Michael A. Levine, MD, ML, Children’s Hospital of Philadelphia, discusses positive topline results from the CALIBRATE trial of encaleret in patients with autosomal dominant hypocalcemia type 1 (ADH1).
ADH1 is a rare form of hypoparathyroidism caused by variants of the calcium‐sensing receptor gene (CASR). Inherited variants of CASR alter the set point for extracellular calcium, resulting in inadequate parathyroid hormone (PTH) secretion and inappropriate renal calcium excretion leading to hypocalcemia and hypercalciuria. The most common symptoms of ADH1 include muscle spasms in the hands and feet, muscle cramping, prickling or tingling sensations, and twitching of the nerves and muscles in various parts of the body.
Positive topline results from the CALIBRATE clinical trial were recently announced. CALIBRATE is a global phase 3 study evaluating the safety and efficacy of encaleret in patients with ADH1. The trial enrolled 70 adults with ADH1 and randomized 67 participants to encaleret and standard of care. Encaleret is an investigational, orally administered small molecule designed to selectively negatively modulate the calcium sensing receptor, targeting the underlying cause of ADH1.
The study met its primary endpoint, defined as the proportion of participants randomized to receive encaleret achieving both serum calcium and urine calcium levels in the respective target ranges. This was achieved by 76% of encaleret-treated participants compared to 4% for these same participants while on conventional therapy. The pre-specified key secondary analyses comparing encaleret to standard of care included a between group comparison on the proportion of participants achieving both target albumin-corrected serum and urine calcium, and comparisons of intact PTH above the lower limit of the reference range.
Additionally, by day 3 after randomization, 71% of participants assigned to encaleret had an albumin-corrected serum calcium within the reference range. At the end of the titration period at week 20, 98% of participants receiving encaleret had an albumin-corrected serum calcium in the target range, compared with 33% of participants on conventional therapy. Among encaleret responders at week 24, none required conventional therapy during Period 3. Encaleret achieved a mean increase in change from baseline of corrected calcium by 0.82 mg/dL from week 4 to week 24.
Encaleret achieved a mean reduction in change from baseline of 200 mg/day in 24-hour urine calcium from week 4 to week 24. Encaleret was well-tolerated with safety findings generally consistent with known ADH1 biology or related to the mechanism of action of encaleret.
There are plans to submit a New Drug Application (NDA) for encaleret to the U.S. Food and Drug Administration (FDA) in the first half of 2026. Future plans also include the initiation of a registrational trial of encaleret in pediatric patients with ADH1 in quarter 1 of 2026 and a phase 3 study of encaleret in adults with chronic hypoparathyroidism in 2026.
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To learn more about ADH1 and other rare endocrine disorders, visit https://checkrare.com/diseases/endocrine-disorders/
