SEP-631 was evaluated in a randomized, double-blind, placebo-controlled Phase 1 trial in healthy volunteers across single-ascending dose, multiple-ascending dose and food-effect cohorts. The compound showed complete inhibition of icatibant-induced skin wheals at doses ≥10 mg daily and near-complete blockade at 90–200 mg, with a 24-hour half-life, no serious adverse events and pharmacokinetics supporting once-daily oral dosing.

Septerna plans to initiate a randomized, double-blind, placebo-controlled Phase 2b trial of SEP-631 in moderate-to-severe chronic spontaneous urticaria during the second half of 2026, enrolling patients symptomatic despite second-generation antihistamines. An open-label study for chronic inducible urticaria in dermatographism patients will follow, alongside exploratory assessments in atopic dermatitis, interstitial cystitis, migraine and asthma.

SEP-631 functions as a negative allosteric modulator of the MRGPRX2 receptor, providing insurmountable blockade of mast cell activation. The data validate Septerna’s Native Complex Platform® approach to GPCR drug discovery and support further development in mast cell-driven diseases with high unmet need.