Background: Hypoparathyroidism (HP) is characterized by low serum calcium (sCa) and high serum phosphate (sP). Standard of care (SoC), active vitamin D and calcium, raises sCa and sP and increases burden of illness on HP patients by worsening hypercalciuria and the CaxP product. Parathyroid hormone (PTH)(1–84)(t1/2 ~2–3 hrs) is approved and can raise sCa and allow partial withdrawal of SoC, but does not sufficiently control urine calcium or symptomatic hypo- or hypercalcemia. [NATPARA Package Insert; Khurana M et al. 2019] TransCon PTH, an investigational prodrug of PTH(1–34) transiently bound to an inert carrier via a linker, is under development for the treatment of HP. Linker auto-cleavage occurs under physiologic conditions, releasing active PTH at a controlled rate with a t1/2 ~60 hrs.
Methods: PaTH Forward is a phase 2, double-blind, placebo-controlled trial evaluating TransCon PTH in adult HP patients treated with SoC. Subjects received fixed-dose TransCon PTH 15, 18, or 21 µg/day or placebo for 4 weeks, followed by an open-label extension period during which subjects could titrate their individual TransCon PTH dose (6–30 µg/day). The primary composite endpoint at Week 4 required 1) normal sCa, 2) normal (or ≥50% decrease from baseline) fractional excretion of calcium (FECa), 3) not taking active vitamin D, and 4) taking ≤1000 mg/day of calcium.
Results: At Week 4, significantly more subjects (50%) on TransCon PTH achieved the primary endpoint vs (15%) subjects on placebo (Table). sP decreased from baseline by 20% in subjects on TransCon PTH vs 1% on placebo. Increase from baseline in subjects meeting FECa endpoint was 42% on TransCon PTH vs 0% on placebo. Free PTH showed stable levels in the lower half of the normal range at both 2 and 4 weeks. TransCon PTH was well-tolerated; no subjects discontinued treatment or withdrew from the trial during the 4-week period, and no SAEs or severe AEs were reported. No subjects on TransCon PTH showed symptomatic hypocalcemia vs 7% on placebo.
Conclusions: Results from the initial 4 weeks of the PaTH Forward Trial demonstrated the TransCon PTH met the primary endpoint without increased incidence of symptomatic hypocalcemia despite a fixed dose. This trial will help inform the starting dose and SoC titration schedule for the phase 3 trial.
|TransCon PTH (n = 44)||Placebo (n = 13)||P-value|
|Off active vitamin D and ≤ 500 mg/day calcium||82%||15%||P < 0.0001|
|Off active vitamin D and calcium||50%||0%||P = 0.0008|
|Primary Endpoint||50%||15%||P = 0.0305|
23 May 2020 - 26 Feb 2020