21-05-2025
Palopegteriparatide Benefits Sustained in Hypoparathyroidism
ORLANDO, Fla. — After 2 years of treatment with the parathyroid hormone (PTH) analog palopegteriparatide (Yorvipath), adults with chronic hypoparathyroidism demonstrated continued improvement in renal function and skeletal dynamics, with no new safety issues identified.
In hypoparathyroidism, low levels of PTH lead to hypocalcemia, hypercalciuria, and kidney damage, as well as reduced bone turnover and elevated fracture risk. Conventional treatment doesn't address the underlying defect and imposes a significant pill burden on patients, Lynn A. Kohlmeier, MD, director of endocrinology at Endocrinology and Spokane Osteoporosis, Spokane, Washington, explained at American Association of Clinical Endocrinology (AACE) Annual Meeting 2025.
'Conventional therapy for hypoparathyroidism consists of active D, prescription calcitriol, and multiple calcium supplements, which we know are really tough for our patients to take. It alleviates the hypocalcemic symptoms and hopefully keeps them from crashing and having laryngospasm or tetany or seizures. But if they're overtreated, or if they're dehydrated, the calcium could get too high and they can have renal concerns. The bottom line is this doesn't restore parathyroid hormone physiology,' Kohlmeier said.
For PTH replacement therapy in hypoparathyroidism, 'we want something that provides PTH levels at a physiologic range to restore downstream calcitriol, active D production, promoting independence from conventional therapy, but…[also] normalizing serum calcium and urine calcium and phosphate, skeletal health, and quality of life. Palopegteriparatide is essentially that,' she explained.
Palopegteriparatide, a once-daily injectable, was approved in the United States in August 2024 for the treatment of adults with hypoparathyroidism. That approval was based on the phase 3 randomized, double-blind, placebo-controlled PaTHway trial of 82 adults with hypoparathyroidism. In week 26 of this this study, 79% (48/61) vs just 5% (1/21) of patients randomized to palopegteriparatide vs placebo met the primary efficacy endpoint of achieving normal serum calcium levels without requiring conventional therapy (no active vitamin D and ≤ 600 mg/d calcium; P < .0001).
The 26-week double-blind period was followed by a 182-week open-label period during which all participants were given palopegteriparatide, titrated to optimal dose. At week 104 (2 years), data were available for 76 of the original participants. Of that group, 97% (74/76) achieved independence from conventional therapy, with mean serum calcium and phosphate in the normal ranges. Independence from active vitamin D supplementation was achieved by 100% of the subjects, regardless of baseline kidney function.
Asked to comment, endocrinologist Sean Ho Yoon, MD, assistant professor of medicine at the Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, told Medscape Medical News , 'This study, in the short term, proved that it is working. And the significance of this extension data is that even after 104 weeks, it still maintains the efficacy without complications.'
Yoon also noted that the dosing did not appear to be a problem in the study, although Kohlmeier didn't present the titration details. 'Giving too much PTH can lead to too much bone turnover and high calcium in the body. But I think the study proved that as long as you're monitoring calcium regularly and titrating the dosage accordingly, that initial efficacy can be maintained while minimizing the complications.'
At 2 years, independence from therapeutic doses of calcium was achieved by 95% (21/22) of participants with a baseline estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 and 98% (53/54) of those with a baseline eGFR ≥ 60 mL/min/1.73 m2. Improvements in eGFR from baseline to week 104 occurred overall but were numerically greater in those with lower eGFR at baseline.
Normalization of mean 24-hour urine calcium excretion was seen by week 26 in the treatment group, and reductions continued through week 104, from 393 mg/d at baseline to 151 mg/d in the 43 patients initially randomized to palopegteriparatide and from 330 mg/d to 183 mg/d in 14 from the placebo group who were switched to the drug after 26 weeks. (Normal urine calcium levels are ≤ 300 mg/d for men and ≤ 250 mg/d for women.)
Mean levels of the bone turnover markers procollagen type 1 N-terminal propeptide and C-terminal telopeptide of type 1 collagen initially rose from baseline to week 26 with palopegteriparatide and then were maintained in the normal range at week 104, consistently in men, postmenopausal women, and premenopausal women. Mean bone mineral density T-scores and Z-scores declined from elevated baseline levels and stabilized within the normal range through week 104 across sex and menopausal status groups.
Yoon said it was noteworthy that 'they were able to chemically prove with the bone markers that bone turnover is happening again with the PTH replacement. I'm curious, for the longer term, whether that actually helps reduce fractures. I think it's too premature to say that about the bone benefit, but it is promising that biochemically the bone turnover increased back to the age and sex-matched normal range.'
Treatment-emergent adverse events (TEAEs) occurring in 5% or more of the 80 participants for whom data are available included injection site reactions (26.2%), hypercalcemia (13.8%), nausea (8.8%), headache (7.5%), hypocalcemia (7.5%), and postural orthostatic tachycardia syndrome (5.0%). Most TEAEs were mild or moderate and generally reported at similar rates across baseline eGFR groups, Kohlmeier said.
The sole exception was the occurrence of TEAEs related to hyper- or hypocalcemia leading to an emergency or urgent care visit and/or hospitalization. These events were reported in 7.5% of patients overall, with four instances in the lower baseline eGFR group and two in the higher eGFR group. There was one death, a fatal cardiac arrest, not believed to be related to the drug.
Overall, palopegteriparatide was associated with significant and sustained improvement in renal function and skeletal dynamics in adults with chronic hypoparathyroidism and was generally well-tolerated with no new safety signals identified, Kohlmeier concluded.
The study was funded by Ascendis Pharma. Kohlmeier reported receiving research funding from Alexion/Amolyt and Ascendis Pharma, being on the speakers bureau and receiving honoraria from Amgen and Ascendis Pharma, and being a consultant/advisor for Alexion and Ascendis Pharma. Yoon had no disclosures.
