Rachel Gafni, MD, Senior Research Physician at the National Institutes of Health, discusses results from the CALIBRATE clinical trial 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 muscles.
CALIBRATE (NCT05680818) is a global, phase 3, randomized, controlled, open-label trial testing encaleret to treat patients with ADH1. Encaleret is an investigational, oral, negative allosteric modulator of the CASR.
All participants entered period 1, a 4-week standard of care maintenance period. Participants were then randomized to receive encaleret or continue standard of care in period 2, a 20 week dose titration period. Both treatment groups then entered period 3, a 4 week dose maintenance period, with the final follow-up at week 24. Standard of care treatment includes calcium and active vitamin D, which has been shown to worsen hypercalciuria, which may result in renal calcifications and/or chronic kidney disease.
A total of 67 patients with ADH1 due to 46 distinct CASR variants were randomized and 66 completed period 3. The composite primary endpoint assessed the proportion of those randomized to encaleret achieving target mean albumin-corrected blood calciumn (cCa) and 24-hour urine calcium excretion (UCa) at week 24 of period 3 compared to themselves when on standard of care at week 4 of period 1.
The endpoint was met in 75.6% of encaleret-treated participants at week 24 of period 3, compared to only 4.4% at period 1 week 4 of period 1. Encaleret increased mean cCa by day 3 and decreased mean UCa by week 3 during the dose escalation stage (period 2). These improvements were maintained throughout the study. Within the encaleret group, 91.1% had PTH greater than or equal to 15 pg/mL at week 24 of period 3 compared with only 6.7% at week 4 of period 1. Additionally, 91.1% achieved normal serum phosphate at week 24 compared with 55.6% at week 4.
Additional analyses showed that more participants randomized to encaleret (75.6%) had cCa and UCa within the target ranges by the end of the study compared to those randomized to standard of care (19%).
Encaleret was well-tolerated with no discontinuations in the encaleret arm. Few serious adverse events were reported with frequency similar between treatment arms.
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To learn more about ADH1 and other rare endocrine disorders, visit https://checkrare.com/diseases/endocrine-disorders/