On Oct. 13, 2023, the National Institute of health (NIH) announced that an investigational drug, encaleret, restored calcium levels in people with autosomal dominant hypocalcemia type 1 (ADH1), a rare genetic disorder marked by an imbalance of calcium in the blood and urine, as well as abnormally low levels of parathyroid hormone, which regulates blood calcium levels. The results from the clinical trial were published in the New England Journal of Medicine.

In the mid-phase clinical trial, 13 participants with ADH1 received oral doses of the investigational drug for about 24 weeks. By the end of the trial, the treatment restored every participantﾒs blood calcium level to normal, and urine calcium approached normal levels. Levels of parathyroid hormone also normalized.

Our bodies need calcium for proper functioning of many organs and tissues, including the bones, teeth, heart, muscles, and nerves. However, in people with ADH1, calcium levels in the blood are unusually low, leading to symptoms that can range from tingling limbs, muscle cramps, and brain fog to life-threatening seizures. Between 1.4 and 3.9 in 100,000 people in the U.S. are affected by the disease. While current therapies can help manage symptoms, there are no approved treatments that address the root cause of the condition.

Encaleret is thought to exert its effects by acting on faulty calcium-sensing receptors that are peppered throughout the kidneys and pea-sized organs in the neck called parathyroid glands. In healthy people, these receptors act like thermostats to monitor and control calcium levels. However, in patients with ADH1, the receptors are too sensitive and falsely interpret normal blood calcium levels as high. As a result, the parathyroid glands do not make enough parathyroid hormone and the kidneys flush too much calcium out of the body. This leads to low calcium levels in the blood and high levels in the urine.

Encaleret appeared to be safe and caused no serious side effects. However, because parathyroid hormone raises blood calcium levels in part by drawing calcium from the bones, the researchers noted a need to assess the treatment’s long-term effects on the skeleton. The researchers also speculate encaleret may have broader implications. An ongoing clinical trial led by Dr. Collins and NIDCR staff clinician Iris Hartley, M.D., is testing whether the treatment can help correct calcium levels in people whose parathyroid glands have been damaged by surgery.