Ca sensing receptor antagonist for autosomal dominant hypocalcemia type 1 (ADH1)
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Autosomal dominant hypocalcemia type 1 and hypoparathyroidism
Encaleret is an investigational small molecule antagonist of the calcium sensing receptor (CaSR) being studied in disorders of calcium homeostasis, including autosomal dominant hypocalcemia type 1 (ADH1). Individuals with ADH1 have gain-of-function mutations in the CaSR, causing low serum calcium and a range of debilitating symptoms. ADH1 may also lead to relatively high levels of calcium in urine, a condition called hypercalciuria, which can result in impaired kidney function and can cause kidney stone formation. Encaleret has been administered to approximately 1,300 healthy volunteers and osteoporosis patients, demonstrating tolerability and showing clear modification of ADH1 disease drivers, encouraging our investigation of the compound in ADH1 patients. Encaleret is a potential first-in-class CaSR antagonist for ADH1 and initiation of Phase 3 is planned in 2022.
ADH1 is a genetic disease of calcium homeostasis that typically results in hypocalcemia and affects multiple organ systems.
Calcium is the most abundant mineral in the body and is essential for the strengthening of bones and teeth, muscle contraction, the normal functioning of many enzymes, blood clotting and normal heart rhythm. As such, blood levels of calcium are tightly controlled. One mechanism to control calcium levels involves the calcium-sensing receptor (CaSR), which is an integral component of a feedback system that also regulates parathyroid hormone synthesis/secretion and reabsorption of calcium in the kidneys. Disruptions of this CaSR feedback system can result in autosomal dominant hypocalcemia type 1 (ADH1).
Role of the CaSR in Calcium Regulation
Calcium-sensing receptor helps maintain calcium homeostasis
ADH1 is caused by rare gain-of-function mutations in the calcium-sensing receptor gene and is characterized by increased sensitivity of the CaSR to calcium levels, which results in a physiological ‘perception’ that normal blood calcium levels are high, leading to decreased production of parathyroid hormone (PTH) and increased urinary calcium excretion.
Individuals with ADH1 present with low serum calcium, low or low-normal parathyroid hormone levels and elevated urinary excretion of calcium. Symptoms resulting from low levels of serum calcium, or hypocalcemia, may include severe muscle cramping, tetany, and seizures. In addition, relatively high levels of calcium in urine, a condition called hypercalciuria, may result in impaired kidney function and can cause kidney stone formation.
BridgeBio is investigating a small molecule, named encaleret, as a potential therapeutic for ADH1. Encaleret targets hypocalcemia and hypercalciluria by selectively antagonizing the CaSR.
The CaSR is a G-protein-coupled receptor primarily expressed in the parathyroid glands and kidneys for which extracellular calcium is the primary ligand. The major physiologic role of the CaSR is to function conceptually as a ‘calciostat’ and maintain serum calcium levels by regulating the release of PTH and calcium reabsorption.
Antagonizing CaSR is expected to increase PTH secretion in parathyroid cells and increase calcium reabsorption in the renal tubule, which may normalize serum calcium levels.
Prior clinical experience enables accelerated development of encaleret. It has been shown to be well tolerated in over 1,300 human subjects participating in prior clinical studies, with the exception of dose-dependent increase in serum calcium, which is the desired target effect in ADH1 patients.
The initiation of the Phase 3 trial is planned in 2022.If successful, encaleret has the potential to be a first-in-class CaSR antagonist with a differentiated profile for ADH1. The initial development of encaleret is focused on ADH1, driven by activating mutations to the CaSR, which are estimated to be carried by about 12,000 people in the United States.
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