Simply Stated: Updates in Facioscapulohumeral muscular dystrophy (FSHD)

Facioscapulohumeral muscular dystrophy (FSHD) is a genetic disorder that may affect all muscles across the lifespan of an individual. While FSHD has historically been detected in muscles in the face (facio), shoulders (scapulo), and upper arms (humeral), new data derived from AI analysis of whole-body MRI scans challenges the historical view that FSHD is limited to specific muscle groups. FSHD is one of the most common forms of muscular dystrophy, affecting about 1 in 8000 people.

Symptoms of FSHD

The onset, severity, symptoms, and rate of progression of FSHD can vary widely between individuals. Most people with FSHD begin experiencing symptoms by their teens or twenties, however, a small number show symptoms in infancy. Muscle weakness begins in the face, shoulders, and upper arms, often in an asymmetric pattern, before slowly progressing to other muscle groups. Some people with FSHD experience “extra-muscular” symptoms, such as hearing loss and weakness in the eyelids. About 20% of people with FSHD experience more severe disease leading to wheelchair dependence. FSHD does not, however, typically affect life expectancy.

Cause of FSHD

FSHD is caused by genetic changes that cause inappropriate expression of the DUX4 gene. This creates a toxic environment in muscles that result in cell death and progressive weakness and atrophy (loss) of muscles throughout the body.

Additional reading and resources about FSHD

For a clear introduction to signs, symptoms, and genetic basis of FSHD, see the earlier post Simply Stated: Research Updates in Facioscapulohumeral Muscular Dystrophy (FSHD). For a more detailed overview, consult the updated review article by Preston and Wang (July 2025). Additional information and resources are also available through the FSHD Society website.

Current management of FSHD

An FSHD diagnosis is typically based on a combination of clinical symptoms and genetic testing. Once a diagnosis has been obtained, therapies and strategies are available to help manage the symptoms and improve the overall health of people with FSHD. Based on their symptoms, physical therapy, occupational therapy, exercise regimens, assistive devices (e.g., orthotics), medications (e.g., corticosteroids), and sometimes surgery (for contractures) may be recommended for people with FSHD.

Disease-modifying therapies for FSHD are not yet available; however, genetic and RNA-based approaches are in clinical trials. Among these, RNA-based therapies are further along in development and showing promising signs of efficacy.

Evolving treatment landscape

While the standard of care is still symptom management, research advances and the promise of better therapeutics on the horizon offer hope for people living with FSHD. Understanding of the genetic elements that cause FSHD have led to improved diagnosis and are guiding the development of new treatment strategies. The following is a selection of promising therapies currently in clinical development, though is not a complete list.

DUX4-targeting therapies

ARO-DUX4 (Arrowhead Pharmaceuticals) – An RNA interference (RNAi) therapy designed to silence DUX4 mRNA. A phase 1/2a dose-escalation study in adults (ARODUX4-1001) has been initiated in Australia, New Zealand, and Thailand, and is currently recruiting participants. In November 2024, Sarepta acquired the rights to ARO-DUX4 and will lead its future phase 3 development and eventual commercialization.

Clenbuterol (University of Kansas Medical Center) – A small molecule, classified as a β2-adrenergic agonist, that was shown preclinically to suppress DUX4 expression. Clenbuterol is approved in some European countries to treat the respiratory disease COPD. It is now being studied in a phase 1 trial that is recruiting participants in several states to examine its safety and tolerability in people with FSHD.

Delpacibart braxlosiran (Del-brax or AOC 1020) (Avidity Biosciences) – A targeted therapy that links an antibody to siRNA (small interfering RNA) to block DUX4 gene expression. The phase 1/2 FORTITUDE trial of del-brax showed favorable safety and tolerability, reductions (greater than 50%) in DUX4-regulated gene expression, and signals of improved muscle function in treated participants. The sponsor is pursuing accelerated FDA approval based on these positive results. A confirmatory phase 3 trial (FORWARD or FORTITUDE-3) is now underway and enrolling participants at about 45 global sites across the U.S., Canada, Europe, and Japan.

EPI-321 (Epicrispr Biotechnologies) – A single-dose therapy that uses a CRISPR-based genome editing system to silence the DUX4 gene by adding a methyl group to the DNA. A first-in-human phase 1/2 trial of EPI-321 began in August 2025, with initial data expected in early 2026. This trial is currently recruiting participants.

Muscle growth therapies

RO7204239 (Hoffmann-La Roche) – An anti-myostatin antibody designed to increase muscle mass and strength. A phase 2 trial (MANOEUVRE) of R07204239 in people with FSHD is active, but  not recruiting participants.

Umbilical cord lining-derived (ULSC) stem cell product (Restem, LLC) – This therapy aims to regenerate or replace damaged muscle cells using stem cells. A phase 1 trial is planned, but not yet recruiting participants.

These various therapies are still in the early stages of development and may not be available for widespread use for some time. They represent promising areas of research, however, that could lead to new and effective treatments for FSHD.

Insights from past therapeutic efforts

Losmapimod (Fulcrum Therapeutics) – A small molecule that inhibits the p38MAPK enzyme, thereby reducing expression of the DUX4 gene. Although early studies were promising, the phase 3 REACH trial of losmapimod did not meet its primary or secondary endpoints, including shoulder and proximal arm mobility (reachable workspace), and the program was discontinued in September 2024. Although the program was discontinued, the REACH trial provided critical knowledge for designing more effective trials, selecting appropriate endpoints, and accurately interpreting treatments effects. The trial highlighted that current outcome measures, such as reachable workspace, may not be sensitive enough to capture subtle changes in muscle function. Furthermore, the unexpected stability in the placebo group underscored the need to further understand the natural history of the disease.

Natural history studies

The limitations of clinical trials such as the REACH trial have elevated the importance of natural history studies, which aim to clarify how the disease evolves over time and to validate outcome measures and biomarkers that can strengthen future clinical trials. Two notable efforts include:

MOVE and MOVE+ (University of Kansas Medical Center) – The largest natural history studies of FSHD to date, designed to track how the disease affects muscles, movement, and daily life, while generating data to improve clinical trial design and patient care. Participants in MOVE and MOVE+ need to complete at least three visits over three years with strength tests, movement assessments, and questionnaires. MOVE+ also includes tests such as blood/saliva samples, MRI, and biopsy, and is limited to adults aged 18–75 with lower leg weakness who can walk 30 meters without assistance. The studies are currently enrolling participants in about 20 sites across the U.S., Canada, the U.K., and Brazil.

MDA’s work to further cutting-edge FSHD research

Since its inception, MDA has invested more than $27 million in FSHD research. Strategic investments from MDA and other advocacy organizations, alongside support from the National Institutes of Health (NIH), are accelerating FSHD research and offering new hope for people living with the disease.

MDA’s Resource Center provides support, guidance, and resources for patients and families, including information about facioscapulohumeral muscular dystrophy, open clinical trials, and other services. Contact the MDA Resource Center at 1-833-ASK-MDA1 or ResourceCenter@mdausa.org.