Ascendis Publishes Preclinical Findings Supporting Use of TransCon PTH in Human Patients

TransCon PTH normalizes blood levels of calcium and phosphate, and reduces the amount of calcium released in the urine in different animal models, a study shows. These preclinical results support the therapy’s use by people with hypoparathyroidism, the researchers say.

The results, “Design and Preclinical Development of TransCon PTH, an Investigational Sustained‐Release PTH Replacement Therapy for Hypoparathyroidism,” were published in the Journal of Bone and Mineral Research (JBMR).

Hypoparathyroidism is caused by low levels of the parathyroid hormone (PTH) in the body, which often results in an imbalance of minerals, especially calcium and phosphate.

Conventional treatments, including vitamin D and calcium supplements, fail to completely mimic the effects of PTH in the body. They also can cause discomfort to patients due to their side effects.

Natpara [PTH(1‐84)] — a synthetic form of PTH that can be injected in the body — was approved by the U.S. Food and Drug Administration (FDA) in 2015 for the treatment of osteoporosis and hypoparathyroidism. While it is able to deliver PTH and simulate some of its effects, the therapy doesn’t last long in the body, requiring daily injections to be effective.

Researchers noted in this study that neither conventional treatments nor Natpara “optimally control urinary calcium or significantly reduce the incidence of hypercalcemia and hypocalcemia.” Hypercalcemia is abnormally high levels of calcium in the blood, while hypocalcemia is abnormally low levels.

Ascendis Pharma developed TransCon PTH, a long-acting experimental pro-drug — a compound that needs to be metabolized to release the active agent — to treat hypoparathyroidism. The investigational therapy is designed to restore the levels of PTH within 24 hours in people with the disorder. In doing so, the therapy also promotes the normalization of calcium levels in the blood and urine. Researchers say it also helps normalize serum phosphate levels and bone turnover, overcoming most of the limitations found in other forms of therapy.

In this study, a team from Ascendis described the properties and effects of the compound in different animal models. They sought to analyze TransCon PTH’s pharmacokinetic and pharmacodynamic properties — how the drug is absorbed, distributed, metabolized, and eliminated from the body.

The investigators started by administering a single dose of the compound to healthy male rats between 9 and 12 weeks old, and healthy male monkeys between 2 and 3 years old through a subcutaneous (under the skin) injection.

Rats were treated with either 2.4 or 7.3 nmol/kg of TransCon PTH, whereas monkeys received the compound at a dose of 0.24 nmol/kg, followed by a 1.2 nmol/kg TransCon PTH injection one week later.

Results showed that, in rats, the mean half-life of TransCon PTH was 28 hours, while in monkeys it reached 34 hours. The half-life of a medicine refers to the period of time it takes for the levels of the compound to drop to half.

Next, researchers treated male and female rats (8 weeks old) and female monkeys (between 2 and 3 years old) with daily injections of the compound for 28 days. Rats were treated with either 2.4, 7.3, and 14.6 nmol/kg/day of TransCon PTH, while monkeys received the compound at a dose of 0.049, 0.12, and 0.36 nmol/kg/day.

Results showed that, when administered continuously, TransCon PTH was able to keep the levels of PTH stable over long periods of time in both species. The therapy “demonstrated an infusion-like pharmacokinetic profile, more closely mimicking” a continuous release inside the body.

Moreover, the investigators found that treatment with TransCon PTH led to an increase in calcium levels, and a decrease in phosphate levels in the blood of both rats and monkeys. Despite the increase in the calcium levels in the blood, the amount of calcium released in the urine in rats and monkeys receiving continuous TransCon PTH was identical to controls.

Finally, to assess the effects of TransCon PTH in the context of disease, researchers treated female rats that had undergone surgery to remove both the thyroid and parathyroid glands — creating a hypoparathyroidism model. These rats were administered the compound at a dose of 1.2 or 2.4 nmol/kg/day for four weeks. For comparison, some of the animals were treated with Natpara, administered at a dose of 7.4 nmol/kg/day, for the same period of time.

Results showed that animals treated with TransCon PTH were able to maintain their calcium and phosphate blood levels within the normal range for 24 hours after administration. On the other hand, rats treated with Natpara only showed a tendency toward normalization after receiving a dose that was approximately six times higher than that of TransCon PTH.

Despite increasing slightly during the treatment period, the levels of calcium in the urine of rats treated with TransCon PTH returned to normal by the end of the treatment, the results showed.

Safety assessments indicated that TransCon PTH was well-tolerated by all animals.

“The data supports further development of TransCon PTH in the clinical setting, potentially representing an important advance in treatment of HP patients,” the scientists said.

Ascendis is currently awaiting FDA approval to launch a Phase 2 trial to assess the safety and efficacy of TransCon PTH in adults with hypoparathyroidism.