Reachable Workspace to Evaluate Efficacy of Losmapimod in Subjects with FSHD in Two Phase 2 Studies

Topic:

Clinical Trials

Poster Number: 57

Author(s):

Michelle L Mellion, MD, Fulcrum Therapeutics, Inc., Rabi Tawil, MD, University of Rochester, Jay Han, MD, University of California, Irvine, Jordi Diaz Manera, MD, Hospital de la Santa Cruz, Barcelona Spain, Miriam Freimer, MD, Ohio State University Medical Center, Angela Genge, MD, FRCP©, Montreal Neurological Institute and Hospital, Summer Gibson, MD, University of Utah, Nuria Gomez, MD, PhD, Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe,Valencia, Spain, Namita Goyol, MD, University of California, Irvine, Johanna Hamel, MD, University of Rochester Medical Center, Lawrence Hayward, MD, PhD, University of Massachusetts Medical School, Nicholas Johnson, MD, Virginia Commonwealth University, Joost Kools, MD, Radboud University Medical Centre (Radboudumc), Nijmegen, NL, David Reyes Levia, Hospital de la Santa Cruz, Barcelona Spain, Doris Leung, MD, Kennedy Krieger Institute, Hanns Lochmuller, MD, Childrens Hospital of Eastern Ontario Research Institute, Samantha LoRusso, MD, Ohio State University Medical Center, Alan Pestronak, MD, Washington University, Sabrina Sacconi, MD, Nice University, Perry Shieh, MD, University of California, Los Angeles, David Geffen School of Medicine, Jeffrey Statland, MD, University of Kansas School of Medicine, S H Subramony, MD, University of Florida College of Medicine, Baziel van Engelen, MD, PhD, Radboud University Medical Centre (Radboudumc), Nijmegen, NL, Juan Vilchez, MD, Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe,Valencia, Spain, Kathryn Wagner, MD, PhD, Kennedy Krieger Institute, Leo Wang, MD, University of Washington, John Jiang, PhD, Fulcrum Therapeutics, Inc., Anthony Accorsi, PhD, Fulcrum Therapeutics, Inc., Christopher Morabito, MD, Fulcrum Therapeutics, Inc., L. Alejandro Rojas, PhD, Fulcrum Therapeutics, Inc., Jennifer Shoskes, PharmD, Fulcrum Therapeutics, Inc.

Objective:
Assess clinical efficacy of losmapimod to slow or stop disease progression with Reachable Workspace (RWS).

Background:
RWS is a 3D assessment of function that measures upper extremity mobility. Fulcrum is developing losmapimod, a small molecule inhibitor of p38 ?/? MAPK, to treat FSHD.

Design/Methods:
ReDUX4 is a placebo-controlled study assessing 80 subjects aged 18 to 65 years with genetically confirmed FSHD1, clinical severity score 2 to 4 (range 0-5) randomized 1:1 to 15 mg losmapimod or placebo PO twice daily for 48 weeks. Open-label study (OLS) is a single-site study evaluating efficacy of losmapimod for 52 weeks in 14 subjects with same inclusion criteria. RWS was performed with and without 500 g wrist weights in the dominant (D) and non-dominant (ND) arm at baseline and at individual timepoints through end of study. Quantitative assessment includes total relative surface area (RSA) composed of 5 quintants Q1-Q5 measured on a 0-1.25 scale representing frontal and posterior inferior reachable area with each quintant measuring 0.25.

Results:
In ReDUX4, losmapimod resulted in significant clinical improvements in total RSA, losmapimod vs. placebo D: 0.019 vs. -0.048; difference 0.067; p=0.01; ND: 0.021 vs. -0.024, difference 0.045; p<0.05. Placebo subjects lost 2.6-3.6% total RSA without weights and 1.9-3.8% with weights. In OLS, improvements were measured bilaterally; range 0.03-0.04. In ReDUX4, annualized rate of change (%) in total RSA in losmapimod vs. placebo D: -0.44 vs. -8.42; p=0.07; ND: 4.88 vs. -4.02; p=0.01 and in OLS range 3.28-5.68. RSA by domain showed that the losmapimod arm had either improvements or no worsening, particularly in Q1 and Q3 (above shoulder), and Q5 (posterior inferior).

Conclusions: RWS is a clinically meaningful upper extremity assessment of function that can be used to assess disease progression and treatment efficacy accurately. RWS demonstrated that losmapimod significantly preserves or improves function.