How Fulcrum Therapeutics’ Phase 3 REACH Clinical Trial Will Continue to Power the Path Forward 

Author: Ashley Ferreira, FSHD Society 

The REACH Phase 3 clinical trial, conducted by Fulcrum Therapeutics, aimed to evaluate the efficacy of losmapimod in treating facioscapulohumeral muscular dystrophy (FSHD). Despite promising results in earlier phases, the trial did not meet its primary endpoint, leading to the discontinuation of the program in September 2024. The recent post-mortem analysis of Fulcrum Therapeutics’ Phase 3 REACH clinical trial, presented by Dr. Jeffrey Statland, offers valuable insights into the challenges and future directions in treating FSHD. Despite the trial’s early termination due to not meeting its primary endpoint, the findings contribute significantly to the understanding of FSHD and the development of potential therapies.  

 

Understanding the REACH Trial 

In the REACH trial, 260 participants aged 18–65 with genetically confirmed FSHD were randomized to receive either losmapimod or a placebo over 48 weeks. Losmapimod was hypothesized to reduce the loss of muscle mass, preserve muscle function, and slow disease progression by inhibiting DUX4 expression, a gene implicated in FSHD pathology. The primary measure was the change in reachable workspace (RWS), assessing upper limb mobility. Secondary measures included muscle fat infiltration (MFI) via MRI, shoulder strength, and patient-reported outcomes.  

 

Key Findings and Challenges 

While losmapimod demonstrated target engagement and was generally well-tolerated, the trial did not achieve its primary endpoint. Several factors contributed to this outcome: 

• Heterogeneity in DUX4 Expression: Muscle biopsies revealed significant variability in DUX4-driven gene expression among patients, complicating the assessment of losmapimod’s efficacy.  

• Outcome Measure Sensitivity: The RWS assessment, while innovative, may not have been sensitive enough to detect subtle functional improvements over the study period. 

• Unexpected Stability in Placebo Group: Contrary to expectations based on previous studies, participants in the placebo group did not exhibit the anticipated decline in functional status over the 48-week study period. This stability in the placebo group made it more challenging to detect any potential benefits of losmapimod, as the lack of deterioration in the control group reduced the observable difference between the treatment and placebo arms. 

• Disease Progression Variability: FSHD progression varies widely among individuals, making it challenging to measure treatment effects within a relatively short trial duration. 

 

Impact on Future FSHD Research  

The REACH trial’s outcomes underscore the challenges in developing treatments for rare diseases like FSHD. Despite the trial’s discontinuation, the REACH study provides critical lessons for future FSHD research and the knowledge gained lays the groundwork for future studies and therapeutic strategies. 

• Enhanced Understanding of Outcome Measures: The trial’s use of the Reachable Workspace (RWS) as a primary endpoint highlighted challenges in measuring functional improvements in FSHD patients. The lack of significant differences between the losmapimod and placebo groups suggests a need to reassess and refine outcome measures to better capture subtle changes in muscle function over time. The need for reliable biomarkers to assess disease activity and treatment response is evident. 

• Importance of Placebo Group Data: An unexpected stability in the placebo group underscored the variability in disease progression among FSHD patients. This finding stresses the necessity of understanding natural disease trajectories to design more effective trials and interpret results accurately. 

• Data Sharing for Continued Research: Recognizing the value of the collected data, Fulcrum Therapeutics has agreed to transfer the trial data and biospecimens to the FSHD Society. This move ensures that researchers have access to a rich dataset, including MRI imaging, muscle strength assessments, and patient-reported outcomes, facilitating further analyses and hypothesis generation.  

• Guidance for Future Trial Designs: The REACH trial’s outcomes provide critical insights into trial design, including patient selection, endpoint determination, and duration. These lessons will inform the structure of future studies, aiming to enhance their sensitivity and relevance to patient experiences.
  

Conclusion 

The REACH trial’s findings underscore the complexities of developing therapies for FSHD but also highlight the progress made in understanding the disease. The knowledge gained will inform the design of future studies, bringing the scientific community closer to effective treatments for FSHD. 

 

About Dr. Jeffrey Statland 

Dr. Jeffrey M. Statland is a Professor of Neurology at the University of Kansas Medical Center in Kansas City, Kansas. His research focuses on neuromuscular diseases, particularly FSHD, and he serves as a principal investigator for several clinical studies aimed at developing effective therapies  

For a more detailed discussion of the REACH trial’s findings, you can watch Dr. Statland’s presentation here.