Septerna (SEPN) investor relations material

Key program updates

• Phase I data for SEP-631, an MRGPRX2 negative allosteric modulator, showed strong safety, tolerability, and full inhibition of inflammatory skin response, supporting once-daily oral dosing and best-in-class potential.

• SEP-631 demonstrated >99% receptor occupancy, no food effect, and a 24-hour half-life, with plans to initiate a phase II trial in chronic spontaneous urticaria in the second half of the year.

• SEP-479, an oral PTH agonist for hyperparathyroidism, normalized calcium in preclinical models and is set to enter clinical trials soon, with IND-enabling studies completed.

• Chronic toxicology studies for SEP-631 are ongoing, with six-month rat and nine-month dog studies expected to complete mid-year to support long-term extension trials.

• The pipeline also includes a TSH receptor program for Graves' disease and a collaboration with Novo on incretin receptors.

Scientific and clinical insights

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

• The compound’s high affinity and slow off-rate ensure sustained receptor inhibition, with excess circulating drug maintaining full coverage.

• SEP-631’s mechanism is relevant for diseases with mast cell involvement, including urticaria, atopic dermatitis, asthma, and others, with CSU as the lead indication.

• SEP-479’s preclinical data in monkeys showed robust suppression of endogenous PTH and meaningful increases in calcium, supporting its clinical potential.

• Titration and monitoring strategies for SEP-479 in phase I/II will be informed by its long half-life and parallels to existing therapies like Yorvipath.

Forward-looking statements and strategy

• SEP-631 phase II will be a 12-week, placebo-controlled, dose-ranging study with a possible open-label extension; chronic tox data will be available before trial initiation.

• Additional indications for SEP-631 are under evaluation, including atopic dermatitis, interstitial cystitis, migraine, and asthma.

• SEP-479 phase I will use single and multiple ascending dose cohorts, with careful titration to avoid calcium extremes; phase II will involve individualized titration and monitoring.

• The company is well-capitalized with cash runway into at least 2029, supporting ongoing and future clinical development.

• Collaboration with Novo on incretin and other GPCR targets continues to progress alongside internal pipeline advancement.