Safety and Efficacy of 5 Years of Treatment With Recombinant Human Parathyroid Hormone in Adults With Hypoparathyroidism

Michael Mannstadt; Bart L. Clarke; John P. Bilezikian; Henry Bone; Douglas Denham; Michael A. Levine; Munro Peacock; Jeffrey Rothman; Dolores M. Shoback; Mark L. Warren; Nelson B. Watts; Hak-Myung Lee; Nicole Sherry; Tamara J. Vokes

Disclosures

J Clin Endocrinol Metab. 2019;104(11):5136-5147. 

In This Article

Abstract and Introduction

Abstract

Context: Conventional hypoparathyroidism treatment with oral calcium and active vitamin D is aimed at correcting hypocalcemia but does not address other physiologic defects caused by PTH deficiency.

Objective: To evaluate long-term safety and tolerability of recombinant human PTH (1–84) [rhPTH(1–84)].

Design: Open-label extension study; 5-year interim analysis.

Setting: 12 US centers.

Patients: Adults (N = 49) with chronic hypoparathyroidism.

Intervention(s): rhPTH(1–84) 25 or 50 μg/d initially, with 25-μg adjustments permitted to a 100 μg/d maximum.

Main Outcome Measure(s): Safety parameters; composite efficacy outcome was the proportion of patients with ≥50% reduction in oral calcium (or ≤500 mg/d) and calcitriol (or ≤0.25 μg/d) doses, and albumin-corrected serum calcium normalized or maintained compared with baseline, not exceeding upper limit of normal.

Results: Forty patients completed 60 months of treatment. Mean albumin-corrected serum calcium levels remained between 8.2 and 8.7 mg/dL. Between baseline and month 60, levels ± SD of urinary calcium, serum phosphorus, and calcium-phosphorus product decreased by 101.2 ± 236.24 mg/24 hours, 1.0 ± 0.78 mg/dL, and 8.5 ± 8.29 mg2/dL2, respectively. Serum creatinine level and estimated glomerular filtration rate were unchanged. Treatment-emergent adverse events (AEs) were reported in 48 patients (98.0%; hypocalcemia, 36.7%; muscle spasms, 32.7%; paresthesia, 30.6%; sinusitis, 30.6%; nausea, 30.6%) and serious AEs in 13 (26.5%). At month 60, 28 patients (70.0%) achieved the composite efficacy outcome. Bone turnover markers increased, peaked at ~12 months, and then declined to values that remained above baseline.

Conclusion: Treatment with rhPTH(1–84) for 5 years demonstrated a safety profile consistent with previous studies and improved key biochemical parameters.

Introduction

PTH plays a central role in mineral homeostasis by stimulating renal reabsorption of calcium, promoting renal phosphate excretion, and stimulating conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (1,25[OH]2D), the fully active form of vitamin D. Moreover, 1,25[OH]2D enhances absorption of calcium and phosphate from the gastrointestinal tract.[1] In addition, PTH is a potent regulator of bone turnover (i.e., the coupled process of bone resorption and bone formation);[2–4] deficiency of PTH results in decreased bone turnover.[2,4] Conventional therapy for hypoparathyroidism includes oral calcium and active vitamin D (e.g., calcitriol), as well as thiazide diuretics and magnesium supplementation as needed. Although this approach can correct the hypocalcemia associated with hypoparathyroidism, it does not replace other functions of PTH and can lead to or worsen hypercalciuria.[2,5] Other concerns with conventional therapy include unpredictable episodes of hypocalcemia and hypercalcemia; increased serum calcium-phosphorus (Ca × P) product; and complications such as extraskeletal calcifications, nephrolithiasis, nephrocalcinosis, and decreased kidney function.[2,5–7] Reduced quality of life and symptoms of hypocalcemia are consistent findings among patients with hypoparathyroidism receiving conventional treatment.[8–13]

Recombinant human PTH [rhPTH(1–84)] is full-length PTH that is approved in the United States and Europe as an adjunctive treatment of adults with hypoparathyroidism.[14,15] Safety and efficacy of rhPTH(1–84) in patients with hypoparathyroidism have been demonstrated in short-term, placebo-controlled and open-label studies.[16–20] In the pivotal REPLACE (Use of NPSP558 in the Treatment of Hypoparathyroidism) Study, a 24-week, double-blind, placebo-controlled, randomized phase 3 study conducted with 134 patients, 53% of patients receiving rhPTH(1–84) vs 2% of patients receiving placebo met the primary study end point (≥50% reduction from baseline in oral calcium and calcitriol doses with maintenance of normal albumin-corrected serum calcium).[17] In addition, patients receiving rhPTH(1–84) in REPLACE showed significant reductions in serum phosphorus throughout the 24-week study compared with patients receiving placebo.[21] In both study groups, urinary calcium excretion declined from baseline, but at week 24 in both groups, the mean urinary calcium excretion remained above the upper limit of normal (ULN) for women and near the ULN for men.[17,21]

RACE (Open-label Study Investigating the Safety and Tolerability of NPSP558, a Recombinant Human Parathyroid Hormone [rhPTH(1–84)], for the Treatment of Adults With Hypoparathyroidism—A Clinical Extension Study; ClinicalTrials.gov identifier, NCT01297309) was an open-label extension study designed to assess long-term safety and efficacy of rhPTH(1–84) in patients with hypoparathyroidism. This article reports 5-year safety and efficacy of treatment with rhPTH(1–84) and examines changes in mineral homeostasis, kidney function, and skeletal parameters.

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