TY - JOUR
T1 - A phase 2, double-blind, randomized, dose-ranging trial of reldesemtiv in patients with ALS.
AU - Shefner, Jeremy
AU - Andrews, Jinsy
AU - Genge, Angela
AU - Jackson, Carlayne
AU - Lechtzin, Noah
AU - Miller, Timothy M.
AU - Cockroft, Bettina M.
AU - Meng, Lisa
AU - Wei, Jenny
AU - Wolff, Andrew A.
AU - Malik, Fady I.
AU - Bodkin, Cynthia
AU - Brooks, Benjamin R.
AU - Caress, James
AU - Dionne, Annie
AU - Fee, Dominic
AU - Goutman, Stephen A.
AU - Goyal, Namita A.
AU - Hardiman, Orla
AU - Hayat, Ghazala
AU - Heiman-Patterson, Terry
AU - Heitzman, Daragh
AU - Henderson, Robert D.
AU - Johnston, Wendy
AU - Karam, Chafic
AU - Kiernan, Matthew
AU - Kolb, Stephen J.
AU - Korngut, Lawrence
AU - Ladha, Shafeeq
AU - Matte, Genevieve
AU - Mora, Jesus S.
AU - Needham, Merrilee
AU - Oskarsson, Bjorn
AU - Pattee, Gary L.
AU - Pioro, Erik P.
AU - Pulley, Michael
AU - Quan, Dianna
AU - Rezania, Kourosh
AU - Schellenberg, Kerri L.
AU - Schultz, David
AU - Shoesmith, Christen
AU - Simmons, Zachary
AU - Statland, Jeffrey
AU - Sultan, Shumaila
AU - Swenson, Andrea
AU - van den Berg, Leonard H.
AU - Vu, Tuan
AU - Vucic, Steve
AU - Weiss, Michael
AU - Whyte-Rayson, Ashley
AU - Wymer, James
AU - Zinman, Lorne
AU - Rudnicki, Stacy A.
N1 - This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
PY - 2020/9/24
Y1 - 2020/9/24
N2 - 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)
AB - 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)
KW - Randomized clinical trial
KW - amyotrophic lateral sclerosis
KW - reldesemtiv
UR - http://www.scopus.com/inward/record.url?scp=85091435875&partnerID=8YFLogxK
U2 - 10.1080/21678421.2020.1822410
DO - 10.1080/21678421.2020.1822410
M3 - Article
AN - SCOPUS:85091435875
JO - Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
JF - Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
SN - 2167-8421
ER -