A phase 2, proof-of-concept, placebo-controlled, randomized, multicenter, double-blind study to evaluate the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of Usnoflast (ZYIL1) in patients with amyotrophic lateral sclerosis

<i>Objective</i>: To assess the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of Usnoflast (ZYIL1) in patients with amyotrophic lateral sclerosis (ALS). <i>Methods</i>: Patients with a probable or definite ALS diagnosis were randomized to receive twice daily oral doses (for 12 weeks) of Usnoflast (25 mg, 50 mg, or 75 mg) or placebo. The primary outcome was the change in ALS functional rating scale-revised (ALSFRS-R) total score from baseline to week 12. Secondary outcomes were assessment of PK, change in slow vital capacity (SVC) and serum and cerebrospinal fluid (CSF) levels of neurofilament light (NfL) chain from baseline to week 12, and safety up to 12 weeks. <i>Results</i>: Total 24 patients were enrolled; 71% of those who received Usnoflast had the drug above therapeutic concentration in CSF. In the modified intent-to-treat (mITT) population, least square mean changes (ANCOVA) in ALSFRS-R total score from baseline to week 12 were -1.91 for Usnoflast 25 mg, -3.84 for Usnoflast 50 mg, 0.52 for Usnoflast 75 mg, and -2.26 for placebo arm. Though not significant (<i>p</i> > 0.05), compared with placebo, Usnoflast 75 mg demonstrated a difference of 2.78 (mITT) and 3.28 (per-protocol) in ALSFRS-R total score. Statistical non-significant differences were also observed in changes of SVC% and CSF NfL levels. Usnoflast was well-tolerated at tested doses, and there was no treatment-emergent serious adverse event or death during the study duration. <i>Conclusion</i>: Usnoflast 50 and 75 mg doses were well-tolerated in ALS patients, providing rationale for further studies of Usnoflast in ALS.