Gálvez, RafaelMayoral, VíctorCebrecos, JesúsMedel, Francisco J.Morte, AdelaidaSust, MarianoVaqué, AnnaMontes Pérez, AntonioNeira-Reina, FernandoCánovas, LuzMargarit, CésarBouhassira, Didier2025-11-122025-11-122025Galvez R, Mayoral V, Cebrecos J, Medel FJ, Morte A, Sust M, Vaque A, Montes-Perez A, Neira-Reina F, Canovas L, Margarit C, Bouhassira D. 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. Eur J Pain. 2025 Jan;29(1):e4755. DOI: 10.1002/ejp.47551090-3801http://hdl.handle.net/10230/71872Background: 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.application/pdfeng© 2024 Esteve Pharmaceuticals, S.A and The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Neuropatiainfo:eu-repo/semantics/article2025-11-12http://dx.doi.org/10.1002/ejp.4755info:eu-repo/semantics/openAccess