Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Takeda Pharmaceuticals International AG Ireland Branch, Block 3 Miesian Plaza, 50 – 58 Baggot Street Lower, Dublin 2, Ireland
Pharmacotherapeutic group: Calcium homeostasis, parathyroid hormones and analogues
ATC code: H05AA03
Endogenous parathyroid hormone (PTH) is secreted by the parathyroid glands as a polypeptide of 84 amino acids. PTH exerts its action via cell-surface parathyroid hormone receptors, present in bone, kidney and nerve tissue. Parathyroid hormone receptors belong to the family of G-coupled protein receptors.
PTH has a variety of critical physiological functions that include its central role in modulating serum calcium and phosphate levels within tightly regulated levels, regulating renal calcium and phosphate excretion, activating vitamin D, and maintaining normal bone turnover.
Natpar is produced in E. coli using recombinant DNA technology, and is identical to the 84 amino acid sequence of endogenous human parathyroid hormone.
PTH (1-84) is the principal regulator of plasma calcium homeostasis. In the kidney, PTH (1-84) increases renal tubular reabsorption of calcium and promotes phosphate excretion.
The overall effect of PTH is to increase serum calcium concentration, to reduce urinary excretion of calcium and to lower serum phosphate concentration.
Natpar has the same primary amino acid sequence as endogenous parathyroid hormone and may be anticipated to have the same physiological actions.
The safety and clinical efficacy of Natpar in adults with hypoparathyroidism is derived from 1 randomised, placebo-controlled study and an open-label extension study. In these studies, Natpar was self-administered, with daily doses ranging from 25 to 100 micrograms per subcutaneous injection.
The objective of this trial was to maintain serum calcium with Natpar while reducing or replacing oral calcium and active vitamin D. The study was a 24-week, randomised, double-blind, placebo-controlled, multicentre trial. In this trial, patients with chronic hypoparathyroidism receiving calcium and active forms of vitamin D (vitamin D metabolite or analogues) were randomised to Natpar (n=84) or placebo (n=40). The mean age was 47.3 years (range 19 to 74 years); 79% were females. Patients had hypoparathyroidism for an average of 13.6 years.
At randomisation, active forms of vitamin D were reduced by 50% and patients were allocated to Natpar 50 micrograms daily or placebo. Randomisation was followed by a 12-week Natpar titration phase and a 12-week Natpar dose maintenance phase.
Ninety percent of patients who were randomised completed 24 weeks of treatment.
For the efficacy analysis, subjects that fulfilled three components of a three-part response criterion were considered responders. A responder was defined using a composite primary efficacy endpoint of at least a 50% reduction from the baseline active vitamin D dose AND at least a 50% reduction from the baseline oral calcium AND an albumin-corrected total serum calcium concentration maintained or normalised compared with the baseline value (≥1.875 mmol/L) and did not exceed the upper limit of the laboratory normal range.
At the end of treatment, 46/84 (54.8%) patients treated with Natpar achieved the primary endpoint versus 1/40 (2.5%) with placebo (p<0.001).
At Week 24, for patients who completed the study, 34/79 (43%) Natpar patients were independent of active vitamin D treatment and were receiving no more than 500 mg of calcium citrate, compared with 2/33 (6.1%) placebo patients (p<0.001).
Sixty-nine percent (58/84) of subjects randomised to Natpar showed a reduction in oral calcium of ≥50% compared to 7.5% (3/40) of subjects randomised to placebo. The mean percent change from baseline in oral calcium was -51.8% (SD 44.6) in subjects receiving Natpar compared to 6.5% (SD 38.5) in the placebo group (p<0.001). In addition, 87% (73/84) of patients treated with Natpar showed a ≥50% reduction in oral active vitamin D versus 45% (18/40) in the placebo group.
Study 2 is a six year long-term, open-label extension study of daily subcutaneous dosing of Natpar in hypoparathyroidism subjects who completed prior studies with Natpar.
A total of 49 subjects were enrolled in the study. Subjects received doses of 25 micrograms, 50 micrograms, 75 micrograms or 100 micrograms/day for up to approximately 72 months (mean 2038 days (~5.6 years). The minimum time of exposure to Natpar was 41 days, and the maximum was 2497 days (~6.8 years).
61.2% (30/49) of subjects met the primary efficacy endpoint at end of treatment, defined as albumincorrected total serum calcium concentration that was normalized or maintained compared to the baseline value and not exceeding the upper limit of normal values; ≥50% reduction from baseline or ≤500 mg of daily calcium supplementation; and ≥50% reduction from baseline or ≤0.25 μg of daily calcitriol supplementation.
The results demonstrate durability of the physiological effects of Natpar over 72 months including maintenance of mean albumin-corrected serum calcium levels (n=49, 2.09 (SD 0.174) mmol/L at baseline; n=38, 2.08 (SD 0.167) mmol/L at 72 months), a decrease in serum phosphate (n=49, 1.56 (SD 0.188) mmol/L at baseline; n=36, 1.26 (SD 0.198) mmol/L at 72 months) and the maintenance of normal calcium phosphate product (<4.4mmol2/L2) for all subjects (n=49 at baseline, n=36 at 72
months).
The long-term effects included a decrease in mean urinary calcium excretion to the normal range (n=48, 8.92 (SD 5.009) mmol/day at baseline; n=32, 5.63 (SD 3.207) mmol/day at 72 months), and stabilization of normal mean serum creatinine levels (n=49, 84.7 (SD 18.16) µmol/L at baseline; n=38, 78.2 (SD 18.52) µmol/L at 72 months). In addition, there was maintenance of normal bone mineral density.
The European Medicines Agency has deferred the obligation to submit the results of studies with Natpar in one or more subsets of the paediatric population in hypoparathyroidism (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited.
The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
The pharmacokinetics of Natpar following subcutaneous administration in the thigh of hypoparathyroidism subjects was consistent with that observed in healthy post-menopausal women who received parathyroid hormone in the thigh and abdomen.
Natpar administered subcutaneously had an absolute bioavailability of 53%.
Following intravenous administration, Natpar has a volume of distribution of 5.35 L at steady state.
In vitro and in vivo studies demonstrated that the clearance of Natpar is primarily a hepatic process with a lesser role played by the kidneys.
In the liver, parathyroid hormone is cleaved by cathepsins. In the kidney, parathyroid hormone and C-terminal fragments are cleared by glomerular filtration.
Parathyroid hormone (rDNA) was evaluated in an open-label PK/PD study in which 7 patients with hypoparathyroidism received single subcutaneous doses of 50 and 100 micrograms with a 7-day washout interval between doses.
Peak plasma concentrations (mean Tmax) of Natpar occur within 5 to 30 minutes and a second usually smaller peak at 1 to 2 hours. The apparent terminal half-life (t1/2) was 3.02 and 2.83 hours for the 50 and 100 micrograms dose, respectively. The maximum mean increases of serum calcium, which occurred at 12 hours, were approximately 0.125 mmol/L and 0.175 mmol/L with the 50 micrograms and 100 micrograms dose, respectively.
Treatment with Natpar increases serum calcium concentration in hypoparathyroidism patients, and this increase occurs in a dose-related manner. After a single injection of parathyroid hormone (rDNA), the mean serum total calcium reached its peak level between 10 and 12 hours. The calcaemic response is sustained for more than 24 hours after administration.
Treatment with Natpar produces a decrease in urinary calcium excretion by 13 and 23% (50 and 100 microgram dose, respectively) to a nadir in the 3 to 6 hour time point, which returns to pre-dosing levels by 16 to 24 hours.
Following injection with Natpar, serum phosphate levels decrease proportionally to PTH levels over the first 4 hours and persist over 24 hours post-injection.
Serum 1,25-(OH)2D increases following a single dose of Natpar to maximum levels at about 12 hours with a return to near baseline levels by 24 hours. A greater increase in the levels of 1,25-(OH)2D in serum were observed with the 50 micrograms dose than with the 100 micrograms dose, likely due to direct inhibition of the renal 25-hydroxyvitamin D-1-hydroxylase enzyme by serum calcium.
A pharmacokinetic study in non-hypoparathyroidism subjects was conducted in 6 men and 6 women with moderate hepatic impairment (Child-Pugh Classification of 7-9 [Grade B]) as compared with a matched group of 12 subjects with normal hepatic function. Following a single 100 micrograms subcutaneous dose, the mean Cmax and baseline-corrected Cmax values were 18% to 20% greater in the moderately impaired subjects than in those with normal function. There were no apparent differences in the serum total calcium concentration-time profiles between the 2 hepatic function groups. No dose adjustment for Natpar is recommended in patients with mild to moderate hepatic impairment. There are no data in patients with severe hepatic impairment.
Pharmacokinetics following a single 100 micrograms subcutaneous dose of Natpar was evaluated in 16 non-impaired subjects (creatinine clearance (CLcr) >80 mL/min) and 16 subjects with renal impairment. The mean maximum concentration (Cmax) of PTH following 100 micrograms parathyroid hormone (rDNA) in subjects with mild-to-moderate renal impairment (CLcr 30 to 80 mL/min) was approximately 23% higher than that observed in subjects with normal renal function. Exposure to PTH as measured by AUC0-last and baseline-corrected AUC0-last was approximately 3.9% and 2.5%, respectively, higher than that observed for subjects with normal renal function.
Based on these results, no dose adjustment is necessary in patients with mild-to-moderate renal impairment (CLcr 30 to 80 mL/min). No studies were conducted in patients on renal dialysis. There are no data in patients with severe renal impairment.
Pharmacokinetic data in paediatric patients are not available.
Clinical studies with Natpar did not include sufficient numbers of subjects aged 65 and over to determine whether response in these subjects is different from younger subjects.
No clinically relevant gender differences were observed in the REPLACE study.
No dose adjustment is necessary based on weight.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, mutagenicity, toxicity to fertility and general reproduction, and local tolerance.
Rats treated with daily injections of Natpar for 2 years had dose-dependent exaggerated bone formation and an increased incidence of bone tumours, including osteosarcoma, most probably due to a non-genotoxic mechanism. Due to the differences in bone physiology in rats and humans, the clinical relevance of these findings is unknown. No osteosarcomas have been observed in clinical trials.
Natpar did not adversely affect fertility or early embryonic development in rats, embryo-foetal development in rats and rabbits, or pre/post-natal development in rats. A minimal amount of Natpar is excreted in the milk of lactating rats.
In monkeys receiving daily subcutaneous doses for 6 months, there was an increased occurrence of renal tubular mineralisation at exposure levels 2.7 times the clinical exposure levels at the highest dose.
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