M. Mellion, L. Ronco, L. Thompson
Apr 14, 2020
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Journal
Neurology
Abstract
Objective: Investigate safety, tolerability, pharmacokinetics (PK), and target engagement (TE) of losmapimod in healthy volunteers (HV) and FSHD1 patients. Background: FSHD is caused by the aberrant expression of the homeobox transcription factor DUX4 in skeletal muscle. DUX4 activates a transcriptional program resulting in muscle loss and disability. Losmapimod is a selective small molecule inhibitor of p38α/β being developed to reduce DUX4 expression, the root cause of FSHD. Design/Methods: This was a three-part study. Part A: 10 HV randomized to single oral doses of losmapimod (7.5 mg then 15 mg; n=8) or placebo (both dosing periods; n=2). Part B: Parallel-group study of losmapimod15 FSHD1 patients randomized to placebo (n=3), losmapimod 7.5 mg (n=6) or 15 mg (n=6) twice daily for 14 days. Part C: Open-label losmapimod 15 mg (n=5) twice daily for 14 days. Muscle biopsies were performed at baseline and during treatment, targeting MRI normal appearing (Part B) and STIR + (Part C) muscle tissue. PK and TE, measured by phosphorylated and total HSP27, were assessed in blood and muscle. Results: Preliminary blinded analysis showed that adverse events (AE) were mild and self-limited. PK profiles were similar between HV and FSHD patients: mean Cmax in blood of 36.6 (HV) and 40.9 ng/mL (FSHD) for 7.5 mg, and 74.6 ng/mL (HV) and 85.0 ng/mL (FSHD1) for 15 mg. Dose-dependent concentrations in muscle (42.1 and 63.6 ng/g) were observed, with a plasma to muscle ratio of approximately 1:1. Dose-dependent TE was observed in blood with robust and sustained target engagement at 15 mg. Conclusions: Losmapimod was well tolerated with no SAEs reported and achieved dose-dependent exposure in plasma and muscle at concentrations predicted by pre-clinical models to provide efficacy by reducing DUX4 activity. These results support advancing the 15 mg dose into Phase 2. Final data will be presented. Disclosure: Dr. Mellion has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Fulcrum Therapeutics and Vertex Pharmaceuticals. Dr. Mellion holds stock and/or stock options in Vertex Pharmaceuticals which sponsored research in which Dr. Mellion was involved as an investigator. Dr. Mellion holds stock and/or stock options in Vertex Pharmaceuticals. Dr. Mellion has received research support from Fulcrum Therapeutics and Vertex Pharmaceuticals. Dr. Ronco has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Fulcrum Therapeutics. Dr. Ronco has received compensation for serving on the Board of Directors of Fulcrum Therapeutics. Dr. Ronco has received royalty, license fees, or contractual rights payments from Fulcrum Therapeutics. Dr. Ronco holds stock and/or stock options in Fulcrum Therapeutics which sponsored research in which Dr. Ronco was involved as an investigator. Dr. Ronco holds stock and/or stock options in Fulcrum Therapeutics. Dr. Thompson has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Fulcrum Therapeutics. Dr. Thompson has received research support from Fulcrum Therapeutics. Dr. Hage has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Fulcrum Therapeutics.Dr. Brooks has nothing to disclose. Dr. van Brummelen has nothing to disclose. Dr. Pagan has nothing to disclose. Dr. Badrising has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Dr. Badrising’s institution (The LUMC) received compensation for consultancy and clinical trial fees from Novartis and consultancy compensation from Argen X for work done by U.B.. Dr. Raines has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Fulcrum Therapeutics. Dr. Tracewell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Fulcrum Therapuetics. Dr. van Engelen has nothing to disclose. Dr. Groeneveld has nothing to disclose. Dr. Cadavid has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Fulcrum Therapeutics. Dr. Cadavid has received research support from Fulcrum Therapeutics.