O-195 Vipoglanstat, an oral non-hormonal treatment in clinical development for endometriosis

Abstract Study question Evaluation of vipoglanstat, a potent and selective mPGES-1 inhibitor, as a potential new non-hormonal, non-opioid oral treatment for endometriosis. Summary answer Vipoglanstat is safe and tolerable at doses anticipated to have beneficial effects in endometriosis and is currently under clinical development for this condition. What is known already Prostaglandin E2 (PGE2) is a key driver of endometriosis pathogenesis and progression1. Microsomal Prostaglandin E Synthase-1 (mPGES-1), the terminal enzyme in proinflammatory PGE2 biosynthesis, is upregulated in endometriotic lesions2. Disease models demonstrate reduced lesion growth in mPGES-1 KO mice3 and attenuated pain with mPGES-1 inhibitor treatment4. Hence, mPGES-1 is a promising target for non-hormonal treatment of endometriosis. Vipoglanstat is an orally active, potent mPGES-1 inhibitor that has demonstrated excellent pain relief and lesion reduction in an advanced disease model. 1Sacco K et al 2012; 2Rakhila et al 2013; 3Numao A et al 2011; 4Koppitz M et al 2019 Study design, size, duration In a Phase I trial 72 healthy volunteers aged 18-69 years (35 women) received oral single (1-300mg) or 10-day repeated (20-180mg) doses of vipoglanstat or placebo (randomised 3:1). In a subsequent, placebo-controlled, randomised (1:1), Phase II trial 69 subjects aged 23-71 years (60 women) with chronic inflammatory disease (systemic sclerosis) received 120mg vipoglanstat or placebo daily for one month. Participants/materials, setting, methods Both trials (healthy volunteers and subjects with chronic inflammation) evaluated safety/tolerability, pharmacokinetics, LPS-induced PGE2 production in whole blood, and biosynthesis of PGE2 and prostacyclin assessed by analysis of urinary metabolites. Main results and the role of chance Vipoglanstat displayed a mean terminal half-live of 6 - 11 h with proportionality between dose and systemic exposure (Cmax and AUC0-last) over the dose range 20-300 mg. Pharmacokinetic profile supports once/twice daily oral dosing. Vipoglanstat was safe and well tolerated in healthy subjects and those with chronic inflammatory disease at doses giving full mPGES-1 inhibition and adverse events profiles were similar in the placebo and vipoglanstat-treated cohorts. Single doses ≥40mg completely inhibited mPGES-1 ex vivo in whole blood for 24 hours (IC50=0.3 nM) in healthy subjects. In patients with chronic inflammatory disease complete inhibition of mPGES-1 by vipoglanstat was also demonstrated. Both trials confirmed inhibition through reduced urinary excretion of PGE2 metabolites after repeat dosing (42 - 60% at 20 - 180 mg and 57% at 120 mg, respectively). Concomitantly, an increase in urinary prostacyclin metabolites compared to baseline was seen (83 - 204% and 50%, respectively), demonstrating selective inhibition of the proinflammatory PGE2, while preserving production of the vasoprotective prostacyclin – a key advantage over commonly used coxibs and NSAIDs. The results from these studies confirm that both safety/tolerability, pharmacodynamics and pharmacokinetics of vipoglanstat are robust, and support further clinical investigation in endometriosis patients. Limitations, reasons for caution Based on the strong scientific rationale for mPGES-1 inhibitors in endometriosis, the utility of vipoglanstat in women with endometriosis should be confirmed in a clinical setting. Wider implications of the findings A 4-months, placebo-controlled Phase II trial starting in 2025 will investigate the safety and efficacy of two doses of vipoglanstat in patients with moderate to severe endometriosis. Primary objective will be effects on endometriosis-related pain. Lesion load assessed by trans-vaginal-sonography (TVS) and magnetic resonance imaging (MRI) will also be evaluated. Trial registration number Yes