ORF16-05 - Characterization of SEP-479, a Novel Oral Small Molecule PTH1R Agonist for the Treatment of Hypoparathyroidism

Hypoparathyroidism (HypoPT) is a rare endocrine disorder caused by insufficient production of parathyroid hormone (PTH), resulting in hypocalcemia and hyperphosphatemia. Patients with HypoPT suffer from severe muscle cramps, tingling, numbness, brain fog, and reduced quality of life. HypoPT has traditionally been managed with calcium and vitamin D supplements; however, these do not fully ameliorate the disease and may contribute to tissue calcification and renal disease. Recently approved PTH replacement therapies have been effective; however, they require life-long injections. Here we characterize SEP-479, a novel oral small-molecule parathyroid hormone 1 receptor (PTH1R) agonist drug candidate that demonstrates robust pharmacologic activity in vitro and in vivo and has the potential to offer clinical advantages.

In the rat osteosarcoma UMR-106 cell line, treatment with SEP-479 produced robust and dose-dependent modulation of osteogenic and osteoclastogenic gene expression, including Bglap (osteocalcin), Sost (sclerostin), Tnfsf11 (RANKL), and Tnfrsf11b (osteoprotegerin). These genes play central and coordinated roles in the regulation of bone remodeling by controlling osteoblast activity, osteocyte signaling, and osteoclast differentiation. The observed changes in gene expression are consistent with PTH-mediated pharmacologic mechanisms that influence both bone formation and resorption pathways.

In vivo, oral administration of SEP-479 to normal rats and non-human primates resulted in dose-dependent increases in serum calcium concentrations accompanied by corresponding reductions in endogenous PTH levels. These reciprocal changes are consistent with physiological feedback regulation and provide evidence of target engagement and downstream biological activity across species, recapitulating effects previously demonstrated following PTH treatment.

In a rat thyroparathyroidectomy (TPTx) model, which reproduces key features of HypoPT, once-daily oral dosing of SEP-479 over 28 days achieved sustained normalization of serum calcium and phosphate levels. Treatment was also associated with modulation of key biomarkers of bone turnover, reflecting effects on skeletal remodeling, as well as changes in circulating active vitamin D. Collectively, these findings demonstrate that SEP-479 exerts pharmacodynamic effects on mineral homeostasis and bone metabolism following chronic administration, with a profile that closely mirrors the physiological effects of PTH treatment.

For patients with HypoPT, functional PTH replacement with an oral small-molecule PTH1R agonist that effectively controls serum calcium has the potential to reduce calcium and vitamin D supplementation, lower the risk of tissue calcification and renal disease, improve quality of life, and offer an alternative to injectable PTH peptide therapies.