To evaluate elismetrep in the acute treatment of migraine

TRPM8, a cation channel expressed in trigeminal and other nociceptive neurons, is associated with migraine in genome-wide association studies suggesting potential as a therapeutic target.  No trials testing TRPM8 antagonism in migraine have been reported.  Elismetrep is a selective oral TRPM8 antagonist.

We conducted a randomized, placebo-controlled, double-blind Phase 2b study (NCT# 06848075). Participants with 2-10 migraine attacks/month were randomized 2:1:2:2:1 to treat one migraine of moderate-severe pain with placebo or 2, 5, 10, or 20 mg elismetrep.  Randomization was stratified by use of migraine preventive agents.  An eDiary was used to collect efficacy data pre- and post-dose. Efficacy endpoints, assessed at 2h, were pain freedom (primary), freedom from most bothersome symptom (secondary), and pain relief (secondary).  Primary analyses used only eDiary data. A pre-specified analysis of the primary endpoint used data collected by recall if 2h entries were missed.                   

Of 431 participants randomized, 398 treated a qualifying migraine (mean age 46; 87% female; 35% on migraine preventive agents, 31% triptan resistant). In the primary and supporting analyses for pain freedom response rates for elismetrep 20 mg vs. placebo were 17.6% vs. 9.1% (odds ratio [OR]=2.1, P= 0.0650); and 19.6% vs. 9.1% (OR=2.4, nominal P=0.0344), respectively.  Response rates for freedom from most bothersome symptom for elismetrep 20 mg vs. placebo were 38.3 % vs. 24.2% (OR=1.9, nominal P=0.0425). Response rates for pain relief for elismetrep 20 mg vs. placebo were 58.8% vs. 42.4% (OR=1.9, nominal P=0.0293). There were no serious AEs. At 20 mg, all AEs were mild (70%) or moderate. The most common AEs in the 20 mg group were oral paresthesia (9.8%), feeling hot (9.8%), paresthesia (7.8%), hot flush (7.8.%), and flushing (5.9%).

Elismetrep represents an entirely novel direction for treatment of migraine.