Septerna (SEPN) Study result summary

Study Background and Rationale

• SEP-631 is an oral negative allosteric modulator (NAM) targeting MRGPRX2, a key regulator of mast cell degranulation implicated in allergic and inflammatory diseases.

• MRGPRX2 activation leads to pain, itch, inflammation, and edema, making it a promising target for conditions like chronic urticaria, atopic dermatitis, and asthma.

• SEP-631 binds a novel allosteric site, potently inhibits MRGPRX2 activation, and demonstrates high binding affinity and slow dissociation.

• Preclinical studies showed potent inhibition of MRGPRX2-mediated responses and favorable pharmacokinetics supporting once-daily dosing.

• The program aims to address high unmet needs in mast cell-driven diseases, especially chronic spontaneous urticaria (CSU).

Phase I Study Design and Objectives

• Conducted a randomized, double-blind, placebo-controlled phase I trial with single and multiple ascending dose cohorts, plus a food effect arm.

• Doses ranged from 10 mg to 400 mg (single) and up to 200 mg once daily for 10 days (multiple).

• SAD (n=48) and MAD (n=64) cohorts evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics.

• Food effect was assessed in a crossover design (n=8), comparing SEP-631 exposure in fed versus fasted states.

• Pharmacodynamics were measured using an icatibant skin challenge and AllergyScope™ imaging.

Safety and Tolerability Results

• Adverse event rates were comparable to placebo across all dose cohorts, with no severe or serious adverse events.

• Mild, transient transaminase elevations occurred at similar rates in both SEP-631 and placebo groups.

• No dose-related or persistent safety signals emerged with repeat dosing.

• SEP-631 was well-tolerated in both preclinical and clinical studies, supporting a wide dosing range for future trials.

• Most adverse events were mild or moderate.