Fulcrum Therapeutics' Phase 3 REACH trial evaluating losmapimod for the treatment of facioscapulohumeral muscular dystrophy (FSHD) has failed to meet its primary endpoint. The results, announced recently, revealed that losmapimod did not demonstrate a statistically significant improvement in reachable workspace (RWS), a measure of upper limb function, compared to placebo at week 48 (p-value = 0.75).
The multi-center, randomized, double-blind, placebo-controlled trial enrolled 260 patients with FSHD who were randomized 1:1 to receive either losmapimod (15 mg twice daily) or placebo. In addition to the primary endpoint, secondary endpoints including muscle fat infiltration (MFI), shoulder abductor strength, and patient-reported outcomes also did not achieve nominal statistical significance.
Discontinuation of Losmapimod Program
In light of the disappointing results, Fulcrum Therapeutics has decided to suspend the development of losmapimod for FSHD. This decision marks a significant setback for the company, which had previously observed promising clinical results in a Phase 2 trial. "We are deeply disappointed that the REACH trial did not replicate the clinical results observed in the Phase 2 ReDUX4 trial," said Alex C. Sapir, Fulcrum’s president and chief executive officer.
Unexpected Placebo Response
One notable observation from the REACH trial was the lack of decline in functional status among patients receiving placebo, which contrasted with previous FSHD studies. "In contrast to what was seen in the ReDUX4 study as well as what has been reported in other FSHD studies, the patients receiving placebo in REACH did not show a decline in functional status as measured by RWS and shoulder dynamometry over the 48 weeks of the study," explained Dr. Pat Horn, Fulcrum’s chief medical officer.
Focus Shift to Pociredir and Other Programs
With the losmapimod program on hold, Fulcrum Therapeutics plans to concentrate its resources on advancing pociredir, a small molecule in development for sickle cell disease (SCD), as well as novel therapeutic agents for Diamond-Blackfan Anemia (DBA) and early discovery programs. As of June 30, 2024, Fulcrum had approximately $273.8 million in cash, cash equivalents, and marketable securities.
About FSHD
FSHD is a rare, progressive, and debilitating genetic muscle disorder characterized by muscle weakness primarily affecting the face, shoulders, and upper arms. It affects an estimated 30,000 people in the United States alone, and there are currently no approved treatments for the condition.
Losmapimod's Mechanism of Action
Losmapimod is a selective p38α/β mitogen-activated protein kinase (MAPK) inhibitor. It was initially in-licensed by Fulcrum from GSK following the discovery of the role of p38α/β inhibitors in reducing DUX4 expression, a protein implicated in the pathogenesis of FSHD.
Financial Impact and Future Outlook
The failure of the REACH trial has had a significant impact on Fulcrum Therapeutics' stock price, with shares plummeting by over 60%. Analysts have expressed concerns about the company's future prospects, particularly regarding its ability to generate value from its remaining clinical programs. The company's ability to rebound hinges on the success of pociredir and its other pipeline assets.
