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Parsabiv ® (etelcalcetide) - the first intravenous drug approved for the treatment of secondary hype

Tuesday, November 21, 2017  
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Mandee Noval, PharmD Candidate 2018
Cole Cecchini, PharmD Candidate 2019
Preceptor - Nicole M. Sifontis, PharmD
Temple University School of Pharmacy

Secondary hyperparathyroidism (HPT) is a common complication in Stage 5 chronic kidney disease (CKD) patients who are on hemodialysis (HD), affecting approximately 88% of these patients.1 Characterized by an increased secretion of parathyroid hormone (PTH), secondary HPT can lead to severe complications if left untreated including increased bone fractures, vascular calcification, and coronary artery disease. PTH levels rise due to a decline in renal function and impaired mineral metabolism, causing increased rates of bone turnover and a net efflux of phosphate and calcium. Data from the Dialysis Outcomes and Practice Pattern Study (DOPPS) suggests that PTH levels are rising globally and that PTH concentrations greater than 600 pg/ml are associated with increased mortality.2

 Evidence based guidelines recommend the use of phosphate binders, active vitamin D analogs, and an oral calcimimetic (cinacalcet) for the prevention and treatment of secondary HPT. However, these therapies are not without their own adverse effects and are highly contingent upon patient adherence. 1 Parsabiv (etelcalcetide) is the first approved therapy for secondary HPT in 12 years, and it is the only calcimimetic agent that can be administered intravenously by the dialysis health care team, thus removing the potential for non-adherence with the alternative calcimimetic which is prescribed orally once daily. Etelcalcetide acts by binding to and activating the calcium-sensitizing receptor at a site distinct from cinacalcet on the parathyroid gland, causing a decrease in PTH secretion. The prolonged half-life of etelcalcetide allows thrice-weekly administration while still sustaining reductions in PTH over the 48-72 hour dosing interval. 3

The approval of etelcalcetide was based on a trial that combined two parallel, 27-week, Phase 3, randomized, placebo-controlled studies designed to evaluate its efficacy and safety in patients receiving hemodialysis with moderate to severe secondary HPT. 4 The studies were both multicenter and international with baseline characteristics being well-matched in both groups. Patients with end-stage renal disease (ESRD) and severe secondary HPT (PTH >400) were randomized to receive etelcalcetide or placebo three times weekly following hemodialysis. The primary efficacy endpoint of patients with greater than 30% reduction from baseline in mean PTH at weeks 20-27 was found to be statistically significantly different with the use of etelcalcetide compared to placebo (74.0% vs 8.3% in Study A and 75.3% vs 9.6% in Study B; P < .001, respectively for both). The adverse effect most commonly reported was decreased blood calcium levels in patients receiving etelcalcetide in both studies (61.0% and 66.7% vs 8.3% and 12% with placebo). In addition, patients who were administered etelcalcetide reported more muscle spasms (12.0% and 11.1% vs 7.1% and 6.2% with placebo), nausea (12.4% and 9.1% vs 5.1% and 7.3% with placebo), and vomiting (10.4% and 7.5% vs 7.1% and 3.1% with placebo), though not at statistically significantly higher rates.4

 In addition, a head-to-head, multinational, randomized, active control, double blind, double dummy, Phase 3 clinical trial was conducted comparing IV etelcalcetide to oral cinacalcet. 5 The primary efficacy endpoint was non-inferiority of etelcalcetide compared to cinacalcet in achieving a >30% reduction in PTH concentrations. The study concluded that 68.2% of patients receiving etelcalcetide achieved a >30% PTH reduction compared to 57.7% of those on cinacalcet (estimated difference: -10.5%, 95% CI, -17.5% to -3.5%), showing non-inferiority of etelcalcetide compared to cinacalcet (Table 1). In addition, secondary efficacy analysis revealed that etelcalcetide demonstrated superiority to cinacalcet in reducing PTH concentrations by >50% in 52.4% of patients compared to 40.2% of patients on cinacalcet (difference in proportions,12.2%; 95% CI, 4.7% to 19.5%; P=0.001) during weeks 20-27. There were more reports of hypocalcemia with etelcalcetide compared to cinacalcet (68.9% vs. 59.8%) prompting the labeling to include caution in patients with serum calcium levels less than 7.5 mg/dl. One hypothesized advantage of the IV formulation was a theorized decrease in the incidence of gastrointestinal disturbance compared to oral cinacalcet due to the ability of etelcalcetide to bypass the stomach. This advantage was not inherently apparent with the incidence of self-reported GI disturbance being similar in both groups (Table 2; 18.3% vs. 22.6% reporting nausea with etelcalcetide vs. cinacalcet respectively and 13.3% vs. 13.8% reporting vomiting), suggesting that the mechanism responsible for these adverse effects likely involves receptors not specific to the parathyroid gland. 5

Etelcalcetide is recommended to be initiated as a 5 mg, undiluted IV bolus dose to be given through a venous line immediately following hemodialysis three times a week, during or after rinse back. The dose may be titrated in 2.5 or 5 mg increments based on PTH and corrected calcium response, with the suggested dose ranging from to 2.5 to 15 mg three times per week. Doses should be changed no more frequently than every 4 weeks, and serum calcium should be measured within 1 week after initiation or dose adjustment. 6  When switching from cinacalcet to etelcalcetide it is recommended to allow a 7-day washout period before initiating etelcalcetide. In addition, serum calcium levels should be checked prior to initiating the 5 mg etelcalcetide dose. Caution should be taken in patients experiencing hypocalcemia and the drug should not be initiated in patients with a serum calcium below the lower limit of normal.4-6 Patients predisposed to QT interval prolongation, ventricular arrhythmias and seizures may be at increased risk for adverse events and should be monitored closely.6

Etelcalcetide stands alone in its class as an IV calcimimetic, without a US generic counterpart. Benchmark pricing for cinacalcet oral 30 mg dose (30 pills) is $968.04, 60 mg (30) for $1936.08, and 90 mg (30) is $2904.12. Although pricing for etelcalcetide has not yet been confirmed by Amgen, it is expected to align with a one month supply of cinacalcet. Amgen reassures coverage to patients on medicare, commercially insured patients and to eligible uninsured or underinsured patients through the Amgen Safety Net Foundation.  

The safety and efficacy of etelcalcetide should continuously be monitored through post-market surveillance. There is hope that based on the convenient route of administration and efficacy profile seen here in short term studies, etelcalcetide may potentially alleviate many issues related to secondary HPT in CKD patients and reduce non-adherence that often results with oral agents. Studies are needed to truly assess the mortality benefit of etelcalcetide gained from treating secondary HPT and the long-term safety profile of this agent, particularly from a cardiovascular standpoint due to its effects in promoting hypocalcemia. Nevertheless, the proven reduction in PTH levels looks promising.

Table 1: Comparison of efficacy data between IV etelcalcetide and oral cinacalcet5

Primary End-point

Etelcalcetide (n=340)

Cinacalcet (n=343)

CI*

Reduction in mean PTH >30% from baseline during weeks 20-27

232 (68.2%)

198 (57.7%)

−10.5% (−17.5% to −3.5%)

 *Non inferiority margin, 12%

Table 2: Comparison of safety data between IV etelcalcetide and oral cinacalcet5

Treatment Emergent

Adverse Effects

Etelcalcetide (n=338)

Cinacalcet (n=341)

Decreased blood calcium level

233 (68.9%)

204 (57.7%)

Nausea

62 (18.3%)

77 (22.6%)

Vomiting

45 (13.3%)

47 (13.8%)

Diarrhea

21 (6.2%)

35 (10.3%)

 


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