By June Kinoshita, Director of Research and Patient Engagement
“Positive benefit/risk supports losmapimod’s potential to be a transformative therapy for the treatment of FSHD”—Fulcrum Therapeutics
Fulcrum Therapeutics announced today that losmapimod, its experimental therapy for facioscapulohumeral muscular dystrophy, produced statistically significant improvements in function and decreased fatty infiltration of muscle in its ReDUX4 clinical trial. ReDUX4 was a randomized, double-blind, placebo-controlled Phase 2b clinical trial in 80 participants. The trial was conducted in multiple sites internationally and was designed to investigate the efficacy and safety of losmapimod taken in 15-mg pills twice per day. Based on today’s results, Fulcrum said it “plans to meet with health authorities, including the U.S. Food and Drug Administration (FDA), in the second half of 2021 to determine the regulatory path for losmapimod in FSHD.”
ReDUX4 looked at a variety of indicators of patient physiology and function, including muscle biopsies, magnetic resonance imaging (MRI), muscle strength and function, and patient questionnaires. Some of these measures included tools, such as MRI-informed biopsies to look for genes activated by DUX4 (the gene that causes FSHD), whole-body MRI, reachable workspace (RWS), and FSHD timed-up-and-go (FSHD TUG), which were developed in preparation for this trial. The COVID pandemic forced Fulcrum to extend its trial from 24 to 48 weeks—enabling the collection of additional data that allowed these positive outcomes to be more clearly demonstrated.
Other companies will be keenly interested in Fulcrum’s data because they indicate which outcome measures are the most robust for future FSHD clinical trials. They will also help trial researchers model the number of patients and duration of trial needed to demonstrate the effect of future drug candidates.
The entire FSHD community owes deep gratitude to the patients, caregivers, researchers, clinicians, funders, and advocacy groups that have brought us to this milestone.
What did the data show?
There’s a lot to take in so we created this summary table:
What does this mean for future FSHD trials?
The primary endpoint—a change in DUX4-driven gene expression—was negative. Isn’t that bad? Not necessarily. It is disappointing, but hardly fatal. Analyzing muscle tissue from needle biopsies seemed promising in the laboratory. But in the actual trial, it proved to be challenging. DUX4 is expressed unpredictably and in only 1 in 1,000 muscle nuclei. It is the proverbial needle in a haystack. “We were pretty confident this drug would have effects on DUX4,” said Christopher Morabito, MD, chief medical officer at Fulcrum, but “were unable to see DUX4-driven gene expression due to the fact that it is stochastic and sparse.” Failing to meet the primary endpoint does not mean that the drug did not reduce DUX4 expression, only that the method used was not robust enough to show it.
The secondary endpoints were included in the trial to gather preliminary data on whether losmapimod might show some clinically meaningful benefit—which is what the FDA ultimately wants to see. Such endpoints were assumed to be too high a bar for a phase 2 trial. Ironically, it is these secondary endpoints that turned out to show a significant change. That’s what we mean when we say this trial exceeded expectations. In sports terms, we hoped to hit a single but ended up hitting a double or maybe even a triple.
Importantly, slowing or stopping progression, as these ReDUX4 data indicate, is the highest priority for patients, as determined from our Voice of the Patient Report. Fulcrum referenced the report in their presentation and said this consideration “was front and center” in their approach to designing the trial.
Judging from the FDA’s recent accelerated approval of Biogen’s Aduhelm treatment for Alzheimer disease, losmapimod has a very strong case in our opinion to receive accelerated approval as well. Aduhelm was approved on the basis of changes to brain amyloid (which is a controversial biomarker for AD) despite the lack of any functional improvement. In contrast, there is a strong scientific consensus on the central role of DUX4 in FSHD and on losmapimod’s ability to reduce DUX4 expression, and Fulcrum was able to show meaningful benefit to patients. And as we mentioned above, meaningful benefit is the gold standard for the FDA.
If losmapimod were to receive accelerated approval so that the drug can be marketed, the FDA would likely still require a post-market clinical trial to gather more robust data on the drug’s clinically meaningful benefits. It’s unlikely that the trial would require the collection of muscle biopsies, as biomarker data in a phase 3 trial would not carry weight with regulatory agencies.
What does this mean for people with FSHD?
There are still hoops to jump through before people will be able to get a prescription for losmapimod. Fulcrum needs to meet with regulators and determine its path forward. The FDA (and in Europe, the EMA) needs to review the data and make a decision on whether to grant an accelerated approval or require additional clinical trials before allowing losmapimod onto the market. The fact that losmapimod has been given a Fast Track designation is like getting TSA Pre-check to get through airport security screening faster.
Fulcrum is evaluating all populations, including children and individuals who were excluded from the ReDUX4 trial, and “working with regulators to find the best path forward to get losmapimod to patients as quickly as possible,” said Michelle Mellion, senior medical director at Fulcrum. Here’s the company’s expanded access policy, which explains what types of patients are eligible and the process for requesting expanded access.
“These results provide strong support that treatment with losmapimod has a meaningful clinical benefit in relevant measures of FSHD disease progression, despite the challenges of measuring DUX4,” said Rabi Tawil, MD, ReDUX4 principal investigator and professor of neurology at University of Rochester Medical Center. “I am enthusiastic about the potential for losmapimod to offer meaningful improvements in preserving muscle function and patient quality of life.”
Read Fulcrum’s press release for more details: Fulcrum Therapeutics Announces Results from ReDUX4 Trial with Losmapimod in Facioscapulohumeral Muscular Dystrophy (FSHD) Demonstrating Slowed Disease Progression and Improved Function