Sarepta Reports Encouraging Clinical Data from siRNA Pipeline for FSHD1 and DM1

Rare Daily Staff

Sarepta Therapeutics reported the first human data from two experimental RNA-based drugs for rare muscle diseases, saying early trial results show the medicines reached muscle tissue at high levels without causing serious side effects that would limit dosing.

The preliminary findings come from ongoing phase 1/2 studies of SRP-1001 in facioscapulohumeral muscular dystrophy type 1, or FSHD1, and SRP-1003 in myotonic dystrophy type 1, or DM1, two inherited conditions that gradually weaken muscles and currently have no approved treatments that slow or halt disease progression.

Sarepta said the drugs showed dose-dependent exposure in muscle, early signs they are affecting biological markers of disease, and a safety profile in which most side effects were mild to moderate and did not worsen with higher doses.

In both studies, a single dose of the experimental medicines led to a reduction of their genetic targets — either a disease-driving protein or the messenger RNA that carries its genetic instructions — providing proof of concept that the company’s delivery technology can get small interfering RNA, or siRNA, into muscle cells.

Facioscapulohumeral muscular dystrophy is a rare genetic disorder that causes progressive weakness in skeletal muscles, often beginning in the face, shoulders, and upper arms before involving the abdomen, hips, and legs. The disease is driven by abnormal activation of a gene called DUX4 on chromosome 4, which leads to production of a toxic protein that damages muscle cells and causes them to degenerate. Symptoms and severity can vary widely, but many people with FSHD eventually have difficulty lifting their arms, walking long distances, or performing everyday tasks, and there is currently no cure or disease-modifying therapy.

SRP-1001 is an investigational siRNA medicine designed to reduce production of the DUX4 protein in skeletal muscle, with the goal of slowing or preventing the muscle damage seen in FSHD1. The drug is being tested in a randomized, placebo-controlled phase 1/2 trial known as Study 1001-101 that includes both single-ascending-dose and multiple-ascending-dose cohorts in participants ages 16 to 70. Sarepta said the therapy uses optimized siRNA chemistry linked to a proprietary targeting molecule that binds to a protein called αvβ6 integrin on the surface of cells, helping the drug enter muscle tissue more efficiently.

Myotonic dystrophy type 1 is the most common form of muscular dystrophy that starts in adulthood and is caused by an expanded DNA repeat in the DMPK gene. It is a progressive, multisystem disease that affects skeletal and smooth muscles, as well as the heart, lungs, eyes, endocrine system, digestive tract, and brain, and is often associated with muscle weakness, daytime sleepiness, breathing problems, and heart rhythm abnormalities. As with FSHD1, there are no approved treatments that address the underlying cause of DM1, and current care focuses on managing symptoms and complications over time.

SRP-1003 is an experimental siRNA treatment designed to bind to and silence DMPK messenger RNA, which contains the expanded repeat that drives DM1, in an effort to reduce the toxic RNA buildup that underlies the disease. The drug is being studied in SRP-1003-101, a first-in-human phase 1/2 trial that includes single and multiple ascending doses and randomly assigns adults ages 18 to 65 with DM1 to receive SRP-1003 or placebo.

Like SRP-1001, SRP-1003 uses Sarepta’s αvβ6 integrin-targeted delivery system, which the company says may allow higher dosing and more effective targeting of muscle while avoiding some of the safety and delivery challenges seen with other RNA-based approaches.

Sarepta’s siRNA platform, licensed from Arrowhead Pharmaceuticals, is aimed at chronic treatments for neurodegenerative, muscle, and lung diseases and currently includes five named drug candidates: SRP-1001 for FSHD, SRP-1002 for idiopathic pulmonary fibrosis, SRP-1003 for DM1, SRP-1004 for spinocerebellar ataxia type 2, and SRP-1005 for Huntington’s disease. The company is also advancing earlier-stage programs for spinocerebellar ataxia types 1 and 3 and other muscle or central nervous system disorders.

“We are pleased that these early clinical results showed high levels of siRNA delivery to muscle, with no saturation of muscle siRNA uptake or dose-limiting safety signals to date,” said Louise Rodino-Klapac, Sarepta’s president of research, development, and technical operations. She said the data strengthen the company’s belief that the platform could “meaningfully change the treatment landscape” for people with FSHD1 and DM1.

Photo: Louise Rodino-Klapac, Sarepta’s president of research, development, and technical operations.