Repurposing of a Long-Acting Parathyroid Hormone Analog for the Treatment of Hypoparathyroidism

Hypoparathyroidism is a rare hormone deficiency syndrome in which the body lacks parathyroid hormone (PTH). Due to PTH’s central role in maintaining the balance of calcium and phosphate in the blood, symptoms of hypoparathyroidism include muscle cramping, convulsions, intellectual disabilities, cataracts and abnormal heart rhythm. Hypoparathyroidism can occur after an injury to the parathyroid glands or following surgery or radiation treatment for thyroid cancer. It also may occur as a consequence of other rare genetic disorders or toxic exposures.

Attempts to replace PTH have shown limited usefulness. Due to a persistent lack of calcium, patients must receive high-dose calcium supplements, which can have negative effects on the kidneys. The goal of this project is to develop a PTH replacement that will demonstrate a more normal, stable physiological level of PTH activity and lessen the need for chronic high-dose calcium supplements.

Scientific Synopsis

The primary symptoms of hypoparathyroidism are due to low serum calcium (hypocalcemia). Replacement of PTH has been explored to remedy the calcium deficiency, but maintaining an optimal calcium level has proven problematic because hypercalcemia can occur as a result of excess PTH. Multiple efforts are under way targeting either full-length PTH (PTH 1–84) or the active amino-terminal domain (PTH 1–34), but these molecules have undesirable pharmacokinetic properties for chronic daily management of calcium levels in patients with hypoparathyroidism.

Eli Lilly scientists have identified a long-acting PTH receptor modulator (PTH-RM) that can normalize serum calcium. At fairly low doses, the PTH-RM was shown to normalize calcium levels in parathyroidectomized rats. The investigators are collaborating with TRND to develop this PTH-RM toward a Phase 2 proof-of-concept study for hypoparathyroidism by leveraging the existing data package.

Lead Collaborator

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis

Henry U. Bryant, Ph.D.

Public Health Impact

Insufficient PTH causes a range of symptoms, which must be managed in part through lifelong, high-dose supplements of calcium and vitamin D. Hospital and emergency room visits are common, and the high-dose supplements can cause kidney damage.


TRND scientists, in collaboration with researchers from Eli Lilly and Company, have further developed and validated the rat thyroparathyroidectomy model of hypoparathyroidism to generate robust efficacy data, including development of bioanalytical methods and assays. If all preclinical milestones are achieved, TRND plans to support the preparation and filing of the Investigational New Drug application with the Food and Drug Administration, as well as partnering with NIH clinical experts to support subsequent clinical trials in patients.