Septerna, Inc. has announced the dosing of the first participants in its Phase 1 clinical trial of SEP-631, a selective oral small molecule Mas-related G protein-coupled receptor X2 (MRGPRX2) negative allosteric modulator being developed for chronic spontaneous urticaria (CSU) and other mast cell-driven diseases. The milestone marks the first-in-human testing of this novel therapeutic approach targeting mast cell activation.
The Phase 1 single-ascending dose (SAD) and multiple-ascending dose (MAD) clinical trial will evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of SEP-631 in healthy adult volunteers. The randomized, placebo-controlled study is expected to enroll up to approximately 150 participants.
Addressing Significant Unmet Medical Need
"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, M.D., chief medical officer of Septerna. "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."
CSU is a systemic inflammatory skin disease characterized by the spontaneous and persistent recurrence of itchy, painful hives and angioedema. While there is no known trigger, the activation and degranulation of mast cells and release of histamine and other inflammatory mediators lead to these debilitating symptoms. While patients are initially treated with antihistamines, a significant portion do not respond to therapy, underscoring the need for new oral treatment options.
Novel Mechanism of Action
SEP-631 works as a negative allosteric modulator of MRGPRX2, a receptor that has emerged as a key player 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. The compound aims to selectively inhibit MRGPRX2 signaling, potentially reducing inappropriate mast cell activation.
In preclinical studies, SEP-631 demonstrated potent and long-lasting inhibition of MRGPRX2 and blocked mediator-induced skin extravasation in mice engineered to express the human MRGPRX2 receptor, suggesting translational potential for human disease.
Trial Design and Endpoints
The Phase 1 trial includes both SAD and MAD components. Dosing is currently underway in the SAD portion, which will evaluate the safety and tolerability of SEP-631 at escalating oral doses. The MAD portion will assess the safety and tolerability of oral doses over the treatment period, with pharmacodynamic activity measured through an icatibant skin challenge model.
Broader Therapeutic Potential
Beyond CSU, mast cells are implicated in multiple other diseases, including asthma, atopic dermatitis, interstitial cystitis, and migraine, representing additional potential opportunities for an MRGPRX2-targeted therapy. Given the receptor's selective expression on mast cells, MRGPRX2 inhibition could represent a broader therapeutic strategy for diseases characterized by inappropriate mast cell activation.
Platform Technology Advancement
SEP-631 represents the first clinical candidate to advance from Septerna's proprietary Native Complex Platform™, designed to enable new approaches to GPCR drug discovery. The platform aims to address the structural complexity of GPCR drug development by enabling the discovery of small molecules that modulate GPCRs with higher selectivity and precision.
"SEP-631 has the potential to provide a convenient oral treatment option for patients with CSU and other mast cell-driven diseases," Kim added. "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."
