Patient Recruitment Complete for High-Dose Cohort of Oral Fasudil in Phase 2 ALS Study

Sven Jacobson, chief executive officer at Woolsey

According to a recent announcement, patient recruitment for the high-dose cohort of a phase 2 study (NCT05218668) assessing oral fasudil (Bravyl; Woolsey Pharmaceuticals), a stroke therapy in development for amyotrophic lateral sclerosis (ALS), is now complete. Study results from this group, who will receive 300 mg/day doses of fasudil, are expected to be released by mid-2025.¹

Fasudil is a small molecule inhibitor of rho-associated kinase (ROCK) and is approved for the treatment of subarachnoid hemorrhage. Otherwise known as REAL, the high dose cohort for the study includes 31 patients with a diagnosis of probable or definite ALS, as defined by El Escorial Revised ALS diagnostic criteria. The study primarily looks at safety, though incidence of adverse events (AEs) and serious AEs, but also other secondary outcomes such as change in ALS Functional Rating Scale-Revised (ALSFRS-R), slow vital capacity (SVC), and change in the slope of decline in muscle strength.

The previous cohort, the low-dose cohort A that studied fasudil at doses of 180 mg/day, demonstrated promising results on biomarkers related to ALS progression. In this patient population, patients saw a 15% decrease in neurofilament light (NfL), a biomarker of neuroaxonal damage, over a 6-month treatment period. In addition, when compared with a matched historical control, investigators observed a 17% lower decline in ALSFRS-R, a 37% lower decline in SVC, and a 56% lower decline in muscle strength. Above all, greater decreases in NfL were correlated with less deterioration on the ALSFRS-R (P = .028).

"Experience with this higher dose in ALS patients will be invaluable as we progress to a larger study," Sven Jacobson, chief executive officer at Woolsey, said in a statement. "Furthermore, recently published results from a university-led, three-arm, double-blind study of fasudil in patients with ALS found a relationship between dose and improved motor neuron function, which is very encouraging for our ongoing research."

Participants in Cohort 2, the high-dose cohort, will only attend one screening visit (Screening 1, V1) instead of two. Their rate of decline for study entry will be calculated from the date their ALS symptoms began. If they qualify at this visit, they’ll be enrolled and return within 28 days to start treatment on Day 1. Notably, since Cohort 2 will not have a two-month pre-treatment lead-in period, they won’t be included in comparisons of decline rates before and during treatment. However, their results will be compared to historical data.

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Fasudil was previously tested in a phase 2 study of patients with ALS, dubbed ROCK-ALS (NCT03792490) that was published in The Lancet Neurology. In this double-blind, placebo-controlled study, the intent-to-treat population comprised 35 patients in the fasudil 30 mg group, 39 in the fasudil 60 mg group, and 44 in the placebo group. Over the 4-week treatment period, the therapy was considered safe and well tolerated, with AEs mainly related to disease progression.²

Data from that study showed that the estimated proportion without a drug-related serious AE was 1.00 (95% CI, 0.91-1.00) with placebo, 1.00 (0.89-1.00) with fasudil 30 mg, and 1.00 (0.90-1.00) with fasudil 60 mg. Treatment tolerability (the estimated proportion who did not discontinue) was 0·93 (95% CI 0.81-0.99) with placebo, 1·00 (0.90-1.00) with fasudil 30 mg, and 0·90 (0.76-0.97) with fasudil 60 mg. Notably, there were 2 deaths in the placeo group, 4 deaths in the fasudil 30 mg group and 2 deaths in the fasudil 60 mg group. Most deaths were related to respiratory failure as part of disease progression; none was judged to be related to the study drug or study procedures.

In ROCK-ALS, survival outcomes until the end of the trial did not significantly differ across the treatment groups. In terms of efficacy, the expected marginal means for the difference in the ALSFRS-R score from baseline to day 180 did not differ between groups: –6.50 (95% CI –8.16 to –4.84) with placebo, –7.94 (–9.72 to –6.17) with fasudil 30 mg, and –6.85 (–8.63 to –5.07) with fasudil 60 mg. Respiratory function, assessed by SVC, declined over time in all groups. Notably, in an exploratory analysis, a significant reduction in serum glial fibrillary acidic protein (GFAP) was observed on day 180 in the fasudil 60 mg group (0.75; 95% CI, 0.60-0.95) compared with placebo (0.90; 95% CI, 0.75-1.08; P = .041).

REFERENCES
1. Woolsey Pharmaceuticals Completes Patient Recruitment for High-Dose Cohort of ALS Study. Woolsey Pharmaceuticals. November 12, 2024. Accessed November 15, 2024. https://www.prnewswire.com/news-releases/woolsey-pharmaceuticals-completes-patient-recruitment-for-high-dose-cohort-of-als-study-302299710.html
2. Koch JC, Leha A, Bidner H, et al. Safety, tolerability, and efficacy of fasudil in amyotrophic lateral sclerosis (ROCK-ALS): a phase 2, randomized, double-blind, placebo-controlled trial. Lancet Neurol. 2024;23(11):1133-1146