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

Abstract

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).

Keywords: Randomized clinical trial; amyotrophic lateral sclerosis; reldesemtiv.

Conflict of interest statement

Declaration of interest

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.

Figures

Figure 1.

Patient disposition. *All patients randomized contributed to the primary and secondary efficacy analyses, except for 1 patient who withdrew consent right after randomization and did not receive any treatment in the placebo group; all dosed patients contributed to the safety analysis. †2 patients were off study drug too long due to prolonged hospitalization. ‡1 patient no longer wanted to participate in the study due to factors other than the study treatment or study procedures, 1 patient had difficulty traveling to clinic visits, 1 patient withdrew for personal reasons. §1 patient could not continue the study and required visits due to unforeseen work events, 1 patient withdrew due to family circumstances. ¶2 patients did not feel were benefiting from treatment and decided to discontinue, 1 patient had difficulty traveling to clinic visits. AE: adverse event; bid: twice daily; ET: early termination.

Figure 2.

LS mean change from baseline for each group from a mixed model analysis of (A) percent predicted SVC (primary endpoint), (C) ALSFRS-R total score, and (E) muscle strength mega-score. Post hoc analysis of LS mean change from baseline from a mixed model analysis for all reldesemtiv-treated patients versus placebo for (B) percent predicted SVC, (D) ALSFRS-R Total Score, and (F) muscle strength mega-score. ALSFRS-R: Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised; bid, twice daily; BL: baseline; LS: least squares; SE: standard error; SVC: slow vital capacity; wk: week.

Figure 3.

Forest plots from post hoc analyses of LS mean differences between treatment with reldesemtiv and placebo by subgroups for (A) percent predicted SVC, (B) ALSFRS-R, and (C) muscle strength mega-score. *Pretrial reduction of ALSFRS-R total score per month. ALSFRS-R: Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised; CI: confidence interval; LSM: least squares mean; pbo: placebo SVC: slow vital capacity.

Figure 4.

Post hoc analysis of change from baseline in (A) ALSFRS-R Total Score, (B) ALSFRS-R Fine Motor Domain and (C) ALSFRS-R Gross Motor Domain score by progressor tertiles. ALSFRS-R: Amyotrophic Lateral Sclerosis Functional Rating Scale Revised; FP: fastest progressors; LS: least squares; MP: middle progressors; SP: slowest progressors.

Figure 5.

eGFR (based on cystatin C) over time. bid: twice daily; BL: baseline; eGFR: estimated glomerular filtration rate; LS: least squares; wk: week.