a limit to them. And the limit to them is that they are a neutrally charged molecule. They have a very short half-life in the system, about 4 hours in the system. And therefore, the ability -- dosing up doesn't create an inflection point in the therapy, at least not in the preclinical models. And we've said this before, we're even looking right now -- as part of our post-marketing commitment to look at other dosing and higher doses for eteplirsen, which we're certainly excited to keep going with. But truthfully, that -- it's difficult to envision that there's going to be a massive inflection point even as you significantly dose because you just have this natural limitation of the therapy being able to get into cells. The PPMO is just very different from a PK/PD perspective because with this peptide, it's positively charged peptide conjugated to it, which will interact with the negatively charged proteoglycans on the face of the membrane, will drag the PMO into the cells. And at least empirically, in animal data, I think for anybody who is forgetting, you really have to remember, it's always risky to correlate between animal data and humans and imagine that this is perfectly predictive. But if there is a -- but broadly speaking, what we've seen repeatedly with our animal data is you get a fairly nonlinear inflection point and -- at least in animal models, it maybe something above 20 mgs per kg -- whether it is in patients or not, well, we'll wait and see. I don't want to over -- I don't want to create overexpectations. But certainly, we're very excited to find out what we see at 30 mgs per kg and what we'll see at 40 mgs per kg as well. Dr. O'Neill?

I think the key thing -- I think you made the key points, which are that we have seen, to date, empirically a good correlation or high degree of congruence between our nonclinical and our clinical, our human studies. And Doug is correct to say one should be careful at speculating. But with that congruence to date and the fact that we're now dose escalating in Duchenne patients, we hope to be able to confirm or validate what we've seen in preclinical experiments in the very near future.

Our next question comes from Ritu Baral with Cowen.

One, have you seen any rises in the plasma kidney markers that are usually -- that front run any kidney effects? I'm wondering if there's a slope that might indicate maximum dose. And two, I have a couple of discussions going with clients about the [ TAEs ] in the 10-milligram dose, all 3 of them were deemed related. Can you go into a little more detail and whether the exposure data when you correct for the biopsy timing fits the exposure curve that you would have modeled for the 10 mgs and 20?

Yes. I'll let Dr. O'Neill answer. I'll give you the short answer on the very first question. The answer is no. Interestingly enough and surprisingly enough, we've not yet seen negative labs on the -- with any signals on renal so far. So that's very heartening as we move to the 30 mgs per kg. But Dr. O'Neill, why don't you provide more detail on the safety profile?

Yes. Thanks, Doug. And thanks for the question. We obviously monitor not just plasma or serum markers but actually also monitor urine. We have not seen signal for -- or trends that would indicate a signal for renal. And I'm glad you raised that, because obviously, the kidney is the target organ of toxicity according to our nonclinical tox or preclinical tox study. And with regard to the treatment of emerging AE and the relationship to drug, I think the key point to make is that we did not see any alteration in -- what we're seeing is sort of a common degree of TAEs or common incidents accruals. And so we're not actually seeing an apparent dose response, which is what is giving us confidence. And these treatment-emerging AEs, while called drug-related, were -- what one can commonly see in clinical studies and in the context of Duchenne. But I think the key point is -- with the incidents not being substantially different across those groups, that is what's giving us confidence that we should and will continue to dose escalate. And I will tell you that it's also -- our dose escalation criteria are predefined in the protocol and then also supported by a Safety Review Committee.

Yes. I will note. There was only one serious AE in the trial at all. It was at the 40 mgs per kg. It was related to a fracture that a boy had. Excuse me?

4, not 40.

Very good point.

[indiscernible] 4.

Apologies. That was a misstatement. 4 mgs per kg. It was a related fracture. A child unfortunately had a fracture in. That's what it was related to. So it wasn't therapy-related. Other than that, things are looking very good from a safety perspective so far.

[Operator Instructions] Our next question comes from Gil Blum with Needham & Co.

Congrats on all the progress. Do you guys believe that even considering the delays in the biopsies with the PPMO, does this measure still reflect steady state exposure? It was a multi-dose study?

Yes. It was 3 doses across. There was at least 3 doses. But really 3 doses consistently across 3 months. I think we're -- I don't think it's steady state. I think that dystrophin -- both exon skipping and dystrophin build over time. So of course, we have this confounding variable of having taken the biopsy outside the half-life, double the half-life, which we don't know what that means. Obviously, it means we've created even a higher bar for ourselves, and we're still seeing exon skipping and dystrophin production in significant doubling of tissue exposure. That alone probably potentially underestimates what we should be seeing if we had taken the biopsy closer to when the dose occurred. And then, of course, you've seen, and I think one of the first slides that Dr. O'Neill provided was the fact that we are -- our history tells us over and over again that dystrophin -- but exon skipping to some extent and definitely dystrophin build over a significant period of time. So in essence, we should see not only a continuing benefit, but maybe even an increasing benefit over time as we look out from the therapy, both from continued chronic therapy as well as from dose escalation as we move to 30 and to 40 as well.

Our next question comes from Joel Beatty with Citi.

Could you discuss if you have any data on CK levels that you saw in the study? Or would CK levels be a marker that you would expect to see an impact on over time with higher dosing or longer dosing?

Dr. O'Neill, do we have that?

Yes. So our CK data essentially to date -- and remember, we're following these patients -- or the announcement we've done are out to 12 weeks. We basically saw essentially a stability or even very minor reductions in CK. But those reductions were big order -- single order magnitude. And this is against a background of patients with Duchenne having CK levels in the 10,000s. So I'm not sure that we would have expected to see any effect yet. And the good news is we didn't see anything as substantial increases. More importantly, what we actually saw were, in general, a trend towards minor reductions.

Our next question comes from Martin Auster with Crédit Suisse.

I was curious, Dr. O'Neill or Doug, if you could speak to the specifics in the 4 biopsy patients with the 20 mg per kg dosing. If you could talk about the patient-specific or the range of exon skipping either as absolute or as relative to the person comp. And then also how that kind of correlated to the 2 patients where you're able to get dystrophin expression measures achieved.

Dr. O'Neill?

Yes. So with regard to the 4 subjects, what you could actually -- or 4 patients per, pardon me, is you actually -- you'd be able to see the slide, but as we presented, where we had good tissue was for exon skipping for all 4. I think the error bars in there, what I would tell you is I don't -- we have not actually done a strict correlation patient-by-patient of the tissue exposure to exon skipping or dystrophin. However, with the nature of the error bars, we're actually confident within the context of 4 subjects that we were actually seeing a good correlation. And the reason that I believe that, that we are confident about that is because, again, we see -- we saw a dose-dependent effect with even a single dose of PPMO on tissue exposures on exon skipping in the human healthy volunteers. And that congruence within healthy human volunteers and Duchenne patients actually also reflects that which we've seen across multiple nonclinical species, including mice and nonhuman primates, and indeed, in in-vitro in patients -- or Duchenne patient-derived myotube.

Our next question comes from Difei Yang with Mizuho Securities.

Just 2 here. The first one is that how should we think about the effects of PPMO is more pronounced in dystrophin versus exon skipping? And then secondarily, when you do the dose escalation, et cetera, it seems like you'll have significant ability to get dystrophin level up. And is there -- ultimately, is there a optimum level you'll try to target or is it as high as possible?

Yes. Thanks for the question. Now it's dangerous to speculate on why the dystrophin even looks greater than the exon skipping, but I will. I'll speculate, and then we'll see as we get to the 30 mgs per kg and the like how this all bears out. But remember, as we've said repeatedly, the biopsies for the 20 mgs per kg would have -- were as a result of the COVID pandemic we've taken significantly outside of the window that we would have hoped for, 16.5 days or twice the half-life versus about 6 days for the 10 mgs per kg. That would likely have a differential impact on exon skipping versus dystrophin production. Exon skipping would fall fairly rapidly with tissue exposure decreasing over time. But dystrophin would persist longer. Dystrophin lasts longer as we know and has done half-life. And so there is at least a signal here that explains that this really is an artifact of when we took the biopsies. And if that is true, it would suggest, and certainly it makes sense on its face, it would suggest that if we had taken this closer to when the dosing had occurred in the same way we did with 10 mgs per kg, we would have seen a more significant tissue exposure even than what we saw. So we saw double the tissue exposure. We would have seen something even more significant than that, and that would be consistent with what we saw, not only preclinically, but in the healthy human volunteers. We would have seen a more significant increase even than what we saw at exon skipping. And we would probably have even seen an increase in dystrophin production versus what we saw in the 20 mgs per kg. Now of course, I do want to make it absolutely clear that there's a speculation to that. We need to see the 30 mgs per kg. We need to take -- pandemic-permitting, we need to take these biopsies in the window, in the proper window, which is about 6 days post dosing. And then we'll get a confirmation for that. But that would be the best explanation both from our preclinical data and the way it works mechanistically, and our healthy human volunteer study. And that would explain why the exon skipping goes up but doesn't even go up as much as dystrophin production when you would expect to see a more direct correlate. On the dystrophin levels, in one sense, we already have the PMOs. And the PMOs are providing a real benefit to patients with Duchenne muscular dystrophy. And hopefully, if we are -- it all goes well, and we believe it will, they will even have a third one of those PMOs approved in February of next year, which can treat about 29% altogether of Duchenne muscular dystrophy children. And against that, of course, what we're looking for is just a benefit over that and the greatest benefit we can get. We know if we can get this therapy, if this therapy bears out as we're seeing right now, we'll already have a benefit because it will be 1/4 of the dosing for these children far more convenient. We're already seeing signals of significant increases in dystrophin. And of course, if we can get up, I would say -- most people would say something like 5% would be a tremendous benefit to children with Duchenne muscular dystrophy as an example. But we'll have to make all of that decision with data in hand and a proper risk benefit, both safety, both efficacy and timing for these kids to make decisions about what the proper dose is to go into -- for this trial Part B and then what we target for the other constructs that we have.

Our next question comes from Vincent Chen with Bernstein.

Congrats on the results. I'm curious what your latest thinking is on how you think about increasing exon skipping translating into increasing dystrophin production. So based on the totality of your clinical and your preclinical data as well as the underlying biology, as you go up, say, twofold on exon skipping in this range, how much would you expect dystrophin levels to increase and why?

Dr. O'Neill, do you have a view on this?

Well, our old -- I would say our experience with PMO and PPMO is in the nonclinical data set. They suggest a sort of 2:1 or 2.5:1 correlation for exon to dystrophin. I'm kind of glad you asked that question because while it is very tempting to try and do type correlation when we -- with our small data set here, I think one has to be extraordinarily careful particularly because you put your finger on the key issue, which is, do we have a strong mechanistic explanation to sort of explain or define that correlation? And I would say 2 things. First of all, I think it's too soon with our data set and a small data set at that point to actually draw those tight correlations in the clinical setting. But I think we can say with confidence, because of the congruence with regard to dose response across dosing, exposure, exon skipping and disposing that the PPMO is doing part of it [indiscernible]. I think from a mechanistic point of view, because I think you asked for that, there is an important balance which we don't necessarily fully understand. Obviously, we do know that it takes about 14 to 16 hours to transcribe the RNA for disposal. We know that the half-life, or we believe, from in vitro, these are myotube experiments that the half-life of [Technical Difficulty] is approximately 40 hours. And we also know from myotubes that the half-life of dystrophin is about 1 to 2 months. Those data alone suggests that there is a complex interaction mechanistically between the transcripts, the synthesis and the dystrophin translation and persistence. So with that, I have to say is that we have a lot more work to do to truly understand that mechanistic interaction. But again, I am confident with the congruence of the nonclinical and then the clinical data from healthy volunteers and Duchenne patients, that we are seeing a dose trend effect for exposure and downstream exon skipping and dystrophin expression.

Our next question comes from Tim Lugo with William Blair.

This is John on for Tim. Just more of a forward-looking question from us. We were just wondering if you had any plans in the future to combine a PPMO with a gene therapy or if you can speak to any thoughts on combinations you may be thinking about.

Yes. It's something that we are looking at preclinically now. So we should have some views on that perhaps in the latter half of next year from a truly preclinical perspective, because, of course, that is an interesting question. Is there a benefit to patients of a combination of a -- significant onetime transformational therapy? And of course, in this regard, I'm talking about the potential for SRP-9001, our gene therapy, followed by a chronic therapy. Is that the best answer for children and young adults? And hopefully, we're not talking about children and young adults only, in the future, but of folks with Duchenne muscular dystrophy. We don't have those answers yet. We have hypotheses right now. There is a real potential for that, and we should have some significant views on that later next year. There already will be a benefit to the PPMO. Even in the face of a transformative gene therapy, there will be children -- even before that, remember, there will be children who have pre-existing neutralizing antibodies that would otherwise screen out from a gene therapy that would be -- would allow us to continue to treat them with the transformational PPMO such as the case after the trial progresses. There'll be likely places around the world that could have access to a chronic RNA therapy before they would get gene therapy. There's already some data in the literature, some interesting published peer review data that says, at least, in animal models, the use of a PPMO to pretreat in advance of gene therapy will enhance the benefits of gene therapy. So we know there's going to be a place for both of them. Whether there's a place for combination therapy as well is something that is very tantalizing and it might be a real benefit to patients, but we need to do additional work and then come out with some evidence-based views on that before perhaps the end of next year. But thank you for that question.

And I'm not showing any further questions at this time. I would now like to turn the call back over to Doug Ingram for any further remarks.

Thank you all for joining us today. We are obviously very pleased with what we have seen thus far. And we're excited to continue to dose-escalate. As Dr. O'Neill mentioned, we're already dosing at the 30 mgs per kg level. We'll be moving to the -- hopefully, the data supports it, we'll be moving to the 40 mgs per kg dosing very shortly. And we look forward to further updates next year on the PPMO program, both SRP-5051 and other therapies for Duchenne muscular dystrophy for other of our -- of the mutations and patient populations. With that, again, thanks, everyone, for joining us, and stay safe.

Thank you. Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.