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CHICAGO — Most patients with hypoparathyroidism treated with the long-acting synthetic parathyroid hormone (PTH) prodrug palopegteriparatide (Yorvipath) achieved independence from high-dose calcium and vitamin D supplementation, with benefits sustained beyond 3 years, according to final results from the phase 3 PaTHway trial. 

“These final results showed high rates of independence from conventional therapy and normocalcemia, consistent with those observed at earlier timepoints,” said first author Bart L. Clarke, MD, of the Mayo Clinic in Rochester, Minnesota, during a presentation at ENDO 2026: The Endocrine Society Annual Meeting.

“In addition, substantial improvements in renal function and multiple patient-reported outcome domains were sustained through the end of the trial,” he said. 

Limitations of Conventional Therapy 

Hypoparathyroidism is a rare disease characterized by insufficient PTH production, resulting in hypocalcemia and hyperphosphatemia. The condition is most commonly caused by inadvertent removal of the parathyroid glands during neck surgery.

Conventional treatment with vitamin D and calcium addresses symptoms but does not replace the missing hormone. Patients often require high-dose supplementation, which can compromise kidney function and bone health, and contribute to other complications. 

Palopegteriparatide functions as a hormone replacement therapy for PTH, restoring the hormonal balance necessary to regulate sufficient parathyroid levels.

Previously reported results from the randomized, double-blind phase 3 PaTHway trial showed that most patients treated with palopegteriparatide achieved independence from calcium and vitamin D along with other key benefits, findings that helped support US Food and Drug Administration approval of the drug in August 2024.

Earlier PaTHway Trial Results

Investigators at 21 European and North American sites enrolled 82 adults with hypoparathyroidism. Participants were randomly assigned to palopegteriparatide or placebo during a 26-week double-blind phase, followed by a 156-week open-label extension. 

At baseline, mean age was 49 years in the palopegteriparatide group and 47 years in the placebo group. Women comprised 75% and 86% of the groups, respectively, and mean hypoparathyroidism duration was 12 and 11.1 years, respectively.

During the initial 26-week period, 61 patients received palopegteriparatide and 21 received placebo. Treatment began at 18 µg daily by subcutaneous injection and was administered alongside conventional calcium and vitamin D. In both groups, treatment was adjusted according to the albumin-corrected serum calcium levels.

As previously reported, 79% of patients receiving palopegteriparatide maintained normal calcium levels without active vitamin D or high-dose calcium supplementation at week 26, compared with just 5% in the placebo group.

Final Results: Durable Benefits Through Week 182

Among the 73 participants who remained in the study through week 182, 96% achieved independence from therapeutic calcium supplementation, and none required active vitamin D. Most participants (89%) maintained normal albumin-adjusted serum calcium, with a mean value of 8.8 mg/dL.

Mean 24-hour urine calcium normalized within 26 weeks of palopegteriparatide treatment and remained within the normal range throughout follow-up, Clarke reported.

Although mean bone turnover markers increased initially, as expected, levels subsequently stabilized within normal ranges. Elevated baseline bone mineral density Z-scores shifted toward age- and sex-matched norms by week 26 and remained stable through week 182.

Notably, improvements were consistent across sex and menopausal-status subgroups, despite a higher proportion of postmenopausal women in the treatment group.

Kidney function also improved. Mean estimated glomerular filtration rate (eGFR) increased by 10.97 mL/min/1.73 m² from baseline to week 182. 

“The mean increase in eGFR by the end of the study was substantial and offers hope for the future that perhaps this will be a property of the drug that can further benefit our patients,” Clarke said.

Patient-reported outcomes also improved across multiple domains, including physical functioning, cognition, and daily activities. These benefits generally emerged within the first year and were maintained throughout the study. 

Treatment-related adverse events (TEAEs) were mild in 36.3% of patients and moderate in 40%. Serious TEAEs occurred in 25% of patients overall. Three patients discontinued treatment due to TEAEs. 

“Palopegteriparatide was generally well tolerated, with no new safety signals identified,” Clarke said. “Overall, these were very successful outcomes and impressive data.”

Hope for Long-Term Options

Commenting on the study, Tiffany Kim, MD, of the Endocrine Research Unit at the San Francisco Veterans Affairs Health Care System in California, agreed that the reductions in calcium and vitamin D requirements were particularly noteworthy.

“These patients required quite a bit of supplementation at baseline, so this is impressive,” she told Medscape Medical News. “It is also great to have long-term renal, skeletal, and quality-of-life outcomes, which is important for a chronic treatment.”

Long-term durability is key, given that these therapies are expected to be used lifelong, she added. The findings are also notable because current treatment options remained limited.

“Conventional therapy with calcium and vitamin D supplementation is associated with renal complications with elevated urinary calcium,” Kim said. “This is a more targeted treatment and actually lowers urinary calcium.”

She noted that several additional therapies are in development and may further expand treatment options for hypoparathyroidism in the future.

The study was funded by Ascendis Pharma. Clarke reported consulting and other relationships with Ascendis Pharma, Takeda, EnteraBio, Extend Biosciences, and Amolyt Pharma. Kim reported no relevant financial relationships.