SARM1 inhibition to prevent chemotherapy-induced peripheral neuropathy: Translational and early clinical evaluation of SIR2501.

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.