Long-acting PTH for hypoparathyroidism

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Project Summary Hypoparathyroidism is a rare disease that results from a deficiency or inability to make sufficient amounts of parathyroid hormone (PTH). Untreated or inadequately treated hypoparathyroidism leads to clinically significant mineral-related metabolic issues including hypocalcemia, which leads to heart arrhythmias, spasms of the vocal cords, and seizures. Current management of the disease for the majority of patients consists of supplemental doses of calcium and active vitamin D to manage the hypocalcemia. While this approach is intended to maintain serum calcium, it does not correct the underlying PTH deficiency and the physiological aspects of hypoparathyroidism can still occur. Moreover, supplementation is associated with long-term complications from the use of supraphysiological doses of calcium in the absence of endogenous PTH hormone, which contribute to renal function deterioration, kidney stones, soft tissue calcifications and abnormalities in bone remodeling. Natpara (PTH 1-84), is approved by the FDA for a subset of hypoparathyroidism patients, but only partially alleviates the need for vitamin supplementation due to its short half-life, and some patients still must take >10 pills/day. Clinical trials have demonstrated that if PTH(1-34) is dosed continuously via a pump in humans, it can mimic physiological levels of PTH to restore normal levels of calcium, phosphorus and markers of bone turnover. However, a pump-mediated, continuous infusion of PTH would be costly and inconvenient for patients. Extend Biosciences has developed a long-acting version of PTH(1-34) (EXT608) that could be dosed once a week and achieve a prolonged pharmacokinetic profile that approximates endogenous PTH levels. SBIR Phase II results showed that EXT608 is more efficacious than native PTH, and based on the retention time in rat and NHP, EXT608 is projected to be dosed once-weekly in humans. In a rat model of hypoparathyroidism, EXT608 was able to normalize calcium and phosphate levels while returning markers of bone turnover and bone mineral density to wild-type levels over the four-week study. Additional studies completed are the standard toxicology studies and the development of a GMP process. The studies proposed in this Phase IIB application will focus on completing the few remaining IND-enabling studies, produce a GMP batch for clinical trials, and to prepare and file an IND. Once the IND application is approved by the FDA, we will begin a Phase 1 clinical trial to determine safety and tolerability of EXT608 in healthy volunteers. This long-acting PTH(1-34) derivative will provide a true replacement therapy to treat hypoparathyroidism that returns serum and urinary calcium and phosphate to physiological levels and maintains it over the course of week, thereby significantly improving quality of life for patients.