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

National Center For Advancing Translational Sciences

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Abstract

The primary symptoms of hypoparathyroidism include muscle cramping, convulsions, intellectual disabilities, cataracts and abnormal heart rhythm. Symptoms are due to low serum calcium (hypocalcemia). Replacement of parathyroid hormone (PTH) has been explored to remedy the calcium deficiency characteristic of hypoparathyroidism, 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 184) or the active amino-terminal domain (PTH 134), 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 II proof-of-concept study for hypoparathyroidism by leveraging the existing data package. TRND scientists, in collaboration with researchers from Eli Lilly & Company, have further developed and validated the rat thyroidectomy model of hypoparathyroidism to generate robust efficacy data. Analytical and sensitive bioanalytical methods have been developed and validated, and TRND scientists manufactured active pharmaceutical ingredient under Good Laboratory Practice (GLP) guidelines. Achievement of these milestones will enable Eli Lilly & Company to continue development of PTH-RM for hypoparathyroidism.