Palopegteriparatide 420micrograms/1.4ml solution for injection pre-filled disposable devices

Background Hypoparathyroidism (HypoPT) is a rare endocrine disorder characterized by insufficient or absent secretion of parathyroid hormone (PTH), which results in hypocalcemia, hyperphosphatemia, and disruption of calcium phosphate homeostasis. Despite advances in understanding its pathophysiology and management, HypoPT remains a complex and impactful condition associated with significant morbidity, impaired quality of life, and long-term complications affecting the skeletal, renal, and neurological systems. Methods A literature search was performed on PubMed. Articles were selected based on their relevance to the main topic of the review, with particular attention to recent studies. Results This review provides a comprehensive synthesis of the current knowledge on HypoPT, addressing its epidemiology, underlying pathophysiological mechanisms, genetic and acquired etiologies, clinical manifestations, diagnostic strategies, and chronic disease-related complications. Emphasis is placed on the genetic spectrum of the disease, challenges of postsurgical management, and burden of conventional therapy, which often fails to fully restore mineral homeostasis and patient well-being. The evolving therapeutic landscape is detailed, highlighting advances from traditional calcium and active vitamin D supplementation to innovative PTH replacement strategies. Among these, palopegteriparatide and eneboparatide (phase 3 clinical trial ongoing) are reshaping treatment paradigms by enabling more physiological restoration of calcium-phosphate balance, reducing complications, and improving patient-centered outcomes, including renal function and quality of life. Conclusions By integrating clinical expertise with the latest research developments, this review offers an updated and holistic perspective on HypoPT management, aiming to support clinicians in delivering effective and individualized care to patients across the spectrum of disease severity.

Abstract licence: CC BY-NC-ND

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

Abstract Hypoparathyroidism is an endocrine disease caused by insufficient levels of 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, ≤600 mg/d calcium) and maintained serum biochemistries within normal ranges. The current analyses describe patterns of change in BMD, serum bone turnover markers, and serum and urine calcium in adults with chronic hypoparathyroidism treated with palopegteriparatide through 3 years of the PaTH Forward trial. Baseline BMD Z-scores for the LS, TH, FN, 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 weeks 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

Abstract Background Replacement therapy with recombinant human PTH (rhPTH1-84) represents a causal treatment for patients with chronic hypoparathyroidism (HypoPT). Recently, palopegteriparatide (TransCon PTH), a novel long-acting drug with slow release of PTH1-34, was approved by the European Medicines Agency and Food and Drug Administration for treatment of HypoPT. To date, no data exist on the treatment switch from rhPTH1-84 to TransCon PTH. Methods We retrospectively analyzed clinical data from 40 patients with chronic HypoPT during the switch from rhPTH1-84 to TransCon PTH. Independent of the last prior rhPTH1-84 dose, all patients were started on 18 µg of TransCon PTH as recommended by the manufacturer. TransCon PTH dose adjustments, changes in additional medication, and adverse events were documented during the treatment switch. Results Within the first month after the treatment switch, 80% (n = 32) of patients needed individual adjustment of their TransCon PTH dose to achieve normocalcemia. Dose reduction (to 9-15 µg) was necessary in 38% (n = 15) and an increase (to 21-27 µg) in 43% (n = 17) of patients. Adjustments occurred predominantly (in 62% cases) according to serum calcium levels, partly dependent on symptoms. The prior applied rhPTH1-84 dose correlated significantly with the adjusted TransCon PTH dose (r = 0.4; P = .01). The treatment change was associated with moderate or mild adverse events in 24/40 patients. Conclusion We hereby report the first clinical data on switching treatment from rhPTH1-84 to 18 µg TransCon PTH independent of the prior rhPTH1-84 dose. Our data support discrete adaptation of the starting dose depending on the prior rhPTH1-84 dosage.

Abstract licence: CC BY

IntroductionThe study objective was to determine the value contribution of palopegteriparatide to the treatment of adults with chronic hypoparathyroidism, a rare endocrine disease, through a multi-criteria decision analysis (MCDA).MethodsThe Orphar-SEFH group framework for evaluating orphan drugs was used, along with the weighting performed by 98 national and regional evaluators. A multidisciplinary panel of seven experts individually scored the evidence matrix. The scores were collected and analysed using Microsoft Excel software programmed for MCDA study analysis. The results were discussed in a reflective discussion session.ResultsThe expert panel considered chronic hypoparathyroidism to be a moderate-to-severe disease (mean ± SD: 3.3 ± 0.5) due to its multiorgan impact and associated comorbidities, with significant unmet needs (3.6 ± 1.0), particularly related to the lack of the physiological effect due to insufficient levels of parathyroid hormone. The experts found palopegteriparatide as an add-on treatment to conventional therapy (calcium and active vitamin D) to be much more effective than placebo plus conventional therapy, with this criterion receiving the highest score. The safety profile was considered acceptable (1.6 ± 1.1). The participants highlighted the positive impact of palopegteriparatide on patient-reported outcomes (2.9 ± 0.9) compared to placebo because of improvements in quality of life (QoL). Palopegteriparatide was seen as a potentially disease-modifying treatment, which could lead to savings in "other medical costs" (3.1 ± 1.1) and "non-medical/indirect costs" (2.0 ± 0.8), although no evidence was available, especially in the long term. The quality of the evidence was perceived as high (3.6 ± 0.5). The overall value contribution of palopegteriparatide was 0.58 (+ 1 = maximum value) compared to placebo. The study has some limitations, including a relatively small panel size and the exclusion of treatment cost as a criterion due to lack of pricing information at the time of evaluation.ConclusionAccording to MCDA, palopegteriparatide represents a valuable therapeutic option for chronic hypoparathyroidism treatment, particularly due to its demonstrated efficacy, which had an impact on patients' QoL, and the current unmet needs in this therapeutic area.

Abstract licence: CC BY-NC 4.0