encaleret, a negative allosteric modulator of the calcium-sensing receptor for ADH1

Encaleret is an investigational small molecule that targets low calcium levels in the blood (hypocalcemia) and high levels of calcium in the urine (hypercalciuria) by selectively modulating the calcium-sensing receptor protein (CaSR).¹ BridgeBio is investigating encaleret as a potential therapeutic for autosomal dominant hypocalcemia type 1 (ADH1).²

father holding son with autosomal dominant hypocalcemia type 1

normal casr versus adh1 versus adh1 + encaleret

our approach

The calcium-sensing receptor (CaSR) maintains blood calcium (Ca²⁺) levels by regulating the release of parathyroid hormone (PTH). People with ADH1 carry an activating variant in the CASR gene that causes the protein to become too sensitive, leading to hypocalcemia, hypercalciuria, and low levels of PTH.¹

Encaleret is an investigational, orally administered, negative allosteric modulator of the CaSR designed to restore normal levels of PTH, blood calcium, and urine calcium, with the goal of resolving key symptoms of ADH1.^1,3

In a Phase 2b clinical study, encaleret was well-tolerated and demonstrated rapid and sustained normalization of calcium (blood and urine) and PTH levels.⁴ CALIBRATE, the registrational Phase 3 clinical study of encaleret, is ongoing.² If successful, encaleret has the potential to be the first targeted therapeutic for ADH1.

References

Roszko KL, et al. Autosomal Dominant Hypocalcemia Type 1: A Systematic Review. J Bone Miner Res. 2022;37(10):1926 – 1935.
Efficacy and Safety of Encaleret Compared to Standard of Care in Participants With ADH1 (CALIBRATE). ClinicalTrials.gov identifier: NCT05680818. Updated September 26, 2023. Accessed October 24, 2023. https://clinicaltrials.gov/study/NCT05680818.
Mannstadt M, et al. Hypoparathyroidism: Genetics and Diagnosis. J Bone Miner Res. 2022;37(12):2615 – 2629.
Gafni RI, et al. Efficacy and Safety of Encaleret in Autosomal Dominant Hypocalcemia Type 1. N Engl J Med. 2023;389(13):1245 – 1247.
CLARIFY: ADH1 and ADH2 Disease Monitoring Study (DMS). ClinicalTrials.gov identifier: NCT05227287. Updated September 1, 2023. Accessed October 24, 2023. https://clinicaltrials.gov/study/NCT05227287.