Septerna (SEPN) TD Cowen 46th Annual Health Care Conference summary

Key program updates

• SEP-631, a potent MRGPRX2 negative allosteric modulator, showed strong phase I results with full inhibition of skin wheal formation and a favorable safety and PK profile, supporting once-daily oral dosing.

• SEP-631 phase II trial in chronic spontaneous urticaria is planned for the second half of the year, with a 12-week, dose-ranging, placebo-controlled design and potential long-term extension.

• Chronic toxicology studies for SEP-631 (six-month rat, nine-month dog) will be completed mid-year to support long-term extension and further de-risk the program.

• SEP-479, an oral PTH agonist for hyperparathyroidism, has completed IND-enabling studies and is set to enter phase I trials in Australia within months.

• SEP-479 demonstrated normalization of serum calcium in preclinical models and a long projected human half-life, with titration and monitoring strategies to be refined in phase II.

Platform and pipeline strategy

• The Native Complex Platform enables targeting of difficult GPCRs, focusing on well-validated targets with early clinical readouts.

• Pipeline includes TSH receptor program for Graves' disease and a Novo collaboration on incretin receptors, with additional early-stage assets.

• Cash runway extends into at least 2029, supporting ongoing and future clinical development.

Mechanistic and clinical insights

• SEP-631 binds a novel, inducible cryptic pocket in the MRGPRX2 receptor, causing conformational changes that block activation by endogenous agonists.

• The compound’s high binding affinity and slow off-rate ensure sustained receptor coverage, with no significant preclinical liver toxicity or expected drug-drug interactions.

• MRGPRX2 pathway is implicated in multiple diseases beyond urticaria, including atopic dermatitis, asthma, and pain syndromes, with further indications under evaluation.