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A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With ALS.

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).

SUBMITTER: Shefner JM

PROVIDER: S-EPMC8117790 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of <i>Reldesemtiv</i> In Patients With ALS.

Shefner Jeremy M JM Andrews Jinsy A JA Genge Angela A Jackson Carlayne C Lechtzin Noah N Miller Timothy M TM Cockroft Bettina M BM Meng Lisa L Wei Jenny J Wolff Andrew A AA Malik Fady I FI Bodkin Cynthia C Brooks Benjamin R BR Caress James J Dionne Annie A Fee Dominic D Goutman Stephen A SA Goyal Namita A NA Hardiman Orla O Hayat Ghazala G Heiman-Patterson Terry T Heitzman Daragh D Henderson Robert D RD Johnston Wendy W Karam Chafic C Kiernan Matthew C MC Kolb Stephen J SJ Korngut Lawrence L Ladha Shafeeq S Matte Genevieve G Mora Jesus S JS Needham Merrilee M Oskarsson Bjorn B Pattee Gary L GL Pioro Erik P EP Pulley Michael M Quan Dianna D Rezania Kourosh K Schellenberg Kerri L KL Schultz David D Shoesmith Christen C Simmons Zachary Z Statland Jeffrey J Sultan Shumaila S Swenson Andrea A Berg Leonard H Van Den LHVD Vu Tuan T Vucic Steve S Weiss Michael M Whyte-Rayson Ashley A Wymer James J Zinman Lorne L Rudnicki Stacy A SA

Amyotrophic lateral sclerosis & frontotemporal degeneration 20200924 3-4

<h4>Objective</h4>To evaluate safety, dose response, and preliminary efficacy of <i>reldesemtiv</i> over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). <i>Methods:</i> Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to <i>reldesemtiv</i> 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 ...[more]

PMID: 32969758

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