Septerna Advances MRGPRX2 Inhibitor SEP-631 to Clinical Testing for Chronic Urticaria and Mast Cell Disorders
Key Insights
Septerna will present Phase 1 clinical trial data for SEP-631, an oral MRGPRX2 (search) negative allosteric modulator, at the 2026 AAAAI Annual Meeting in Philadelphia.
SEP-631 targets MRGPRX2 (search), a receptor crucial for mast cell activation and degranulation that contributes to debilitating symptoms in chronic spontaneous urticaria (search) and other inflammatory conditions.
The first-in-human study utilizes innovative short wave infrared imaging to assess drug response through icatibant skin challenge testing.
Septerna, Inc. will present clinical data from its Phase 1 trial of SEP-631, a selective oral small molecule targeting the Mas-related G protein-coupled receptor X2 (MRGPRX2 (search)), at the upcoming 2026 American Academy of Allergy Asthma (search) & Immunology (AAAAI) Annual Meeting. The biotechnology company is developing this negative allosteric modulator for chronic spontaneous urticaria (search) (CSU) and other mast cell-driven diseases.
Novel Mechanism Targets Mast Cell Activation
SEP-631 represents a new therapeutic approach by selectively inhibiting MRGPRX2 (search), a receptor that plays an important role in mast cell activation and degranulation. According to Septerna, this process, combined with other inflammatory mediators, leads to debilitating symptoms for patients with CSU and related conditions.
The MRGPRX2 (search) receptor is highly and uniquely expressed on mast cells implicated in multiple diseases beyond CSU, including asthma (search), atopic dermatitis (search), interstitial cystitis (search), and migraine (search). This broad expression pattern suggests potential applications across various mast cell-mediated disorders.
Innovative Clinical Trial Design
The Phase 1 study, titled "First-In-Human, Proof-of-Mechanism Phase 1 Study of the Oral MRGPRX2 (search) Antagonist SEP-631 Utilizing Short Wave Infrared Imaging to Assess Response to an Icatibant Skin Challenge," employs an innovative approach to measure drug efficacy. The trial uses short wave infrared imaging technology to assess patient response to an icatibant skin challenge, providing objective measurements of the drug's mechanism of action.
The data will be presented as a late-breaking poster (L58) on March 1, 2026, from 9:45-10:45 a.m. ET at the Pennsylvania Convention Center in Philadelphia during the AAAAI Annual Meeting.
Preclinical Foundation
In preclinical studies, SEP-631 demonstrated potent and long-lasting inhibition of MRGPRX2 (search) and successfully blocked mediator-induced skin extravasation in mice engineered to express the human MRGPRX2 receptor. These results provided the scientific foundation for advancing the compound into human clinical testing.
GPCR Drug Discovery Platform
Septerna's development of SEP-631 stems from the company's proprietary Native Complex Platform™, designed to enable new approaches to G protein-coupled receptor (GPCR) drug discovery. The clinical-stage biotechnology company is advancing programs across endocrinology, immunology and inflammation, metabolic diseases, and additional therapeutic areas, both independently and with partners.
The company positions itself as pioneering a new era of GPCR drug discovery, leveraging a team of GPCR experts and drug developers to unlock the full potential of GPCR therapies for patients with significant unmet needs.