The Effects of Fasinumab on Peripheral Nerve Function and Ganglion Anatomy: Results From a Randomized, Double-Blind, Placebo-Controlled Study in Patients With Pain Due to Osteoarthritis of the Knee or Hip, and a Series of Nonclinical Studies.

Purpose: Osteoarthritis (OA) is a chronic disease where breakdown and loss of cartilage leads to pain, primarily in the joints. Nerve growth factor inhibitors (eg, fasinumab) can reduce pain, but have been associated with nervous system adverse events (AEs). Here we describe the results of a Phase 2, randomized, double-blind, placebo-controlled study and a series of nonclinical analyses investigating the effects of fasinumab on peripheral nerve function and ganglion anatomy. Methods: In the Phase 2 study, 180 adults with knee or hip OA and moderate-to-severe pain inadequately controlled with analgesics, who could not tolerate/were unwilling to take opioids, received subcutaneous fasinumab 1 mg every 4 weeks or placebo for 12 weeks. The primary endpoint was change from baseline to Week 16 in conduction velocity and amplitude for the peroneal, sural, and ulnar nerves. Secondary endpoints included peripheral sensory events. The nonclinical analyses involved adult and developing Sprague-Dawley rats and developing cynomolgus monkeys; endpoints included baseline and isoproterenol‑induced hemodynamic parameters, dorsal root ganglia (DRG) and superior cervical ganglia (SCG) volumes, neuron volumes and counts, and volumes and counts of specific neural subsets. Findings: In the Phase 2 study, nerve conduction velocities and action potential amplitudes between baseline and Week 16 were generally within normal ranges. There were no compelling differences in nerve conduction tests between fasinumab- and placebo-treated patients. Incidences of AEs, including peripheral sensory AEs, were similar between fasinumab and placebo. In the nonclinical analyses, neither hemodynamic parameters nor DRG and SCG stereological parameters were statistically significantly different between fasinumab-treated and isotype control antibody-treated rats. Implications: No clinically meaningful differences were observed between fasinumab- and placebo-treated patients for nerve conduction velocities and action potential amplitudes. In the nonclinical studies, no significant changes could be detected in adult rat ganglion anatomical parameters or hemodynamic parameters at a variety of fasinumab doses. Results from these studies demonstrated that fasinumab did not affect the tested nervous system parameters in adult humans or rats.Trial registration number: NCT02447276; https://clinicaltrials.gov/study/NCT02447276.