Ascendis Pharma Announces 5-Year Phase 2 Data for TransCon PTH in Hypoparathyroidism

Ascendis Pharma's TransCon PTH Shows Sustained 5-Year Efficacy in Hypoparathyroidism

Ascendis Pharma A/S announced positive 5-year (Week 266) data from its Phase 2 PaTH Forward Trial for TransCon PTH (palopegteriparatide) in adults with hypoparathyroidism. The long-term treatment demonstrated sustained efficacy and safety, replicating the systemic actions of endogenous PTH. Key benefits included normalized and stable urine calcium, serum calcium, improved quality of life, and bone mineral density, while enabling independence from conventional therapy with active vitamin D and calcium. The trial showed an 82% response rate for a multi-component endpoint and 95% of patients completed the five-year study, with no new safety signals identified.

• Sustained Efficacy and Independence from Conventional Therapy: The trial demonstrated an 82% response rate for a multi-component endpoint, including normal serum calcium, no active vitamin D, and less than 600 mg/day of calcium. Notably, 96% of patients achieved independence from active vitamin D and 95% from therapeutic calcium, highlighting the drug's ability to replace conventional symptom management.
• Significant Renal and Bone Health Improvements: TransCon PTH maintained significant improvements in kidney function, with a mean eGFR increase of 9.4 mL/min/1.73 m2 from baseline, contrasting with expected age-related decline. Mean 24-hour urine calcium normalized within 26 weeks and remained stable. Additionally, mean BMD Z-scores corrected from high baseline levels and remained above 0, indicating positive skeletal health impact.
• Enhanced Quality of Life and Favorable Safety Profile: Patients reported rapid and sustained improvements in hypoparathyroidism-related physical and cognitive symptoms, as well as overall health-related quality of life, as measured by HPES and SF-36 scores. The treatment was generally well-tolerated over five years, with mostly mild or moderate treatment-emergent adverse events and no new safety signals, reinforcing its long-term safety.

The Persistent Challenges in Managing Chronic Hypoparathyroidism

Current hypoparathyroidism management faces significant therapeutic challenges that impact both immediate disease control and long-term patient outcomes. These limitations span across conventional treatments, disease monitoring, and emerging therapeutic approaches. The complexity of achieving optimal biochemical control while minimizing adverse effects remains a persistent clinical concern.

Conventional Calcium and Vitamin D Therapy Limitations:
• Difficulty maintaining normocalcemia with standard calcium and vitamin D supplements despite adequate dosing
• Worsening of hypercalciuria and its consequences including nephrocalcinosis, renal insufficiency, and ectopic calcification
• Association with decreased renal function over time while only addressing hypocalcemia symptoms rather than replacing the missing parathyroid hormone
• Requirement for large supplement doses that carry attendant side effects and compliance challenges

Suboptimal Disease Control Outcomes:
• Approximately 15% of patients demonstrate poor disease control in nationwide cohort studies, requiring higher doses of oral calcium and calcitriol
• Not adequately controlled patients exhibit significantly higher hospitalization rates compared to well-controlled patients (35.9% vs. 10.9%, P<0.001)
• Inadequate control correlates with significantly lower postoperative PTH concentrations, indicating more severe hormonal deficiency

Specific Vitamin D Agent Challenges:
• Vitamin D3 preparations carry risk of chronic intoxication due to very long biological half-life
• 1,25-dihydroxyvitamin D3 formulations present acute intoxication risks despite potency, have short half-lives requiring frequent dosing, and involve higher costs
• Limited clinical intervention trial data to guide optimal therapy selection and management protocols

Recombinant PTH Treatment Barriers:
• Current unlicensed status for hypoparathyroidism treatment creates regulatory and access challenges
• Significant cost-effectiveness concerns with incremental cost-effectiveness ratios exceeding $800,000/QALY, well above standard willingness-to-pay thresholds
• Historical osteosarcoma safety concerns that restricted pediatric use for over two decades, though recent data suggests these fears may have been overstated
• Need for additional long-term safety and efficacy data from larger prospective trials

TransCon PTH's Sustained Efficacy and Safety in 5-Year PaTH Forward Data

Recent clinical studies have demonstrated significant advances in hypoparathyroidism treatment, particularly with novel PTH replacement therapies. These investigations span from real-world evidence programs to early-phase clinical trials, providing comprehensive data on both established and emerging therapeutic options.

• US Expanded Access Program for Palopegteriparatide (2024) evaluated 135 patients receiving TransCon PTH at 18 μg/day starting dose, demonstrating increased rates of independence from conventional therapy (defined as no calcitriol and ≤600 mg/day elemental calcium) over 12 months, with mean serum calcium maintained within reference range and no new safety signals identified

• Phase 1 Canvuparatide Study (NCT05158335) tested single subcutaneous doses (50-600 μg) of this once-weekly PTH analog in healthy volunteers, showing dose-proportional pharmacokinetics with geometric mean half-lives of 81-101 hours (prodrug) and 133-186 hours (active peptide), supporting once-weekly dosing with good tolerability

• Real-world transition case report (2024) documented successful switch from rhPTH(1-84) to palopegteriparatide in chronic postsurgical hypoparathyroidism, achieving complete withdrawal of calcium and magnesium supplements while maintaining stable biochemical values and improved patient well-being with no adverse events

• Kenny-Caffey Syndrome Type 2 case study reported the first use of rhPTH in a two-month-old infant with KCS2 over 14 months, representing the first reported application in this rare genetic condition when conventional treatment failed to achieve therapeutic targets

How TransCon PTH is Evolving Hypoparathyroidism Treatment

The most significant advancement in hypoparathyroidism treatment over the past five years has been the development and regulatory approval of TransCon PTH (palopegteriparatide), which received European Medicines Agency approval in November 2023 and FDA approval in August 2024. This represents the first major breakthrough in providing physiologic PTH replacement therapy that addresses the fundamental hormone deficiency rather than merely managing calcium levels. The phase 3 PaTHway trial demonstrated remarkable efficacy, with 79% of patients achieving the composite primary endpoint compared to only 5% on placebo, and 93% of treated patients becoming independent from conventional calcium and vitamin D therapy. TransCon PTH's innovative prodrug design provides sustained PTH release over 24 hours with a 60-hour half-life, normalizing serum calcium while reducing urinary calcium excretion and significantly improving quality of life measures across multiple domains.

The treatment landscape has also expanded with several promising therapies in clinical development, including eneboparatide (a long-acting PTH analog in phase 3 trials), encaleret (a calcilytic molecule in phase 3 for autosomal dominant hypocalcemia), and various other PTH formulations designed to overcome the limitations of short-acting preparations. Real-world evidence from the PARADIGHM registry has provided valuable insights into the patient population that benefits most from PTH replacement therapy, showing that patients with higher symptom burden and reduced quality of life despite biochemically normal parameters are prime candidates for advanced therapies. Additionally, innovative delivery methods such as continuous subcutaneous PTH infusion have emerged as options for refractory cases, while research into delayed-clearance PTH molecules with half-lives 44 times longer than conventional PTH offers future therapeutic possibilities.

Despite these advances, significant challenges in disease management persist, with registry data revealing that approximately 15% of patients remain inadequately controlled on conventional therapy and require higher medication doses with increased hospitalization rates. The limitations of traditional calcium and vitamin D supplementation have become more apparent, particularly regarding hypercalciuria, renal complications, and quality of life impacts. Long-term safety data for PTH replacement therapies have revealed concerns about cortical bone loss and increased porosity with extended use, highlighting the need for careful monitoring and potentially intermittent treatment strategies. These developments collectively represent a paradigm shift toward personalized, physiologic hormone replacement while emphasizing the importance of patient selection and long-term safety surveillance in optimizing hypoparathyroidism care.

Sustained Efficacy: Reshaping Chronic Hypoparathyroidism Management

The recent announcement of compelling 5-year data for TransCon PTH (palopegteriparatide) from the Phase 2 PaTH Forward trial underscores a pivotal moment in the management of chronic hypoparathyroidism. For years, patients have grappled with the limitations of conventional therapy, relying on active vitamin D and calcium supplements that, while alleviating hypocalcemia, often fail to normalize critical biochemical parameters like urinary calcium and can lead to long-term complications such as renal impairment. The withdrawal of previous PTH replacement options further highlighted a significant unmet need for a truly physiological and sustained treatment.

TransCon PTH, designed as a prodrug to provide a continuous, infusion-like release of PTH(1-34) over 24 hours, directly addresses this deficiency. The 5-year data reinforces its ability to maintain normocalcemia, normalize urinary calcium excretion, and significantly reduce or eliminate the need for conventional therapy. Beyond biochemical control, the sustained improvements in patient-reported quality of life and the positive impact on renal function, including increases in eGFR, represent substantial clinical benefits that can profoundly alter the disease trajectory.

However, as with any long-term therapy, careful consideration of its nuances is essential. While the safety profile remains favorable, clinicians must be aware of the potential for a rebound effect, including symptomatic hypocalcemia, if treatment is discontinued, necessitating meticulous patient monitoring and adjustment of conventional therapies. Furthermore, while bone mineral density changes observed over time are described as a return towards natural states, ongoing assessment of skeletal dynamics remains prudent. This robust long-term evidence, coupled with its recent approvals and orphan drug designation, firmly establishes palopegteriparatide as the new standard for PTH replacement, offering renewed hope for patients and a clear path forward for optimizing care in this complex endocrine disorder.