PaTH Forward: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial of TransCon PTH in Adult Hypoparathyroidism

Abstract

Context: Hypoparathyroidism is characterized by insufficient levels of parathyroid hormone (PTH). TransCon PTH is an investigational long-acting prodrug of PTH(1-34) for the treatment of hypoparathyroidism.

Objective: This work aimed to investigate the safety, tolerability, and efficacy of daily TransCon PTH in adults with hypoparathyroidism.

Methods: This phase 2, randomized, double-blind, placebo-controlled 4-week trial with open-label extension enrolled 59 individuals with hypoparathyroidism. Interventions included TransCon PTH 15, 18, or 21 µg PTH(1-34)/day or placebo for 4 weeks, followed by a 22-week extension during which TransCon PTH dose was titrated (6-60 µg PTH[1-34]/day).

Results: By Week 26, 91% of participants treated with TransCon PTH achieved independence from standard of care (SoC, defined as active vitamin D = 0 μg/day and calcium [Ca] ≤ 500 mg/day). Mean 24-hour urine Ca (uCa) decreased from a baseline mean of 415 mg/24h to 178 mg/24h by Week 26 (n = 44) while normal serum Ca (sCa) was maintained and serum phosphate and serum calcium-phosphate product fell within the normal range. By Week 26, mean scores on the generic 36-Item Short Form Health Survey domains increased from below normal at baseline to within the normal range. The Hypoparathyroidism Patient Experience Scale symptom and impact scores improved through 26 weeks. TransCon PTH was well tolerated with no treatment-related serious or severe adverse events.

Conclusion: TransCon PTH enabled independence from oral active vitamin D and reduced Ca supplements (≤ 500 mg/day) for most participants, achieving normal sCa, serum phosphate, uCa, serum calcium-phosphate product, and demonstrating improved health-related quality of life. These results support TransCon PTH as a potential hormone replacement therapy for adults with hypoparathyroidism.

Trial registration: ClinicalTrials.gov NCT04009291.

Keywords: PTH(1-34); TransCon PTH; hypoparathyroidism; parathyroid hormone; prodrug; replacement therapy.

© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.

Figures

Figure 1.

Transient conjugation. TransCon parathyroid hormone (PTH), a sustained-release prodrug consists of a parent drug, PTH(1-34), transiently bound to a carrier via a linker that is autocleaved on exposure to physiologic conditions, releasing active PTH.

Figure 2.

PaTH Forward trial design.

Figure 3.

Participant disposition. FAS, full analysis set; mFAS, modified full analysis set.

Figure 4.

Mean 24-hour urine calcium at baseline and week 26. Gray lines represent individual patient data from baseline to week 26.

Figure 5.

Bone turnover markers from baseline to week 4 and week 26.

Figure 6.

SF-36 Physical and Mental component summaries at A, week 4, and B, week 26. **The dashed lines (between 47 and 53) indicate the lower and upper T score bounds for the US general population’s average level of functioning, with scores below 47 indicating impairment (11).

Figure 7.

SF-36 domain scores at A, week 4, and B, week 26. BP, bodily pain; GH, general health; MCS, mental component summary; MH, mental health; PCS, physical component summary; PF, physical functioning; PTH, parathyroid hormone; RE, role emotional; RP, role physical; SF, social functioning; VT, vitality. The dashed lines (between 47 and 53) indicate the lower and upper T score bounds for the US general population’s average level of functioning, with below 47 indicating impairment (10). *P less than .05 compared with placebo.

Figure 8.

Symptom and impact scales for Hypoparathyroid Patient Experience Scale (HPES) total and domain-level scores at A and B, week 4, and C, at week 26. Lower scores (ie, less radar plot area) indicate less impact/symptoms. *P less than .05 compared with placebo.