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 |
Keywords
- Randomized clinical trial
- amyotrophic lateral sclerosis
- reldesemtiv
ASJC Scopus subject areas
- Neurology
- Clinical Neurology
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A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With ALS. / Shefner, Jeremy M.; Andrews, Jinsy A.; Genge, Angela; Jackson, Carlayne; Lechtzin, Noah; Miller, Timothy M.; Cockroft, Bettina M.; Meng, Lisa; Wei, Jenny; Wolff, Andrew A.; Malik, Fady I.; Bodkin, Cynthia; Brooks, Benjamin R.; Caress, James; Dionne, Annie; Fee, Dominic; Goutman, Stephen A.; Goyal, Namita A.; Hardiman, Orla; Hayat, Ghazala; Heiman-Patterson, Terry; Heitzman, Daragh; Henderson, Robert D.; Johnston, Wendy; Karam, Chafic; Kiernan, Matthew C.; Kolb, Stephen J.; Korngut, Lawrence; Ladha, Shafeeq; Matte, Genevieve; Mora, Jesus S.; Needham, Merrilee; Oskarsson, Bjorn; Pattee, Gary L.; Pioro, Erik P.; Pulley, Michael; Quan, Dianna; Rezania, Kourosh; Schellenberg, Kerri L.; Schultz, David; Shoesmith, Christen; Simmons, Zachary; Statland, Jeffrey; Sultan, Shumaila; Swenson, Andrea; Berg, Leonard H.Van Den; Vu, Tuan; Vucic, Steve; Weiss, Michael; Whyte-Rayson, Ashley; Wymer, James; Zinman, Lorne; Rudnicki, Stacy A.
In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, Vol. 22, No. 3-4, 2021, p. 287-299.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With ALS
AU - Shefner, Jeremy M.
AU - Andrews, Jinsy A.
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 C.
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 - Berg, Leonard H.Van Den
AU - Vu, Tuan
AU - Vucic, Steve
AU - Weiss, Michael
AU - Whyte-Rayson, Ashley
AU - Wymer, James
AU - Zinman, Lorne
AU - Rudnicki, Stacy A.
N1 - Funding Information: JMS received personal compensation from Avexis, Biogen, Brainstorm, Cytokinetics, Mitsubishi Tanabe Pharma America, Neurosense, Orphazyme, Otsuka, and Revalesio; and research support from Amylyx, Brainstorm, Cytokinetics, Medicinova, and Mitsubishi Tanabe Pharma America. JAA served as a consultant for ALS Pharma, Avexis, Biogen and Cytokinetics; is a former employee of Cytokinetics; and received research support from Biogen, Neuraltus, Orion, Roche, Novartis. AG served as a consultant for Alexion, AL-S Pharma, Biogen, Calico, and Cytokinetics. CJ has received grant support from Amylyx and Cytokinetics; served on the DSMB for Anelixis, Brainstorm, and Mallinckrodt; and served as a consultant for Cytokinetics, ITF Pharma, and Mitsubishi Tanabe Pharma America. NL is a consultant for Cytokinetics. TMM is a consultant for Cytokinetics and Disarm Therapeutics; has licensing agreements with C2N Diagnostics and Ionis Pharmaceuticals; and serves on the advisory board and receives research support from Biogen. CB served (uncompensated) on an advisory board for Argenx. BRB has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from AB Science, Biogen, Biohaven, California ALS Research Summit, Cytokinetics, ITF Pharma, Mitsubishi Tanabe Pharma American, and for serving in an editorial capacity for American Journal of Managed Care; and has received research support from Acceleron, Alexion, Biogen, Biohaven, Boston Scientific, Center for Disease Control, Cytokinetics, ITF Pharma, Medicinova, Mitsubishi Tanabe Pharma America, Neuraltus, Orion, and Santhera. DF has served on an advisory board for Biogen Scientific. OH has received consulting fees from Novartis; research funding from Biogen, Cytokinetics, Ionis and Merck; and is Editor-in-Chief of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. GH served on speaker’s bureau and as a consultant for Alexion, CSL Behring, KabaFusion, and Mitsubishi Tanabe Pharma. TH-P has received consulting fees from Amylyx, Cytokinetics, ITF Pharma and Mitsubishi Tanabe Pharma. RDH served on SMA advisory board for Biogen and Pompe advisory board (Sanofi). WJ received honoraria from Mitsubishi Tanabe Pharma Canada advisory board; and served on clinical trials for Alexion Pharmaceuticals, ALS-Pharma SA, Biogen, Cytokinetics, Mallinckrodt, Mitsubishi Tanabe Pharma Development America, and Orion. CK served on advisory boards for Acceleron, Akcea, Alexion, Alnylam, Argenx, Biogen, CSL Behring, Cytokinetics, and Sanofi Genzyme. MCK receives funding from National Health & Medical Research Council of Australia. SJK served as a consultant for AveXis, Biogen, and Roche and receives grant support from AveXis. GM has research contracts with Cytokinetics, Mallinckrodt, Orion, and University of Calgary; and received fees for speaking, advisory board, and travel from Mitsubishi Tanabe Pharma Canada. MN received honoraria from Biogen, Novartis, and Sanofi for chairing and speaking at professional development meetings. BO serves as a consultant for Biogen, Biohaven, MediciNova, Mitsubishi, and Tsumura; and receives research funding from Biogen, Eisai, Genentech, Mitsubishi, and Orion. EPP received clinical trial and research funding from ALS Association, Iron Horse Diagnostics, and NIH/CDC, and served as consultant to Avanir Pharmaceuticals, Biohaven Pharmaceuticals, Cytokinetics, ITF Pharma, Mitsubishi Tanabe Pharma America, and Otsuka America. MP received honoraria from Argenx, Bioproducts Laboratory, CSL Behring, Catalyst, Grifols, and Stealth BioTherapeutics. DQ received research funding from Alnylam, Argenx, Cytokinetics, Flex Pharma, and Momenta. ZS is a consultant for Biogen and Cytokinetics, and received research support from Biogen. JS received grant funding from FSHD Society, Friends of FSH Research, MDA, and NINDS; is a consultant or on advisory boards for Acceleron, Dyne, FACIO, Fulcrum, Genzyme, Mitsubishi Tanabe Pharma, and Sarepta. AS received research support from Amylyx. LHV serves on scientific advisory boards for Biogen, Cytokinetics, and Orion; received an educational grant from Takeda; serves on the editorial boards of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration and the Journal of Neurology, Neurosurgery, and Psychiatry; and receives research support from the Netherlands ALS Foundation, and The Netherlands Organization for Health Research and Development (Vici Scheme, JPND [SOPHIA, STRENGTH, ALSCare]). MW received funding from ALSA Association and ALS Finding a Cure; is a speaker for NuFactor; and is a consultant for Argenx and Ra Pharma. JW received research funding from Cytokinetics as part of the study. LZ received honoraria from Biogen, Cytokinetics, and Mitsubishi Tanabe Pharma. BMC owns stock in and was an employee of Cytokinetics during the conduct of the study. LM, JW, AAW, FIM, and SAR own stock and are employees of Cytokinetics. JC, AD, SAG, NAG, DH, LK, SL, JSM, GLP, KR, KLS, DS, CS, SS, TV, SV, and AW-R report no relevant disclosures. Funding Information: 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. Funding Information: 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. Publisher Copyright: © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
PY - 2021
Y1 - 2021
N2 - 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).
AB - 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).
KW - Randomized clinical trial
KW - amyotrophic lateral sclerosis
KW - reldesemtiv
UR - http://www.scopus.com/inward/record.url?scp=85091435875&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85091435875&partnerID=8YFLogxK
U2 - 10.1080/21678421.2020.1822410
DO - 10.1080/21678421.2020.1822410
M3 - Article
C2 - 32969758
AN - SCOPUS:85091435875
VL - 22
SP - 287
EP - 299
JO - Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
JF - Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
SN - 2167-8421
IS - 3-4
ER -