Slide 1: Characterization of SEP-479, a Novel Oral Small Molecule PTH1R Agonist for Hypoparathyroidism
Characterization of SEP-479, a Novel Oral Small Molecule PTH1R Agonist for the Treatment of Hypoparathyroidism Marko Groeger, Sunny Tang, Xiaohui Du, Jialu Wang, Ryan Strachan, Jasleen K. Sodhi, Matthew S. Holdren, Jun Zhang ENDO 2026 June 13, 2026 © 2026 SEPTERNA
Slide 2: Endocrine Society educational program views statement
The views expressed in this educational program are those of the faculty and do not necessarily represent the views of the Endocrine Society.
Slide 3: Disclosure
Disclosure • All authors are current employees and stockholders of Septerna, Inc., South San Francisco, CA, USA © 2026 SEPTERNA 3
Slide 4: Hypoparathyroidism: Significant Unmet Need for an Oral PTH Replacement
Hypoparathyroidism: Significant Unmet Need for an Oral PTH Replacement Hypoparathyroidism: Low PTH leads to low blood calcium PTH: Master Regulator of Blood Calcium • ~70K patients in US; ~140K patients in EU Challenging patient symptoms • Muscle cramps, tingling, brain fog • Life-threatening compli
Slide 5: SEP-479: Discovered with Native Complex Platform as a Potent Oral PTH1R Agonist
SEP-479: Discovered with Native Complex Platform® as a Potent Oral PTH1R Agonist Clinical Candidate for Hypoparathyroidism Native Complex Platform® Hit Identification and Structure-Based Optimization SEP-479: Clinical Candidate Multiple PTH1R agonists with distinct binding sites identified and optim
Slide 6: SEP-479 Engaged PTH1R Pathway Similar to PTH (1-34) in Bone Cells
SEP-479 Engaged PTH1R Pathway Similar to PTH (1-34) in Bone Cells Gene expression analysis comparing SEP-479 to PTH (1-34) • Rat osteosarcoma UMR-106 cells were treated with PTH (1-34) or SEP-479 for 5 hours; gene expression analyzed by quantitative RT-PCR SEP-479 demonstrated PTH1R-mediated pharmac
Slide 7: Hypoparathyroidism Preclinical Model in Rats: Thyroparathyroidectomy (TPTx)
Hypoparathyroidism Preclinical Model in Rats: Thyroparathyroidectomy (TPTx) Rat surgical model of Robust serum PTH and serum calcium decreases hypoparathyroidism were observed 7 days following TPTx surgery Serum PTH Levels Serum Calcium Levels Rat 300 12 Surgery to remove Serum Calcium (mg/dL) parat
Slide 8: Acute Oral Treatment of SEP-479 Dose Dependently Regulated Serum Calcium and Phosphate
Acute Oral Treatment of SEP-479 Dose Dependently Regulated Serum Calcium and Phosphate in TPTx Rats Dose-dependent increase in serum calcium and decrease in phosphate were observed with SEP-479, with responses comparable to PTH peptide • TPTx rats received a single oral (PO) dose of SEP-479 or subcu
Slide 9: Chronic Daily Oral Treatment of SEP-479 Normalized Serum Calcium and Phosphate
Chronic Daily Oral Treatment of SEP-479 Normalized Serum Calcium and Phosphate in TPTx Rats SEP-479: 28-day TPTx Rat Pharmacodynamic Study 14 Serum Calcium (mg/dL) 12 Sustained Normalization of Serum Calcium Levels 10 8 6 4 hours 6 9 24 6 9 24 6 9 24 6 9 24 Day 1 Day 10 Day 19 Day 28 14 Serum Phosph
Slide 10: Chronic Treatment of SEP-479 Improved Renal Mineral Homeostasis in TPTx Rats
Chronic Treatment of SEP-479 Improved Renal Mineral Homeostasis in TPTx Rats SEP-479 treatment (PO, QD x 28 days) resulted in a PTH-like renal pharmacology profile: • Decrease in urinary calcium concentration • Increase in active Vitamin D (1,25-dihydroxyvitamin D) production Urinary Calcium Active
Slide 11: Chronic Treatment of SEP-479 Engaged Bone Remodeling in TPTx Rats
Chronic Treatment of SEP-479 Engaged Bone Remodeling in TPTx Rats SEP-479 (PO, QD x 28 days) demonstrated PTH-like bone effects: • Dose-dependent decrease in bone mineral density, reflecting a catabolic outcome • Increase in serum bone catabolic marker C-terminal telopeptides of type I collagen (CTX
Slide 12: SEP-479 Lowered Endogenous PTH and Increased Serum Calcium in Monkeys
SEP-479 Lowered Endogenous PTH and Increased Serum Calcium In a Cynomolgus Monkey Pharmacodynamic Study Dose-dependent decrease in serum PTH levels and increase in serum calcium levels were observed with SEP-479 in a 7-day pharmacodynamic study in cynomolgus monkeys Serum PTH Levels Serum Calcium Le
Slide 13: SEP-479 Preclinical Profile Supported Advancement into Phase 1
SEP-479 Preclinical Profile Supported Advancement into Phase 1 • SEP-479 is a novel oral small molecule parathyroid hormone 1 receptor (PTH1R) agonist drug candidate for the treatment of hypoparathyroidism. • SEP-479 demonstrated effects comparable to PTH peptides in cell-based assays and in vivo mo
Slide 14: © 2026 SEPTERNA
© 2026 SEPTERNA