TransCon PTH Normalizes Calcium Levels in Adults in Phase 3 Trial
Daily injections of TransCon PTH can safely and effectively normalize calcium levels in the blood and urine and eliminate the need for conventional therapy in adults with hypoparathyroidism, according to six-month data from the Phase 3 PaTHway clinical trial.
The long-acting hormone therapy, developed by Ascendis Pharma, was also associated with significant reductions in patient-reported symptoms and disease impact, as well as improvements in patients’ functioning relative to a placebo.
Trial results — highlighting that the study met is main and key secondary goals — were recently detailed in a company webcast.
“This is the first Phase 3 trial where more than three quarters of patients achieved control of their hypoparathyroidism, defined as normalization of [blood] calcium and independence from conventional therapy,” Jan Mikkelsen, Ascendis’ president and CEO, said in a press release.
The company plans to submit applications to health authorities in the U.S. and Europe later this year, seeking TransCon PTH’s approval for adults with hypoparathyroidism. It also plans to launch a trial in pediatric patients this year.
“We look forward to discussing the results from this trial and the longer-term data from the Phase 2 PaTH Forward Trial with regulatory agencies in the near future,” said Aimee Shu, MD, Ascendis’ vice president of clinical development, endocrine medicine.
The disease is caused by abnormally low levels of the parathyroid hormone (PTH), resulting in low levels of calcium and high levels of phosphate in the blood, as well as a deficiency in vitamin D, which helps the body absorb calcium.
This can lead to generalized weakness, muscle cramps, seizures, abnormal tingling sensations, headaches, memory loss, and mood swings.
“Conventional therapy with calcium supplements and active vitamin D is aimed at maintaining [blood] calcium in the normal range, with the hope of reducing short-term symptoms, and is not able to address the underlying disease,” Mikkelsen said.
Long-term complications “that include severe diseases such as chronic kidney diseases, liver and [brain] calcifications, cardiovascular complications, and bone damage” can accompany such treatments, Mikkelsen added.
TransCon PTH, administered through a once-daily under-the-skin injection, is a long-lasting precursor of PTH designed to restore PTH levels for 24 hours. As such, it aims to address both the disorder’s short-term symptoms and long-term complications.
Top-line results from the ongoing Phase 2 PaTH Forward trial (NCT04009291) showed that one month of treatment with TransCon PTH was generally safe and superior to a placebo at normalizing calcium levels and eliminating the need for standard therapy.
Also, 58 of the 59 people in the PaTH Forward trial entered its open-label extension portion, and 57 of them have now received the therapy for up to two years. Previous long-term data also highlighted the therapy’s sustainable, positive effects for more than 1.5 years.
The Phase 3 PaTHway trial (NCT04701203) is evaluating the therapy’s six-month safety and effectiveness in 82 adults with hypoparathyroidism; 51 were recruited in North America and 31 in Europe.
Participants’ mean age was between 47.3 and 49 years old, more than 90% were Caucasian, and more than three quarters were women. They were randomly assigned to an under-the-skin injection of either 18 micrograms of TransCon PTH (61 patients) or a placebo (21 patients) once a day for six months.
Top-line, six-month data showed that PaTHway met its main goal, with a significantly greater proportion of TransCon PTH-treated patients both achieving normal blood calcium levels and becoming free of conventional therapy relative to those on a placebo (78.7% vs. 4.8%).
Notably, 95% of patients on TransCon PTH were able to stop standard therapy, classified as vitamin D supplements and up to 600 mg of calcium per day.
The therapy was also significantly superior to placebo at reducing patient-reported, disease-specific physical and cognitive symptoms and patient-reported disease impact, as well as at improving or stabilizing patient-reported physical functioning — attaining all of the trial’s key secondary goals.
While bone turnover — the process of bone resorption followed by replacement with new bone — was lower-than-normal in PaTHway participants at the study’s start, bone turnover markers were higher after six months only in those given TransCon PTH.
Treatment was generally well-tolerated, with most adverse events being mild to moderate in severity and with no discontinuations related to the therapy. A lower proportion of TransCon PTH-treated patients experienced adverse events (82% vs. 100%) and serious adverse events (8.2% vs. 14.3%) relative to those in the placebo group.
The most commonly reported adverse events among the TransCon PTH group included injection site reaction (31.1%), headache (21.3%), abnormal skin sensation (18%), and fatigue (14.8%).
One serious TransCon PTH-related adverse event was reported due to a dosing error, and one patient on the therapy died after going into cardiac arrest (when the heart suddenly stops beating). The death was considered unrelated to treatment.
Despite the observed increase in blood calcium levels in patients given TransCon PTH, their 24-hour urine calcium excretion was also seen to fall significantly to normal levels, suggesting improvements in kidney function.
All 79 patients completing the trial’s six-month randomized period opted to enter its open-label extension portion, in which all are receiving the experimental therapy for up to three years.
The investigational therapy is also being evaluated in adult patients in Phase 3 trials in China and Japan, with top-line data of from the Japan study expected between July and September.
TransCon PTH was designated an orphan drug in the U.S. and in Europe; this status is meant to speed its clinical development and regulatory review.