Septerna (SEPN) investor relations material

Lead PTH1R program

• SEP-479, a long-acting PTH1R agonist for hypoparathyroidism, has a 3–4-day half-life; phase I includes single- and multiple-ascending-dose cohorts, 14 days of once-daily dosing and a food-effect study, with data expected in Q1 next year.

• Healthy-monkey dosing reduced endogenous PTH by ~80% and increased calcium; the target is a starting calcium rise near 0.5 mg/dL, with headroom toward 1 mg/dL.

• SEP-786 was discontinued after two participants developed severe unconjugated bilirubin increases; it inhibited UGT1A1, while SEP-479 uses a different binding pocket and chemical series and does not inhibit the enzyme.

• Following phase I, plans include a global phase II with a few dozen patients and 2–3 starting doses; chronic toxicology studies are planned before phase II, with an open-label extension also intended.

Graves’ disease and thyroid eye disease

• SEP-204 is a selective TSH-receptor negative allosteric modulator; the oral program is designed to avoid inhibiting related FSH and LH receptors.

• In rats, 1 and 3 mg/kg doses normalized thyroid hormone levels, while 10 mg/kg suppressed them; dose selection may allow normalization without replacement, a possibility to test clinically.

• In an eight-week mouse model, two weeks of SEP-204 treatment began to normalize thyroid histology and thyroid size and showed reversal of eye bulging; 28-day rat and dog GLP tox effects were consistent with exaggerated on-target hypothyroidism.

• Planned phase I begins in healthy volunteers to characterize pharmacology, including TSH increases and possible thyroid hormone decreases; Graves’ patient testing is intended once a relevant dose range is established.

• An oral option could address both Graves’ disease and thyroid eye disease; development may pursue Graves’ first or a dual-indication path, guided by emerging data.

Other pipeline programs

• SEP-631 remains in development after a disappointing CSU study; smaller, cost-effective signal-finding studies are planned, potentially in migraine next year, with asthma and interstitial cystitis also under consideration.

• The osteoporosis PTH1R program is at discovery stage with no candidate yet; it requires a separate short-acting molecule with a half-life in single-digit hours, versus days for SEP-479, and preclinical data are hoped for next year.

• BMD is now an acceptable primary endpoint for osteoporosis pivotal studies instead of fracture reduction, potentially enabling smaller, shorter studies; an oral anabolic agent could complement existing antiresorptives and injectable anabolics.