This is a summary of Koch, J.C., Leha, A., Bidner, H., et.al. (2024). Safety, tolerability, and efficacy of the Rho-associated kinase inhibitor fasudil in amyotrophic lateral sclerosis (ROCK-ALS): a phase 2, randomised, double-blind, placebo-controlled trial. Published in The Lancet Neurology. https://doi.org/10.1016/S1474-4422(24)00373-9
The challenge
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative condition marked by the degeneration of motor neurons and gradual muscle weakness, often leading to respiratory failure and death within 3–4 years of the onset of symptoms. Current treatment options relieve some of the symptoms but have limited impact on the progression of the disease. Based on previous cell culture and animal model research, we know that inhibition of the enzyme Rho-associated kinase (ROCK), which is a key player in cellular processes that involve changes in cell shape and movement, improves neuronal survival and axonal regeneration and modulates microglial function. In fact, increased concentrations of ROCK have been found in the tissues of ALS patients. Subsequently, in mouse models of ALS, ROCK inhibition led to improved function and survival of the mice. We, therefore, aimed to investigate the safety, tolerability, and efficacy of a Rho-kinase inhibitor called fasudil – which is licensed in Japan for the treatment of vasospasm after subarachnoid hemorrhage – in a phase 2 trial in individuals with ALS.
Our approach
Between February 2019, and April 2022, 120 participants in Germany, France and Switzerland were randomly assigned to three different groups: 1) placebo, 2) daily 30 mg dose fasudil, 3) daily 60 mg dose fasudil. We followed the participants for 180 days.
Our findings
Fasudil, in both doses, was well tolerated by the patients and considered safe: no treatment-related serious adverse events were recorded in any of the treatment groups. Survival outcomes did not significantly differ across treatment groups until the end of the trial, as expected due to the short treatment duration. Interestingly, we observed, significantly higher values in the secondary outcome MUNIX after fasudil treatment at two time points, which may suggest disease-modifying effects.
Implications
Our results suggest further evaluation of this drug in clinical trials with longer treatment durations. Furthermore, it shows that the neurophysiological MUNIX assessment – which is used as a surrogate marker for the number of lower motor neurons innervating a muscle – is an effective measure that can be used in multicentre trials and might be more sensitive to change than scale-based measures.
Creating SyNergies
The study was led by SyNergy member Paul Lingor. Translating experimental therapies from preclinical in vitro and in vivo data to clinical trials is a main interest of the Lingor group and we look forward to discuss translational ideas in the Translational Hub of SyNergy.
