Demonstration of an anti-hyperalgesic effect of a novel pan Trk inhibitor PF-06273340 in a battery of human evoked pain models.

Abstract

Aim(s)

Inhibitors of nerve growth factor (NGF) reduce pain in several chronic pain indications. NGF signals through tyrosine kinase receptors of the tropomyosin-related kinase (Trk) family and the unrelated p75 receptor. PF-06273340 is a small molecule inhibitor of Trks A, B and C that reduces pain in nonclinical models and this study aimed to investigate the pharmacodynamics of this first in class molecule in humans.

Methods

A randomized, double blind, single dose, placebo and active-controlled 5 period cross-over study was conducted in healthy human subjects (NCT02260947). Subjects received 5 treatments: PF-06273340 50mg, PF-06273340 400mg, pregabalin 300mg, ibuprofen 600mg and placebo. The 5 primary endpoints were the pain detection threshold for the thermal pain tests and the pain tolerance threshold for the cold pressor, electrical stair and pressure pain tests. The trial had pre-defined decision rules based on 95% confidence that the PF-06273340 effect was better than placebo.

Results

20 subjects entered the study, with 18 completing all 5 periods. The high dose of PF-06273340 met the decision rules on the UVB skin thermal pain endpoint (LSMean versus placebo: 1.13, 95% confidence interval: 0.64-1.61), but not on the other 4 primary endpoints. The low dose did not meet the decision criteria for any of the 5 primary endpoints. Pregabalin (cold pressor and electrical stair) and ibuprofen (UVB thermal pain) showed significant analgesic effects on expected endpoints.

Conclusions

This study demonstrated for the first time translation of nonclinical effects into man in an inflammatory pain analgesic pharmacodynamic endpoint using a pan-Trk inhibitor.

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