12148 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, cumulative, and often irreversible toxicity that limits dose intensity, disrupts cancer treatment, and substantially impairs quality of life. Despite its prevalence, no approved disease-modifying therapies exist. Axonal degeneration is a central pathological driver of CIPN. Sterile alpha and TIR motif–containing protein 1 (SARM1) is a key executioner of programmed axon degeneration across neurotoxic insults. Inhibiting SARM1 offers a mechanism-based strategy to prevent axonal injury without compromising anticancer activity. SIR2501 is a potent, selective, orally bioavailable small-molecule SARM1 inhibitor in clinical development for CIPN prevention. Methods: SIR2501 was evaluated in rodent models of paclitaxel (PTX)-induced peripheral neuropathy using prophylactic and therapeutic dosing paradigms. Endpoints included sensory neuropathy (mechanical allodynia), axonal injury biomarkers (serum neurofilament light chain sNfL), and peripheral nerve integrity (intraepidermal nerve fiber density). The impact of SIR2501 on PTX antitumor efficacy was assessed in rodent tumor models.A randomized, double-blind, placebo-controlled Phase 1 study in healthy volunteers evaluated safety, pharmacokinetics (PK), CNS penetration, and pharmacodynamic evidence of SARM1 target engagement following single and multiple ascending doses. Results: SIR2501 robustly attenuated PTX-induced neuropathy in preclinical models, with concordant functional, biomarker, and structural protection, and did not impair PTX-mediated tumor growth inhibition. In Phase 1, 82 volunteers received SIR2501 (up to 600 mg single dose; up to 150 mg once-daily multiple dose). SIR2501 was well tolerated, with no dose-limiting toxicities or clinically meaningful neurologic adverse events. PK supported once-daily dosing with minimal food effect and no CYP3A-mediated drug–drug interaction risk. Dose- and exposure-dependent suppression of circulating cyclic ADP-ribose (cADPR) confirmed SARM1 target engagement at plasma exposures aligned with preclinical efficacy. Conclusions: These translational data support SARM1 inhibition as a disease-modifying approach for CIPN. These data have enabled initiation of a global Phase 1b/2 trial of SIR2501 in patients receiving taxane-based chemotherapy in the United States, Australia, and China.
Yu et al. (Wed,) studied this question.