Septerna Begins First-in-Human Trial of SEP-631 for CSU

Septerna, Inc., a biotechnology company focused on G protein-coupled receptor (GPCR) drug discovery, has announced the initiation of a phase 1 clinical trial (NCT07069036) evaluating SEP-631. The compound is a selective oral small molecule negative allosteric modulator (NAM) of the Mas-related G protein-coupled receptor X2 (MRGPRX2), being developed as a potential therapy for chronic spontaneous urticaria (CSU) and other mast cell-driven diseases.^1,2

The randomized, placebo-controlled trial includes both single-ascending dose (SAD) and multiple-ascending dose (MAD) components, with enrollment anticipated for up to 150 healthy adult volunteers. The SAD portion will assess the safety, tolerability, and pharmacokinetics (PK) of escalating oral doses, while the MAD phase will evaluate repeated dosing. Pharmacodynamic (PD) activity will be measured through an icatibant skin challenge model.

Targeting Mast Cell Activation

CSU, one of the most common mast cell-driven conditions, is a chronic inflammatory skin disease characterized by persistent hives, angioedema, and severe itching. Mast cell activation and subsequent degranulation, leading to the release of histamine and other inflammatory mediators, underlie the disease process. Antihistamines remain the first-line treatment; however, a significant number of patients fail to respond, highlighting the unmet need for novel oral therapies.

MRGPRX2 has emerged as a key receptor involved in mast cell activation. Unlike histamine-driven mechanisms alone, MRGPRX2-mediated pathways contribute to broad mast cell degranulation, positioning it as a therapeutic target across multiple disorders. According to Septerna, SEP-631 aims to selectively inhibit MRGPRX2 signaling, potentially reducing inappropriate mast cell activation.

“Mast cell-driven diseases represent significant unmet medical needs worldwide, affecting millions of patients who often struggle with inadequate symptom relief with current therapies,” said Jae Kim, MD, chief medical officer of Septerna, in a news release. “We are excited to initiate the first-in-human trial for SEP-631, a small molecule NAM that aims to inhibit mast cell activation by selectively blocking MRGPRX2, a GPCR that plays a critical role in mast cell activation and degranulation. SEP-631 has the potential to provide a convenient oral treatment option for patients with CSU and other mast cell-driven diseases. As we initiate this phase 1 trial, we look forward to further demonstrating the potential of our Native Complex Platform to discover new ways to modulate GPCR targets to develop novel medicines for patients in need of better treatment options."

Potential Beyond CSU

In addition to CSU, mast cells are implicated in several other conditions, including asthma, atopic dermatitis, interstitial cystitis, and migraine. Given the receptor’s selective expression on mast cells, Septerna stated MRGPRX2 inhibition could represent a broader therapeutic strategy for diseases characterized by inappropriate mast cell activation.

According to the company, preclinical studies with SEP-631 demonstrated potent and durable inhibition of MRGPRX2. In a mouse model engineered with the human receptor, the compound blocked mediator-induced skin extravasation, suggesting translational potential for human disease.

A Platform for GPCR Drug Discovery

Septerna emphasizes that SEP-631 is the first clinical candidate to advance from its proprietary Native Complex Platform, designed to address the structural complexity of GPCR drug discovery. GPCRs are one of the most widely studied target classes in drug development, with roles spanning endocrinology, immunology, metabolic disorders, and other therapeutic areas. By enabling the discovery of small molecules that modulate GPCRs with higher selectivity and precision, the company aims to expand therapeutic options in diseases with significant unmet needs.

Looking Ahead

While the therapeutic promise of targeting MRGPRX2 remains early in clinical evaluation, the mechanism may represent a novel approach in mast cell-driven disease management. If successful, SEP-631 could provide an alternative to current therapies that often leave patients with limited relief.

For clinicians managing CSU and related conditions, emerging therapies like SEP-631 underscore the evolving landscape of treatment strategies aimed at better controlling mast cell activity and improving patient outcomes.

References

1. Seterna announces dosing of the first participants in phase 1 clinical trial of SEP-631, an oral small molecule MRGPRX2 negative allosteric modulator for the treatment of mast cell-driven diseases. News release. Septerna. August 21, 2025. Published August 21, 2025. https://ir.septerna.com/news-releases/news-release-details/septerna-announces-dosing-first-participants-phase-1-clinical
2. Elieh-Ali-Komi D, Metz M, Kolkhir P, et al. Chronic urticaria and the pathogenic role of mast cells. Allergol Int. 2023;72(3):359-368. doi:10.1016/j.alit.2023.05.003