Safety, tolerability, and efficacy of fasudil in amyotrophic lateral sclerosis (ROCK-ALS): a phase 2, randomised, double-blind, placebo-controlled trial.

BACKGROUND

Fasudil is a small molecule inhibitor of Rho-associated kinase (ROCK) and is approved for the treatment of subarachnoid haemorrhage. In preclinical studies, fasudil has been shown to attenuate neurodegeneration, modulate neuroinflammation, and foster axonal regeneration. We aimed to investigate the safety, tolerability, and efficacy of fasudil in patients with amyotrophic lateral sclerosis.

METHODS

ROCK-ALS was a phase 2, randomised, double-blind, placebo-controlled trial conducted at 19 amyotrophic lateral sclerosis centres in Germany, France, and Switzerland. Individuals (aged 18-80 years) with at least probable amyotrophic lateral sclerosis (as per the revised El Escorial criteria), a disease duration of 6-24 months, and a slow vital capacity greater than 65% of predicted normal were eligible for inclusion. Patients were randomly assigned (1:1:1) to receive 30 mg (15 mg twice daily) or 60 mg (30 mg twice daily) fasudil or matched placebo intravenously for 20 days over a 4-week period. Follow-up assessments were performed at 45, 90, and 180 days after treatment initiation. The co-primary endpoints were safety until day 180 (defined as the proportion without drug-related serious adverse events) and tolerability during the treatment period (defined as the proportion who did not discontinue treatment due to suspected drug-related adverse events). The primary analyses were carried out in the intention-to-treat population, which included all participants who entered the treatment phase. This trial is registered at ClinicalTrials.gov (NCT03792490) and Eudra-CT (2017-003676-31) and is now completed.

FINDINGS

Between Feb 20, 2019, and April 20, 2022, 120 participants were enrolled and randomised; two individuals assigned fasudil 30 mg withdrew consent before the baseline visit. Thus, the intention-to-treat population comprised 35 in the fasudil 30 mg group, 39 in the fasudil 60 mg group, and 44 in the placebo group. The estimated proportion without a drug-related serious adverse event was 1·00 (95% CI 0·91 to 1·00) with placebo, 1·00 (0·89 to 1·00) with fasudil 30 mg, and 1·00 (0·90 to 1·00) with fasudil 60 mg; the difference in proportions was 0·00 (95% CI -0·11 to 0·10; p>0·99) for fasudil 30 mg versus placebo and 0·00 (-0·10 to 0·10; p>0·99) for fasudil 60 mg versus placebo. Treatment tolerability (the estimated proportion who did not discontinue) was 0·93 (95% CI 0·81 to 0·99) with placebo, 1·00 (0·90 to 1·00) with fasudil 30 mg, and 0·90 (0·76 to 0·97) with fasudil 60 mg; the difference in proportions was 0·07 (95% CI -0·05 to 0·20; p=0·25) for fasudil 30 mg versus placebo, and -0·03 (-0·18 to 0·10; p=0·70) for fasudil 60 mg versus placebo. Eight deaths occurred: two in the placebo group, four in the fasudil 30 mg group, and two in the fasudil 60 mg group. The most common serious adverse events were respiratory failure (seven events), gastrostomy (five events), pneumonia (four events), and dysphagia (four events). No serious adverse events or deaths were attributed to study treatment. Adverse events, which were mainly related to disease progression, occurred in 139 participants in the placebo group, 108 in the fasudil 30 mg group, and 105 in the fasudil 60 mg group.

INTERPRETATION

Fasudil was well tolerated and safe in people with amyotrophic lateral sclerosis. The effect of fasudil on efficacy outcomes should be explored in larger clinical trials with a longer treatment duration, oral administration, and potentially higher dose of the trial drug.

FUNDING

Framework of the E-Rare Joint Transnational Call 2016 "Clinical research for new therapeutic uses of already existing molecules (repurposing) in rare diseases".

Informations de copyright

Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests JCK reports a grant from the Deutsche Gesellschaft für Muskelkranke and consulting fees from AbbVie, Biogen, Ipsen, Roche, and Zambon. RG reports grants from the Deutsche Gesellschaft für Muskelkranke, Initiative SMA, and Bundesministerium für Bildung und Forschung, as well as consulting fees from Biogen, Roche, ITF Pharma, and Zambon. DZ has received consulting fees from Novartis and Angelini Pharma and has served on an advisory board for Biogen. NB has received compensations from Mitsubishi Tanabe Pharma. PC serves on the editorial advisory boards of ALS and The Revue Neurologique; reports consultancy work or participation on advisory boards for Amylyx, Biogen, Cytokinetics, Ferrer, Mitsubishi Tanabe Pharma, VectorY, and Zambon; serves on the drug safety monitoring board for Quralis, and has received a research grant from Biogen. EDLC has received travel grants from Biogen and EFFIK. PW reports grants from the Boris Canessa Foundation and the Bundesministerium für Bildung and Forschung; and has received consulting fees from ITF Pharma, Zambon, Novartis, Biogen, and Roche. TM reports institutional grants from Cytokinetics, Ferrer, AL-S Pharma, Sanofi, Amylyx, Mitsubishi Tanabe, and Apellis Pharmaceuticals, as well as personal fees from Biogen, Amylyx, and ITF Pharma; and is co-founder and shareholder of the Ambulanzpartner Soziotechnologie APST. JG has received personal fees from UCB, Alexion, Amylyx, Roche, and Zambon; and is a member of advisory boards of the European Network to Cure ALS, Neuroimaging Society in amyotrophic Lateral Sclerosis, EU ALS coalition, and the World Federation of Neurology Motoneuron Disease group. M-HS received compensations for consulting from Amylyx, Zambon, EFFIK-Italfarmaco, and SOS Oxygene. M-LR reports grants from FightMND, MND Research Australia and the US National Institutes of Health. CN has received fees for non-related services for Biogen, Mitsubishi Tanabe, Roche, and Argenx. JW reports grants from the US National Institutes of Health. JS has received payments for participation on advisory boards, talks, travel, and research projects from Abcuro, Alnylam, Argenx, Biotest, CSL Behring, Grifols, Johnson & Johnson, Kezar, LFB, Lupin, Momenta, Novartis, Octapharma, and UCB, all unrelated to the present study. TF has received personal fees from Actimed, Bayer, Bristol Myers Squibb, Cardior, CSLBehring, Daiichi Sankyo, Galapagos, Immunic, KyowaKirin, LivaNova, Minoryx, Novartis, RECARDIO, Relaxera, Roche, Servier, Viatris, Vifor, Fresenius Kabi, PINK gegen Brustkrebs, Aslan, BionsenseWebster, Enanta, VICO Therapeutics, Pharmaceutical Product Development, and IQVIA, as well as institutional grants from Deutsche Forschungsgemeinschaft, Gemeinsamer Bundesausschuss, and the European Commission. MB reports grants from the US National Institutes of Health, the Muscular Dystrophy Association, and the ALS Association; as well as consulting fees for Alector, Alexion, Annexon, Arrowhead, Biogen, Cartesian, Denali, Eli Lilly, Horizon, Immunovant, Novartis, Roche, Sanofi, Takeda, UCB, and uniQure; the University of Miami has licensed intellectual property to Biogen to support the design of the ATLAS trial (NCT04856982), for which MB is academic lead. PL reports grants from the Bundesministerium für Bildung und Forschung and the Deutsche Forschungsgemeinschaft; consulting fees from AbbVie, Amylyx, Bial, Desitin, ITF Pharma, Novartis, Stadapharm, Raya Therapeutic, Woolsey Pharmaceuticals, and Zambon; and is co-inventor on a patent for the use of fasudil in amyotrophic lateral sclerosis (EP 2825175 B1, US 9.980,972 B2). All other authors declare no competing interests.