Septerna, Inc. (SEPN), a clinical-stage biotechnology company pioneering small-molecule therapies targeting G protein-coupled receptors (GPCRs), announced positive results from its Phase 1 clinical trial of SEP-631 for the treatment of Mast Cell-Driven Diseases. SEP-631, developed by Septerna, is a selective oral small molecule Mas-related G protein-coupled receptor X2 (MRGPRX2) negative allosteric modulator (NAM) for the treatment of patients with chronic spontaneous urticaria (CSU) and other mast-cell driven diseases. The Phase 1 study is a randomised, double-blind, placebo-controlled trial in healthy volunteers, assessing SEP-631's safety, tolerability, pharmacokinetics, and pharmacodynamics across single-ascending-dose, multiple-ascending-dose, and food-effect cohorts.
SEP-631 was well tolerated, showed a pharmacokinetic profile supportive of once-daily dosing, and provide clear evidence of MRGPRX2 pathway inhibition. SEP-631 demonstrated a pharmacokinetic profile supportive of convenient once-daily oral dosing, including a half-life of approximately 24 hours and no clinically meaningful effect of food on exposure, according to Septerna. Pharmacodynamic activity was assessed using Icatibant-induced skin wheal formation, an established skin test that measures mast cell activation and target engagement.Short-wave infrared imaging technology was used to measure wheal formation, providing precise assessment for mast cell activity. Also, SEP-631 produced robust suppression of wheal formation across evaluated dose levels, with complete inhibition observed at doses as low as 10 mg once daily following the 10 µg/mL icatibant challenge. Following the 100 µg/mL icatibant challenge, inhibition was dose-dependent, with progressively greater suppression observed at increasing SEP-631 doses, with near-complete inhibition achieved at 90 and 200 mg once daily. Septerna noted that SEP-631 was well-tolerated across all doses, with an adverse event profile comparable to placebo, no severe adverse events, and no clinically meaningful laboratory or ECG abnormalities. These results also validate Septerna's Native Complex Platform, which enables new approached to GPCR drug discovery by reconstructing functional GPCR complexed outside of cells.
Based on these results, Septerna plans to initiate a Phase 2b clinical trial of SEP-631 in chronic spontaneous urticaria (CSU) in the second half of this year and to continue evaluating additional mast cell-driven indications. The planned Phase 2b study will be a randomized, double-blind, placebo-controlled, global trial evaluating once-daily oral SEP-631 in adult patients with moderate-to-severe CSU who remain symptomatic despite treatment with second-generation antihistamines. Following the expansion to CSU, the firm also plans to pursue an open-label study in chronic inducible urticaria (CIndU), specifically in patients with symptomatic dermatographism.Septerna is also evaluating SEP-631 in other mast cell-driven diseases, including atopic dermatitis, interstitial cystitis, migraine and asthma. Septerna is scheduled to host a conference call and webcast on Monday, March 2, 2026, at 8:00 a.m. ET to discuss the Phase 1 results and initial Phase 2 development strategy for SEP-631. "Overall, we believe the strength and consistency of these results position SEP-631 as a potentially differentiated oral treatment for patients living with mast cell-driven diseases," said Jae Kim, M.D., chief medical officer of Septerna. SEPN has traded between $4.66 and $32.63 in the last one year. The stock closed Friday's trade at $29.02, down 4.16%
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