CHICAGO — Encaleret, an investigational oral drug, shows promise against the difficult-to-treat autosomal dominant hypocalcemia type 1 (ADH1), normalizing calcium, parathyroid (PTH), and phosphate levels, results from a randomized trial show.

“In patients with ADH1, oral encaleret rapidly corrects and maintains normal mineral homeostasis, as demonstrated by an increase in PTH, normalization of mean serum calcium, and mean 24-hour urinary calcium,” said first author Rachel I. Gafni, MD, a senior research physician with the National Institutes of Health’s Skeletal Disorders and Mineral Homeostasis Section, Bethesda, Maryland, in presenting the findings at ENDO 2026: The Endocrine Society Annual Meeting.

In ADH1, gain-of-function variants in the calcium-sensing receptor gene (CaSR) result in decreases in PTH; however, the condition has more extensive implications than other forms of hypoparathyroidism in that it causes disruptions in serum and urinary calcium levels, in addition to hyperphosphatemia and hypomagnesemia.

The standard treatment of calcium and activated vitamin D does not correct ADH1’s underlying pathophysiology and has the potential to worsen long-term complications, Gafni said.

Encaleret is a negative allosteric modulator of the CaSR. In phase 2 research, the drug has shown promise in ADH1 by normalizing blood and urine calcium levels. To further investigate, Gafni and colleagues conducted the global, phase 3 CALIBRATE study.

Rapid Improvement

In the study, 67 patients with ADH1 entered a 4-week standard-of-care (SoC) maintenance period (period 1), after which they were randomly assigned 2:1 to stop SoC and receive encaleret (dose adjusted to achieve target blood calcium) or to continue receiving SoC over a 20-week dose titration period (period 2). Both groups then entered a 4-week dose-maintenance period (period 3), with the final visit at week 24.

The study’s primary endpoint was a composite of those taking encaleret achieving a target serum calcium (8.3 - 10.7 mg/dL) and urinary calcium (< 300 mg/d for men, < 250 mg/d for women) in the last week of period 3, compared with their levels when on the standard of care at week 4 in period 1.

Overall, among 66 patients who completed the study, the composite endpoint was met by 75.6% of patients in the encaleret group, up from only 4.4% of those patients at week 4 of period 1 (P < .0001). Only 19% of patients in the standard-of-care care group showed serum and urinary calcium levels within target ranges in the final week (week 24) of period 3 (P < .0001).

In the encaleret-treated group, the improvements in mean serum calcium were observed by day 3 of period 2 and in urinary calcium by week 3 of period 2, and the improvements were maintained through period 3.

Of note, 91.1% of those treated with encaleret achieved a PTH of at least 15 pg/mL (range 15 - 65 nl) at the study’s end, compared with only 6.7% of those patients at week 4 of period 1 (P < .0001). No patients receiving standard of care achieved PTH levels above 15 pg/mL at the end of period 3 (P < .0001).

In addition, 91.1% treated with encaleret achieved normal serum phosphate levels (2.5 - 4.8 mg/dL) at the study’s conclusion, compared with 55.6% of those patients at week 4 of period 1 (P = .0002). In the standard-of-care group, 52.4% of patients had normal serum phosphate the end of period 3 (P = .0003) 

Encaleret was well-tolerated with no discontinuations due to treatment-related adverse events.

Gafni noted that the responses in PTH were typically rapid, with increases observable within 30 minutes after the first dose, while calcium and other responses take longer.

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

Precision Medicine Tool

Tiffany Kim, MD, of the Endocrine Research Unit, San Francisco Veterans Affairs Health Care System, California, who co-moderated the session, told Medscape Medical News that encaleret will mean clinicians “will be able to practice precision medicine and provide a treatment for a patient’s specific genetic mutation.”

Autosomal dominant hypocalcemia type I is more difficult to treat than the more common form of hypoparathyroidism that occurs as a complication of surgery, Kim noted.

“So, it is great to see an effective and targeted therapy,” she said.

Gafni reported a contracted research relationship with Calcilytix, a subsidiary of encaleret developer BridgeBio Pharma. Kim reported no relevant financial relationships.