TransCon PTH Nears US Approval for Hypoparathyroidism?

Miriam E. Tucker

May 17, 2023

SEATTLE – Palopegteriparatide (TransCon PTH, Ascendis Pharma) is a potential long-term therapy for adults with hypoparathyroidism, new findings suggest.

Findings from 110-week phase 2 data for the once-daily investigational parathyroid hormone (PTH) replacement drug were recently presented at the American Association of Clinical Endocrinology (AACE) Annual Meeting 2023.

Overall, the drug was associated with independence from conventional calcium and active vitamin D therapy in most patients at 110 weeks, with no discontinuations due to adverse effects.  

"Patients with hypoparathyroidism have low serum calcium levels and struggle with quality of life and biochemical abnormalities. The data from the TransCon PTH studies seem to show that a lot of these abnormalities can be reversed," presenter Mishaela R. Rubin, MD, told Medscape Medical News.  

Other PTH replacement therapies such as Nupara (now discontinued) and teriparatide (off-label) have been used in some patients with hypoparathyroidism.

However, "[TransCon PTH] is delivered in such a way as to have a prolonged half-life, so that's kind of a special benefit that it has," added Rubin, of the Division of Endocrinology and Metabolic Bone Disease, Department of Medicine, Columbia University, New York City.

Asked to comment, session moderator Thanh Hoang, DO, of Walter Reed National Military Medical Center, Silver Spring, Maryland, told Medscape Medical News: "I think it's a very promising medication because right now we don't have a lot of options...I think it would help a lot of patients."

Approval Denied, Company Addressing Concerns

On May 1, the US Food and Drug Administration (FDA) issued a complete response letter, signaling denial of approval for the TransCon PTH, citing concerns related to manufacturing control of the product's drug/device combination product, but not about the product's safety and efficacy, according to an Ascendis statement.

The company is now working with the FDA to address these issues and is awaiting a European Union decision later this year.

The FDA did not request that the company conduct further clinical trials of TransCon PTH, which now include published 26-week phase 2 and phase 3 data along with the current longer-term phase 2 data presented at AACE.

"The company has said that they're hopeful the issues will be addressable and that the FDA did not have any concerns about safety," Rubin told Medscape Medical News.

Calcium Normalized, Bone Turnover Improved

Rubin presented long-term efficacy and safety data from the Phase 2 PaTH Forward trial, which involved 57 of the initial 59 participants who completed week 110 of an open-label extension of the trial.

During the first 4 weeks, patients had been randomized to TransCon PTH at fixed doses of 15 µg/day, 18 µg/day, 21 µg/day, or placebo. After week 4, all patients switched to TransCon PTH titrated to doses of 6-60 µg/day along with conventional therapy, with the goal of maintaining normocalcemia.

Participants were a mean age of 50 years, 81% were women, and 92% were White. Causes of hypoparathyroidism were neck surgery in 80%, autoimmune disease in 2%, and idiopathic disease in 19%. Disease duration was 12 years (range 1-39), and all were taking conventional therapy including calcium and active vitamin D (calcitriol or alfacaldiol).

At 110 weeks, all 57 patients were able to stop taking active vitamin D, and 53 of the 57 (93%) patients achieved independence from conventional therapy, defined as taking 0 µg/day of active vitamin D and no more than 600 mg/day of calcium (the dietary supplement dose). A total of 44 (77%) patients were not taking any calcium or active vitamin D.

"This really establishes the durability up to 2 years of keeping people off conventional therapy," Rubin said during her presentation.

There was an initial uptick to 9.4 mg/dL in mean serum calcium, as some participants were still taking active vitamin D, but that dropped to 8.9 mg/dL by week 26. Mean 24-hour urine calcium dropped from 428 mg/day at baseline to 173 mg/day by week 26. Both serum calcium and urine calcium remained in the normal range through week 110 in all patients, at 8.6 mg/dL and 167 mg/day, respectively.

"This is a really important outcome because we know that high urine calcium in these patients sets them at risk for going on to develop nephrocalcinosis, nephrolithiasis, and ultimately, chronic kidney disease," Rubin said.

Serum levels of two bone formation markers peaked at 12 weeks after initiation of TransCon PTH. Both trended downward thereafter through week 110 to levels approximating those of age- and sex-matched controls.  

"Both markers started off low, consistent with hypoparathyroidism, but with initiation of TransCon PTH we see a robust increase in bone turnover markers, almost as if the bone is 'waking up,' if you will. And this is consistent with calcium being mobilized from the skeleton and going into the circulation," Rubin explained.

Bone mineral density assessed by dual-energy X-ray absorptiometry normalized, primarily in the first 26 weeks. For lumbar spine L1-L4, mean Z-scores dropped from 1.6 to 1.0 at 26 weeks and down to 0.7 by week 100. For total hip, those values were 1.0, 0.6, and 0.4, respectively. The values approached age- and sex-matched norms, Rubin noted, to "perhaps where their skeleton would be if they hadn't had hypoparathyroidism."

Overall 56 of the 57 (94.9%) patients reported treatment-emergent adverse events, of which 25 (42.4%) were treatment-related and none were deemed serious. There were no treatment-emergent adverse events related to hypercalcemia or hypocalcemia leading to healthcare visits or hospitalization, none leading to discontinuation of study drug, and none to death.

"So overall, a reassuring safety profile," Rubin said. "We look forward to presenting the next 2 years' worth of data to the end of the open-label extension study."

The study was funded by Ascendis. Rubin is a paid researcher for the company. Hoang has reported no relevant financial relationships.

American Association of Clinical Endocrinology 2023 Annual Meeting. Presented May 5, 2023.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR's Shots blog, and Diabetes Forecast magazine. She is on Twitter: @MiriamETucker.

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