Fulcrum halts losmapimod development

Fulcrum halts losmapimod development

by June Kinoshita

This morning, we received news Fulcrum has decided to halt its development of losmapimod (see press release below). Fulcrum’s decision was based on analysis of data from the Phase 3 REACH trial.

The REACH data reported small improvements in Reachable Workspace (RWS) not only in people taking the drug but in those taking placebo. This contradicts data from more than five years of natural history studies of FSHD, which have never shown an improvement in RWS in untreated individuals. The Phase 2 ReDUX4 trial of losmapimod showed a decline in the placebo group versus improvement in the treated group. In addition, the Open-Label Extension (OLE) study showed sustained benefits of losmapimod up to 96 weeks in those who were on the drug in ReDUX4, and stable symptoms or improvements for those from the placebo group who began taking losmapimod after the ReDUX4 trial ended.

It will be important to dive deeper into REACH data before broader conclusions can be made. For example:

• • Was the REACH cohort different at baseline (the start of the trial) than the ReDUX4 cohort?
  • In ReDUX4, scores from each participant’s dominant arm and non-dominant arm were analyzed separately and showed a larger effect in the non-dominant arm.
  • In contrast, the REACH analysis combined the scores from both arms.
  • What impact did this have on the outcome?

The Society looks forward to exploring the data further with Fulcrum. We’ll be following developments closely and report back.

What does this mean for our community?

For patients, it’s important to remember that there are many promising therapies in development. Losmapimod reduced DUX4 through an indirect pathway. Other companies, such as Avidity Biosciences, Dyne Therapeutics, Arrowhead Pharmaceuticals, and miRecule, are pursuing approaches that knock down DUX4 directly. Avidity’s interim data are already highly encouraging, and the company plans to begin recruiting participants for the next set of clinical trials later this year and next spring.

Though this is a setback, there will be important lessons to learn, and Fulcrum’s work puts us closer to treatment. 

Fulcrum’s press release

CAMBRIDGE, Mass., Sept. 12, 2024 (GLOBE NEWSWIRE) — Fulcrum Therapeutics, Inc.^® (the “Company”) (Nasdaq: FULC), a clinical-stage biopharmaceutical company focused on developing small molecules to improve the lives of patients with genetically defined rare diseases, today announced that its Phase 3 REACH trial evaluating losmapimod in patients with FSHD, did not achieve its primary endpoint of change from baseline in RSA with losmapimod compared to placebo. In addition, secondary endpoints did not achieve nominal statistical significance. The safety and tolerability profile of losmapimod was consistent with previously reported studies. The Company will complete a full evaluation of the data it received this week and plans to share the results at an upcoming medical meeting.

“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. “In light of these results, we plan to suspend the losmapimod program in FSHD. We would like to thank the FSHD patients who participated in losmapimod clinical trials, their families, the investigators, the FSHD Society, and the broader FSHD community for their unwavering support for this program.”

Top-line REACH study results:

• Reachable Workspace (RWS): Participants receiving losmapimod demonstrated a 0.013 (±0.007) improvement in RSA at week 48 compared to placebo patients who showed a 0.010 (±0.007) improvement in RWS (p-value = 0.75).
• Muscle Fat Infiltration (MFI) as measured by Magnetic Resonance Imaging (MRI): Participants receiving losmapimod demonstrated an increase of 0.42% in MFI at week 48 compared to participants receiving placebo who showed an increase of 0.576% in MFI (p-value = 0.16).
• Shoulder Abductor Strength as measured by Hand-Held Dynamometry: Participants receiving losmapimod demonstrated a 9.63% improvement in abductor strength at week 48 compared to a 2.24% improvement in abductor strength seen in the placebo arm of the study (p-value = 0.51).
• Patient Reported Outcomes (PRO): Across the two PRO secondary endpoints in the REACH study, Patient Global Impression of Change (PGIC) and the Neuro QoL Upper Extremity, there were no statistically significant differences observed.
• Safety and Tolerability: The rate of treatment-related adverse events was similar in the two treatment arms, and there were no treatment-related serious adverse events in participants receiving losmapimod.

“These results in patients receiving losmapimod when compared to baseline were similar to those observed in our Phase 2 study,” said Dr. Pat Horn, Fulcrum’s chief medical officer. “However, 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. As the largest interventional study ever completed in FSHD, we intend to share the full trial results with patients, study investigators, and the broader FSHD community to ensure others developing treatments for FSHD can benefit from these data.”

See the full press release from Fulcrum