LY-3526318

Transient receptor potential ankyrin 1 (TRPA1) is implicated in physiological and pathological nociceptive signaling, but the clinical benefit of TRPA1 antagonists in chronic pain is not clearly demonstrated. LY3526318 is an oral, potent, and selective novel TRPA1 antagonist. The Chronic Pain Master Protocol was used to evaluate the safety and efficacy of LY3526318 in 3 randomized, placebo-controlled, proof-of-concept studies in knee osteoarthritis pain (OA), chronic low back pain (CLBP), and diabetic peripheral neuropathic pain (DPNP). Participants were randomized (1:2, placebo:LY3526318, 250 mg daily) into an 8-week double-blinded period. At 4 weeks, participants treated with LY3526318 transitioned to a placebo. The primary endpoint was the self-reported daily pain intensity measured using a Numerical Rating Scale (NRS) at 4 weeks. All endpoints were collected for up to 8 weeks. Change from baseline in average weekly NRS was analyzed using Bayesian mixed model repeated measures in the OA (N = 160), CLBP (N = 159), and DPNP (N = 154) studies. Baseline characteristics were balanced between treatment arms. Mean NRS change from baseline to week 4 did not differ significantly between placebo and LY3526318; however, a numerical improvement was observed in the CLBP, not in the OA or DPNP populations. Safety analysis integrated across studies enhanced understanding of the safety profile of LY3526318. LY3526318 showed a potential drug-induced hepatotoxic effect posing a risk for clinical development. No other safety signals were identified. LY3526318 showed potential for different responses among chronic pain indications and patient subpopulations, highlighting challenges in developing TRPA1 antagonists but supporting their value as a target in managing chronic pain.

Transient receptor potential Ankyrin 1 (TRPA1) is an ion channel expressed by sensory neurons, where it mediates pain signaling. Consequently, it has emerged as a promising target for novel analgesics, yet, to date, no TRPA1 antagonists have been approved for clinical use. In the present translational study, we utilized dermal blood flow changes evoked by TRPA1 agonist cinnamaldehyde as a target engagement biomarker to investigate the in vivo pharmacology of LY3526318, a novel TRPA1 antagonist. In rats, LY3526318 (1, 3, and 10 mg/kg, p.o.) dose‐dependently reduced the cutaneous vasodilation typically observed following topical application of 10% v/v cinnamaldehyde. The inhibition was significant at the site of cinnamaldehyde application and also when including an adjacent area of skin. Similarly, in a cohort of 16 healthy human volunteers, LY3526318 administration (10, 30, and 100 mg, p.o.) dose‐dependently reduced the elevated blood flow surrounding the site of 10% v/v cinnamaldehyde application, with a trend toward inhibition at the site of application. Comparisons between both species reveal that the effects of LY3526318 on the cinnamaldehyde‐induced dermal blood flow are greater in rats relative to humans, even when adjusting for cross‐species differences in potency of the compound at TRPA1. Exposure‐response relationships suggest that a greater magnitude response may be observed in humans if higher antagonist concentrations could be achieved. Taken together, these results demonstrate that cinnamaldehyde‐evoked changes in dermal blood flow can be utilized as a target engagement biomarker for TRPA1 activity and that LY3526318 antagonizes the ion channel both in rats and humans.