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

Background: We 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).

Methods: Adult 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).

Results: In 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%.

Conclusions: E-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 statement: These 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.

FIGURE 1

Study design for the CPSP and PDN studies. CPSP, chronic postsurgical pain; D, day; PDN, painful diabetic neuropathy; QD, once daily; R, randomization.

FIGURE 2

Patient disposition in the (a) CPSP Study and (b) PDN Study. CPSP, chronic postsurgical pain; PDN, painful diabetic neuropathy.

FIGURE 3

Overall mean 24‐h pain intensity by NPRS over the previous 7 days in the CPSP Study (full analysis set): (a) Overall average pain; (b) Overall worst pain; (c) Average pain in patients with non‐spinal surgery; and (d) Worst pain in patients with non‐spinal surgery. Corresponding data for patients with spinal surgery are reported in Figure S1. CI, confidence interval; CPSP, chronic postsurgical pain; LS, least squares; NPRS, numerical pain rating scale; SD, standard deviation.

FIGURE 4

Mean 24‐h average (a) and worst (b) pain intensity by NPRS over the previous 7 days in the PDN Study (full analysis set). CI, confidence interval; LS, least squares; NPRS, numerical pain rating scale; PDN, painful diabetic neuropathy; SD, standard deviation.