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

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 1 2 3 4 5 6 7 8 9 10 11 12 13 14

To evaluate long-term safety and tolerability of recombinant human PTH  [rhPTH ].

Design
Open-label extension study; 5-year interim analysis.
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.
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  (16)(17)(18)(19)(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  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

Study design and patients
RACE was an open-label extension conducted at 12 centers in the United States. The primary objective was to assess long-term safety and tolerability of rhPTH(1-84) in adult patients with hypoparathyroidism ( Fig. 1 Patients were permitted to continue taking most baseline concomitant medications during the trial, including thiazide diuretics, hormone therapy (estrogen with or without progesterone), and antihypertensives. Other drugs known to affect bone or mineral metabolism were prohibited (e.g., calcitonin, cinacalcet, raloxifene, bisphosphonates, fluoride).
Investigators were permitted to introduce thiazide diuretics for control of hypercalciuria at or after week 16 for patients who were on a stable dose of rhPTH(1-84), had a 24-hour urine calcium level of >300 mg (>7.5 mmol) for men or >250 mg (>6.25 mmol) for women, and had not been receiving diuretics before the start of the study. Investigators administered sufficient supplemental cholecalciferol and/or ergocalciferol during the study to maintain patients' serum 25(OH)D levels between 30 and 100 ng/mL.
Patients self-administered rhPTH(1-84) subcutaneously, once daily, in the morning. For this study, a starting dose of 50 µg/d was used for patients with a total serum calcium concentration ≤9.5 mg/dL (≤2.37 mmol/L) and for patients with a serum calcium concentration >9.5 mg/dL who were taking ≥500 mg of calcium and/or any calcitriol. A starting dose of 25 µg/d was used for patients with a total serum calcium concentration >9.5 mg/dL who were taking <500 mg of supplemental calcium and no calcitriol. The dose of rhPTH(1-84) could be increased or decreased by the investigator in stepwise increments of 25 µg up to a maximum dose of 100 µg/d any time during the study, with the goal of achieving or maintaining total serum calcium levels in the target range of 8.0 to 9.0 mg/dL (2.00 to 2.25 mmol/L; Fig. 1). Patients continued taking the dose of rhPTH(1-84) at which their serum calcium levels were stable in the target range and that permitted the lowest possible doses of oral calcium and calcitriol.
The study was conducted in accordance with applicable International Council for Harmonization Guidelines, Good Clinical Practice, and the World Medical Association Declaration of Helsinki and its amendments. The study was approved by central or local institutional review boards, and all patients provided written informed consent.

Outcome measures
Outcome measures included mean change from baseline in albumin-corrected serum calcium, phosphorus, and creatinine levels; estimated glomerular filtration rate (eGFR); 24-hour urinary calcium excretion; and impact of thiazide diuretics on urinary calcium. Other outcome measures included incidence of treatmentemergent adverse events (AEs) and treatment-emergent serious AEs; mean percentage change from baseline in oral calcium and calcitriol doses; and mean change from baseline in serum 1,25(OH) D, bone turnover markers (BTMs), and bone mineral density (BMD). Fractional excretion of calcium (FECa), urinary calcium adjusted for body weight, and mean Ca × P product were also determined as post hoc analyses.
The composite efficacy outcome was the proportion of patients who achieved a reduction in the use of oral calcium supplements (≥50% reduction in dose from baseline or oral calcium dose ≤500 mg/d) and calcitriol (≥50% reduction in dose from baseline or oral calcitriol dose ≤0.25 µg/d) while normalizing or maintaining albumin-corrected serum calcium levels compared with the baseline value and not exceeding the ULN for the central laboratory [10.2 mg/dL (2.55 mmol/L)].

Assessments
On the days of clinic visits, serum for laboratory assessments and measurement of BTMs was collected before the daily injection of study drug. Albumin-corrected serum calcium, total serum calcium, and serum phosphorus levels, and Ca × P product were assessed at baseline, week 4, week 8, every 8 weeks up to week 48, and week 52. Thereafter, total serum calcium and serum phosphorus levels, and Ca × P product were evaluated every 2 months to month 60, and albumin-corrected serum calcium levels were determined yearly. The 24-hour urinary calcium and serum creatinine levels, and eGFR were determined at baseline and at weeks 16, 32, and 52, and then every 4 months to month 60. AEs were assessed at study visits and also could be reported at any time; serious AEs were recorded within 24 hours of awareness. Serum 1,25[OH] D was measured at baseline, weeks 24 and 52, and every 6 months thereafter. Serum BTMs [bone-specific alkaline phosphatase (BAP), cross-linked C-telopeptide of type 1 collagen (CTX), and aminoterminal propeptide of type 1 collagen (P1NP)] were assessed at baseline; at weeks 8, 16, 24, 40, and 52 during the first year of study; then every 4 months to month 60. BMD of the lumbar spine, total hip, femoral neck, and one-third distal radius was assessed via dual-energy x-ray absorptiometry at baseline and yearly thereafter.
Calcium and phosphorus levels were measured using commercially available assays (ADVIA ; Siemens Healthcare Diagnostics, Tarrytown, NY). Inorganic phosphate was measured and expressed as milligrams per deciliter of phosphorus; the standard conversion factor of 0.323 for inorganic phosphate was used to generate the data in International System of Units (mmol/L) (22) Baseline values were defined as those measured just before initiation of rhPTH(1-84) treatment, whether that occurred at the start of REPLACE, RELAY (for patients who did not participate in or received placebo in REPLACE), or RACE (for patients who received placebo in REPLACE and did not participate in RELAY). End points for oral calcium and calcitriol levels were based on investigator-prescribed data. AEs were coded using the Medical Dictionary for Regulatory Activities, version 13.0 (https://www.meddra.org/).

Patient disposition and baseline characteristics
Forty-nine patients who completed RELAY and/or REPLACE were enrolled from 12 US centers. The median interruption between completion of the previous study and initiation of treatment in RACE was 1.0 (interquartile range, 1.0 to 1.0) day. Forty enrolled patients (81.6%) had completed 60 months of rhPTH(1-84) treatment as of 8 May 2017. Nine patients withdrew from the study for the following reasons: patient's decision (n = 5; none were AE-related), investigator's decision (n = 2), AE (n = 1), or patient declined to enter the extension after the first 12 months were completed (n = 1). Table 1 summarizes key patient demographics and baseline characteristics.

Biochemical parameters
Mean albumin-corrected serum calcium concentration was maintained within the target range of 8.0 to 9. Urinary calcium excretion trended downward over 60 months of rhPTH(1-84) treatment [ Fig. 2  A similar eGFR profile was obtained when the prespecified Cockcroft-Gault formula was used to generate the data (data not shown).

Adverse events
No clinically significant changes in vital signs, physical examinations, or ECG parameters were observed over the treatment period. In addition, there were no clinically meaningful trends in safety laboratory results beyond those already discussed. Treatment-emergent AEs were reported in 48 of 49 patients (98.0%) while they were receiving rhPTH(1-84) treatment (Table 2). Five injection site reactions were reported in four patients (8.2%); all were mild. Severe AEs were reported in 17 patients (34.7%). AEs assessed by the investigator as related to treatment with rhPTH(1-84) were reported in 25 patients (51.0%). The most common AEs considered to be related to treatment were nausea (n = 7; 14.3%), hypercalcemia (n = 6; 12.2%), hypocalcemia (n = 4; 8.2%), tetany (n = 4; 8.2%), constipation (n = 3; 6.1%), and paresthesia (n = 3; 6.1%).  . No cases of bone tumors or osteosarcoma were reported. One death was reported during the study. A 52-year-old woman died of acute systolic congestive heart failure thought to be related to her comorbidities (including hypertension, hyperlipidemia, and cardiomyopathy) and to be unrelated to rhPTH(1-84) treatment.

Bone turnover and BMD
Mean serum concentrations of all BTMs increased from baseline with rhPTH(1-84) treatment, reaching a plateau 6 to 16 months after initiation of treatment, then declining and remaining within normal limits for CTX and BAP, and slightly above the normal limit for P1NP (Fig. 7). Baseline, maximum, and month 60 values for BTMs are reported in Table 3. Total serum alkaline phosphatase levels, measured as part of routine safety laboratory screening, responded similarly to BAP over the course of the study (data not shown).
At baseline, mean BMD Z-scores at lumbar spine, total hip, and femoral neck were greater than the normal range for age, sex, and race and were particularly high at the lumbar spine (Table 4). After 60 months of rhPTH(1-84) treatment, the mean BMD Z-score at the distal one-third radius site was reduced compared with baseline. At other sites, mean Z-scores remained stable and above 1 between baseline and month 60.

Discussion
Findings from 5 years of treatment with rhPTH(1-84) in the RACE study provide further evidence supporting the long-term safety and efficacy of rhPTH  in the treatment of adults with hypoparathyroidism. Along with overall reductions in oral supplementation, mean albumin-corrected serum calcium levels were maintained within the target range over 60 months of treatment, suggesting sustained long-term efficacy. Importantly, mean 24-hour urine calcium declined to levels within the normal range, and mean FECa showed an 18% decrease between baseline and 60 months, indicating that renal tubular reabsorption of calcium improved with rhPTH(1-84). Similar beneficial effects on urinary calcium excretion were seen in the only other long-term open-label study of rhPTH(1-84), the single-center HEXT (Hypo-Extended: Effect of PTH on Skeleton in Hypoparathyroidism) Study (16,18). Interestingly, although mean 24-hour urine calcium levels declined, but remained above the ULN for women in the shorter 6-month REPLACE study, the mean urine calcium level continued to decline in this long-term study into the normal range for men and women (urinary calcium decreased by 73.6 mg/24 hours by week 24 in REPLACE compared with a decrease of 101.2 mg/24 hours by month 60 in RACE) (17). This may indicate that longer treatment may be necessary for normalization of urine calcium levels.
RACE provides additional evidence that treatment with rhPTH(1-84) improves other aspects of mineral and skeletal homeostasis. The decrease in serum phosphorus level was similar to that reported from the long-term HEXT study (18). Reductions in serum phosphorus with rhPTH(1-84) treatment likely drove the observed declines in Ca × P product concentrations, which were maintained throughout the study. In addition, kidney function was preserved; serum creatinine remained within the normal range, and eGFR was stable over 5 years in RACE.
BTMs, which are low in patients with hypoparathyroidism, increased from baseline and peaked at around 1 year after the initiation of rhPTH(1-84) treatment, then declined but remained above pretreatment values through year 5. Similar trends in the pattern of BTMs have been reported in the HEXT study (16,18) but with differences in the magnitude of increase and time course of change that may be due to differing treatment regimens. The findings from these studies suggest the initial large increase in BTMs with rhPTH(1-84) treatment is temporary (18,25) and is followed by a new steady state of more normal bone turnover with continued therapy. Changes in calcium and phosphorus flux from bone may at least partially explain the trend for increases in calcium supplements later in the treatment period, but this was not tested directly in this study.
BMD is often elevated in patients with longstanding hypoparathyroidism (26). In this study, no meaningful changes in BMD Z-scores were observed at the lumbar spine, hip (total), and hip (femoral neck), whereas a decrease in Z-score occurred at the distal one-third radius. These results are similar to trends seen in the HEXT trial at 6 years of follow-up (18) and are not unexpected given the differential effects of PTH on cortical and trabecular bone (27)(28)(29). Longer observations will be necessary to obtain more insights into the changes in bone density and bone quality during treatment with rhPTH(1-84).
One patient discontinued this 5-year study because of an AE, which was not considered related to treatment. The AE profile of rhPTH(1-84) was similar to that observed in the 24-week REPLACE (17) and  studies. The most commonly reported AEs were related to the underlying disease (e.g., hypocalcemia, muscle spasms, paresthesia, nephrolithiasis) and common ailments (e.g., sinusitis, nausea).
Limitations of RACE include the open-label design, the lack of a control arm, and insufficient power to perform statistical analyses. Of the 12 patients who did not achieve the three-part efficacy end point in RACE, four did not receive the maximum dose of rhPTH(1-84) of 100 µg/d. Therefore, these patients may have been undertreated. The impact of rhPTH(1-84) on health-related quality of life in adults with hypoparathyroidism was not captured in RACE. The interpretation of BMD data reported here is limited by the small sample size and the use of different densitometers with lack of standardization and crosscalibration.
Continued use of rhPTH(1-84) throughout 5 years resulted in a safety profile that was consistent with other studies; no new safety findings were identified (17,20). Sustained improvements in mineral homeostasis and increases in BTMs were observed. Treatment with rhPTH(1-84) allowed major reductions in oral calcium supplements and active vitamin D analogs while maintaining albumin-corrected serum calcium concentration within the target range. Importantly, over the 5 years of treatment, eGFR and serum creatinine levels remained stable, mean urinary calcium excretion normalized, and serum phosphorus and Ca × P product levels improved.

Data Availability:
The datasets, including redacted study protocol, redacted statistical analysis plan, and individual participant's data behind the results reported in this article, will be available three months after the submission of a request to researchers who provide a methodologically sound proposal after de-  e  r  i  h  s  @  a  t  a  d  l  a  i  r  t  l  a  c  i  n  i  l  c . For approved requests, the researchers will be provided access to de-identified/anonymized data on a password-protected website upon Shire's receipt of a signed Data Sharing Agreement.    Table 3.