Discovery Pre-Clinical Phase 1 Phase 2 Phase 3
PTH Antagonist

Oral PTH Antagonist

Parathyroid hormone (PTH) regulates calcium and phosphate homeostasis in bone and kidney through activation of its receptor, PTHR1. Our team hypothesizes that blocking PTH action via a PTH receptor antagonist may provide an improved therapeutic mechanism to treat patients with primary hyperparathyroidism (PHPT) as well as those with humoral hypercalcemia of malignancy (HHM).

For the Treatment of Primary Hyperparathyroidism (PHPT)

Primary hyperparathyroidism (PHPT) arises from a small, benign tumor on one or more of the parathyroid glands , which results in oversecretion of parathyroid hormone (PTH), leading to increased blood calcium levels (hypercalcemia). Some patients experience no symptoms, many can have surgery to remove the tumor and/or hyperactive gland(s), while some require management with medical therapy. Symptomatic PHPT is characterized by skeletal, renal, gastrointestinal, and neurological manifestations with increased mortality.

For the Treatment of Humoral Hypercalcemia of Malignancy (HHM)

Humoral hypercalcemia of malignancy (HHM) typically arises in patients with advanced-stage cancers. In cases of HHM, oversecretion of parathyroid hormone-related peptide (PTHrP) caused by the malignant tumor results in bone resorption and calcium reabsorption in the kidney, leading to hypercalcemia.

We have identified potent and orally available nonpeptide PTH antagonists that also exhibit good oral exposure in preclinical species, activity in preclinical models, and appropriate drug-like properties. Currently, we are evaluating a subset of potential candidate molecules via a battery of pharmacology and safety studies to identify the optimal one(s) suitable for evaluation in human clinical trials.

Effects of an Orally Bioavailable Nonpeptide Parathyroid Hormone Receptor Type 1 (PTH1R) Antagonist in Rodent Models of Primary Hyperparathyroidism (PHPT)
Agnes S. Antwan, Elizabeth Rico-Bautista, Joseph Pontillo
Poster: Annual Meeting of the Endocrine Society (ENDO); 6/17/2023

Discovery and Characterization of a Potent and Orally Bioavailable Parathyroid Hormone Receptor Type-1 (PTHR1) Antagonist for the Treatment of Hypercalcemia
Elizabeth Rico-Bautista, Joseph Pontillo, Shimiao Wang, et al.
Poster: Annual Meeting of the Endocrine Society (ENDO); 6/11/2022

Discovery of Potent and Orally Bioavailable Nonpeptide Parathyroid Hormone Receptor Type-1 (PTHR1) Antagonists for the Treatment of Primary Hyperparathyroidism (PHPT)
Elizabeth Rico-Bautista, Joseph Pontillo, Melissa A. Fowler, et al.
Poster: Annual Meeting of the American Society for Bone and Mineral Research (ASBMR); 10/3/2021