Annualized Rates of Change from A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 48-Week Study of Losmapimod in Subjects with FSHD: ReDUX4 (S48.010)

Abstract

<h3>Objective:</h3> Evaluate annualized clinical outcome changes in subjects with facioscapulohumeral muscular dystrophy (FSHD) treated with losmapimod compared with placebo. <h3>Background:</h3> FSHD is a relentless, variably progressive disease leading to accumulation of disability over decades. Fulcrum is developing losmapimod, a small molecule p38 α/β MAPK inhibitor, to treat FSHD. An annualized analysis provides data on the slope of disease progression and the potential for treatment with losmapimod to change that slope over time. <h3>Design/Methods:</h3> Subjects aged 18–65 years with FSHD1, CSS 2–4, and MRI-eligible muscles for biopsy were randomized 1:1; losmapimod (15 mg BID): placebo. Assessments included for analysis: MRI assessments of muscle health, reachable workspace (RWS), dynamometry and TUG. Annualized rate of change (%/yr) was calculated using a linear mixed-effects model to estimate slope and percent change per year. Annualized analysis of RWS (measured in Reachable Surface Area, RSA) was prespecified; all other analyses are post-hoc. <h3>Results:</h3> Eighty subjects (N=40/group), mean age 45.7 (±12.5) years, Ricci score 3.2 were enrolled. Annualized rate of change (%/yr) in total RSA for losmapimod vs. placebo dominant arm: −0.44 vs. −8.42; p=0.07; non-dominant arm: 4.88 vs. −4.02; p=0.01. This slowing or improvement is supported by structural measures via MRI and functional outcomes (dynamometry and TUG). MRI annualized rates of change for losmapimod vs. placebo were 0.31 vs 3.82 for MFI, 4.42 vs 5.96 for MFF, and −7.15 vs −4.50 for LMV. Maximum dynamometry in the shoulder abductors showed variability in annualized rate of change for losmapimod vs. placebo (L −1.98 vs 13.62; R −14.39 vs −8.49) and in hand grip (L −8.30 vs −13.44; R −13.95 vs −15.27). In TUG, the annualized rate of change was −0.93 vs 2.23% in the losmapimod vs placebo group. <h3>Conclusions:</h3> Annualized rates of change in clinical outcomes support disease slowing or improvement in losmapimod treated subjects compared to placebo. <b>Disclosure:</b> Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving as a Consultant for DYNE Therapeutics. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arrowhead Pharma. Dr. Tawil has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Fulcrum Therapeutics. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Acceleron Pharma. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for MT Pharma. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche Pharma. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for miRecule. The institution of Dr. Tawil has received research support from Friends of FSH Research. The institution of Dr. Tawil has received research support from FSH Society. The institution of Dr. Tawil has received research support from NIH. The institution of Dr. Tawil has received research support from Fulcrum. Dr. Tawil has received intellectual property interests from a discovery or technology relating to health care. Dr. Tawil has received publishing royalties from a publication relating to health care.