D2.297 - SEP-631: A Novel Selective and Potent Oral MRGPRX2 Inhibitor for the Treatment of Chronic Spontaneous Urticaria

Mast cells play a key role in chronic spontaneous urticaria (CSU), a systemic inflammatory skin disease characterized by hives, itch and angioedema caused by mast cell degranulation and release of histamine and inflammatory mediators. While antihistamines and anti-IgE therapies alleviate symptoms in patients, only ~36% of antihistamine-refractory cases respond to anti-IgE treatment. Identification of Mas-related G-protein coupled receptor member X2 (MRGPRX2) on skin mast cells highlights a novel pathway of activation and degranulation implicated in CSU pathogenesis.

Using Septerna’s Native Complex Platform™, we employed a structure-based drug design approach to identify SEP-631, a potent and selective small molecule that acts as negative allosteric modulator of MRGPRX2.

SEP-631 potently inhibits cortistatin-14 (C-14)-induced MRGPRX2 activation in MRGPRX2-overexpressing HEK293 cells, demonstrating strong suppression of maximal MRGPRX2 agonist effects. SEP-631 also blocks IP1 accumulation triggered by several endogenous MRGPRX2 agonists. SEP-631 binds exclusively to human MRGPRX2 and lacks detectable inhibition of MRGPRX2 species orthologs or human paralogs.

In the human mast cell line LAD2, SEP-631 effectively inhibits C-14-induced degranulation, as evidenced by reduced β-hexosaminidase (β-hex) release and suppression of inflammatory cytokine and chemokine production. Similarly, in primary human cord blood-derived mast cells, SEP-631 robustly blocks β-hex and histamine release triggered by Substance P, a MRGPRX2 agonist implicated in pathogenesis of CSU. Importantly, in primary human skin mast cells, SEP-631 demonstrates potent inhibition of Substance P-stimulated tryptase release, a key mediator in CSU pathobiology contributing to hives and swelling by promoting vascular permeability and inflammation.

Using a humanized MRGPRX2 knock-in mouse model, SEP-631 demonstrates robust inhibition of skin mast cell degranulation in vivo. Oral dosing of SEP-631 completely blocks C-14-induced mast cell-mediated skin extravasation evidenced by reduced Evans Blue dye leakage.

These studies collectively establish SEP-631 as a highly potent and selective MRGPRX2 inhibitor, effectively blocking mast cell activation across a range of endogenous agonists. This targeted mechanism minimizes the risk of broad immunosuppression. Our results support further development of SEP-631 as a promising novel oral therapy for potential treatment of CSU and other mast cell-mediated diseases.