Written By: Pharmacally Medical News Desk
Sarepta Therapeutics has announced important progress in its Phase 1/2 trial of SRP‑1003, an investigational siRNA therapy for myotonic dystrophy type 1 (DM1), including completion of early dosing cohorts, ongoing escalation to higher doses, and triggering of a major milestone payment to Arrowhead Pharmaceuticals. The company expects to advance to a final high‑dose cohort in early 2026, positioning the program for key preliminary readouts and strategic decisions in the coming year.
Background on DM1 and SRP‑1003
Myotonic dystrophy type 1 (DM1) is the most common adult‑onset muscular dystrophy, caused by a CTG repeat expansion in the DMPK gene that produces an abnormally long, toxic messenger RNA (mRNA) leading to multi‑systemic symptoms including muscle weakness, myotonia, cardiac issues, and respiratory problems. SRP‑1003 (formerly ARO‑DM1) is a small interfering RNA (siRNA) designed to selectively reduce expression of the mutant DMPK mRNA, with the goal of decreasing these toxic RNA aggregates and modifying the underlying disease biology rather than only treating symptoms.
Phase 1/2 study design and dose‑escalation status
SRP‑1003 is being evaluated in an ongoing Phase 1/2 multiple‑ascending‑dose (MAD) clinical study in adults with DM1, structured around sequential dosing cohorts to assess safety, tolerability, pharmacokinetics, and pharmacodynamics target engagement across increasing dose levels. The trial has completed cohort 1 at 1.5 mg/kg and cohort 2 at 3 mg/kg, with cohort 3 at 4.5 mg/kg fully enrolled and ongoing, following a pre‑specified review by an independent drug safety committee that has allowed progression to higher‑dose cohorts.
According to Sarepta, patients are now being dosed in cohort 4 at 6 mg/kg, and the company plans to initiate dosing in the final planned cohort, cohort 5 at 12 mg/kg, in early 2026, reflecting continued confidence in the emerging safety and tolerability profile as exposure increases. The study is designed to generate initial signals on DMPK knockdown and downstream biomarkers, along with early functional and clinical measures, to inform dose selection and the structure of subsequent, potentially registrational studies.
Milestone payment and Arrowhead collaboration
Progress in enrollment and dosing has allowed Sarepta to achieve the second pre‑specified development milestone in the Phase 1/2 program, triggering a $200 million payment to Arrowhead Pharmaceuticals under the companies’ existing licensing and collaboration agreement. Arrowhead, which originally developed ARO‑DM1 (now SRP‑1003), has confirmed receipt of this $200 million milestone tied to meeting the second enrollment and development target in the ongoing study.
This latest milestone follows an earlier $100 million payment activated in July 2025 when the trial first reached a prior enrollment and safety milestone, underscoring the strategic value both companies place on SRP‑1003 as a potentially disease‑modifying therapy for DM1. The collaboration also includes broader rights for Sarepta to advance additional RNA interference‑based therapies for skeletal‑muscle and central nervous system disorders, creating a multi‑asset partnership beyond SRP‑1003 alone.
SiRNA platform and broader neuromuscular pipeline context
SRP‑1003 is part of Sarepta’s next‑generation siRNA platform focused on chronically administered therapies for neurodegenerative and pulmonary diseases that require sustained target suppression.
The siRNA pipeline includes additional investigational programs for:
Facioscapulohumeral muscular dystrophy (FSHD),
Spinocerebellar ataxia type 2 (SCA2)
Idiopathic pulmonary fibrosis (IPF),
Huntington’s disease (HD), with preclinical efforts underway in SCA1 and SCA3.
Sarepta’s strategic vision is to complement its established Duchenne muscular dystrophy (DMD) portfolio, including gene therapy and exon‑skipping approaches, with RNAi‑based candidates like SRP‑1003 that can tackle distinct genetic mechanisms in other rare neuromuscular diseases. The company emphasizes that the siRNA platform is intended for chronic administration, aiming for durable target knockdown with infrequent dosing while maintaining an acceptable long‑term safety profile in conditions that often require lifelong treatment.
Anticipated data timelines and future development plans
Sarepta has indicated that preliminary data from the SRP‑1003 Phase 1/2 trial are expected in the second half of 2025, providing the first human proof‑of‑concept for DMPK knockdown and potential early clinical signals in DM1. These initial readouts will likely include safety and tolerability across dose levels, pharmacokinetic parameters, measures of DMPK mRNA reduction, and exploratory functional outcomes, and will help guide dose selection and design for larger, longer‑term efficacy studies.
Reference
Sarepta Provides Progress Update for SRP-1003, its Investigational siRNA treatment for Myotonic Dystrophy Type 1, 24 November 2025, Sarepta Therapeutics, https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-provides-progress-update-srp-1003-its-investigational