Palopegteriparatide Shows Sustained 3-Year Benefits in Hypoparathyroidism Treatment
Key Insights
Palopegteriparatide demonstrated sustained efficacy through 3 years, with 96% of patients achieving independence from conventional therapy and 84% maintaining normal serum calcium levels.
The treatment showed significant kidney benefits, with estimated glomerular filtration rate improving by 8.76 mL/min/1.73 m² overall and 13.98 mL/min/1.73 m² in patients with baseline eGFR below 60.
Mean 24-hour urine calcium excretion decreased to 162 mg per day at 3 years, reaching levels rarely seen in hypoparathyroidism (search) patients.
Most adults with hypoparathyroidism (search) who received long-term therapy with palopegteriparatide achieved normal serum calcium levels independent of conventional therapy at 3 years, according to new data from the PaTHway open-label extension trial presented at the American Association of Clinical Endocrinology Annual Scientific and Clinical Conference.
The FDA-approved therapy (Yorvipath, Ascendis Pharma) demonstrated sustained efficacy and safety through 3 years in adults with hypoparathyroidism (search), with 84% of participants maintaining normal serum calcium levels independent of conventional therapy and 96% able to stop all conventional treatment.
Long-term Efficacy Maintained
Of 73 adults still enrolled in the extension trial at 3 years, 84% had normal albumin-adjusted serum calcium independent of conventional therapy. Normal albumin-adjusted serum calcium levels were achieved by 88% of the study group, representing sustained benefits from the 81% response rate observed at 1 year.
"Treatment with palopegteriparatide [parathyroid hormone] replacement in adults with hyperparathyroidism showed sustained efficacy and safety through 3 years, week 156 in the PaTHway trial," said Lynn Kohlmeier, MD, endocrinologist with Spokane Osteoporosis and Endocrinology – Arthritis Northwest Research. "96% of patients were independent from conventional therapy at year 3, and 100% off active vitamin D."
All 73 adults were able to discontinue active vitamin D at 3 years, and 96% were no longer receiving therapeutic doses of calcium. Extension trial participants maintained serum calcium and serum phosphate levels in the normal range throughout the extension trial.
Significant Kidney Function Improvements
From baseline to 3 years, estimated glomerular filtration rate improved by 8.76 mL/min/1.73 m² for the entire study group and by 13.98 mL/min/1.73 m² for adults with a baseline eGFR of less than 60 mL/min/1.73 m². At 3 years, 59% of participants had an improvement in eGFR of at least 5 mL/min/1.73 m², and 61% of those with a baseline eGFR of less than 60 mL/min/1.73 m² had an increase in eGFR of 10 mL/min/1.73 m² or more.
Kohlmeier noted several possible mechanisms for the eGFR improvement: "Was it [parathyroid hormone's] ability to hold onto calcium in the kidney, its vasodilatory effect in the kidney, [and/or] the combination of its benefits at the glomerulus. These are all important theories as to why [parathyroid hormone] replacement with palopegteriparatide has such a good effect on the kidney."
Dramatic Reduction in Urine Calcium
Mean 24-hour urine calcium excretion decreased into the normal range within 3 months and continued to decline throughout the study period. Levels dropped from 195 mg per day at 1 year to 167 mg per day at 2 years and 162 mg per day at 3 years. Kohlmeier said the urine calcium excretion decline continued after participants stopped conventional therapy, and the mean amount seen at 3 years is "almost unseen" in hypoparathyroidism (search).
"Patients on palopegteriparatide can usually come off their thiazide if on one for high urine calcium excretion, which is common in patients with hypoparathyroidism (search)," Kohlmeier said. "They can also possibly increase their salt intake, after confirming with their provider, since the fear of having a kidney stone on conventional therapy should be considerably lower with normal urine calcium excretion on palopegteriparatide."
Quality of Life Benefits
Improvements in self-reported hypoparathyroidism (search)-related symptoms and health-related quality of life were observed within weeks with palopegteriparatide and maintained at 3 years. Kohlmeier described this as one of the most rewarding benefits for patients with hypoparathyroidism.
"Patients tell me they have their lives back," Kohlmeier said.
Safety Profile
Among all PaTHway participants, 56.3% experienced an adverse event related to the study treatment. Serious adverse events related to the therapy occurred in 2.5% of participants. The most common treatment-emergent adverse events were injection site reaction, hypercalcemia (search), nausea, headache, hypocalcemia (search) and postural orthostatic tachycardia syndrome (search). There was one death due to fatal cardiac arrest during the trial, deemed unrelated to palopegteriparatide.
Clinical Implementation
Kohlmeier emphasized that healthcare professionals should follow the titration protocol when initiating palopegteriparatide and remind patients to continue over-the-counter vitamin D3 supplementation to maintain 25(OH) vitamin D levels at least 20 ng/mL, which was required for enrollment in the PaTHway trial.
"In my experience, a vitamin D level of 30 ng/mL to 40 ng/mL is even better, given this is what palopegteriparatide converts into active D," Kohlmeier said.
The safety data showed that palopegteriparatide is well-tolerated and no new safety signals were identified through the 3-year follow-up period.