By Lucy Piper, medwireNews Reporter
medwireNews: The Rho-associated kinase (ROCK) inhibitor fasudil as an adjunct to riluzole is well tolerated for the treatment of patients with amyotrophic lateral sclerosis (ALS), indicate phase 2 findings from the ROCK-ALS study.
Riluzole is approved globally for the treatment of ALS, but the researchers note that it can be “insufficient at affecting the disease course” in patients with sporadic disease, highlighting the need “for identification of more potent therapies.”
Commentator Jinsy Andrews (Columbia University Irving Medical Center, New York, USA) explains that in animal models “ROCK inhibition increased neuronal survival, attenuated axonal degeneration, increased regeneration of neurons and mitigated microglial activation.”
Therefore, “protein kinase inhibition is an attractive target, and it might be an ideal approach in combination with other potential treatments”, she says.
A total of 118 people (median age 60 years, 54% men) were enrolled in the trial between February 2019 and April 2022 and randomly assigned to receive intravenous fasudil, at a twice daily dose of either 15 mg (n=35) or 30 mg (n=39), or matching placebo (n=44) for 20 days over a 4-week period.
The participants had clinical probable, laboratory-supported probable or definite ALS, either sporadic or familial, and a disease duration of between 6 and 24 months. They were all taking riluzole 50 mg twice daily and continued to do so during the trial. Their predicted slow vital capacity was above 65% of normal.
The co-primary endpoints related to safety up to day 180, based on no drug-related serious adverse events (AEs), and tolerability, according to whether or not patients discontinued treatment due to suspected drug-related AEs during the treatment period.
No drug-related serious AEs occurred over the 180 days in any of the groups, so the estimated proportion of patients without an event was 100%, irrespective of treatment group. Fasudil was therefore “considered safe for all participants”, say Paul Lingor (Technical University Munich, Germany) and colleagues in The Lancet Neurology.
A total of seven patients discontinued treatment due to suspected drug-related AEs – four in the fasduil 30 mg twice daily group and three in the placebo group. The proportion of patients who tolerated treatment was a comparable 100% in the fasudil 15 mg twice daily group, 90% in the fasudil 30 mg twice daily group and 93% in the placebo group.
The frequency of any AEs also did not differ across the groups, occurring in 83% of patients given fasudil 15 mg twice daily, 72% of patients given fasudil 30 mg twice daily and 80% of those given placebo. AEs were mostly related to disease progression, with the most common serious ones being respiratory failure, gastrostomy, pneumonia and dysphagia. There were eight deaths in all, none of which were considered related to treatment, four in the fasudil 15 mg twice daily group and two each in the fasudil 30 mg twice daily and placebo groups.
The study showed no effect of fasudil on the secondary efficacy outcomes of function on the ALS Functional Rating Scale, patient-reported outcomes on the ALS Assessment Questionnaire and the Edinburgh Cognitive and Behavioural ALS Screen or on predicted slow vital capacity.
This was “not unexpected because of the short treatment duration”, say Lingor et al.
However, they note that slow vital capacity decline was significantly slower with fasudil 30 mg twice daily than with placebo in women in a prespecified analysis at days 90 (mean difference 12.6% vs placebo) and 180 (mean difference 21.6%).
There was also a significantly greater slowing in muscle decline in both fasudil treatment groups, with a mean 0.89 Motor Unit Number Index megascore-10 ratio at day 90, relative to a median score of 68 at baseline. This compared with a mean ratio of 0.79 in the placebo group, although this benefit was not sustained at day 180.
The investigators point out that the study was not powered for these secondary outcomes and so the findings should be “interpreted cautiously”, adding that “a longer intervention period is needed to observe more sustainable effects.”
They conclude: “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.”
News stories are provided by medwireNews, which is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group
Lancet Neurol 2024; 23: 1133–1146