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Bone and Mineral Metabolism

ORF16-04 - Encaleret Restores Mineral Homeostasis in Autosomal Dominant Hypocalcemia Type 1 (ADH1): Primary Results from the Phase 3 CALIBRATE Trial

Saturday, June 13, 2026
2:00 PM - 2:15 PM CT
Location: Room W187
Disclosure(s):
Rachel I. Gafni, MD: Calcilytix: Contracted Research (Principal Investigators must provide information, even if received by the institution) ()
Erik A. Imel, MD: Amgen Inc.: Advisory Board (), Clinical Trial Investigator (); Calcilytix: Clinical Trial Investigator (); Kyowa Kirin: Advisory Board (), Clinical Trial Investigator (), Consultant (); Neurocrine: Advisory Board (), Clinical Trial Investigator (); UltraGenyx: Advisory Board (), Clinical Trial Investigator (), Consultant ()
Michael Mannstadt, MD: Alexion Pharmaceutical: Advisory Board (), Clinical Trial Investigator (); BridgeBio: Advisory Board (), Clinical Trial Investigator (); MBX: Advisory Board (); septerna: Consultant (); Shire Pharmaceuticals/Takeda: Advisory Board (), Clinical Trial Investigator (), Consultant ()
Autosomal dominant hypocalcemia type 1 (ADH1), due to gain-of-function variants in the calcium-sensing receptor gene (CASR), manifests as low parathyroid hormone (PTH), hypocalcemia, hypercalciuria, hyperphosphatemia and hypomagnesemia. Standard of care treatment with calcium and active vitamin D (SoC) worsens hypercalciuria, which may result in renal calcifications and/or chronic kidney disease. Encaleret, an investigational, oral, negative allosteric modulator of the CaSR, normalized mean albumin-corrected blood calcium (cCa) and 24-hour urine calcium excretion (UCa) in a Phase 2b study of ADH1.

CALIBRATE (NCT05680818) is a global, Phase 3, randomized, controlled, open-label trial of encaleret for ADH1. After screening and optimization of SoC, all participants entered Period 1 (P1), a 4-week (W) SoC maintenance period. Participants were then randomized 2:1 to receive encaleret or continue SoC in Period 2 (P2), a 20W dose titration period. Those randomized to encaleret stopped SoC prior to encaleret initiation; the encaleret dose was adjusted to achieve target cCa. Both treatment groups then entered Period 3 (P3), a 4W dose maintenance period, with the final visit at W24.

Sixty-seven participants (16-76y) with ADH1 due to 46 distinct CASR variants were randomized; 66 completed P3W24. The composite primary endpoint assessed the proportion of those randomized to encaleret (n=45) achieving target cCa (8.3-10.7 mg/dL) AND UCa ( < 300(M), < 250(F) mg/day) at P3W24 compared to themselves when on SoC at P1W4. This endpoint was met in 75.6% of encaleret-treated participants at P3W24 compared to only 4.4% at P1W4 (p < 0.0001). Encaleret increased mean cCa by P2 Day 3 and decreased mean UCa by P2W3, the first time after encaleret these analytes were measured. These improvements were maintained through P3W24. Within the encaleret group, 91.1% had PTH >/= 15 pg/mL (nl 15-65) at P3W24 compared with only 6.7% at P1W4 (p < 0.0001); 91.1% achieved normal serum phosphate (2.5-4.8 mg/dL) at P3W24 compared with 55.6% at P1W4 (p=0.0002). Additional analyses between groups assessed the proportion of those randomized to encaleret who achieved the composite primary endpoint compared to those randomized to SoC at P3W24. More participants randomized to encaleret (75.6%) had cCa and UCa within the target ranges compared to those randomized to SoC (n=21) at P3W24 (19%; p< 0.0001). In the SoC group, 0% had PTH >/= 15 pg/mL at P3W24 (p < 0.0001 compared to 91.1% in the encaleret group at P3W24), and 52.4% had normal serum phosphate at P3W24 (p=0.0003 compared to 91.1% in the encaleret group at P3W24). Encaleret was well-tolerated with no discontinuations in the encaleret arm. Few serious adverse events (AE) were reported with frequency similar between treatment arms.

These results establish encaleret as a potential disease-specific therapy for ADH1 with clinically meaningful efficacy, safety, and tolerability.

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