Woolsey Pharmaceuticals has announced the completion of patient enrollment for the high-dose cohort of its Phase 2a REAL trial (NCT05218668), which is evaluating the Rho kinase (ROCK) inhibitor Bravyl (oral fasudil) in individuals with amyotrophic lateral sclerosis (ALS). This milestone follows encouraging safety and efficacy findings from the initial group receiving a 180 mg daily dose, prompting the investigation of a higher 300 mg dose to potentially enhance therapeutic benefits. Results from the high-dose cohort are anticipated by mid-2025.
Rationale for ROCK Inhibition in ALS
In ALS patients, elevated levels of ROCK, an enzyme implicated in inflammation and cell death while hindering nerve cell regeneration, are commonly observed. ROCK inhibitors like fasudil are designed to counteract these detrimental processes, potentially reducing nerve cell death and offering a therapeutic avenue for ALS and other neurodegenerative conditions. Fasudil is already approved in Japan for specific stroke types.
Bravyl's Clinical Development
Bravyl, Woolsey's oral formulation of fasudil, has recently been granted three U.S. patents covering its use in slowing the progression of sporadic ALS, as well as solid and liquid formulations tailored for patients with swallowing difficulties (dysphagia), a prevalent symptom of ALS.
The initial phase of the REAL study involved 31 participants receiving a daily 180 mg dose of Bravyl for six months. Data revealed a significant 15% decrease in neurofilament light chain (NfL) levels, a key biomarker of nerve damage, following the treatment period. Furthermore, greater reductions in NfL correlated with slower declines on the ALS Functional Rating Scale-Revised (ALSFRS-R), a standard clinical measure of disease progression.
Compared to an external control group from an ALS database, treated patients demonstrated clinical improvements, including a 17% slower deterioration in ALSFRS-R scores, 37% slower declines in lung function, and 56% slower declines in muscle strength.
Ongoing Research and Future Directions
The promising results from the initial cohort led to the enrollment of a second group of patients receiving the higher 300 mg daily dose. The findings from this group will be crucial in determining the optimal dose for future clinical trials. Participants in both dosing groups have the option to continue receiving Bravyl for up to 2.5 additional years in an open-label extension phase after completing the primary six-month trial.
Data from an investigator-initiated Phase 2 trial, ROCK-ALS (NCT03792490), published in The Lancet Neurology, also supports the therapeutic potential of fasudil in ALS. This study assessed a fasudil formulation administered intravenously to 120 patients with early-stage ALS, in addition to standard therapies. The results indicated that the treatment was well-tolerated and significantly preserved motor neurons compared to placebo. While other outcome measures such as ALSFRS-R scores and survival did not show significant differences, researchers attributed this to the short treatment duration.
Sven Jacobson, Woolsey’s CEO, noted that the ROCK-ALS data are “very encouraging” for Woolsey’s ongoing research into the use of oral fasudil for ALS, even though that trial did not specifically test the Bravyl formulation.
These findings also support Raya Therapeutic's development of RT1968, another version of fasudil, with plans for more extensive clinical studies in ALS patients based on the positive ROCK-ALS results.
