Palo Alto-based Evommune, Inc. (NYSE: EVMN) reported that its oral MRGPRX2 antagonist EVO756 failed to meet its primary endpoint in a Phase IIb trial in moderate-to-severe chronic spontaneous urticaria, closing off what had been the molecule's lead commercial indication and forcing a strategic pivot toward atopic dermatitis and migraine.
The randomized, double-blind, placebo-controlled, dose-ranging study enrolled 160 antihistamine-refractory CSU patients across the US, Europe, Canada, and Japan. Participants received one of three active dose regimens or placebo over 12 weeks. The primary endpoint — mean change in the Urticaria Activity Score over seven days (UAS7) — was not met at any dose. No numerical efficacy data were disclosed. The company described the safety and tolerability profile as acceptable across all doses studied, preserving optionality for the ongoing programs.
The failure is analytically significant because CSU was the indication for which EVO756 had generated the most clinical momentum. Phase I data in 132 healthy volunteers demonstrated clear target engagement via an icatibant skin challenge model. A subsequent Phase II study in chronic inducible urticaria — a related but mechanistically distinct condition — reported clinical responses in 93% of patients at four weeks and a 30% complete response rate, with improvements seen as early as week one. That earlier signal, generated in a smaller, self-controlled trial design, did not translate into statistically significant efficacy against placebo in the larger, more rigorous CSU study. The disconnect raises questions about whether the MRGPRX2 pathway plays a sufficiently central role in antihistamine-refractory CSU to drive meaningful UAS7 improvements over 12 weeks.
The result also complicates the broader MRGPRX2 antagonist thesis in CSU. South San Francisco-based Septerna, Inc. (Nasdaq: SEPN) reported positive Phase I data for its MRGPRX2 negative allosteric modulator SEP-631 in March 2026, demonstrating robust icatibant-induced wheal suppression, and plans to initiate a Phase IIb CSU trial in the second half of 2026. Evommune's CSU failure will raise the bar for how SEP-631's Phase II is designed and interpreted, particularly regarding the translatability of pharmacodynamic skin challenge data to clinical endpoints in spontaneous urticaria.
Pipeline repositioning