TransCon PTH Holds Promise in Treating Hypoparathyroidism, Phase 2 Trial Shows

Ascendis Pharma’s investigational therapy TransCon PTH safely restored calcium and phosphate balance and eliminated the need for current standard care in adults with hypoparathyroidism, top-line data from a Phase 2 clinical trial show.

“With TransCon PTH, our goal has always been to improve the lives of patients with hypoparathyroidism, by designing a replacement therapy that restores physiologic levels of PTH [parathyroid hormone] 24 hours a day and that sets a new standard of care,” David B. Karpf, MD, Ascendis’ vice president of clinical development, said in a press release.

Designed with Ascendis’ TransCon technology, TransCon PTH allows the release of a synthetic PTH at predefined rates, controlled by the body’s pH and temperature, potentially mimicking natural PTH’s mode of action.

By restoring PTH levels in a more “natural” and sustained way, TransCon PTH is expected to normalize blood and urinary calcium levels, blood phosphate levels, and bone turnover, easing both short-term and long-term complications of hypoparathyroidism.

The global Phase 2 PaTH Forward study (NCT04009291) was designed to evaluate the safety and effectiveness of Transcon PTH in adults with hypoparathyroidism. To be eligible, patients had to be managing their condition with vitamin D analogs (calcitriol at least twice a day or alfacalcidol at least once a day) and calcium supplements (calcium citrate or calcium carbonate at least twice a day).

A faster path of enrollment for patients previously treated with Natpara (sold by Takeda; Natpar in Europe) — the only approved therapy for hypoparathyroidism — was established after Natpara’s recall in the U.S over concerns of potential contamination.

A total of 59 patients were recruited in the U.S., Europe, and Canada and randomly assigned to receive once-daily TransCon PTH at either 15, 18, or 21 micrograms or a placebo for four weeks, all given via an under-the-skin injection using a prefilled pen.

The trial’s main goal was to assess whether the proportion of TransCon PTH-treated patients achieving normal levels of calcium in the blood and urine (or a 50% drop in urine) without the need for vitamin D or more than 1 g of a daily calcium supplements was superior to those on placebo.

A secondary goal focused on patients completely eliminating the need for standard care — considered to be no vitamin D and 500 mg or less of calcium supplements per day.

While safety was evaluated in all participants, only 57 were eligible for effectiveness measurements (two patients on placebo were excluded due to low requirement of vitamin D supplements).

Most of the patients were white and women, and had developed hypoparathyroidism after a surgery in the neck area — where the parathyroid glands, responsible for PTH production, are located.

Results showed that the trial met its primary goal, with 50% of TransCon PTH-treated patients (and 60% of those on the highest dose) meeting all four requirements, compared with 15% of those receiving a placebo. Both differences were statistically significant.

While the proportion of patients meeting the secondary goal was also higher for those on TransCon PTH, this difference was only statistically significant for the group receiving the highest dose of the therapy.

Notably, 82% of TransCon PTH-treated patients and 100% of those given the highest dose were able to discontinue standard care.

Effectiveness data revealed that four weeks of TransCon PTH treatment helped normalize the levels of blood and urinary calcium and blood phosphate, while enabling discontinuation of vitamin D and calcium supplements.

All therapy doses were well-tolerated, with no reports of serious or severe adverse events or of treatment discontinuations. The frequency of treatment-related adverse events was similar between TransCon PTH and placebo.

“These PaTH Forward data show the potential to completely remove standard of care while maintaining normal [blood] and urinary calcium levels, which could represent a major advance for patients with this complex, debilitating disease,” Karpf said.

After completing treatment, 58 participants entered the open-label extension portion of the trial, in which all will receive an individually optimized dose of TransCon PTH (6 to 30 micrograms per day). The study is expected to end in March 2023.

Ascendis plans to report six-month data from the extension portion of PaTH Forward between July and September and to submit regulatory filings to start a Phase 3 trial of TransCon PTH in North America, Europe, and Asia by the end of the year.

“Hypoparathyroidism has a significant negative impact on over 200,000 patients worldwide and is one of the last hormonal insufficiency disorders without an effective replacement therapy. With TransCon PTH, we have a unique opportunity to make a meaningful difference for patients on a global basis,” said Jan Mikkelsen, Ascendis’ president and CEO.