Oral therapy improves ADH1 symptoms, boosts bone markers in Phase 3 trial
All treated participants reported improvement in at least 1 symptom at 24 weeks
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Encaleret increased bone turnover markers and improved patient-reported symptoms in people with autosomal dominant hypocalcemia type 1 (ADH1), a genetic form of hypoparathyroidism, in a Phase 3 trial.
At 24 weeks, all participants receiving encaleret reported improvement in at least one ADH1 symptom, compared with 46% of those receiving conventional treatment with calcium supplements and/or active vitamin D. That’s according to data announced by Bridgebio Pharma.
The findings came from the Phase 3 CALIBRATE trial (NCT05680818) and were presented at the American Society for Bone and Mineral Research (ASBMR) annual meeting by Erik Imel, MD, of Indiana University School of Medicine, and Steven Ing, MD, of Ohio State University, a CALIBRATE investigator.
Encaleret aims to restore natural PTH secretion in ADH1
“The observed increases in bone turnover markers following encaleret administration are consistent with the effects of restored [parathyroid hormone (PTH)] secretion,” Imel said in a press release. “These findings suggest that encaleret is addressing the underlying biology of the disease, not just correcting blood calcium.”
Bridgebio also announced that the U.S. Food and Drug Administration has accepted its new drug application for encaleret in ADH1 and granted it priority review. The agency is expected to make a decision by May 8, 2027. Bridgebio also submitted an application for approval to the European Medicines Agency.
The company is also running the Phase 2/3 CALIBRATE-PEDS trial (NCT07080385), which is evaluating encaleret in children and adolescents with ADH1.
Hypoparathyroidism is defined by low PTH levels, which can lead to abnormally low blood calcium, called hypocalcemia. Symptoms can include muscle cramps, spasms, and tingling. People with hypoparathyroidism may also have reduced bone turnover, the continuous process in which old bone tissue is broken down and new bone is formed.
ADH1 is caused by mutations in CASR. The gene provides instructions for making the calcium-sensing receptor (CaSR), which helps regulate calcium levels by controlling PTH secretion and calcium reabsorption in the kidneys.
Encaleret is an investigational oral treatment that decreases CaSR activity, which is intended to help restore the body’s natural PTH secretion and normalize calcium levels in the blood and urine. In a small Phase 2 study (NCT04581629) involving 13 participants with ADH1, encaleret helped normalize blood calcium and reduce excess calcium in the urine over 24 weeks.
The CALIBRATE trial compared encaleret with conventional treatment in 67 patients with ADH1, ages 16 and older. Encaleret increased the body’s own PTH secretion to at least the lower limit of the normal range in 91% of participants, compared with none receiving standard treatment. Markers of both bone formation and breakdown also increased with encaleret.
More patients report symptom improvements with encaleret
Patient-reported outcomes showed that more participants receiving encaleret reported improvements in ADH1 symptoms than those receiving conventional treatment. Improvements included fatigue (61.3% vs. 27.3%), muscle cramps (58.1% vs. 36.4%), muscle spasms (58.1% vs. 18.2%), tingling (51.6% vs. 9.1%), and brain fog (48.4% vs. 9.1%).
Participants receiving encaleret also more often reported improvements in mood and emotions, physical activities, daily life, and work life.
Encaleret is also being developed for chronic hypoparathyroidism. Earlier proof-of-principle findings showed that the treatment helped normalize calcium levels in the blood and urine in most participants within five days.
The treatment was studied in an investigator-initiated Phase 2 clinical trial (NCT05735015) in adults with postsurgical hypoparathyroidism, the most common cause of hypoparathyroidism. Results from 10 participants showed that encaleret increased blood calcium while reducing calcium in the urine.
Encaleret’s safety and efficacy are being evaluated in the Phase 3 RECLAIM-HP trial (NCT07805356), in which the first participant has been dosed. The trial plans to enroll about 160 adults and adolescents with chronic hypoparathyroidism and is recruiting at five sites in the U.S. and Canada. Potential participants must have hypoparathyroidism for at least six months to be eligible.
Patty Keating, executive director of the HypoPARAthyroidism Association, said of the new RECLAIM-HP study: “Our community needs research that asks whether we can do better by reducing the long-term burden of managing the condition day to day.”
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