Early trial data support RNA therapies for two muscular dystrophy types
Sarepta treatments show muscle delivery and early biomarker signals
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SRP-1001 and SRP-1003, Sarepta Therapeutics’ investigational RNA-based therapies for two types of muscular dystrophy, were generally well tolerated in early results, according to data from two Phase 1/2 trials.
SRP-1001, for facioscapulohumeral muscular dystrophy type 1 (FSHD1), and SRP-1003, for myotonic dystrophy type 1, showed high levels of delivery to muscle in early company-reported data. Biomarker analyses in the FSHD1 trial also suggested target engagement and a possible treatment effect.
The two trials — SRP-1001-101 (NCT06131983) in FSHD1 and SRP-1003-101 (NCT06138743) in DM1 — are assessing the safety, tolerability, and pharmacological properties of the experimental treatments. SRP-1001 is being tested in patients ages 16 to 70, while SRP-1003 is being tested in adults ages 18 to 65. Both clinical studies may still be recruiting participants in multiple countries.
Early results show siRNA delivery to muscle in both studies
“We are pleased that these early clinical results showed high levels of siRNA delivery to muscle,” Louise Rodino-Klapac, PhD, president, research and development and technical operations at Sarepta, said in a company press release. “We believe this supports the differentiated potential of this siRNA platform and strengthens our belief that this approach could meaningfully change the treatment landscape for patients with FSHD and DM1.”
FSHD1 and DM1 are genetic disorders characterized by progressive muscle weakness and wasting. In FSHD1, an abnormal shortening of the D4Z4 region of chromosome 4 leads to activation of the DUX4 gene and production of the DUX4 protein. In DM1, disease-causing mutations in the DMPK gene cause the production of an abnormally long messenger RNA molecule that forms toxic clumps in cells, interfering with normal cellular processes. Messenger RNA is a temporary molecule that carries genetic information used to make proteins.
Both SRP-1001, previously known as ARO-DUX4, and SRP-1003, previously known as ARO-DM1, consist of a small interfering RNA (siRNA), a small piece of genetic material designed to bind to a target messenger RNA and trigger its breakdown. The therapies are designed to enter muscle cells, where they can be taken up into structures inside cells that help prolong their activity, according to Sarepta. They also feature an alpha-v-beta-6 integrin-targeting ligand (binding molecule) to help deliver the treatment to muscle cells.
Sarepta acquired the exclusive rights to SRP-1001 and SRP-1003 from Arrowhead Therapeutics, which is sponsoring the ongoing trials.
Both trials are composed of two parts. In the first part, patients are randomly assigned to receive a single ascending dose of the treatment or a placebo. In the second part, participants receive multiple treatment doses.
Early data suggest dose-related increases in drug levels
Early results showed dose-dependent increases in blood and muscle siRNA levels. Both treatments were generally well tolerated. Most adverse effects were mild to moderate and did not appear to increase at higher doses.
The most common adverse events were headache and upper respiratory tract infection. Serious adverse events were reported but were not considered related to the treatments, and no participants stopped treatment due to side effects.
In the FSHD1 study, a single dose of the treatment was associated with a 33% reduction in blood levels of creatine kinase, a marker of muscle damage, after 42 days compared with placebo. Results also showed suppression of DUX4-regulated genes after a single dose, indicating target engagement.
“These preliminary clinical data show consistent dose-dependent increases in [blood] and muscle drug exposures across clinical and nonclinical studies and suggest that the [alpha-v-beta-6] integrin-targeting ligand mediates robust siRNA muscle delivery, which we hypothesize will ultimately enable higher dosing and translate into clinical efficacy for patients with FSHD1 and DM1,” Rodino-Klapac said.
