Fulcrum Therapeutics Reports Phase 3 REACH Trial Results for Losmapimod in FSHD

Fulcrum Therapeutics, Inc., a clinical-stage biopharmaceutical company focused on genetically defined rare diseases, announced that its Phase 3 REACH trial evaluating losmapimod in patients with facioscapulohumeral muscular dystrophy (FSHD) did not meet its primary endpoint. The trial aimed to assess the efficacy of losmapimod by measuring the change in Reachable Surface Area (RSA) from baseline compared to a placebo. Unfortunately, the results showed no significant improvement with losmapimod.

The trial also evaluated secondary endpoints, which also did not achieve nominal statistical significance. Despite the lack of efficacy, the safety and tolerability profile of losmapimod remained consistent with previous studies. Fulcrum plans to conduct a thorough analysis of the trial data and will present the findings at a future medical conference.

Alex C. Sapir, Fulcrum’s president and CEO, expressed disappointment that the REACH trial did not replicate the promising results observed in the earlier Phase 2 ReDUX4 trial. As a result, the company will suspend further development of losmapimod for FSHD. Sapir extended gratitude to the patients, their families, investigators, the FSHD Society, and the broader FSHD community for their support.

The study featured several key findings: Participants receiving losmapimod demonstrated a slight improvement in RSA at week 48 compared to placebo, but the difference was not statistically significant (p-value = 0.75). Muscle Fat Infiltration (MFI), measured via MRI, showed a small increase in both the losmapimod and placebo groups, with no significant difference between them (p-value = 0.16). Shoulder abductor strength, measured by hand-held dynamometry, improved by 9.63% in the losmapimod group versus 2.24% in the placebo group, but again, this was not statistically significant (p-value = 0.51). Patient-reported outcomes also showed no significant differences.

Dr. Pat Horn, Fulcrum’s chief medical officer, noted that while the results were similar to those seen in the Phase 2 study, the placebo group in the REACH trial did not show a decline in functional status over the 48 weeks, contrary to previous expectations. He emphasized the importance of sharing the full trial results with the broader FSHD community to aid future research and development efforts.

Fulcrum Therapeutics reported having approximately $273.8 million in cash, cash equivalents, and marketable securities as of June 30, 2024. These resources will be redirected to advance other therapeutic programs, including pociredir for the treatment of sickle cell disease (SCD) and novel agents for Diamond-Blackfan Anemia (DBA).

The REACH trial (NCT05397470) was a Phase 3 multi-center, randomized, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of losmapimod in treating FSHD. A total of 260 patients were enrolled and randomized 1:1 to receive either losmapimod or a placebo over 48 weeks. The primary endpoint was the change in Reachable Workspace (RWS) from baseline, with secondary endpoints including Muscle Fat Infiltration (MFI), shoulder abductor strength, and patient-reported outcomes.

Losmapimod, a selective p38α/β mitogen-activated protein kinase (MAPK) inhibitor, was exclusively in-licensed by Fulcrum from GSK. It had previously been evaluated in over 3,600 subjects across various indications, with no safety concerns attributed to it. Losmapimod received Fast Track and Orphan Drug Designations from the U.S. FDA for the treatment of FSHD.

FSHD is a severe, rare, progressive muscle-wasting disease with no approved treatments. It primarily affects the face, scapula, shoulders, upper arms, and abdomen, leading to significant muscle loss and disability. An estimated 30,000 individuals in the United States are affected by FSHD.

Fulcrum Therapeutics continues to focus on developing therapies for genetically defined rare diseases with high unmet needs. Its leading programs include losmapimod for FSHD and pociredir for SCD, aiming to modulate gene expression to treat underlying causes of these conditions.