Safety and Efficacy of Oral Human Parathyroid Hormone (1-34) in Hypoparathyroidism: An Open-Label Study

Abstract

The standard treatment of primary hypoparathyroidism (hypoPT) with oral calcium supplementation and calcitriol (or an analog), intended to control hypocalcemia and hyperphosphatemia and avoid hypercalciuria, remains challenging for both patients and clinicians. In 2015, human parathyroid hormone (hPTH) (1-84) administered as a daily subcutaneous injection was approved as an adjunctive treatment in patients who cannot be well controlled on the standard treatments alone. This open-label study aimed to assess the safety and efficacy of an oral hPTH(1-34) formulation as an adjunct to standard treatment in adult subjects with hypoparathyroidism. Oral hPTH(1-34) tablets (0.75 mg human hPTH(1-34) acetate) were administered four times daily for 16 consecutive weeks, and changes in calcium supplementation and alfacalcidol use, albumin-adjusted serum calcium (ACa), serum phosphate, urinary calcium excretion, and quality of life throughout the study were monitored. Of the 19 enrolled subjects, 15 completed the trial per protocol. A median 42% reduction from baseline in exogenous calcium dose was recorded (p = .001), whereas median serum ACa levels remained above the lower target ACa levels for hypoPT patients (>7.5 mg/dL) throughout the study. Median serum phosphate levels rapidly decreased (23%, p = .0003) 2 hours after the first dose and were maintained within the normal range for the duration of the study. A notable, but not statistically significant, median decrease (21%, p = .07) in 24-hour urine calcium excretion was observed between the first and last treatment days. Only four possible drug-related, non-serious adverse events were reported over the 16-week study, all by the same patient. A small but statistically significant increase from baseline quality of life (5%, p = .03) was reported by the end of the treatment period. Oral hPTH(1-34) treatment was generally safe and well tolerated and allowed for a reduction in exogenous calcium supplementation, while maintaining normocalcemia in adult patients with hypoparathyroidism. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Keywords: CALCIUM/PHOSPHATE DISORDERS; HYPOPARATHYROIDISM; ORAL PARATHYROID HORMONE; PARATHYROID HORMONE; PARATHYROID-RELATED DISORDERS.

Fig 1

Change from baseline daily calcium supplement requirements and serum albumin‐adjusted calcium (ACa) levels. (A) Box plot represents the percent of baseline supplemental calcium doses for subjects (n = 15) treated with oral hPTH(1‐34) at the beginning of each treatment week (16 weeks). Bold line represents the median values. Whiskers represent the minimum and maximum values. At weeks 4 to 16, the percent change from baseline supplemental calcium doses was statistically significant (p ≤ 0.006). The p values for percent change from baseline for each visit were calculated using Wilcoxon signed‐rank test. (B) Box plot represents serum ACa levels (n = 15) at each study visit (the last of which occurred at the beginning of week 17). Bold line represents the median values. Whiskers represent the minimum and maximum values.

Fig 2

Median and individual serum albumin‐adjusted calcium (ACa) and mean hPTH(1‐34) levels after each of the first two doses of oral hPTH(1‐34). After the first and second dose of 0.75 mg hPTH(1‐34) on day 1, in the clinic, blood samples were collected at predetermined intervals for hPTH(1‐34) and ACa analysis. The median (bold line) ACa profile (n = 18) is superimposed on the geometric mean (dashed line) drug pharmacokinetic profile (n = 19). See Table 5 for complete pharmacokinetic data analysis. One subject was omitted from the ACa analysis because of their pre‐dose hypercalcemic levels.

Fig 3

Median and individual phosphate and mean hPTH(1‐34) levels after each of the first two doses of oral hPTH(1‐34). After the first and second dose of 0.75 mg hPTH(1‐34) on day 1, in the clinic, blood samples were collected at predetermined intervals for hPTH(1‐34) and serum phosphate analysis. The median (bold line) phosphate profile (n = 17) is superimposed on the geometric mean (dashed line) drug pharmacokinetic profile (n = 19). See Table 5 for complete pharmacokinetic data analysis. Two subjects were omitted from the serum phosphate analysis, one because of pre‐dose hypercalcemic levels and the second was on a phosphate binder medication. The gray dashed line represents the upper level of the reference range for serum phosphate in adults (4.5 mg/dL).

Fig 4

Serum phosphate levels after oral hPTH(1‐34) administration. At each treatment visit over the 16‐week treatment period, blood sampling for serum phosphate analysis was performed before and 1 hour after oral hPTH(1‐34) administration. Box plot represents the serum phosphate levels at T = 0 and T = 60 minutes post‐dose at each study visit (the last of which occurred at the beginning of week 17). Whiskers represent the minimum and maximum values. The gray dashed line represents the upper level of the reference range for serum phosphate in adults (4.5 mg/dL). The bold line shows the change in median phosphate levels from T = 0 to T = 60 per visit. p ≤ .04 when comparing pre‐dose to 1 hour post‐dose values at each study visit. The p values were calculated using t test for paired samples.