Phase 3 Data Show TransCon® PTH Replicated Systemic Actions of Endogenous PTH Through Week 182 in Adults with Hypoparathyroidism

Ascendis Pharma's TransCon PTH Shows Sustained Efficacy and Safety in Phase 3 PaTHway Trial

Ascendis Pharma announced positive Week 182 data from its completed Phase 3 PaTHway Trial for TransCon PTH (palopegteriparatide) in adults with hypoparathyroidism. The long-term treatment demonstrated sustained efficacy and safety, effectively replicating the systemic actions of endogenous parathyroid hormone. Key outcomes included an 86% response rate for a multi-component endpoint (normal serum calcium, no active vitamin D, ≤600 mg/day calcium) and significant improvements in quality of life, kidney function, and bone mineral density. These benefits were maintained over three and a half years, enabling patients to achieve independence from conventional therapy. The trial, which saw 89% patient completion, also reported a generally well-tolerated safety profile with no new signals.

• Sustained Efficacy and Independence from Conventional Therapy: The Phase 3 PaTHway Trial demonstrated an 86% response rate for its multi-component endpoint, which included achieving normal serum calcium, discontinuing active vitamin D, and reducing calcium intake to ≤600 mg/day. Notably, 100% of patients achieved independence from active vitamin D, and 96% achieved independence from therapeutic doses of calcium, sustaining these benefits over 182 weeks (three and a half years).
• Multi-Organ System and Quality of Life Benefits: TransCon PTH treatment led to significant and sustained improvements across multiple organ systems. Patients experienced normalized and stable 24-hour urine calcium, a mean eGFR increase of 11.0 mL/min/1.73 m2 from baseline, and corrected bone mineral density Z-scores. Furthermore, patients reported rapid and clinically meaningful improvements in hypoparathyroidism-related symptoms and health-related quality of life, as measured by HPES and SF-36 scores, which were maintained throughout the trial duration.
• Favorable Long-Term Safety Profile: Over the three-and-a-half-year treatment period, TransCon PTH was generally well-tolerated, with no new safety signals identified. Treatment-emergent adverse events were predominantly mild or moderate, and no discontinuations were attributed to the study drug. Crucially, no patients developed anti-PTH antibodies, reinforcing the long-term safety and immunogenicity profile of TransCon PTH.

Addressing the Unmet Needs in Hypoparathyroidism Treatment

Current hypoparathyroidism treatment faces significant limitations that impact patient outcomes and quality of life. Conventional calcium and vitamin D therapy, while addressing hypocalcemia, creates additional complications and fails to restore normal calcium-phosphate homeostasis. These challenges highlight the urgent need for more physiological treatment approaches.

• Inadequate disease control with conventional therapy - In a nationwide cohort of 260 patients with hypoparathyroidism, 15% had poor disease control despite treatment, with these patients requiring higher doses of oral calcium and calcitriol and experiencing significantly higher hospitalization rates (35.9% vs. 10.9%, P<0.001)

• Paradoxical worsening of calcium homeostasis - Conventional therapy effectively increases serum calcium levels but simultaneously worsens hypercalciuria, leading to consequences such as nephrocalcinosis and renal insufficiency

• Persistent quality of life impairment - Even in adequately substituted patients, hypoparathyroidism remains associated with impaired quality of life, hypothesized to correlate with the lack of parathyroid hormone in the central nervous system

• Increased comorbidity burden - Patients face elevated risks of nephrolithiasis/nephrocalcinosis, neuropsychiatric disease, cardiovascular complications, and increased susceptibility to infections

• Challenges maintaining normocalcemia - It is difficult to achieve stable normocalcemia with conventional calcium and vitamin D supplements, requiring careful monitoring to avoid both hypocalcemia and hypercalcemia

• Limited therapeutic options - Clinical intervention trials concerning optimal therapy and management strategies for hypoparathyroidism are lacking, and recombinant PTH therapies require additional long-term safety data for widespread adoption

• Complications from vitamin D formulations - Genuine vitamin D3 has a very long biological half-life with risk of chronic intoxication, while 1,25-dihydroxyvitamin D3 is highly potent but carries acute intoxication risks and has a short half-life

Sustained Efficacy and Safety of TransCon PTH in PaTHway

The US Expanded Access Program for palopegteriparatide (YORVIPATH®; TransCon® PTH) provided real-world evidence from 135 enrolled patients with hypoparathyroidism as of October 2024. In this study, patients received palopegteriparatide at a recommended starting dose of 18 μg/day, titrated alongside conventional therapy with calcitriol and calcium. The majority of participants (95.1%) had previously been treated with short-lived PTH therapy. Key efficacy outcomes demonstrated that the proportion of patients achieving independence from conventional therapy increased over 12 months, with mean serum calcium levels maintained within the reference range of 8.3-10.6 mg/dL. No new safety signals were identified during up to 12 months of treatment, and no clinically meaningful dose differences were observed between patients who switched directly from other PTH therapies versus those who did not.

A Phase 1 randomized, placebo-controlled study (NCT05158335) evaluated canvuparatide (formerly MBX 2109), a once-weekly investigational PTH analog that undergoes controlled-release conversion through intramolecular cyclization. Single subcutaneous doses ranging from 50-600 μg were administered to healthy volunteers and demonstrated favorable pharmacokinetic profiles with geometric mean half-lives of 81-101 hours for the prodrug and 133-186 hours for the active peptide, supporting once-weekly dosing. Preclinical studies in parathyroidectomized rats showed dose-proportional normalization of serum calcium levels and increased bone formation at doses of 10-40 nmol/kg. The single doses were well tolerated in healthy volunteers with no significant safety concerns reported.

Several case reports have documented successful transitions and novel applications of PTH replacement therapies. A notable case report described the first use of recombinant human parathyroid hormone (rhPTH) in a two-month-old infant with Kenny-Caffey syndrome type 2, who received treatment for 14 months with no detailed safety concerns reported. Additionally, a transition case from rhPTH(1-84) to palopegteriparatide in a patient with chronic postsurgical hypoparathyroidism demonstrated successful maintenance of stable biochemical values, complete withdrawal of calcium and magnesium supplements, improved patient well-being, and no adverse events during the transition period.

TransCon PTH's Impact on the Hypoparathyroidism Treatment Landscape

The treatment landscape for hypoparathyroidism has undergone significant transformation over the past five years, primarily driven by the introduction of advanced parathyroid hormone replacement therapies. The most notable breakthrough has been the development and approval of palopegteriparatide (TransCon PTH), which demonstrated remarkable efficacy in the phase 3 PaTHway trial. In this 26-week, double-blind, placebo-controlled study of 84 participants, 79% of patients treated with TransCon PTH achieved the composite primary endpoint compared to only 5% in the placebo group, with 93% achieving independence from conventional therapy. This once-daily therapy, designed with a 60-hour half-life to provide stable physiological PTH levels for 24 hours, has been approved by both the FDA and EMA, representing a paradigm shift toward more physiologic treatment approaches.

Long-term safety and efficacy data have reinforced the value of PTH replacement therapy, particularly through extended studies of rhPTH(1-84). A three-year extension study demonstrated that patients maintained biochemical stability with mean exposure to rhPTH(1-84) of 10.8 years, showing sustained normalization of serum calcium, phosphate, and urinary calcium levels without waning therapeutic effects. Real-world evidence from the PARADIGHM registry, analyzing 737 patients across 64 centers, revealed that patients requiring PTH replacement therapy typically presented with greater disease burden despite normal biochemistry, including higher rates of fatigue, paresthesia, and muscle symptoms compared to those managed with conventional therapy alone.

The therapeutic pipeline continues to expand with several promising investigational agents in development. Eneboparatide, a long-acting PTH analog, is currently being evaluated in phase 3 clinical trials, while encaleret, a calcilytic molecule specifically targeting autosomal dominant hypocalcemia type 1, has also entered phase 3 development. Additionally, novel formulations including an oral PTH1 receptor agonist in phase 1 trials and a weekly PTH molecule in phase 2 studies suggest continued innovation in this space. These developments collectively indicate a shift from symptom management with calcium and vitamin D supplementation toward more targeted, physiologic hormone replacement strategies that address the underlying pathophysiology of hypoparathyroidism.

TransCon PTH: Redefining Long-Term Hypoparathyroidism Care

The latest Week 182 data for Ascendis Pharma's TransCon PTH represents a pivotal moment for adults living with hypoparathyroidism. This long-term evidence from the PaTHway trial reinforces the drug's potential to fundamentally reshape the treatment landscape, moving beyond the symptomatic management offered by conventional therapies like active vitamin D and calcium. For years, patients have grappled with a rare endocrine disease that not only causes debilitating physical and cognitive symptoms but also carries the burden of complex daily regimens and the risk of long-term complications, including renal dysfunction.

TransCon PTH offers a true physiologic replacement for parathyroid hormone, addressing the root cause of the disease. The sustained efficacy, highlighted by an impressive 86% response rate for a multi-component endpoint—achieving normal serum calcium while becoming independent from conventional therapy—is a testament to its transformative potential. Beyond symptom control, the data reveal significant improvements in patient quality of life, enhanced kidney function as evidenced by increased eGFR, and positive impacts on bone mineral density. These benefits, maintained over three and a half years, underscore the drug's ability to offer a more holistic and sustained therapeutic solution.

However, as with any novel therapy, strategic considerations and potential risks must be carefully weighed. While the overall response is strong, existing literature suggests that individual patient responses to PTH therapy can vary, particularly concerning skeletal outcomes. This highlights the importance of careful patient selection and ongoing monitoring to ensure optimal benefits for each individual. Furthermore, while TransCon PTH reduces reliance on conventional vitamin D, which has been linked to artery calcification, continued long-term surveillance of cardiovascular health and calcification pathways will be crucial. Finally, the successful integration of this innovative treatment into clinical practice will depend on overcoming potential adoption challenges, including physician education and patient support, to ensure its full impact is realized. Ultimately, TransCon PTH stands poised to redefine long-term care for hypoparathyroidism, offering patients a path toward greater independence and improved health outcomes.