Palopegteriparatide 294micrograms/0.98ml solution for injection pre-filled disposable devices

Abstract Context Chronic hypoparathyroidism (HypoPT) is a rare endocrine disorder characterized by hypocalcemia and hyperphosphatemia, requiring lifelong treatment with activated vitamin-D and oral calcium supplements. Palopegteriparatide, a novel long-acting prodrug of PTH (1-34), has demonstrated efficacy in randomized controlled trials, but real-world data on its long-term effectiveness and safety remain limited. Objective To evaluate the efficacy and safety of long-term palopegteriparatide therapy in a real-world cohort of patients with HypoPT. Design and Setting Multicenter prospective cohort study conducted in tertiary referral hospitals. The study is registered at ClinicalTrials.gov under the identifier NCT07299838. Patients and Intervention Ninety-two adults with HypoPT (79 females, 13 males), previously treated with recombinant human PTH (1-84) or conventional therapy, initiated palopegteriparatide according to the National Hellenic Guidelines for the management of HypoPT. Results Patients were treated for a median duration of 6.5 months (range 2-14), with significant improvements in biochemical control of calcium-phosphate metabolism. Albumin-adjusted calcium increased from 8.14 ± 0.73 to 8.99 ± 0.94 mg/dL, and magnesium from 1.79 ± 0.17 to 1.96 ± 0.17 mg/dL (both P < .001). Phosphate decreased from 4.74 ± 0.97 to 4.02 ± 0.63 mg/dL, Ca × P product from 38.27 ± 6.92 to 36.04 ± 6.55 mg2/dL2, and 24-hour urinary calcium from 245.7 ± 125.5 to 164.5 ± 88.3 mg/24 h (all P < .001). Daily pill burden was markedly reduced; 58% of patients achieved independence from calcium supplements and alfacalcidol after a mean of 61 days. Adverse events were mostly mild and transient. Conclusions In a real-world setting, palopegteriparatide effectively normalizes calcium–phosphate homeostasis, reduces hypercalciuria, and substantially decreases reliance on conventional therapy, with a favorable safety profile.

Abstract licence: CC BY-NC 4.0

Individuals with chronic hypoparathyroidism managed with conventional therapy (active vitamin D and calcium) have an increased risk for renal dysfunction versus age- and sex-matched controls. Treatments that replace the physiologic effects of parathyroid hormone (PTH) while reducing the need for conventional therapy may help prevent a decline in renal function in this population. This post hoc analysis examined the impact of palopegteriparatide treatment on renal function in adults with chronic hypoparathyroidism. PaTHway is a phase 3 trial of palopegteriparatide in adults with chronic hypoparathyroidism that included a randomized, double-blind, placebo-controlled 26-week period followed by an ongoing 156-week open-label extension (OLE) period. Changes in renal function over 52 weeks (26 weeks blinded + 26 weeks OLE) were assessed using estimated glomerular filtration rate (eGFR). A subgroup analysis was performed with participants stratified by baseline eGFR 600 mg/day]). After 52 weeks of treatment with palopegteriparatide, significant improvements were seen in a measure of kidney function called estimated glomerular filtration rate (eGFR). Improvements in eGFR from the beginning of the trial to week 52 were considered clinically meaningful for over 57% of participants. In participants with impaired kidney function at the beginning of the trial, eGFR improvements were even greater, and 74% of participants had a clinically meaningful improvement. These results suggest that palopegteriparatide treatment may be beneficial for kidney function in adults with chronic hypoparathyroidism, especially those with impaired kidney function.

Abstract licence: CC BY-NC 4.0

Hypoparathyroidism is an endocrine disease caused by insufficient levels of parathyroid hormone (PTH), which acts directly on bone and kidney and indirectly on the intestine to regulate calcium and phosphate balance. In clinical trials, palopegteriparatide (TransCon PTH) treatment enabled independence from conventional therapy (no active vitamin D, ≤500 mg/d calcium) and maintained serum biochemistries within normal ranges. The current analyses describe patterns of change in bone mineral density (BMD), serum bone turnover markers, and serum and urine calcium in adults with chronic hypoparathyroidism treated with palopegteriparatide through 3 yr of the PaTH Forward trial. Baseline BMD Z-scores for the lumbar spine, total hip, femoral neck, and 1/3 distal radius were above zero, indicating bone mass exceeding age-adjusted normative values. BMD decreased from these elevated baseline levels with palopegteriparatide treatment, with larger reductions during the first 26 wk and modest declines thereafter. Mean BMD Z-scores at week 162 remained above zero for all 4 sites. Participants with lower baseline BMD (Z-scores below -1 and T-scores below -2.5) generally exhibited lesser declines in BMD versus those with higher baseline BMD. Palopegteriparatide treatment was associated with early increases in bone resorption (serum C-terminal telopeptide of type I collagen, CTx) and bone formation (serum procollagen type 1 N-terminal propeptide, P1NP) that peaked at weeks 12 and 26, respectively, followed by declines to levels moderately higher than baseline at week 162. Mean CTx and P1NP in the overall population and the subgroup of postmenopausal women were below their upper limits of normal from weeks 58-162. At week 162, mean serum and median urine calcium remained within normal ranges and 91% of participants were independent from conventional therapy. These results suggest that long-term palopegteriparatide therapy in adults with chronic hypoparathyroidism gradually returns the skeleton toward its natural state thereby enhancing the skeleton's contribution to calcium homeostasis.

Abstract licence: CC BY 4.0

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract licence: CC BY 4.0

CONTEXT: Individuals with hypoparathyroidism experience a range of physical and cognitive symptoms and reduced quality of life (QoL) despite management with conventional therapy (active vitamin D and calcium). OBJECTIVE: This analysis investigated the long-term impact of parathyroid hormone (PTH) replacement therapy with palopegteriparatide (YORVIPATH®) on symptoms, daily functioning, and well-being in adults with chronic hypoparathyroidism. Associations between patient characteristics and changes in patient-reported outcomes (PROs) were also analyzed. METHODS: PaTH Forward was a phase 2 clinical trial of palopegteriparatide with a 4-week randomized, double-blind, placebo-controlled period followed by an open-label extension period lasting through trial week 266. PRO measures were collected at baseline, weeks 4, 12, 26, 58, and annually thereafter through the end of the trial. The Hypoparathyroidism Patient Experience Scales (HPES) assess disease-specific symptoms and impacts on functioning and well-being. The Short Form Health Survey (SF-36v2) measures general health-related QoL. Data were analyzed using descriptive statistics and Mixed Models for Repeated Measures. RESULTS: Palopegteriparatide treatment demonstrated significant improvements from baseline in disease-specific symptoms and impacts on daily functioning and well-being at week 12, which were sustained through week 110. Mean changes in PROs met thresholds for clinically meaningful within-patient improvement. Significant improvements in general health-related QoL were also shown in SF-36v2 scores. Results were generally similar across demographics and patient characteristics. CONCLUSION: Through week 110 of the PaTH Forward trial, PTH replacement therapy with palopegteriparatide was associated with significant improvements in disease-specific symptoms and impacts on daily functioning and well-being, as well as general health-related QoL.

Abstract licence: CC BY 4.0

Hypoparathyroidism (HypoPT) is a rare endocrine disorder characterized by insufficient parathyroid hormone (PTH) levels, leading to hypocalcemia and hyperphosphatemia. Affecting approximately 70 000-90 000 individuals in the United States, HypoPT can arise from genetic mutations or, most commonly, as a result of surgical removal of the parathyroid glands. Traditional treatments involve calcium and vitamin D supplementation, which can pose long-term risks such as renal complications. On 9 August 2024, the U.S. Food and Drug Administration (FDA) approved Palopegteriparatide (Yorvipath, Ascendis, Denmark), a synthetic long-acting PTH analog, for subcutaneous use in adult patients with chronic HypoPT. Palopegteriparatide is designed as a pro-drug that undergoes auto-cleavage, offering sustained release and prolonged systemic exposure to recombinant PTH (1-34). Clinical trials have demonstrated its ability to maintain normocalcemia with minimal need for supplemental calcium or vitamin D. The treatment also showed a favorable safety profile, with mild transient side effects and no significant toxicity. Unlike standard-of-care therapies, Palopegteriparatide maintains balanced calcium-phosphate levels with less renal strain, making it a particularly promising option for patients with compromised kidney function. Although concerns remain regarding long-term safety, its FDA approval and orphan drug designation underscore its importance in addressing the unmet therapeutic needs of HypoPT. Continued investigation is warranted to optimize patient outcomes and further define its risk-benefit profile. This approval marks a critical milestone in endocrine therapeutics and offers renewed hope for patients struggling with the burdens of chronic HypoPT.

Abstract licence: CC BY 4.0