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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Conflict of interest statement

G. Block has been a consultant for Amgen Inc., Ardelyx, Keryx, AstraZeneca, Celgene, ZS, Relypsa, Akebia, Daiichi-Sankyo, Sanifit, and OPKO; has ownership interest in Ardelyx and Nephroceuticals; has received research funding from Keryx and NIH; received honoraria from Amgen Inc., Sanofi, Keryx, AstraZeneca, Celgene, Akebia, Daiichi-Sankyo, ONO, and OPKO; has been a scientific advisor for Amgen Inc., Akebia, Celgene, and AstraZeneca; has participated in speakers bureau with OPKO; and is a Medical Director with DaVita. G. Chertow has been a consultant for Akebia, AMAG, Amgen Inc., Ardelyx, AstraZeneca, Durect, Gilead, and Keryx; has ownership interest in Ardelyx, Durect, Outset, PuraCath, and Physiowave; and has received research funding from Amgen and Janssen. J. Sullivan holds stock in Nektar Therapeutics, NantHealth, Sage Therapeutics, and Marinus Pharmaceuticals; and is an employee and stockholder of Amgen Inc. O. Mather is an employee and stockholder of Amgen Inc. H. Deng was an employee at the time these trials were completed and is a stockholder of Amgen Inc. H. Tomlin and M. Serenko were employees and stockholders of Amgen Inc. at the time these trials were completed. M. Serenko holds stock in Editas, Ionis, Juno, Intelia, Bioverativ Inc., Celgene, and WAVE Life Sciences.

Figures

Fig 1. Trials included in the integrated safety analysis.

*Trial NCT01785875 also contains data from patients enrolled from a single-arm parent trial (i.e., trial NCT01932970). †Trial NCT02102204 also contains data from patients enrolled from a phase 2 parent trial (i.e., trial NCT01576146). ‡Indicates unique patients in the OLE pool. Ca = calcium; QD = every day; IV = intravenous; sHPT = secondary hyperparathyroidism; TIW = three times weekly.