A Phase 2 trial exploring the novel microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitor vipoglanstat in patients with systemic sclerosis-related Raynaud’s phenomenon (RP) did not meet its primary efficacy endpoint, despite achieving robust pharmacologic inhibition and a favorable safety profile.
The randomized, double-blind, placebo-controlled trial enrolled 69 individuals with systemic sclerosis and frequent RP attacks. Participants were assigned to receive either vipoglanstat 120 mg daily or placebo for four weeks. Eligible patients reported at least seven RP attacks in the week prior to randomization. A daily electronic diary was used to capture attack frequency, duration, pain, and the Raynaud’s Condition Score. The primary outcome was the change in weekly RP attacks, while secondary and exploratory assessments included cold challenge recovery, global impression of change, patient-reported outcomes, and biochemical markers of drug activity.
Although both groups showed a reduction in weekly RP attacks from baseline, by 3.4 in the vipoglanstat group and 4.2 in the placebo group, the difference was not statistically significant. Similarly, improvements in patient-reported outcomes such as pain and symptom severity were observed in both arms without meaningful separation. Peripheral blood flow recovery following cold challenges also failed to distinguish the treatment from the placebo. Pharmacodynamically, vipoglanstat performed as expected. Complete inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) was confirmed, with a 57% reduction in urinary prostaglandin E2 levels and a 50% increase in prostacyclin metabolites, underscoring successful target engagement. The treatment was well tolerated, with no new safety concerns.
One potential strategy to enhance blood flow to the fingers in patients with systemic sclerosis involves targeting the prostacyclin pathway. A novel method for augmenting this pathway is through inhibition of mPGES-1, a terminal enzyme that converts the unstable cyclooxygenase-derived intermediate prostaglandin H2 (PGH2) into prostaglandin E2 (PGE2). In the arachidonic acid cascade, alternative synthases can convert PGH2 into prostacyclin, thromboxane, and other bioactive lipids. Inhibiting mPGES-1 redirects PGH2 towards these alternate pathways, promoting increased synthesis of prostacyclin. This shift has been observed in mouse peritoneal macrophages, mPGES-1 knockout models, and in humans following pharmacological mPGES-1 inhibition. Enhancing prostacyclin production in this manner may offer therapeutic benefits for patients with SSc-associated Raynaud’s phenomenon.
Vipoglanstat (also known as GS-248 and BI 1029539), developed by Gesynta Pharma, is currently undergoing Phase II clinical trials for endometriosis, a condition in which mPGES-1 is thought to play a key role in driving inflammation, pain, and lesion formation. Preclinical studies have shown that vipoglanstat significantly reduces both pain and the number of endometrial lesions, supporting its potential as a disease-modifying therapy.
Although a recent study did not demonstrate clinical efficacy in systemic sclerosis-associated Raynaud’s phenomenon, vipoglanstat showed a favorable safety profile and evidence of biological activity. These findings suggest that future development may be better directed toward conditions where the pathogenic role of mPGES-1 is more clearly defined, such as endometriosis.
Reference
Tornling G, Edenius C, Pauling JD, Denton CP, Olsson A, Kowalski J, et al. A phase 2 trial investigating the efficacy and safety of the mPGES-1 inhibitor vipoglanstat in systemic sclerosis-related Raynaud’s. Rheumatology (Oxford). 2025 Feb 1;64(2):704-713.