E‐52862—A selective sigma‐1 receptor antagonist, in peripheral neuropathic pain: Two randomized, double‐blind, phase 2 studies in patients with chronic postsurgical pain and painful diabetic neuropathy

Abstract

BackgroundWe report the efficacy and safety of E‐52862—a selective, sigma‐1 receptor antagonist—from phase 2, randomized, proof‐of‐concept studies in patients with moderate‐to‐severe, neuropathic, chronic postsurgical pain (CPSP) and painful diabetic neuropathy (PDN).MethodsAdult patients (CPSP [N = 116]; PDN [N = 163]) were randomized at a 1:1 ratio to 4 weeks of treatment with E‐52862 (CPSP [n = 55]; PDN [n = 85]) or placebo (CPSP [n = 61]; PDN [n = 78]) orally once daily. Pain intensity scores were measured using a numerical pain rating scale from 0 (no pain) to 10 (worst pain imaginable). The primary analysis population comprised patients who received study drug with ≥1 baseline and on‐treatment observation (full analysis set).ResultsIn CPSP, mean baseline average pain was 6.2 for E‐52862 vs. 6.5 for placebo. Week 4 mean change from baseline (CFB) for average pain was −1.6 for E‐52862 vs. –0.9 for placebo (least squares mean difference [LSMD]: −0.9; p = 0.029). In PDN, mean baseline average pain was 5.3 for E‐52862 vs. 5.4 for placebo. Week 4 mean CFB for average pain was −2.2 for E‐52862 vs. –2.1 for placebo (LSMD: –0.1; p = 0.766). Treatment‐emergent adverse events (TEAEs) were reported in 90.9% of E‐52862‐treated patients vs. 76.7% of placebo‐treated patients in CPSP and 34.1% vs. 26.9% in PDN. Serious TEAEs occurred in CPSP only: E‐52862: 5.5%; placebo: 6.7%.ConclusionsE‐52862 demonstrated superior relief of CPSP vs. placebo after 4 weeks. Reductions in pain intensity were seen in PDN with E‐52862; high placebo response rates may have prevented differentiation between treatments. E‐52862 had acceptable tolerability in both populations.Significance StatementThese proof‐of‐concept studies validate the mode of action of E‐52862, a selective sigma‐1 receptor antagonist. In CPSP, E‐52862 resulted in clinically meaningful pain relief. In PDN, reductions in pain intensity were seen with E‐52862; high placebo response rates may have prevented differentiation between E‐52862 and placebo. These findings are clinically relevant given that neuropathic pain is highly incapacitating, lacking effective treatments and representing a significant unmet medical need, and support further development of sigma‐1 receptor antagonists for peripheral neuropathic pain.