Rare Daily Staff
The U.S. Food and Drug Administration granted Fast Track designation to BridgeBio Pharma’s encaleret for the treatment of autosomal dominant hypocalcemia, a rare, genetic form of hypoparathyroidism.
Fast Track designation is intended to facilitate the development and expedite the review of drugs to treat serious conditions and get new drugs to patients earlier. Through Fast Track, BridgeBio is eligible to submit a rolling New Drug Application for encaleret if relevant criteria are met. The designation is granted to experimental medicines that could fill an unmet medical need defined as providing a therapy where none exists or improving upon available therapies and is based on whether a drug will impact factors such as survival, day-to-day functioning, or if left untreated, progression to a more serious condition.
Autosomal dominant hypocalcemia type 1 (ADH1) is caused by pathogenic variants in the calcium-sensing receptor gene (CASR). It is estimated that about 12,000 individuals in the United States carry such variants in CASR. The calcium-sensing receptor gene encodes the receptor, CaSR, which senses the level of calcium in the body and regulates the amount of calcium in the blood through its effects on the parathyroid glands, the kidney, and bone. Gain-of-function variants in CASR result in sensing low calcium as normal. As a result, patients with ADH1 have low blood calcium (hypocalcemia), low or low-normal parathyroid hormone levels, and excess urinary excretion of calcium (hypercalciuria). Hypocalcemia can cause severe muscle cramping and seizures, while hypercalciuria can lead to impaired kidney function and kidney stone formation. The current standard-of-care for ADH1 patients consists of oral calcium supplements in excess of typical dietary requirements for people with normal CaSR function, and activated vitamin D, which can partially correct hypocalcemia but typically worsens both hypoparathyroidism and hypercalciuria.
“Balancing near-normal blood and avoiding excess urinary calcium is a daily struggle for patients with ADH1 as the range of symptoms produced by the highs and lows of the condition cannot adequately be addressed by current standard of care,” said Jonathan Fox, chief medical officer of the cardio-renal affiliates at BridgeBio, including Calcilytix, which is focused on developing encaleret. “With respect to the mechanism of disease, which is driven by gain-of-function variants in CASR, encaleret, as an allosteric negative modulator of the receptor’s calcium sensing activity, has the potential to correct the disease mechanism at its source.”
Promising early results from its ongoing phase 2b proof-of-concept, open-label study of encaleret, orally administered, for patients with ADH1 were presented at the Endocrine Society’s 2021 Annual Meeting, which showed the normalization of blood calcium and urine calcium in six of six ADH1 participants evaluated over five days and demonstrated clinical proof-of-concept. BridgeBio plans to engage with regulatory health authorities to discuss the design of a phase 3 registrational study in patients with ADH1. If the development program is successful, encaleret could be the first approved therapy indicated specifically for the treatment of ADH1.
Photo: Jonathan Fox, chief medical officer of the cardio-renal affiliates at BridgeBio