Sarepta Therapeutics, Inc. ($SRPT)

Good morning, and welcome to Sarepta's preliminary data readout of its Phase I/II studies for DM1 and FSHD. As a reminder, today's program is being recorded. At this time, I'll turn the call over to Doug Ingram, Sarepta's Chief Executive Officer. Please go ahead.

Thank you, Shannon. Good morning, everyone, and thank you for joining our first readout of our clinical data from our programs for FSHD and DM1. In a moment, you will hear from our President of R&D and Technical Operations, Dr. Louise Rodino-Klapac; our Chief Medical Officer, Dr. James Richardson; and during our Q&A session, our President and Chief Operating Officer, Ian Estepan; and importantly, our Chief Scientific Officer, Dr. Rachael Potter. But before that, let me make a very -- a few very short introductory remarks. Now first, I must remind you that we will be making forward-looking statements today, so please refer to our various public filings for the risks and uncertainties that come when making predictions about the future. Sarepta has long been committed to improving and extending the lives of families with Duchenne muscular dystrophy. And with our 4 approved therapies and our ongoing research, we will continue that mission with all of the passion, dedication and expertise we have built and demonstrated to date. If the results we present today are further confirmed in upcoming readouts, SRP-1001 and SRP-1003 hold the promise of changing the treatment landscape for these debilitating diseases. And we are as exhilarated by this new chapter as we remain fiercely dedicated to the Duchenne community that we serve. As we all know, both DM1 and FSHD are life-limiting muscular dystrophies without adequate therapy today. What is also common for both is that each involves a monogenic mutation that results in the presence of either a toxic mutant mRNA or toxic protein that causes system-wide downstream harm. In this context, the goal of a disease-modifying therapy is to remove as great an amount of the mutant protein or mutant mRNA as is possible. As we contemplated the Arrowhead partnership back in late 2024, what got us excited about these programs from all of the animal models was the potential of the TRiM platform's unique approach to drive enhanced muscle concentration, often one of the crucial impediments to the effectiveness in muscle programs, to drive efficacy with a strong next-generation siRNA target engagement and to offer an improved safety profile, which in addition to a better [risk-benefit profile] should permit us to continue to dose escalate without the dose-limiting toxicities that have to set some other approaches that have been taken. The clinical experience you will see today is, of course, early and thus limited, but consistent with the animal models, it strengthens the proposition that SRP-1001 for FSHD and SRP-1003 for DM1 could be best-in-class therapies to treat these difficult and life-limiting diseases. First, our clinical data to show -- data to date shows that the TRiM platform's alpha-V-beta-6 integrin targeting ligand drives multiples greater construct into the muscle than other approaches with dose-dependent increases in plasma and muscle concentration and no saturation of siRNA uptake to date. While early and limited, we are seeing even at 1 dose, good target engagement and positive impacts on biomarkers. And to date, we have seen no dose-related safety signals that limit our ability to continue to dose escalate. Again, I will emphasize the obvious, these data are early. We will have more evidence later this year as we present our more cohorts and the multi-ascending dose data, but we are very excited with what we have seen to date, which strengthens our conviction in the potential of both SRP-1001 and SRP-1003. And with that, I will turn the call to our President of R&D and Technical Operations, Dr. Rodino Klapak. Louise?

Thanks, Doug, and good morning, everyone. Shortly, I'll turn the call over to our Chief Medical Officer, Dr. James Richardson, to go through the proof-of-concept data for FSHD1 in myotonic dystrophy type 1 or DM1. First, I'd like to take a few moments to highlight our rationale and our enthusiasm for the siRNA platform. Today is an important day for Sarepta and for the FSHD1 and DM1 patient communities as we share with you the progress we've made in advancing our programs and the foundational science that underpins them. From the very beginning and as we have assessed numerous approaches, programs and data, Arrowhead programs became the obvious choice for us as we thought about our future, grounded in making a difference in the lives of rare disease patients by leveraging the best science and continuing our leadership in neuromuscular rare diseases. Our commitment, mission and values are steadfast, including our continuing leadership and long-term focus on rare diseases, including Duchenne, having achieved approval of 4 therapies to treat the disease and its ultra-rare genetic subtypes. Next, we are building on our expertise in neuromuscular disease to expand and treat neurodegenerative diseases with unmet needs. We are developing technologies where the foundational science is well understood, the proof of concept is established and the mechanism of action is validated and knowing that every day, we allow the science to lead our mission to serve patients. We believe the targeted RNAi molecular TRiM platform is applicable across a wide variety of tissue types and capable of deep and durable target gene knockdown. The potential strength of this technology has been demonstrated in preclinical studies across multiple tissue types. This is why we have confidence that our TRiM-based therapies could be truly differentiated and best-in-class approaches. While RNA therapies hold tremendous potential, challenges in delivery and dose-limiting toxicity have been an obstacle for maximizing the therapeutic benefit of these molecules. To overcome delivery challenges we often see with RNA therapies, the TRiM technology employs proprietary tissue targeting ligands. This combination of siRNA chemistry and its ligand delivery platform are designed to enable us to achieve robust knockdown of overexpressed mRNAs and proteins associated with many neuromuscular and CNS-related diseases and reach areas of the body that are traditionally difficult to penetrate, including muscle and deep brain. Specialized linker chemistries are designed to provide stability to prove efficacy and PK/PD structures such as lipids enhance delivery. Now this slide highlights the unique siRNA mechanism deployed by the TRiM platform. What you see in this graphic depiction is siRNA taken up by tissue and into an endosome by a specific ligand. That ligand is important for creating metabolic stability and efficient RNA silencing complex or RISC loading essential for enhancing efficacy. More specifically, native siRNA is rapidly degraded by nucleases and can activate immune responses. TRIM incorporates chemical modifications with the goal of improving nuclease resistance, reducing immunogenicity and maintaining high affinity for RISC. RISC is a ribonucleo protein complex that uses siRNAs or micro RNAs as templates to recognize and silence complementary mRNA targets, which serve as a key regulator in gene silencing or knockdown. These modifications are designed to ensure the guide strand is loaded into RISC for efficient gene silencing, enabling greater potency since the catalytically active RISC cleaves multiple targeted mRNAs. Further, we are applying stabilizing chemistries at the 5 prime ends of both guide and passenger strands to resist 5 prime exonucleases during trafficking and loading. The 5 prime terminal phosphate on the guide is crucial for domain binding and RISC loading to drive potency and durability. In summary, by targeting miRNA directly, we believe these therapies can target any disease-causing mRNA or protein, thereby increasing the number of potential drug targets. Importantly, using siRNA rather than, for instance, an ASO should be far more potent since the catalytically active RISC repeatedly cleaves multiple targeted mRNAs and is not limited to available RNaseH1 as is the ASO. As we all appreciate, greater muscle uptake has been associated with better efficacy and clinical outcomes. This slide shows we are encouraged by the potential of our targeting integrin alpha-v-beta-6 What's particularly exciting about these data is the ability of alpha-v-beta-6 integrin to highly express in muscle, making it optimal for targeted siRNA delivery, which we believe will result in enhanced efficacy and clinical impact to the patient. As shown here from published literature, TfR1 was able to bind to only approximately 5% of available receptors at any one time versus alpha-v-beta-6 which was able to bind to approximately 40% of available receptors at any one time, resulting in higher muscle expression than TfR1. The binding capabilities of alpha-v-beta-6 led to how we established our goals for advancing SRP-1001 for FSHD and SRP-1003 for DM1 in our first-in-human studies. This slide summarizes why we're excited about the potential of our integrin targeting ligand to produce best-in-class therapies for FSHD and DM1. Like TfR1, integrin receptors are not exclusive to one tissue, but are highly expressed throughout the body. Also, like TfR1, they are actively tracked between the cell surface and endosomal compartments through relatively well-understood pathways. Nonclinical data show that targeting these integrin receptors via small peptides leads to enhanced skeletal muscle uptake compared to using a much larger TfR1 antibody. Further, the peptide targeting integrin shows better muscle uptake compared to the TfR1 monoclonal antibody and siRNAs are more potent than ASOs due to the mechanism of action and stability of siRNA to categorically degrade more mRNA transcripts as compared to the RNA-H1dependent mechanism of ASOs. Lastly, it's important to note that nonclinical data supports a potentially large safety margin for siRNA integrin peptide conjugates. Others using TfR1 monoclonal antibodies to deliver siRNA to muscle have halted at lower doses and have seen some issues with anemia. The TfR1 fragment antibody appears to have the same limitations. Now on this slide, you will see the preclinical validation of our scientific hypothesis and the power of the TRiM technology bearing out to support both our SRP-1001 therapy to treat FSHD1 and our SRP-1003 to treat DM1. The data demonstrates 2 important points in nonhuman primates and rat models. First, as we dose escalate across 5 doses, we see an absence of saturation, which means the drug has the potential to achieve maximal therapeutic effect. Secondly, a dose-dependent increase in plasma is observed, which should enhance -- enable enhanced muscle delivery and strong PD effect. Now further preclinical supportive trend is shown here, specifically to SRP-1003 for DM1. An increase in plasma exposure has translated into enhanced dose-dependent delivery to the muscle, resulting in robust target engagement and maximal DMPK mRNA knockdown. Enhanced muscle delivery, robust target engagement and maximal knockdown represent the gold standard for our disease categories. We are thrilled to see our scientific hypothesis bearing out in this way as a potentially differentiated approach to tackling FSHD and DM1. And I'll now turn the call over to our Chief Medical Officer, Dr. James Richardson, who will share our single ascending dose or SAD study results. James?

Thank you, Louise, and good morning, everyone. I'm very happy to share with you the clinical results from our 2 lead siRNA-based programs to treat FSHD1 and DM1. Specifically, as these are first-in-human studies, we will discuss the data we observed on safety, muscle concentration and evidence of impact on pathways known to drive pathology in these 2 diseases. I also intend to highlight that these preliminary data build on our preclinical evidence that our proprietary approach could lead to potential best-in-class treatments based on the ability of the alpha-v-beta-6 ligand to provide superior muscle concentration to transferrin-based approaches without dose-limiting toxicity. As you are aware, this is our first readout from these ongoing and actively enrolling studies, and these data are necessarily limited by the stage of development. The data available comes predominantly from the single ascending dose portions of both of these studies. For this upcoming FSHD section, we have data on muscle PK for cohorts 1 to 3 and DUX4 gene expression. The latter is analyzed as a pooled treatment arm due to the sample size availability. Overall, data availability is driven by the stage of the study recruitment, loss of data due to study conduct issues and the availability of muscle tissue for retesting as we transition from fit-or-purpose assays to validated assays suitable to support regulatory submissions. These very promising data that will be built upon in the second half of this year when we plan to release data from the currently enrolling MAD cohorts. To begin with FSHD, it's important to understand the disease and its impact on the body. FSHD is a rare genetic disease and one of the most prevalent forms of muscular dystrophy. It causes weakness in the skeletal muscles that classically begins in the face and scapular girdle. And while progression is variable, progressive weakness in the upper limb, pelvic girdle and abdominal and leg muscles usually follow. It is an autosomal dominant condition, meaning that the child and affected parent has a 50% chance of inheriting the disease. So 10% to 30% of cases occur in the absence of a family history, secondary to spontaneous mutation in the gene. No treatments currently exist. What this slide shows -- if we can move on to the next slide. Thank you. What this slide shows is that FSHD is caused by genetic mutation of the double homeobox protein 4 gene, also known as DUX4 on chromosome 4 that leads to abnormal activation of the DUX4 gene and expression of the DUX4 protein. DUX4 is a transcription factor, meaning that it has an impact on the expression of multiple other genes within the muscle. It is normally only expressed in muscle during embryonic development and its later activation in FSHD essentially switches the intracellular environment of that muscle fiber back to the embryonic stage. An environment that is helpful during embryogenesis is toxic for muscle fiber in a child or adult and leads to muscle degeneration. This underlying pathology is well understood and the pathological role of DUX4 in the progression of the disease is well accepted. Our lead program, SRP-1001, is designed to reduce or knock down the production of DUX4 protein in skeletal muscle in patients living with FSHD1. Our Phase I/II clinical trial is a combined single ascending, multiple ascending dose, randomized placebo-controlled trial in participants aged 16 through 70. For your orientation, we normally dose this product by total drug dose, but to allow better comparison to other products in development, we show here the siRNA doses. So for example, for Cohort 1, the 1.02 mg per kg siRNA dose shown here equates to our per protocol total drug dose of 1.5 mg per kg. These are the baseline characteristics showing balance across cohorts with a baseline clinical severity score representing moderate disease. Let me now share the clinical data. So here, you see the plasma exposure at 4 dose levels up to an siRNA dose of just over 8 mg per kg, roughly 4x the siRNA dose of the further advanced clinical siRNA program in this disease space. This dose-dependent linear increase in plasma exposure supports our hypothesis that we can dose escalate without saturation or toxicity. As mentioned, and as you should all appreciate, delivering drug to the muscle in a robust way should make an important difference in what constitutes clinical relevance and impact to patient health. Building on the dose-dependent changes in plasma exposure, what you're seeing here on the left is a dose-dependent increase in muscle concentration up to an siRNA dose of 4.08 mg per kg. A single dose of SRP-1001 measured at 42 days after dosing, mediates a sixfold higher concentration of siRNA than multiple doses of a transferrin targeting ligand siRNA approach measured 30 days after the last dose. Earlier in the presentation, Louis spoke of the power of our alpha-v-beta-6 integrin targeting ligand. These data support our scientific hypothesis that this approach enables much greater siRNA muscle delivery with no evidence of receptor saturation. This is distinctly different from what has been observed in transferrin targeting ligand approaches used in FSHD and DM1, where absolute muscle concentrations are significantly lower. The potential to drive high muscle concentrations without concerns that will saturate the receptor and without dose-limiting toxicities offers a potentially differentiated approach that may be of important therapeutic relevance in treating FSHD. As discussed, DUX4 protein leads to a misregulation of a number of genes, creating a myotoxic environment for the muscle. What you're seeing here on this slide is pooled data from the 3 lowest single ascending doses looking at the correction of erroneously expressed DUX4 regulated genes following the administration of SRP-1001. From left to right, you see a 4, 6 and 8 gene composite panel. Importantly, the 4 and 6 gene panels are comparable to Avidity 4 gene and ReDUX panels being composed of the same DUX4 regulated target genes. You see a single dose of SRP-1001 is providing suppression equal to or in excess of 90% across all 3 panels when adjusted to placebo. To our understanding, this represents the greatest DUX4 gene reduction in the field observed to date. Creatine kinase is a well-established biomarker of muscle injury and therapeutic effect. This pool analysis of the 4.08 mg per kg and 8.17 mg per kg doses of SRP-1001 versus placebo shows a 33% reduction in creatinine kinase, providing a proximal measure of the impact of SRP-1001 on muscle health after a single dose. SRP-1001 has demonstrated a favorable safety and tolerability profile to date. Of note, the majority of adverse events were mild to moderate and most have resolved. One serious adverse event unrelated to treatment was reported. This was chest discomfort, 78 days post a single dose of SRP-1001 in a patient with multiple RISC factors for coronary artery disease. The diagnosis made by the treating physician was of an unstable angina or missed acute coronary syndrome. With this early exposure, there is no discernible dose-dependent or idiocratic safety signal. No treatment-emergent events have occurred in 20% or more of patients and no treatment-emergent adverse events led to death, study drug discontinuation or study discontinuation. The strong safety profile so far exhibited by SRP-1001 provides a foundation for which we will continue to dose escalate, supporting our hypothesis that higher dosing could result in greater knockdown and therefore, greater functional benefit. So let me summarize what we've observed in the available clinical data to date and what we believe supports the unique attributes of SRP-1001. Favorable safety and tolerability profile, dose-dependent increase in plasma exposure up to the highest dose cohort, superior delivery to muscle enabled by differentiated approach with the alpha-v-beta-6 integrin, including no saturation of drug uptake and potentially unprecedented suppression of DUX4 regulated genes with a rapid and robust reduction in CK. Moving now to DM1. DM1 is the most common form of adult onset muscular dystrophy. It is caused by a repeat expansion in the DMPK gene and presents as a multisystem disorder that affects skeletal and smooth muscle as well as the eye, the heart and in particular, normal electrical conduction within the heart, the endocrine system, the gastrointestinal system and the central nervous system. There is currently no cure and there are no disease-modifying treatments available. As I just mentioned, DM1 is driven by an expanded CUG trinucleotide repeat in DMPK transcripts, causing mutant DMPK mRNA to accumulate in the nucleus and disrupt normal RNA splicing. As a result, for any therapy to be therapeutically effective, it must effectively target and knock down or silence DMPK in the target gene. We believe our therapy SRP-1003 has the potential to achieve exactly that. Study SRP-1003, 101 is a first-in-human Phase I/II randomized placebo-controlled SAD/MAD clinical trial being conducted in participants aged 18 to 65. Today, we have data available from Cohort 1, and we'll be focusing on the muscle concentration. We have also seen impressive impact on DMPK knockdown in this cohort. Right now, we're seeing a 50% reduction placebo adjusted. But given the small end, some variability in placebo and that 50% would actually exceed our preclinical predictions, we believe it is more appropriate to defer a definitive assessment until the MAD data is in hand. These are the baseline characteristics showing balance across the cohorts. Next slide. Like we saw with FSHD, we see a dose-dependent increase in plasma exposure. While we are limited today by the availability of muscle samples, given the use of identical targeting ligand and identical target organ in skeletal muscle and now with a very similar plasma exposure profile, we believe that with the availability of additional samples later this year, we will replicate the dose-dependent increase in muscle concentrations seen in FSHD in DM1. Focusing on the muscle concentration provided at the lowest dose of SRP-1003, we observed a manyfold higher muscle concentration than seen at comparable doses of a clinical stage transferrin monoclonal antibody targeted siRNA and a Fab tansferrin-targeted ASO-mediated approach. We know from published data that the mAb approach shows a very modest increase in concentration with increasing dose, which likely explains the limited improvement in PD markers with dose. Conversely, a Fab approach has shown a more robust increase in muscle concentration with increasing dose, but again, a limited dose-related response in PD. This is likely driven by the reduced efficiency of the ASO approach versus the efficiency of siRNA. SRP-1003 has demonstrated a favorable safety and tolerability profile to date. The majority of adverse events were mild to moderate in severity, 9 adverse events were assessed as related to study drug. All were mild and resolved without sequelae. No adverse events occurred in 20% or more participants. One unrelated fatal serious adverse event occurred in Cohort 1 due to a cardiac arrhythmia. The event occurred several weeks after a single low-dose administration of SRP-1003 and is aligned with a recognized RISC in the natural history of DM1. The investigator, sponsor and an independent corner each concluded the event was unrelated to SRP-1003. Subsequently, more than 60 patients have been treated with either SRP-1003 or SRP-1001 without a further adverse event of arrhythmia or any other emergence of a pattern suggestive of a treatment-related safety signal. Further, it is important to note that because the fatal event occurred early in the study, it was included in and reviewed as part of the subsequently approved clinical trial application by regulators in the U.K., EU and Canada. Based on these observations, there is no indication to date of a dose-related safety signal that would preclude continued dose escalation. In both diseases, the alpha-v-beta-6 ligand has shown the clinical potential to drive higher muscle concentrations without dose-limiting toxicity. In FSHD, this differentiated delivery is driving early evidence of an impact on key markers of pathology. In the coming year, we will have the opportunity to present data from the MAD cohorts from both programs, along with data from further validated markers of the therapeutic impact, building on this promising early data in both FSHD and DM1. Before turning the call over to Doug for closing remarks, on behalf of Sarepta, I'd like to extend our thanks and gratitude to the FSHD and DM1 patient communities and the clinicians who participated in these trials. Participation in clinical trials is how science moves forward, especially for diseases without treatment. We are grateful for your participation and courage. Doug?

Thank you, James. SRP-1001 for FSHD and SRP-1003 for DM1 represent the first clinical readouts from our Arrowhead partnership. To remind you, we have 5 programs in clinical development right now. We have FSHD and DM1. We have IPF, SCA2 and Huntington's disease. We have 2 other programs in animal testing, and we have 6 research programs that make up this portfolio of siRNA. Our 5 clinical programs alone offer potential therapy to as many as 160,000 patients in the United States and multiples greater than that worldwide. Looking forward, we plan to present updated data on SRP-1001 and SRP-1003, including more PD and PK data from the MAD arms of these studies in the second half of this year. With respect to Huntington's disease, a devastating and largely untreated condition impacting as many as around 40,000 patients in the United States, we will commence dosing in the second quarter, and we anticipate having proof of biology data to present in the first half of 2027. And with that, Shannon, let's open the line for questions.

[Operator Instructions] Our first question comes from the line of Anupam Rama with JPMorgan.

Can you clarify or maybe I misheard, did you comment that you're planning on dosing higher for 1001 in FSHD? And can you speak to the plans for this?

Yes. Thank you for that question. James, maybe you could highlight where we are in our dosing in the -- for FSHD in terms of the MAD dosing.

Yes. No, absolutely. Thank you for the question. So the data we largely presented here was cohorts 1 and 3, which is a maximal dose of around 4 mg per kg of siRNA. We have opened and actually fully recruited both a SAD and MAD cohort up to 8 mg per kg of siRNA.

Our next question comes from the line of Konstantinos Biliouris with Oppenheimer.

Congrats on the promising data here. Maybe one question on the differences between the number of patients across the different markers. From what I understand, based on the differences, some of the patient data are not shown. Can you talk a little bit about those patient data and whether we should expect to get those data in the second half of this year? Congrats again.

Sure. Just to clarify your question. So you're just asking for both programs, how many patients we've dosed and what we expect later this year? Just clarifying.

Yes. Just in some biomarker data, the number of patients between slides is different. Maybe why, in some cases, the number is lower than others, what happened to these patient data?

Sure. James, would you like to highlight that?

Yes. No, of course. So just to answer the first part of the question. So we dosed 36 patients in DM1 and 56 patients in FSHD. What you're seeing here is the available data we have. We have been transferring across to a fully validated regulatory-ready set of assays. That's caused some data dropout, particularly where samples have been insufficient to rerun the second time, now though have been inappropriate to run. So that's what's driving the difference in delta. I think overall, though, we've only included numbers that I think are represented overall of our data, and I think we're very confident in the conclusions that we've drawn.

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

I was wondering if there's anything more you could tell us on the baseline characteristics for the patients in the FSHD part of the study. Maybe just how that compares to studies from competitors on things like disease severity and clinical scores. And then just, I guess, how you think functional outcomes will end up looking relative to competitors, just given the higher PD effects you're seeing on the DUX4 related genes -- DUX4 regulated genes.

Thanks for that. James, would you want to highlight the FSHD baseline characteristics?

Yes. So our inclusion criteria for the clinical severity score was between 3 and 8, with a mean of around about 5 across the cohorts. We're using a 1 to 10 scoring scale. Avidity, I think, is a 1 to 15 score. But if you translate between the 2, we have fairly similar populations, I think both moderately severe. And I think that otherwise, the populations are fairly similar. So I think that, obviously, the sample size will be relatively small and the time follow-up will be relatively short for functional outcome. But I mean, a, we're very confident that these PD markers will carry through to function and I think could be reasonably comparable to what you've seen from the Avidity program.

Let me also comment briefly, Brian, to your point. And really, we're talking more at a sort of a predicted theoretical level. And one of the things that gets us excited about these programs is the opportunity to drive more functionality in patients both with DM1 and FSHD. And so what gets us excited about these things is these features should, as we confirm them in multi-ascending dose and beyond, should translate into enhanced efficacy. So we all know that one of the most difficult things in muscle-directed therapies is getting to the muscle and getting into the muscle. And so seeing really enhanced muscle concentration validates what we would imagine based on the preclinical work and one of the reasons we got so excited about the Arrowhead deal, it should result in efficacy. The same with the idea that using the integrin receptor, avoiding things like anemia that come with using the transferrin receptor and therefore, avoiding some of the dose-limiting toxicity that you might otherwise have should allow us to continue to dose up, which again should -- if all is consistent with what we've seen preclinical result in enhanced efficacy. And finally, the fact that we're using an siRNA approach and in the case of the TRiM platform, a next-generation version of the siRNA approach, we think is going to enhance efficacy because, as we know, siRNA is a really potent, efficient way to knock down through the use of RISC, which has a real fast recycling ability and the fact to knock down a ton of mRNA. So again, we don't want to -- we can't predict exactly what we're going to see going forward, but we have a lot of excitement about what we're seeing so far. And it really does relate the overall RISC benefit, but really to the potential benefit of this therapy.

Our next question comes from the line of Andrew Tsai with Jefferies.

So like you said, we're going to get more MAD data in second half 2026 now. So what exactly are your go/no-go thresholds or criteria to advance both assets into pivotal studies? For example, if you see strong DUX4 or continue to see that or if you see strong splicing vHOT changes, is that enough to you? Or are you waiting for longer-term outcomes data like 6-minute walk, for instance?

Thank you for that question. I'm going to make a few comments, and I'll turn it over to James. I think what we're seeing so far is that we're extremely excited about what we had. I think what we're seeing now in the SAD data was really one of the things that we are looking for in terms of muscle concentration. Doug spoke to it, but the fact that we are achieving these high levels of muscle concentration at low doses with just one dose was really significant, and we're not seeing dose blending toxicity. So we continue to dose up. And our preclinical data shows that there's a correlation with muscle concentration and the PE effect, which we're seeing early signs of clinically. So in terms of hurdles and what we would like to see to move these programs forward, I think we're really happy where we are. Obviously, we're going to -- we're excited to see the MAD data as well. And I'll have James talk about what we're looking for in terms of data from that. But in terms of where we're at right now, we're really pleased with the status of the SAD data. James, do you want to add?

Frankly, I mean just very much the same. I think we're fantastically excited by the PK and the PD data we've seen already at dose. We'll be adding more data at higher doses, assuming we continue to see the same pattern. I think that we would be -- it would be a very easy decision to move this forward. I think specifically in on both programs, in terms of the biomarker versus functional data, I think given the nature of FSHD and the well-established natural history supporting the use of both the gene suppression biomarker and circulating biomarkers that we'll be presenting later this year. They are likely to be the stronger sign to move the trial forward rather than efficacy, which is going to be, I think, in a slowly progressing disease, a lagging marker. But I think based on what we've seen so far, we're extremely likely to move these programs forward. For DM1, again, very well-established data supporting the predictiveness of biomarkers like CASI and then early functional change like vHOT. These will be things that we're looking at in the second half of the year and will, I'm sure, give us the reassurance that what we've seen today is indicative of what we think are going to be differentiated therapies in the market.

Our next question comes from the line of Ellie Merle with Barclays.

Can you just elaborate a little bit more on what you're seeing on the DMPK reductions? I think you mentioned a 50% reduction, but just could you elaborate on which cohorts that was seen in and your expectation for what you might see at higher doses?

James, do you want to reiterate?

Yes. Thanks, Louise. So we saw a placebo-adjusted change of just over 50% in Cohort 1. I think based on the fact that the sample size is relatively small and that these estimates are a little higher than what we are predicting, we are, A, extremely excited, but B, keen to validate these findings in a larger sample size with that data later in the year.

Our next question comes from the line of Yigal Nochomovitz with Citigroup.

Can you hear me? I just had a question on the way you did the bucketing for these biomarkers, the [CS4, the CS6 and CS]8 for 01. Obviously, there's some unique ones there in the list in the footnotes and then there's some that are overlapping, obviously, across all of the different buckets. So could you just help elaborate on the significance of the way you did that analysis and how one should interpret them perhaps differently or the same? I mean, obviously, it all points in the same direction to a very good effect. I'm just wondering if there's any specific interpretations regarding the choices of the biomarkers for each of those groups, [CS4, CS6 and CS8].

Yes. Thank you for that. I'm going to have Rachael comment on the gene panel.

Thank you. Yes. So we wanted to evaluate a comprehensive look across the 4, 6 and 8 gene panels. And again, as James mentioned, the 4-gene panel is the same as the Avidity panel and the 6 gene panel is the same as the ReDUX panel. All of these have similarities across them. The 8 gene panel has 2 additional genes included. But importantly, they're all DUX4-related genes. And some are more tightly and specifically linked to DUX4 activity while others show greater biological variability. And as DUX4 is a transcription factor, it directly affects gene expression related to cell cycle, apoptosis, inflammation and immune response. So that's why we're looking across all 3 panels to capture pathway level modulation and reduce the impact of variability from individual genes to give us a comprehensive look.

Our next question comes from the line of Ry Forseth with Guggenheim.

This is Ry from Debjit's team. For the TRiM platform, how might we think about skeletal muscle concentrations as a proxy for brain and/or cardiac tissue exposure? And for the DM1 muscle concentrations, can you differentiate between nuclear versus cytoplasmic exposure? And for the second half data, will you have foci reduction data in the context of DM1?

Sure. I'm going to take that in 2 parts. So just I'll comment on the first part of your question on the TRiM platform, and then I'm going to turn it to Rachael to talk about the second part with DUX4. So in terms of the TRiM platform, for these 2 muscle programs, we're using alpha-v-beta-6. In terms of other programs that we are looking at, we're using different targeting ligands using the transferrin receptor in some cases, with the subcutaneous delivery. And so for each program, we're being very specific about which targeting ligand we're doing. In terms of any potential cardiac programs, that would be a different targeting ligand as well. So we're being very specific and thoughtful around both the target tissue, the route of delivery and the intended efficacy of that particular therapy. For Huntington's, for example, we are using a subcu delivery with the transferrin receptor to be able to get into the deep brain regions. Rachael, do you want to comment on the DUX4?

Yes. So your question was about the nuclear versus cytoplasmic knockdown. And so what we've seen in our previously disclosed data with Arrowhead is that there is an equivalent reduction in knockdown in animal models in the nucleus versus the cytoplasm. So we're confident that this knockdown is nuclear. We've also tested in a DM1 animal mouse model that has human mutant DMPK in the nucleus, and that shows a greater than 50% reduction in the nucleus that corresponds to a 75% restoration of missplicing. And so we're very confident in the siRNA approach is effective at targeting the nuclear DMPK and root cause of the disease. And then in terms of the DM1 foci reduction, we're evaluating the opportunity to look at this, but we have data preclinically that demonstrates a nice reduction in the RNA foci.

Our next question comes from the line of Ritu Baral with TD Cowen.

This is Joshua Fleishman on the line for Ritu. Congratulations on today's data. Could we please go into more detail on the loss of participants due to study conduct issues? How many patients and what specific issues with conduct? And then I'm curious for the second half '26 data, what specific functional endpoints should we be expecting for FSHD?

James, I'm going to turn that one to you.

Yes. Thank you, Louise. So thank you for the question. So the participants excluded were essentially excluded based on missed dosing. So we had a very small number of missed doses due to administration errors in both the DM1 and FSHD study. So these patients have been excluded on the analysis you've seen. It's as I said, I think it's 3 patients in DM1 and a similar number in FSHD.

And the second part was on the functional outcomes in the MAD.

So in the MAD study for FSHD, we should be looking at a wide range of functional outcomes. I think essentially the standard panel, including Timed Up and Go, Reachable Workspace, 6-minute walk test. And I think that measures of muscle strength. So I think these will all be interesting signals. I think as I said earlier, for FSHD is a slowly progressive disease. The significant changes in functional outcome are likely to be seen over a longer-term, larger study and a lot of our decision-making will be made from a biomarker perspective, building on what we've seen, I think, which is the very high muscle concentration with the alpha-v-beta-6 approach and I think really impressive PD data within FSHD. Within DM1, again, similar, I think, battery of TFTs -- sorry, time function tests, including Timed Up and Go and 6-minute walk test and obviously, vHOT being the, I think, differentiated outcome between the 2 programs being something that I think we will likely see a signal on. We've already seen some positive signs in vHOT based on a very small number of single ascending dose. I'd be confident that we'll be able to produce more robust vHOT data in the DM1 program at the end of this year as well.

Our next question comes from the line of David Hoang with Deutsche Bank.

I'm just curious about the correlation or maybe the relationship between the DUX4-related gene knockdown and the CK reduction that you're showing here. And the knockdown, I think, is obviously pretty impressive. CK looks maybe more along the lines of what competitors have shown. Any thoughts on this relationship and would potentially -- you expect CK reduction to deepen with multiple doses?

Yes. Thank you for that. So just a few comments on the knockdown. I think what we're seeing in terms of the DUX4-related genes, we're really pleased with. As you mentioned, I think the level of correction that we're seeing is significant. I'll turn to James to talk about the CK levels in DM1 in FSHD patients and what we think although we're encouraged by that signal, we think that there are -- we're looking at the totality of data and not CK in isolation. But James, would you like to make a few comments on in FSHD?

Yes. So I mean, I think that first and foremost, that the sign in CK, I think, is an incredibly strong signal of proof of concept with this treatment, which I think after a single dose administration is really, really something to be excited about with this program. I think in terms of the biomarker itself, there is some inherent variability with that at both the patient level and a visit-to-visit level. I think that you can often find yourself confounded with treatments in the neuromuscular space with CK because obviously, an effective treatment increases the patient's ability to ambulate and do tasks that they may not have been doing historically and that itself can drive the CK up. So I think that CK should be viewed as to me, a more qualitative proximal signal of the drug acting on muscle health and something that really supports the continued development of the program. I think in terms of an objective biomarker that is less variable from patient to patient and is something that I think is less prone to the subsequent therapeutic effects of the drug in terms of increased mobility and the like, I would veer towards the gene suppression. I think that in both ways, is extremely strong and promising data for a single dose administration program. I would probably limit the comparison between programs based on the CK given the variability of that biomarker.

Our next question comes from the line of Mike Ulz with Morgan Stanley.

Maybe just one on FSHD. Can you just talk about the dosing frequency you're exploring in the MAD cohorts? And just given some of the potency we're seeing early on here, is there opportunity to even lower that frequency in the future?

Thank you. James, would you like to take this one?

Yes. So the current dosing paradigm is 12 weekly in the MAD study based on the data we're seeing here, we're going to amend that to 10 weekly. That would be also true in the DM1 program.

And just Mike, beyond that, just so we're clear, yes, there is a potential to have an enhanced more moderated frequency of these therapies. But we are taking a careful look at that because if you think about the 2 issues, basically convenience and efficacy, we really want to ensure as we go forward that we're prioritizing efficacy. So we might have an enhanced benefit over frequency versus other programs, but we're going to take a careful look at this, and we're always going to choose maximal efficacy over convenience, if that makes sense, Mike.

[Operator Instructions] Our next question comes from the line of Uy Ear with Mizuho.

Congrats on the early data. It looks very promising. Maybe just help us understand the regulatory pathway that maybe you're considering would you -- after the MAD data, would you either start a Phase III immediately? Or would you perhaps consider another route such as maybe an expansion cohort that could be registrational?

Yes. Thank you for that question. James, would you like to comment?

Yes, absolutely. I think that we are continuing to learn and understand both our science here and the regulatory environment. But from -- in terms of a development plan perspective, we think that the most appropriate way is to move forward to Phase III and do that in such a way that gives us the flexibility to pursue multiple different regulatory approaches to approval, and that would be true globally.

Our next question comes from the line of Salveen Richter with Goldman Sachs.

This is Tommy, on for Salveen. Congratulations on these results. We just had a follow-up on the registrational trial question. Wondering just checking in at this point, how you're thinking about regulatory discussions to that end and potential to accelerate your time to market. And then just a quick one. You mentioned that you had been doing some assay work. Maybe if you could go into more detail behind that and your confidence in these now.

Sure. First, James, maybe you could comment on any other comments in terms of the registrational trial. And Rachael, if you just want to comment generally on the assay approach across the board.

Yes. So we'll be looking at the MAD data later on this year and then taking that along with the protocol for the Phase III that we're currently working up to global regulators, including the U.S. to kick off Phase III trials in '27 in both indications, assuming the data remains as strongly positive as it currently is.

Can I just -- before Rachael goes, let me just amplify what Dr. Richardson is saying. We have a lot of work to do. We want to start a Phase III next year. Nobody on this call will be surprised to hear that we want to find the most urgent, but thoughtful pathway to bring these therapies to patients waiting for them. DM1 and FSHD like DMD are debilitating degenerative diseases, and we want to get to them as fast as possible. With that said, we're going to learn from others, but we're going to do our own work as well. We have a unique expertise broadly in muscle programs. We need to learn even more about DM1 and FSHD to match what we already know about DMD. And on top of that, we need to talk to regulators. So we've got a lot of work to do, but you won't be surprised to know that our overarching goal is to get these therapies -- get the evidence for these therapies as rapidly as possible and get to these patients, both in the U.S. and around the world as rapidly as possible. But we don't have a lot of detail on that because humbly, we've got a lot of work to do before we commence our Phase III in both of these programs. I'm sorry, and then Rachael, I apologize for jumping in before you.

Thanks, Doug. We work to transition the assays that were fit for purpose from our partners into regulatory approved and validated assays. And so that was what was mentioned for the PK and the PD assays as we move forward.

Our next question comes from the line of Andy Chen with Wolfe Research.

This is Emma on for Andy. You touched on the targeting ligands, but can you share any additional insight on how consistent muscle uptake is across the different muscle groups, just given how these diseases affect different regions?

Yes, it's a great question. So obviously, the strongest data we have is from preclinical data. So Rachael, perhaps you could touch on what we're seeing across multiple muscle groups preclinically.

Thanks, Louise. Yes, we see a consistent uptake with the integrin-based approaches across lower limb and upper limb skeletal muscles as well as the diaphragm and the cardiac muscle. And so it's very consistent across the skeletal targeted approach.

Our next question comes from the line of Yun Zhong with Wedbush.

Congratulations on the positive initial data. Just wanted to confirm, did I see it correctly that you pulled different doses of siRNA when looking at gene panel analysis. Did you see a dose-dependent target gene knockdown? And have you seen any signals suggesting that the knockdown efficiency may approach in plateauing, please?

So for the -- for that target gene knockdown based on the number of samples, we did a pooled analysis across different doses. The N is too small to do a dose response at this point. So when we look to -- for the additional MAD data, we'll be looking for that. But right now, we've pooled just based on the N. Rachael, anything to add to that?

No. That's all.

Our next question comes from the line of Biren Amin with Piper Sandler.

On FSHD, did you measure for circulating DUX4? And if so, what were your observations in the SAD portion? And for the fatal arrhythmia event, I know the patients are predisposed, but have you done hERG channel studies with 1003.

Yes. So we'll take that in 2 parts. First, Rachael, could you comment on the circulating DUX4 assay potential for that? And then James, you can comment on the second part of the question.

Thanks, Louise. We are working on a circulating DUX4 assay, and we will -- we anticipate that data to be ready in the second half of 2026.

And James on the cardiac arrhythmia?

Thanks, Rachael. Thank you, Louise. Yes. So I mean, as you've rightly pointed out, I mean, cardiac arrhythmia occurs in roughly 4% of the DM1 population or fatal cardiac arrhythmia in [indiscernible] of the population annually. It's the leading or second leading cause of death in that population. It's tragic, it's not entirely unexpected. Yes, we have done studies with SRP-1001. We had ECG studies in nonhuman primates with no obvious cardiac toxicity and a tenfold safety margin at the highest dose.

Our next question comes from the line of Yanan Zhu with Wells Fargo.

This is [indiscernible] on for Yanan. So on DUX4 gene panel, I know the number is small, but can you comment on the error bar for the placebo group? It seems a little bit high.

Rachael ?

Thanks, Louise. The DUX4 expression is known to be stochastic and episodic in muscle, which introduces inherent biological variability, particularly in the small early phase cohorts. So as a result, the downstream target gene expression can fluctuate in untreated or placebo patients. And so this variability has been well recognized across the field and is often larger than differences attributable to assay platform or normalization strategy. So that is why we are adjusting for placebo approach. And so that's what's shown in the data.

Our next question comes from the line of William Pickering with Bernstein.

Congrats on the data. I have 2, if I may. So the first is on FSHD. To what do you attribute the very large jump in muscle concentration of the drug when you go from 2 MPK to 4 MPK. It looks like it's going from like 5 to 28, which is like a sixfold increase. So do you think that's reliable? And then for DM1, do you have the DMPK knockdown data for the 2 MPK and 3 MPK cohorts? I believe you said it was 50% for the 1 MPK, but just wondering how that data looked like at the higher dose cohorts.

Yes. Rachael, do you want to comment on the increase in the muscle concentration for FSHD?

Yes, happy to. So the muscle concentration in our FSHD program corresponds to what we've seen preclinically. So we were very happy to see that dose-dependent increase with the increasing dose. And importantly, we don't see any saturation demonstrated preclinically or with this early clinical data. So we're very happy to see that. With the preclinical data, also, I want to highlight that we've seen this dose-dependent increase in muscle concentration and the relationship between the knockdown and higher magnitude of effect with the reduction in DUX4 regulated gene. So there's consistency that we're seeing preclinically into the clinical program that gives us confidence in the muscle concentration data here that we're showing.

And James, do you just want to comment on DMPK?

Yes. So as regards to Cohort 2 and Cohort 3, as we said at the start, we have had some issues with sample availability for retesting our validated assays. So we don't have DMPK data currently for -- [indiscernible] insufficient samples. Hopefully, we'll be able to provide more robust, and I'm sure we will have more robust DMPK data later this year from the MAD studies.

Can I just emphasize something that Dr. Richardson made during the presentation that we are in a lower dose, we're seeing already a greater than 50% knockdown placebo adjusted for DMPK, but you will see that it is not on any of our slides. I mean we want you to see that to know that we are seeing a very encouraging effect on knockdown for DM1, which, of course, is exciting. But we don't want you to pivot and anchor to 50%. We're going to have MAD data later this year, and we don't frankly want to set a bar for ourselves that is too high. These are small ends. It's exciting that we're seeing such great knockdown, but really we should wait for the MAD study to get a look at DMP knockdown and the effect of DMP knockdown of multiple doses and multiple dosing. So I say that only because I don't want people to start thinking that that's the beginning, 50%. I want you to wait for the MAD data. But good news. we're seeing a nice significant impact on biomarkers. And then we'll see the full extent of the increase in knockdown as we look at the MAD data across doses and across multiple dosing.

Our next question comes from the line of Gavin Clark-Gartner with Evercore ISI.

I just wanted to follow up on the one death that happened. Could you just give us some more details on how everyone concluded this was unrelated to dosing? And was this on the first dose where this happened? Or was this like a subsequent dose in the MAD? And it's probably worthwhile to share some details on like the patient history of arrhythmia, severity of arrhythmia and maybe just a reminder on ABV6 cardiomyocyte expression.

James?

Yes, sure. Thank you for the question. So I mean we thoroughly investigated this, obviously, as you would expect, as part of our due diligence before acquiring these assets from Arrowhead. We agreed with their independent conclusions and those from the investigator and the coroner who performed an autopsy following the death, this was unrelated to treatment. I think there are really 3 key reasons for this, why we're confident that it was unrelated. I mean, first and foremost, the lack of biological plausibility, particularly at this low dose, single-dose exposure. As you rightly point out, this was the first low-dose cohort of 1.5 mg per kg or roughly 1 mg per kg of siRNA. I think secondly, and importantly, arrhythmia is one of the most, if not the most common causes of death in DM1, an annual fatality of around -- around 4% and some cohorts have reported as a cause of death up to 40% with secondary to cardiac arrhythmia. -- sorry, that would be overall rate. I think thirdly, if you look across the data, we now dosed 60 patients subsequently at increasing doses with this platform across DM1 and FSHD without any further adverse events of arrhythmia without any other concerns from a cardiac perspective. And I think with that and with that data package, because this data -- because this event occurred early, all that data was provided as part of the clinical trial application submitted and reviewed by regulators in Europe, the U.K. and Canada, and all of them subsequently approved the study with the current protocol. The patient in question, apart from having DM1, which as we know, is an extremely strong RISC factor for arrhythmic death had no other indications prior to her passing away, which is not unusual in this disease state. I think there was a follow-on question about alpha-v-beta-6 expression on cardiac tissue. Maybe I could hand that to Rachael.

Thanks, James. The alpha-v-beta-6 integrin ligand does target both skeletal muscles, upper limb and lower limb skeletal muscles as well as the diaphragm and the heart. We have not seen any indication of arrhythmia in nonhuman primates and with ECG studies. we have a highest safety margin at our highest dose of greater than tenfold. So we haven't seen any abuse arrhythmic signs preclinically either.

I'm sorry, let me just jump in to make sure that we've answered one of the parts of the question you had. This was the lowest dose, okay? And it was a single dose. And I know I'm just repeating what Dr. Richardson will say more eloquently, but as someone who's been involved a little bit in this disease. Just remember, 80% of DM1 patients have cardiac involvement, longitudinally, 30% to 40% of DM1 patients have arrhythmia. And for those who are severe patients and as I understand this patient was a severe patient, the RISC in any year of sudden death from arrhythmia is somewhere in the 3% to 5%. So it's not surprising at all that the investigator or the sponsor of the DSMB independent cardiologists all concluded this was unrelated or more importantly related to the disease as obviously, so did the various regulatory bodies who subsequently reviewed this as we went into other regions and dose escalated. And remember, we've dosed a lot of patients since then. So just to be very clear about this, this is -- arrhythmia is associated significantly with DM1 sorry.

And I'm currently showing no further questions at this time. I'd like to hand the call back over to Doug Ingram for closing remarks.

Thank you very much, everyone, and thank you, James, Louis, Rachael, for your answers, and thank you all for your questions. The evidence from our SAD study -- studies in DM1 and FSHD, including exceptional muscle delivery and target engagement and dose and safety validate our decision to acquire this broad platform of siRNA therapies from Arrowhead back in 2024. We will have our next readout for these 2 programs in the second half of this year. We're very excited about that. The data continue to mature, consistent with what we have seen so far. There is a very real possibility that SRP-1001 and SRP-1003 could become best-in-class treatments for both FSHD and DM1, respectively. And that, of course, should drive significant shareholder value. But from my perspective, not only as the CEO of a mission-driven organization, but as someone whose immediate family has been upended by multiple diagnoses of DM1. These data offer far more than that. They offer the potential, the hope of bringing a better freer life to those living with DM1 and FSHD. From personal experience, I cannot adequately express to you the heartbreaking and frightening experience that comes to families with a diagnosis of one of these debilitating muscular dystrophies. But I can at least take some comfort in knowing that with all of the impressive progress made to date by brilliant scientists and by dedicated and passionate organizations, organizations like Avidity and like Dyne and like PepGen and like Sarepta and others, there could be no more hopeful moment in history to get this painful diagnosis. We will fight for DM1 and FSHD communities with the passion that we bring to DMD, and I do look forward to updating you all as we progress across this year. And with that, have a nice day.

This concludes today's conference. Thank you for your participation. You may now disconnect.