Septerna announced that its oral MRGPRX2 negative allosteric modulator, SEP‑631, achieved dose‑dependent inhibition of icatibant‑induced skin wheal formation in a randomized, double‑blind, placebo‑controlled Phase 1 trial in healthy volunteers. Complete inhibition was observed at a 10 mg once‑daily dose, with higher doses producing progressively greater suppression. The safety profile was comparable to placebo, and no serious adverse events were reported.
Pharmacokinetic analysis showed a half‑life of approximately 24 hours and no significant food effect, supporting the drug’s once‑daily oral dosing schedule. The pharmacodynamic data provide clinical proof‑of‑mechanism for the MRGPRX2 pathway, a target implicated in a range of mast‑cell‑driven disorders.
The results validate Septerna’s Native Complex Platform™ and reinforce the company’s strategy of developing orally available GPCR modulators. SEP‑631’s success positions the company to address chronic spontaneous urticaria (CSU) and other mast‑cell‑mediated conditions such as chronic inducible urticaria, atopic dermatitis, interstitial cystitis, migraine, and asthma.
Septerna plans to initiate a Phase 2b trial in CSU in the second half of 2026, pending completion of long‑term toxicology studies. The company also intends to pursue the additional indications mentioned above and has a collaboration with Novo Nordisk that provides financial backing and validates the platform’s broader therapeutic potential.
Financially, Septerna maintains a strong cash position that supports operations through early 2028. The company reported a net loss of $71.8 million for the full year 2024, but the cash reserves and ongoing pipeline activities provide a solid runway for continued development.
"Importantly, the robust inhibition of icatibant‑induced wheal formation observed is consistent with the differentiated insurmountable NAM mechanism we characterized preclinically and provides clinical proof‑of‑mechanism for the MRGPRX2 pathway. Overall, we believe the strength and consistency of these results position SEP‑631 as a potentially differentiated oral treatment for patients living with mast cell‑driven diseases," said Jae Kim, M.D., Chief Medical Officer of Septerna. "These data mark an important milestone for the SEP‑631 program and more broadly for our Native Complex Platform®, which enables new approaches to GPCR drug discovery by reconstituting functional GPCR complexes outside of cells."
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