Sarepta Therapeutics (NASDAQ:SRPT) presented preliminary clinical data from ongoing phase I/II studies of two investigational siRNA therapies aimed at facioscapulohumeral muscular dystrophy type 1 (FSHD1) and myotonic dystrophy type 1 (DM1), highlighting early safety findings, drug exposure in plasma and muscle, and initial biomarker effects.
Focus on SRP-1001 (FSHD1): muscle exposure and biomarker effects
Chief Medical Officer Dr. James Richardson said SRP-1001 is designed to reduce production of DUX4 protein in skeletal muscle for patients with FSHD1, a disease driven by abnormal activation of DUX4 that leads to downstream toxic gene misregulation and progressive muscle degeneration. Sarepta described FSHD as a life-limiting muscular dystrophy with no current treatments.
In the SAD portion, Sarepta reported dose-dependent, linear increases in plasma exposure at four dose levels up to an siRNA dose of just over 8 mg/kg. Richardson emphasized that the company views dose escalation without saturation or toxicity as important for muscle-directed therapies. Sarepta also reported a dose-dependent increase in muscle concentration up to an siRNA dose of 4.08 mg/kg.
Richardson said a single dose of SRP-1001 measured 42 days after dosing resulted in a sixfold higher concentration of siRNA in muscle compared with multiple doses of a transferrin-targeting ligand siRNA approach measured 30 days after the last dose, and said Sarepta saw no evidence of receptor saturation. Management framed these findings as supportive of its use of an αvβ6 integrin-targeting ligand intended to enhance delivery to muscle.
On pharmacodynamics, Sarepta presented pooled data from the three lowest SAD dose cohorts showing suppression of DUX4-regulated gene panels (4-, 6-, and 8-gene composite panels). Richardson said suppression was “equal to or in excess of 90%” across panels when adjusted to placebo, which he characterized as the greatest DUX4 gene reduction observed to date in the field. Chief Scientific Officer Dr. Rachael Potter said the three panels were used to capture pathway-level modulation and reduce the impact of variability from individual genes, noting that some genes are more tightly linked to DUX4 activity while others show greater variability.
Sarepta also discussed creatine kinase (CK), describing it as a biomarker of muscle injury and therapeutic effect. Richardson said a pooled analysis of the 4.08 mg/kg and 8.17 mg/kg doses of SRP-1001 versus placebo showed a 33% reduction in CK after a single dose.
FSHD1 safety: no dose-limiting signal to date
On SRP-1001 safety, Richardson said most adverse events were mild to moderate and generally resolved. Sarepta reported one serious adverse event deemed unrelated to treatment: chest discomfort 78 days after a single SRP-1001 dose in a patient with multiple coronary artery disease risk factors, diagnosed by the treating physician as unstable angina or missed acute coronary syndrome. Richardson said there was no discernible dose-dependent or idiosyncratic safety signal, no treatment-emergent adverse events (TEAEs) occurred in 20% or more of patients, and no TEAEs led to death or study drug discontinuation.
In Q&A, Richardson said the company has opened and fully recruited SAD and MAD cohorts up to 8 mg/kg of siRNA in the FSHD program. He also said the MAD study includes a standard set of functional assessments, including Timed Up and Go, Reachable Workspace, six-minute walk test, and measures of muscle strength, while noting that functional changes may require longer-term, larger studies due to the slow progression of FSHD.
SRP-1003 (DM1): early muscle concentration and preliminary knockdown signal
For DM1, Richardson described the disease as the most common adult-onset muscular dystrophy and a multisystem disorder affecting skeletal and smooth muscle, the eye, heart conduction, endocrine and gastrointestinal systems, and the central nervous system. DM1 is driven by expanded repeats in DMPK transcripts, with mutant DMPK mRNA accumulating in the nucleus and disrupting normal RNA splicing.
Sarepta’s SRP-1003-101 study is a first-in-human phase I/II randomized placebo-controlled SAD/MAD trial in participants ages 18 to 65. The company said it currently has data available from cohort 1, focusing on muscle concentration and early evidence of DMPK knockdown.
Richardson said SRP-1003 cohort 1 showed a placebo-adjusted DMPK reduction of “just over 50%,” but he cautioned that due to small sample size and variability, Sarepta plans to defer a definitive assessment until MAD data are available. In a later exchange, management noted that DMPK knockdown was not shown on the slide deck and said it did not want the market to anchor on the early estimate.
Richardson said SRP-1003 also showed dose-dependent increases in plasma exposure. While muscle samples were limited, he said the company expects additional samples later this year to support evaluation of dose-dependent muscle concentrations similar to what was observed in FSHD, given the identical targeting ligand and target organ.
DM1 safety: one unrelated fatal arrhythmia; study continues
Richardson said SRP-1003 has shown a favorable safety and tolerability profile to date, with most adverse events mild to moderate. He said nine adverse events were assessed as related to study drug, all mild and resolved. Sarepta reported one unrelated fatal serious adverse event in cohort 1 due to cardiac arrhythmia several weeks after a single low dose. Richardson said the investigator, sponsor, and an independent coroner each concluded the event was unrelated to SRP-1003 and aligned with known DM1 risks. He also said that after the event, more than 60 patients have been treated with either SRP-1003 or SRP-1001 without a further arrhythmia event or a pattern suggestive of a treatment-related safety signal.
Richardson added that because the fatal event occurred early, it was included in submissions reviewed by regulators in the U.K., EU, and Canada as part of a clinical trial application that was subsequently approved. In response to a question on cardiac risk, he said Sarepta had conducted ECG studies in non-human primates and reported no obvious cardiac toxicity with a tenfold safety margin at the highest dose.
Next data updates and development plans
CEO Doug Ingram and the R&D team repeatedly emphasized that the results are early and limited, with additional cohorts and multi-ascending dose readouts expected later this year. Richardson said Sarepta plans to release additional PK/PD data from currently enrolling MAD cohorts in the second half of the year and noted that assay transitions—from “fit-for-purpose” to validated, regulatory-ready assays—have contributed to missing data where samples were insufficient to rerun. Richardson also said a small number of patients were excluded from analyses due to misdosing from administration errors (he cited three patients in DM1 and a similar number in FSHD).
In discussion of future trials, Richardson said Sarepta believes the “most appropriate way” is to move toward phase III studies in a way that preserves flexibility for multiple regulatory approaches globally. In Q&A, he said Sarepta is preparing for phase III trials in 2027 in both indications, assuming data remain positive.
Management also discussed dosing cadence. Richardson said the current MAD paradigm is every 12 weeks and that Sarepta plans to amend it to every 10 weeks for both FSHD and DM1.
Ingram described SRP-1001 and SRP-1003 as the first clinical readouts from Sarepta’s Arrowhead partnership and said updated data from both programs would be presented in the second half of the year.
About Sarepta Therapeutics (NASDAQ:SRPT)
Sarepta Therapeutics, Inc is a biopharmaceutical company focused on the discovery and development of precision genetic medicines for rare neuromuscular diseases. Headquartered in Cambridge, Massachusetts, Sarepta’s core expertise lies in designing RNA-targeted therapies and gene therapies that address underlying genetic mutations. The company’s mission is to transform the treatment paradigm for patients with Duchenne muscular dystrophy (DMD) and related disorders through innovative modalities.
Sarepta’s commercial products include several exon-skipping therapies approved by the U.S.
