Redafamdastat (PF-04457845): A Comprehensive Pharmacological and Clinical Development Monograph of a Selective FAAH Inhibitor

Executive Summary

Redafamdastat, also known by its developmental codes PF-04457845 and JZP-150, is an investigational small molecule designed as a highly potent, selective, and irreversible inhibitor of the enzyme Fatty Acid Amide Hydrolase (FAAH). The therapeutic rationale for its development was centered on the hypothesis that inhibiting FAAH would elevate levels of the endogenous cannabinoid anandamide and other fatty acid amides, thereby producing therapeutic benefits such as analgesia and anxiolysis without the adverse effects associated with direct cannabinoid receptor agonists. The compound's medicinal chemistry design was highly successful, yielding a molecule with excellent oral bioavailability, central nervous system (CNS) penetration, and a pharmacodynamic profile suitable for once-daily dosing.

The clinical development of Redafamdastat is a study in contrasts, marked by a significant translational failure and a promising, mechanism-aligned success. A well-controlled Phase 2 trial for osteoarthritis of the knee (NCT00981357) failed to demonstrate any analgesic efficacy compared to placebo, despite achieving profound target engagement with over 96% inhibition of FAAH activity in patients. This definitive negative result, which stood in stark opposition to robust efficacy in preclinical pain models, effectively invalidated the therapeutic hypothesis for this indication and significantly curtailed the drug's commercial prospects. Conversely, a Phase 2a trial in men with cannabis use disorder (CUD) (NCT01618656) yielded compelling positive results, published in The Lancet Psychiatry. Treatment with Redafamdastat significantly reduced cannabis withdrawal symptoms, decreased cannabis use, and attenuated withdrawal-induced sleep disturbances. This outcome provided strong clinical validation for the role of FAAH inhibitio