Fulcrum’s ReDUX4 Trial Results Provide Fresh Hope for FSHD Patients

Fulcrum Therapeutics has announced positive results with its ReDUX4 trial for losmapimod, providing new hope for the Facioscapulohumeral muscular dystrophy (FSHD) community after decades of unsuccessful clinical trials. These past trials have sought to use compounds ranging from anti- inflammatories to muscle boosters in an attempt to circumvent the deterioration, such as using a bucket to bail out water from a leaking boat. On the other hand, ReDUX4 with losmapimod fixes the leak as it is
the very first trial to actually target the cause of FSHD, the toxic protein DUX4. The results of this trial has therefore been hotly anticipated by patients like myself who so far have no options for slowing the progression of this disease. ReDUX4 was a randomized, double-blind (as in neither participant nor evaluator knows if the drug or placebo was given), placebo-controlled phase 2b clinical trial in 80 participants originally set to run for 24 weeks. Due to delays associated with COVID, the trial was
extended to 48 weeks which while delaying results, may have increased the ability to detect the impact of losmapimod on the study’s outcome measures: biomarkers, MRI, and functional changes.

The primary endpoint was to look at the impact of losmapimod on DUX4 activity in muscle biopsies since blockade of this protein is how the drug became a clinical trial candidate. This is done by looking at the expression of genes known to be upregulated by DUX4, typically referred to as FSHD biomarkers. These biomarkers serve as a proxy for DUX4 because they are expressed at much higher levels and are thus easier to detect. Unfortunately, no change in DUX4 driven gene expression was determined, a rather surprising finding due to how well the drug reduces biomarkers in cell culture. However, this does not mean that losmapimod was ineffective at blocking DUX4, instead there are several explanations. First, DUX4 expression itself is very rare and sporadic, only present in around 1 in 1,000 muscle nuclei. Therefore, with these needle biopsies a sample could be taken with higher or lower biomarker levels by chance. Second, there is great variability in biomarker levels between patients with some showing 1,000 fold greater levels at baseline than others. This further hinders the ability to measure a drug-dependent change in expression. In the end, it means that biomarker detection as currently performed is not very robust and needs further optimization.

Magnetic Resonance Imaging (MRI)
One powerful aspect of this trial was the use of MRI to analyze the changes in participants’ muscles over time. Advantages of this tool include less of a chance for bias and subjectivity and that unlike functional tests, it can be done on all patients no matter their disease severity. The key observation with MRI in this trial was the fatty infiltration into muscles, a significant feature of FSHD as replacement of muscle with fat leads to a loss of function. Importantly, losmapimod decreased the progression of fatty infiltrates in intermediate muscles, those that are in an active state of fat infiltration/disease progression but have not undergone complete fat replacement. Additionally, ‘normal’ muscles appeared to be preserved with losmapimod suggesting that it may keep healthy muscles healthy, although a longer observation period is needed to test that. Overall, these MRI results show promise in
losmapimod’s ability to slow/halt disease progression in muscle.

Functional Changes
The most anticipated results of ReDUX4 was the assessment of functional changes due to its impact on the quality of life for FSHD patients. For this trial, impact on muscle function was a secondary outcome measure intended only for preliminary results as the number of participants in a phase 2 study were not thought to be enough to show meaningful data. Surprisingly, there were some statistically significant changes in several assessments of muscle function designed to measure tasks relevant to FSHD patients.

One such improvement was with the Reachable Workspace (RWS), which detects upper extremity range of motion and function with losmapimod having a 1.5% increase from the baseline in accessible surface area. Importantly, there was improvement in Patient Global Impression of Change (PGIC), which assessed self-reported change in how a patient feels and functions. While caution should be taken with explanation of these results since participants may interpret the level of change differently, more
losmapimod participants reported improvement at 48 weeks than placebo. Additionally, fewer losmapimod treated patients reported worsening with none describing their condition as much worse. Several other functional measures showed trends towards improvement as well although not statistically significant including muscle strength through dynamometry and mobility through Timed Up and Go (TUG).

Overall, these results suggest that while not a wonder drug that completely reverses all disease symptoms, losmapimod may provide some clinical benefit that ranges from slowing down or halting disease progression to providing some functional improvement. More than likely its impact will be dependent on the severity of the patients. It is important to note that FSHD is typically a slowly progressive disease and therefore the effect of losmapimod may be difficult to measure even over a 48 week time-frame. It is possible that with longer term administration of this drug, differences would be in disease progression and muscle function would become clearer.

So then what is next? Unfortunately this drug will not be available any time soon as there are still many regulatory hurdles to pass. Fulcrum will be meeting with regulators to determine the best path forward and the data will need to be looked at by the FDA (for those residing in the US, other countries/regions will have their own regulatory agencies such as the EMA for Europe) to determine if there will be accelerated approval or if further clinical trials are required. Importantly, losmapimod has already been given fast track designation by the FDA which will allow for an expedited review process. Another benefit is that due to clinical trials of losmapimod for other diseases, this drug has already been shown to be well tolerated in over 3600 individuals and therefore there are unlikely to be delays related to its safety profile. However, the question remains whether a drug can be approved without meeting its primary endpoint, in this case the reduction of DUX4 activity. While it will still be up to the regulators, since losmapimod has shown a functional benefit in patients, the ultimate goal of any FSHD drug, it may not be as big of an issue.

No matter what happens next, I am now hopeful for the future. ReDUX4 was essential in determining the strength of outcome measures currently being used in FSHD research and whether the timeframe of clinical trials may need to be optimized. With these results, future clinical trials, whether for losmapimod or another FSHD therapy will be more robust, shortening the time until a viable therapy is finally available for FSHD patients.

For more information on previous trials please see:
Cohen, J., DeSimone, A., Lek, M., & Lek, A. (2020). Therapeutic Approaches in Facioscapulohumeral Muscular Dystrophy. Trends Mol Med. doi: 10.1016/j.molmed.2020.09.008

Justin Cohen, PhD is an FSHD patient and scientist who has the privilege of being able to work on his own disease. He can be found on twitter @TheChair1130

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