CALIBRATE: Encaleret Achieves Mineral Homeostasis in Patients With ADH1, With Rachel Gafni, MD

Encaleret, an investigational oral calcilytic in development by Calcilytix Therapeutics, has displayed potential as a disease-specific therapy for autosomal dominant hypocalcemia type 1 (ADH1) in the phase 3 CALIBRATE trial.1

Presented at the Endocrine Society (ENDO) Annual Meeting 2026 in Chicago, Illinois, by Rachel Gafni, MD, a senior research physician at the National Institutes of Health, this trial presents a possible alternative to the historically limited treatment options for patients with ADH1.1

ADH1 generally manifests as low parathyroid hormone (PTH), hypercalciuria, hyperphosphatemia, hypocalcemia, and hypomagnesemia, due in large part to gain-of-function variants in the calcium-sensing receptor gene (CaSR). Standard of care treatment, which includes calcium and active vitamin D (SoC) worsens hypercalciuria, potentially causing chronic kidney disease.1

“Conventional therapy or standard of care with calcium and activated vitamin D doesn’t really correct the abnormal physiology in patients with ADH1 – you’re just sort of filling the leaky bucket,” Gafni told HCPLive in an exclusive interview. “You give them calcium and they urinate it out, but that can damage the kidney. So, a more precision medicine that actually targets the pathogenesis of ADH1, in this case the activated calcium sensing receptor, is the dream.”

To this end, Gafni and colleagues conducted the global, phase 3, randomized, controlled, open-label CALIBRATE trial across 25 locations worldwide. The team included patients with a documented pathogenic or likely pathogenic activating variant of the CaSR gene and a documented history of symptoms or signs of ADH1. Additionally, patients receiving thiazide diuretics, phosphate binders, magnesium or potassium supplements, or potassium-sparing diuretics were required to discontinue their treatment prior to the first dose of encaleret.2

Patients with a history of hypocalcemic seizure within the 3 months prior to screening, as well as thyroid or parathyroid surgery, renal transplantation, or treatment with parathyroid hormone 1-84 or 1-34, among other criteria, were excluded. The study’s primary endpoint was the number of responders achieving both albumin-corrected blood calcium (cCa) and 24-hour urinary calcium (UCa) within the target range, defined as 8.3-10.7 mg/dL and 300 mg/day for men or 250 mg/day for women, respectively. Secondary outcomes included the number of patients with intact parathyroid hormone (PTH) within or above the reference range, the number of participants with blood magnesium within the reference range, and change from baseline in blood vitamin D, among others.2

All screened participants entered the first study period, a 4-week SoC maintenance period; after this, 67 patients were randomly assigned in a 2:1 ratio to receive encaleret or SoC for 20 weeks during the second dose titration period. Following this, both treatment groups entered a 4-week dose maintenance period that lasted until week 24.1

Gafni and colleagues found that 75.6% of participants treated with encaleret achieved both target cCa and UCa by week 24, compared to 4.4% at week 4 (P <.0001). Encaleret also increased mean cCa by day 3 of part 2 and decreased mean UCa by week 3 of part 2. These improvements were maintained through week 24.1

Additionally, within the encaleret group, 91.1% had PTH ≥15 pg/mL at week 24, versus only 6.7% at week 4 of part 1 (P <.0001), and 91.1% achieved normal serum phosphate compared to 55.6% at week 4 of part 1 (P = .0002). Further analyses showed that more participants randomized to encaleret had cCa and UCa within target ranges versus those assigned to SoC at week 24 (75.6% vs 19%; P <.0001).1

The team ultimately concluded that encaleret, based on these data, is a potential disease-specific therapy for ADH1, given its clinically meaningful safety, tolerability, and efficacy. Gafni also discusses her aspirations for once encaleret becomes available to patients with this difficult-to-treat disease.1

“My hope is that, ultimately, if this drug becomes available to younger and younger patients, they will never develop the renal complications that are associated with conventional treatment in ADH, one that 80% of the patients in CALIBRATE already had,” Gafni said. “Whether or not starting the drug in adulthood will help reverse that or improve renal function, we don’t know at this point – continued research is really important to assess these potential complications associated with the underlying disease and conventional treatment.”

Editors’ Note: Gafni reports no relevant disclosures.

References

1. Gafni R, Ing S, Giustina A, et al. Encaleret Restores Mineral Homeostasis in Autosomal Dominant Hypocalcemia Type 1 (ADH1): Primary Results from the Phase 3 CALIBRATE Trial. Abstract presented at the Endocrine Society (ENDO) Annual Meeting 2026, Chicago, IL. June 13-15, 2026.

2. Calcilytix Therapeutics, Inc. Efficacy and Safety of Encaleret Compared to Standard of Care in Participants With ADH1 (CALIBRATE). ClinicalTrials.gov Identifier: NCT05680818. Updated June 11, 2026. Accessed June 18, 2026. https://clinicaltrials.gov/study/NCT05680818