Abstract
Objective: To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength mega-score, p = 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898).
| Original language | English (US) |
|---|---|
| Pages (from-to) | 287-299 |
| Number of pages | 13 |
| Journal | Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration |
| Volume | 22 |
| Issue number | 3-4 |
| DOIs | |
| State | Published - 2021 |
Funding
We thank Kakuri Omari, PhD, CMPP (Evidence Scientific Solutions, Philadelphia, PA) for assistance in collating/incorporating author comments, editing, and formatting, which was funded by Cytokinetics, Inc. The study was conducted by Cytokinetics, Inc., South San Francisco, CA, USA and funded by Astellas Pharma Inc., Tokyo, Japan, as part of the collaboration between Cytokinetics and Astellas. Cytokinetics, Inc., provided funding for editorial support provided by Kakuri Omari, PhD, CMPP (Evidence Scientific Solutions, Inc., Philadelphia, PA, USA). We wish to thank the participants of FORTITUDE-ALS and their families for their contributions to this clinical trial, the investigators of FORTITUDE-ALS, and members of the Data Monitoring Committee and Steering Committee. We also wish to thank Dr. Elham Bayat (The George Washington University, Washington, DC), Dr. Richard Bedlack (Duke University School of Medicine, Durham, NC), Dr. Deborah Bradshaw (SUNY Syracuse, Syracuse), Dr. Robert Brown (University of Massachusetts Worcester, Worcester), Dr. Ted Burns (University of Virginia, Charlottesville), Dr. Peter Donofrio (Vanderbilt University Medical Center, Nashville, TN), Dr. Jonathan Glass (Emory University, Atlanta, GA), Dr. Kimberly Goslin (Providence ALS Center, Portland, OR), Dr. Jonathan Katz (California Pacific Medical Center, San Francisco), Dr. Dale Lange (Weill Medical College of Cornell University, New York, NY), Dr. Richard Lewis (Cedar Sinai Medical Center, Los Angeles, CA), Dr. Samuel Maiser (Twin Cities ALS Research Consortium, Minneapolis, MN), Dr. Nicholas Maragakis (Johns Hopkins Hospital, Baltimore, MD), Dr. Hiroshi Mitsumoto (Columbia University Medical Center, New York, NY), Dr. Daniel Newman (Henry Ford Hospital, Detroit, MI), Dr. Alan Pestronk (Washington University, St. Louis, MO), Dr. Ericka Simpson (Houston Methodist, Houston, TX), Dr. Yuen So (Stanford University Medical Center, Palo Alto, CA), Dr. Rup Tandan (University of Vermont, Burlington), Dr. John Turnbull (McMaster University Medical Center, Hamilton, ON), and Dr. Scott A. Vota (Virginia Commonwealth University, Richmond) for their contributions to the study. Statistical analysis was performed by Lisa Meng and Jenny Wei (Cytokinetics, Inc., South San Francisco, CA, USA). We thank Kakuri Omari, PhD, CMPP (Evidence Scientific Solutions, Philadelphia, PA) for assistance in collating/incorporating author comments, editing, and formatting, which was funded by Cytokinetics, Inc.
Keywords
- Randomized clinical trial
- amyotrophic lateral sclerosis
- reldesemtiv
ASJC Scopus subject areas
- Neurology
- Clinical Neurology