Targeting MRGPRX2: Early Human Data for a Novel CSU Approach

Chronic spontaneous urticaria (CSU) remains a frustrating condition for both patients and clinicians. Despite the availability of antihistamines, omalizumab, and immunosuppressive options, a meaningful subset of patients continue to experience persistent wheals, angioedema, and impaired quality of life.¹ This ongoing unmet need has driven interest in mast cell pathways beyond the classic IgE–FcεRI axis.

At the upcoming 2026 American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting, Septerna will present phase 1 data for SEP-631, an oral small molecule targeting Mas-related G protein-coupled receptor X2 (MRGPRX2). The poster will describe a first-in-human, proof-of-mechanism study designed to explore whether selective inhibition of MRGPRX2 can attenuate mast cell–mediated skin responses in humans.²

Why MRGPRX2?

MRGPRX2 has emerged over the past decade as a clinically relevant mast cell receptor distinct from IgE-mediated activation. It is highly expressed on connective tissue mast cells, particularly in the skin, and responds to a broad range of cationic ligands, including neuropeptides, antimicrobial peptides, and several drugs known to cause pseudoallergic reactions. Activation of MRGPRX2 leads to rapid mast cell degranulation and release of histamine and other mediators.

In CSU, where mast cell activation is central but often not fully explained by IgE-driven mechanisms, MRGPRX2 has been proposed as a contributor to disease activity, particularly in patients who respond incompletely to anti-IgE therapy. This has made the receptor an attractive target for drug development, though clinical translation has remained limited until recently.

SEP-631: Mechanism and Rationale

SEP-631 is a selective, oral small molecule negative allosteric modulator of MRGPRX2. Rather than competing directly with endogenous ligands at the primary binding site, negative allosteric modulation aims to dampen receptor signaling by altering receptor conformation. In theory, this approach may offer greater selectivity and reduce off-target effects, a common concern with GPCR-directed therapies.

Preclinical studies cited by the company have shown that SEP-631 produces potent and sustained inhibition of human MRGPRX2 signaling. In mouse models engineered to express the human receptor, the compound blocked mediator-induced vascular leakage in the skin, a surrogate for mast cell–driven inflammation. These findings provided the rationale for advancing SEP-631 into first-in-human studies.

Phase 1 Study Design

The phase 1 trial being presented at AAAAI was designed as a proof-of-mechanism study rather than an efficacy trial in patients with CSU. According to the poster title, investigators used an icatibant skin challenge to provoke a localized mast cell–mediated response. Icatibant, a bradykinin B2 receptor antagonist, is known to induce wheal-and-flare reactions when injected intradermally, serving as a controlled inflammatory stimulus.

A notable feature of the study is the use of short-wave infrared (SWIR) imaging to assess treatment response. SWIR imaging allows for noninvasive visualization of changes in tissue perfusion and fluid extravasation beneath the skin surface, potentially offering a more quantitative and objective assessment than traditional visual scoring alone.

The poster, titled “First-In-Human, Proof-of-Mechanism Phase 1 Study of the Oral MRGPRX2 Antagonist SEP-631 Utilizing Short Wave Infrared Imaging to Assess Response to an Icatibant Skin Challenge,” will be presented during the Late Breaking Poster Session at the meeting.

Interpreting Early-Phase Data

As with all phase 1 studies, the primary goals are safety, tolerability, and evidence of biological activity, not clinical efficacy. While inhibition of a provoked skin response would support target engagement, it does not necessarily predict benefit in the chronic, multifactorial setting of CSU.

That said, demonstrating measurable modulation of mast cell–driven responses in humans would represent an important step forward for the field. It would also help validate MRGPRX2 as a druggable target and inform the design of subsequent trials in patients with CSU or other mast cell–driven diseases.

Broader Implications

Beyond CSU, MRGPRX2 has been implicated in a range of conditions where mast cells play a role, including asthma, atopic dermatitis, interstitial cystitis, and migraine. Whether inhibition of this receptor will translate into meaningful clinical benefit across these indications remains an open question.

For clinicians, SEP-631 and similar agents raise the possibility of more targeted oral therapies that address non-IgE mast cell activation pathways. However, questions around patient selection, long-term safety, and combination with existing treatments will need to be addressed in later-phase trials.

Looking Ahead

The data presented at AAAAI 2026 will provide an early glimpse into the clinical feasibility of MRGPRX2 inhibition. While it is too early to draw conclusions about therapeutic impact, the study reflects a growing effort to move beyond symptom control and toward mechanism-based treatment strategies in CSU.

As additional details emerge, clinicians will be watching closely to see whether this approach can meaningfully expand the treatment landscape for patients with refractory disease.

References

1. Greenberger PA. Chronic urticaria: new management options. World Allergy Organ J. 2014;7(1):31. Published 2014 Nov 5. doi:10.1186/1939-4551-7-31
2. Septerna to present data from phase 1 clinical trial of SEP-631 for the treatment of mast cell-driven diseases at 2026 AAAAI annual meeting. News release. Septerna. Published February 10, 2026. Accessed February 10, 2026. https://ir.septerna.com/news-releases/news-release-details/septerna-present-data-phase-1-clinical-trial-sep-631-treatment