IV administration of fasudil safe, well tolerated in ALS

Key takeaways:

• No serious adverse events or deaths were linked to fasudil treatment.
• Efficacy may be best determined with future clinical trials focusing on larger doses and longer treatment, researchers wrote.

IV administration of fasudil at two separate doses was safe and well tolerated in a small cohort of individuals with suspected or confirmed ALS, according to new research published in The Lancet.

“Rho-associated kinase (ROCK) is a serine-threonine kinase and ubiquitously expressed,” Jan C. Koch, MD, from the department of neurology at University Medicine in Gottingen, Germany, and colleagues wrote. “In vitro models of neurodegenerative disorders have shown that pharmacological inhibition of ROCK increases neuronal survival, increases regeneration and mitigates microglial activation.”

As preclinical research has established that fasudil tempers neurodegeneration, modulates neuroinflammation and promotes axonal regeneration, Koch and colleagues sought to examine IV administration of the drug for safety, efficacy and tolerability in those with ALS.

They conducted a phase 2 double-blind, placebo-controlled study called ROCK-ALS at 19 ALS centers within Germany, France and Switzerland between February 2019 and April 2022.

A total of 120 adults with at least probable ALS or an ALS diagnosis and disease duration between 6 and 24 months were randomly assigned on a 1:1:1 basis to receive either 30 mg (15 mg twice daily) or 60 mg (30 mg twice daily) IV fasudil or matching placebo for 45 minutes per day for 20 days over a 4-week period, with 6 to 8 hours in between each administration.

Follow-up assessments were performed at 45, 90, and 180 days after treatment initiation, for a total of 24 planned study visits per patient.

The primary study endpoints were safety from baseline through day 180 (those who did not register any drug-related serious adverse events) and tolerability during the treatment period (proportion who maintained treatment despite suspected drug-related adverse events).

Primary analyses were carried out in the intention-to-treat (ITT) population, which included all participants who entered the treatment phase. After excluding two enrollees in the 30 mg fasudil group who withdrew consent prior to baseline, the ITT population numbered 118 (fasudil 30 mg group, n = 35; fasudil 60 mg group, n = 39; placebo group, n = 44).

According to the results, the proportion estimates of enrollees without treatment-related serious events was 1 (95% CI, 0.91-1) for placebo, 1 (0.89-1) for fasudil 30 mg and 1 (0.9 to 1) for fasudil 60 mg; the difference in proportions was 0 (95% CI –0.11 to 0.1) for fasudil 30 mg vs. placebo and 0 (–0.1 to 0.1) for fasudil 60 mg vs. placebo.

Data further showed that treatment was tolerable for all 35 individuals given 30 mg fasudil, for 35 of 39 for those given 60 mg fasudil and for 41 of 44 participants in the placebo group.

Adverse events occurred in 108 patients in the fasudil 30 mg group, 105 patients in the fasudil 60 mg group and 139 participants in the placebo group. Serious adverse events, which included respiratory failure, gastrostomy, pneumonia and dysphagia, were few, while no serious adverse events or deaths were related to treatment, according to the researchers. Eight deaths unrelated to treatment were recorded: six in the fasudil cohorts and two in the placebo cohort.

The researchers acknowledged that efficacy could be better determined with a better sustained treatment framework, longer treatment duration and focus on oral administration in higher doses.

“Our results suggest that fasudil 30 mg and 60 mg delivered intravenously is safe and tolerable,” Koch and colleagues wrote. “These findings support further investigation of this drug as a potential disease-modifying treatment for patients with ALS.”