A Phase 2a/b, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Study to Evaluate the Efficacy and Safety of Linustedastat (OG-6219) in Women with Moderate to Severe Endometriosis-Related Pain

Felipe Arbelaez,1 Julia Yureneva,2 Per Larsson,3 Daniela Colaci,1 Keith Gordon,4 Leon Dupclay,5 Krzysztof Wilk61Department of Global Clinical Research, Organon, Jersey, NJ, USA; 2Department of Drug Safety, Organon, Jersey, NJ, USA; 3Department of Global Clinical Data Sciences, Organon, Stockholm, Sweden; 4Department of Global Medical Strategy, Organon, Jersey, NJ, USA; 5Department of Outcomes Research, Organon, Jersey, NJ, USA; 6NZOZ Medem, Katowice, PolandCorrespondence: Felipe Arbelaez, Department of Global Clinical Research, Organon, Jersey, NJ, USA, Tel +1551-430-6292, Email [email protected]: Endometriosis causes pelvic pain, dysmenorrhea (DYS), dyspareunia, and fertility issues. Linustedastat (OG-6219) is an oral, selective inhibitor of 17β-hydroxysteroid dehydrogenase type 1 (HSD17β 1), an enzyme involved in local estradiol biosynthesis. This study evaluated the efficacy, safety, and tolerability of linustedastat in pre-menopausal women aged 18– 49 years with moderate to severe endometriosis-related pain (ERP).Patients and Methods: In this global, phase 2a/b randomized, double-blind, placebo-controlled, multicenter study, eligible participants were randomized (1:1:1:1) to linustedastat 50/100/150mg twice daily, or placebo, for up to 12 weeks. Primary efficacy and safety endpoints were change in mean overall pelvic pain (OPP) score from baseline cycle (BC) to treatment cycle 3 (TRC3) and the proportion of participants reporting treatment-emergent adverse events (TEAEs), or serious adverse events (SAEs) during the study period, respectively. Secondary efficacy endpoints included change in DYS, non-menstrual pelvic pain (NMPP) and dyspareunia scores, and mean number of rescue medication tablets used from BC to TRC3. Key pharmacodynamic parameters were assessed. Pairwise comparisons were conducted between each dose group and placebo, and the differences were presented with 95% CI and two-sided p-values.Results: Overall, 353 patients (mean age of 35.2 years) were included. No statistically significant differences were reported between linustedastat and placebo for OPP, DYS, NMPP, or dyspareunia scores or in the number of rescue medication tablets used compared to placebo (p> 0.05) at any dose. Serum estrogens levels showed statistically significant differences versus placebo at visit 5 and visit 7; serum progesterone levels showed no differences. Linustedastat was generally well tolerated, with TEAEs of mild to moderate severity. A dose-related trend of methemoglobinemia was observed.Conclusion: Despite a theoretical rationale, selective inhibition of HSD17β 1 with linustedastat did not show any trends indicative of clinical efficacy in reducing ERP. Linustedastat was safe and well tolerated in pre-menopausal women with moderate to severe ERP.Clinical Trial Registration Information: A Study to Investigate Efficacy and Safety of OG-6219 BID in 3 Dose Levels Compared With Placebo in Participants Aged 18 to 49 With Moderate to Severe Endometriosis-related Pain (ELENA); NCT05560646; https://clinicaltrials.gov/study/NCT05560646.Keywords: dysmenorrhea, dyspareunia, endometriotic lesions, estrogen, HSD17β 1, overall pelvic pain