New Form of Parathyroid Hormone Cuts Need for Conventional Therapy in Chronic Hypoparathyroidism

By Scott Baltic

September 15, 2021

NEW YORK (Reuters Health) - In adults with chronic hypoparathyroidism, an investigational prodrug of parathyroid hormone, TransCon PTH, allowed most participants in a small randomized trial to reduce or forgo conventional therapy of vitamin D and calcium supplements.

TransCon PTH from Ascendis Pharma is being developed as a long-acting, once-daily, subcutaneous hormone-replacement therapy for adult hypoparathyroidism that will replace parathyroid hormone at physiologic levels over a 24-hour period, researchers explain in the Journal of Clinical Endocrinology and Metabolism.

In an email to Reuters Health, corresponding author Dr. Aimee D. Shu of Ascendis Pharma, in Palo Alto, California, described the challenges of treating patients with hypoparathyroidism using conventional therapy, including residual symptoms (such as brain fog and low energy) and complications (such as excess urinary calcium excretion).

She added that based on the study's findings, she is "most enthusiastic that this phase 2 study suggests TransCon PTH can do what other therapies have not yet been able to do."

Beyond reducing symptoms and improving quality of life, Dr. Shu explained, that means delivering enough parathyroid hormone over the course of the day to reduce urinary calcium excretion, in most cases back to the normal range. That in turn means lower risk for kidney stones and renal calcifications and therefore potentially lower risk for kidney failure over the long term.

To the researchers' knowledge, this was the first double-blind, placebo-controlled trial in patients with chronic hypoparathyroidism to show that a study drug significantly enhanced health-related quality of life.

The 59 participants in the double-blind, placebo-controlled study were 18 or older and had postsurgical, autoimmune, genetic, or idiopathic hypoparathyroidism, and a BMI between 17 and 40. All were receiving conventional therapy of active vitamin D plus calcium.

Patients were randomized to receive either TransCon PTH 15, 18, or 21 ug daily or placebo. The four-week blinded period was followed by a 22-week open-label extension period, during which study drug dosages were adjusted based on the need for active vitamin D, as indicated by serum calcium, urine calcium, and other measures.

The primary endpoint was determined at the end of the four-week blinded period based on serum calcium within normal range, fractional excretion of calcium from a spot AM urine sample either within normal range (i.e., <= 2%) or reduced by at least 50%, discontinuation of all active vitamin D supplements, and a reduction of calcium supplementation to at most 1,000 mg/day.

At week 4, 50% of patients receiving TransCon PTH achieved the primary endpoint versus 15% of placebo-treated patients (P<0.03). In addition, 50% of the actively treated patients were able to stop taking active vitamin D and reduce supplemental calcium, versus none of the patients receiving placebo.

As of week 26, 91% of subjects treated with TransCon PTH no longer required conventional therapy, stopping oral active vitamin D and reducing calcium supplementation to no more than 500 mg per day. And 76% of participants were able to eliminate both supplements entirely.

Two measures of health-related quality of life increased over the 26 weeks. There were no serious adverse events related to TransCon PTH, and no adverse events that led to treatment discontinuation or death.

Dr. David Goltzman, professor in the departments of medicine and physiology at McGill University, in Montreal, Canada, told Reuters Health by email. "The study suggests that TransCon PTH will be useful in replacing conventional treatment, i.e., active vitamin D and high-calcium intake and thus in preventing kidney calcifications, kidney stones and kidney failure, which are possible side effects of conventional treatment. It also improved the quality of life of the patients in the study and seemed to improve bone physiology (bone turnover)."

"The major novelty of this agent is that it has a longer half-life in blood than other PTH forms and therefore may act slightly differently, and potentially more advantageously," added Dr. Goltzman, who is also director of the Calcium Research Lab at the Research Institute of the McGill University Health Centre.

Dr. Goltzman, who was not involved in the research, cautioned that a phase-3 study is needed to assess the recommended dose of TransCon PTH and further assess possible adverse events. Head-to-head comparisons with other forms of PTH would also be valuable, he said.

The study was sponsored by Ascendis Pharma Bone Diseases A/S, in Hellerup, Denmark.

SOURCE: The Journal of Clinical Endocrinology and Metabolism, online August 4, 2021.