Research Article: An integrated analysis of safety and tolerability of etelcalcetide in patients receiving hemodialysis with secondary hyperparathyroidism

Date Published: March 15, 2019

Publisher: Public Library of Science

Author(s): Geoffrey A. Block, Glenn M. Chertow, John T. Sullivan, Hongjie Deng, Omar Mather, Holly Tomlin, Michael Serenko, Mario Cozzolino.

http://doi.org/10.1371/journal.pone.0213774

Abstract

Calcimimetics have been shown to be effective and safe therapies for the treatment of secondary hyperparathyroidism (sHPT), a serious complication of disordered mineral metabolism associated with dialysis-dependent chronic kidney disease. Etelcalcetide, a recently approved intravenous calcimimetic, reduces serum parathyroid hormone (PTH), calcium, phosphorus, and fibroblast growth factor-23 concentrations. Here we report the first integrated safety profile of etelcalcetide using pooled data from five pivotal clinical trials.

This analysis included data from patients receiving hemodialysis with moderate to severe sHPT enrolled in two randomized, placebo-controlled trials; a randomized active-controlled (with cinacalcet) trial; and two single-arm, open-label extension trials. Patients initially received etelcalcetide intravenously 5 mg three times weekly (TIW) after hemodialysis; with potential dose increases of 2.5 or 5 mg at 4-week intervals to a maximum dose of 15 mg TIW, depending on serum PTH and calcium levels. The nature, frequency, and severity of treatment-emergent adverse events (AEs) and changes in laboratory parameters were assessed.

Overall, we evaluated 1023 patients from the placebo-controlled trials, 683 from the active-controlled trial, and 1299 from open-label extensions. The frequency and nature of common treatment-emergent AEs reported for the etelcalcetide arm were consistent among the placebo-controlled and active-controlled trials. The most common AEs were those related to mineral metabolism (decreased blood calcium, hypophosphatemia, muscle spasms) or gastrointestinal abnormalities (diarrhea, nausea, vomiting). Hypocalcemia leading to discontinuation of either calcimimetic was experienced in ≤ 1% of patients.

This integrated safety assessment of etelcalcetide across placebo- and active-controlled trials showed an overall favorable risk/benefit profile, with safety similar to that of cinacalcet. Consistent with its mechanism of action, the most important risks associated with etelcalcetide were serum calcium reductions and hypocalcemia-related AEs; no new safety findings were identified in the pooled long-term extension trials.

Partial Text

Calcimimetics are effective and safe therapies for the treatment of secondary hyperparathyroidism (sHPT), a serious complication of disordered mineral metabolism affecting approximately 80% to 90% of patients receiving maintenance dialysis [1–4]. Secondary hyperparathyroidism begins as an adaptive response to maintain serum calcium and phosphorus homeostasis and is characterized by elevated serum concentrations of parathyroid hormone (PTH) mediated in part via the calcium sensing receptor (CaSR) on the parathyroid gland [1, 4]. If left untreated, sHPT often becomes refractory to therapy, which can contribute to demineralization of bone; ectopic vascular and visceral calcification; bone, joint, and muscle pain; pruritus; irritability; and hypertension, and has been associated with heightened risk of cardiovascular disease, hospitalization, and death [2, 5].

This integrated assessment of the etelcalcetide safety profile did not reveal any safety signals beyond those already reported in the pivotal trials [8, 9]. Assessments were based on the pooled data from the two phase 3 placebo-controlled trials, the active-controlled trial, and two open-label extension trials with exposure up to 1063 days. Adverse drug reactions (i.e., events considered related to etelcalcetide) were mainly those secondary to decreased blood calcium (QT prolongation, parasthesia, muscle spasms, and myalgia) or related to gastrointestinal symptoms (diarrhea, nausea, and vomiting); other adverse drug reactions were hyperkalemia, heart failure, hypophosphatemia, and headache [7, 17, 18].

In this integrated safety analysis, etelcalcetide exhibited a safety profile similar to that of cinacalcet; however, because of the limited experience with etelcalcetide in clinical practice, uncertainty remains regarding its safety profile in the real-world setting. Fortunately, an abundance of safety data exists for cinacalcet, which has a similar mechanism of action to etelcalcetide, and the many similarities in safety between these two calcimimetics should provide assurance for clinicians. Overall, these results indicate that risks associated with etelcalcetide use should be manageable with careful dose titration, periodic monitoring of serum calcium, and vigilance for AEs that may be prompted by hypocalcemia.

 

Source:

http://doi.org/10.1371/journal.pone.0213774

 

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