EXT608 for Hypoparathyroidism

Our lead program is a long-acting PTH(1-34) for the treatment of hypoparathyroidism. This rare disease is characterized by inappropriately low circulating levels of parathyroid hormone (PTH), and is most commonly caused by inadvertent removal of the parathyroid glands during neck surgery, and less commonly by autoimmune diseases and rare genetic disorders. PTH is a key regulator of calcium and phosphorous homeostasis through resorption of calcium and elimination of phosphate in the kidneys, movement of calcium from the skeleton, and the production of the active form of vitamin D in the kidneys. A lack of continuous PTH production leads to low blood calcium (hypocalcemia), high serum phosphate (hyperphosphatemia), high urinary calcium (hypercalciuria) due to decreased renal reabsorption, and increased bone density, characterized by increased cortical and trabecular bone density.

If left untreated, hypoparathyroidism affects nearly every organ system in the body. These physiological changes (hypocalcemia, hypercalciuria, hyperphosphatemia and the near absence of PTH) alone or in combination with each other, will cause neuromuscular symptoms (persistent muscle cramps, paresthesia, tetany, seizures, cardiac arrhythmias), ischemic heart disease, kidney stones and nephrocalcinosis, and increased risk of vertebral fractures despite the increased bone mineral density measurements. Additionally, hypoparathyroidism patients suffer from emotional and cognitive disorders such as anxiety, depression, memory problems, and general “brain fog” which have been attributed to lack of PTH. Importantly, patients with improperly controlled hypoparathyroidism report a significantly reduced quality of life, with 75% of patients reporting that their disease affects their ability to work, and 63% of patients reporting negative effects on their family relationships (Siggelkow et al., 2020).

It has been several years since formal guidelines were in place for the therapeutic management of hypoparathyroidism (Bollerslev et al., 2015; Brandi et al., 2016). Conventional treatment (calcium and active vitamin D supplements) focuses on maintaining serum calcium levels while preventing the risk of hypercalciuria, or excessive urinary calcium secretion, which can lead to kidney failure. Until the approval of recombinant full-length PTH(1-84) by the FDA in early 2015 (Natpara®, Takeda), there were no approved hormone replacement therapies available for hypoparathyroidism, making it the last remaining endocrine deficiency for which the missing hormone was not an approved therapy. Natpara was only approved for the most refractory patients, and as an adjunct to the standard of care. Natpara is currently under recall due to autoinjector issues, and is only available to a limited number of seriously ill patients through a Special Use Program. Moreover, Takeda announced that manufacturing will cease in 2024, leaving patients without an option to control their disease with a PTH-based therapy.

Our long-acting PTH is a subcutaneously administered PTH derivative with an attractive value proposition. The pharmacokinetic profile our D-VITylated PTH(1-34) conjugate mimics the physiological levels of PTH, thereby returning and maintaining serum calcium and phosphate levels within the normal range. EXT608 is currently in Phase 1 clinical trials.

For more information, see the ClinicalTrials.gov website (NCT05408663).