Etelcalcetide: Novel calcimimetic to treat secondary hyperparathyroidism
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Abstract
Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease (CKD), characterized by excessive serum parathyroid hormone (PTH) levels, parathyroid gland hyperplasia, and the imbalance of mineral metabolism. Clinically, SHPT shows renal osteodystrophy, vascular calcification, cardiovascular damage and fatal outcome. Calcium sensing receptors (CaSR) are the main physiological regulators of PTH secretion, which can rapidly inhibit the secretion of parathyroid hormone. Vitamin D receptors also play an important role in regulating mineral metabolism. Current therapeutic approaches for SHPT consist of dietary phosphate control, vitamin D and calcimimetic agents. Etelcalcetide is a new second-generation of calcimimetics that has been approved by the US Food and Drug Administration to treat SHPT among adult patients with CKD on hemodialysis since February 2017. However, the first-generation of calcimimetics, once-daily oral cinacalcet, etelcalcetide is provided intravenously thrice weekly at the end of the hemodialysis session. Apart from improving drug adherence, etelcalcetide has proven to be more effective in lowering PTH levels compared with cinacalcet. In terms of gastrointestinal adverse effects, intravenous etelcalcetide did not show any significant reduction compared with oral cinacalcet. Etelcalcetide has shown more efficacy in enhanced adherence and strongly reduced PTH, phosphorus, and fibroblast growth factor 23. To indicate the improvement of mineral metabolism and cardiovascular effects, future studies including large scale experimental trials could show that etelcalcetide improve survival outcomes and quality of life.
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References
Tentori F, Wang M, Bieber BA, Karaboyas A, Li Y, Ja cobson SH, et al. Recent changes in therapeutic approaches and association with outcomes among patients with secondary hyperparathyroidism on chronic hemodialysis: the DOPPS study. Clin J Am Soc Nephrol. 2015; 10(1):98-109.
Danese MD, Belozeroff V, Smirnakis K, Rothman KJ. Consistent control ofmineral and bone disorder in incident hemodialysis patients. Clin J Am Soc Nephrol. 2008; 3(5):1423-9.
Rodríguez M, Goodman WG, Liakopoulos V, Messa P, Wiecek A, Cunningham J. The use of calcimimetics for the treatment of secondary hyperparathyroidism: A 10 year evidence review. Semin Dial. 2015; 28(5):497-507.
Lindberg JS, Culleton B, Wong G, Borah MF, Clark RV, Shapiro WB, et al. Cinacalcet HCl, an oral calcimimetic agent for the treatment of secondary hyperparathy roidism in hemodialysis and peritoneal dialysis: a randomized, double-blind, multicenter study. J Am Soc Nephrol. 2005; 16(3):800-7.
Blair HA. Etelcalcetide: first global approval. Drugs. 2016; 76(18):1787-1792.
De Boer IH, Gorodetskaya I, Young B, Hsu CY, Chertow GM. The severity of secondary hyperparathyroidism in chronic renal insufficiency is GFR-dependent, race-dependent, and associated with cardiovascular disease. J Am Soc Nephrol. 2002; 13(11):2762-9.
Cunningham J, Locatelli F, Rodriguez M. Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options. Clin J Am Soc Nephrol. 2011; 6(4):913-21.
Gutierrez OM, Mannstadt M, IsakowaT, Rauh-HainJA, Tamez H, Shah A, et al. Fibroblast growthfactor-23 and mortality among patients
undergoing hemodialysis. New Engl J Med 2008; 359: 58492.
Cunningham J, Locatelli F, Rodriguez M. Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options. Clin J Am Soc Nephrol. 2011; 6(4):913-21.
KidneyDisease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKDMBD). Kidney Int Suppl (2011). 2017; 7(1):1-59.
Behets GJ, Spasovski G, Sterling LR, Goodman WG, Spiegel DM, De Broe ME, et al. Bone histomorphometry before and after long-term treatment with cinacalcet in dialysis patients with secondary hyperparathyroidism. Kidney Int. 2015; 87(4):846-56.
EVOLVE Trial Investigators, Chertow GM, Block GA, Correa-Rotter R, Drüeke TB, Floege J, Goodman WG, et al. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med. 2012; 367(26):2482-94.
Raggi P, Chertow GM, Torres PU, Csiky B, Naso A, Nossuli K, et al. ADVANCE Study Group. The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis. Nephrol Dial Transplant. 2011; 26(4):1327-39.
Palmer SC, Nistor I, Craig JC, Pellegrini F, Messa P, Tonelli M, et al. Cinacalcet in patients with chronic kidney disease: a cumulative meta-analysis of randomized controlled trials. PLoS Med. 2013; 10(4): e1001436.
Walter S, Baruch A, Dong J, Tomlinson JE, Alexander ST, Janes J, et al. Pharmacology of AMG 416 (Velcalcetide), a novel peptide agonist of the calcium-sensing receptor, for the treatment of secondary hyperparathyroidism in hemodialysis patients. J Pharmacol Exp Ther. 2013; 346(2):229-40.
Wu B, Melhem M, Subramanian R, Chen P, Jaramil laSloey B, Fouqueray B, et al. Clinical pharmacokinetics and pharmacodynamics of etelcalcetide, a novel calcimimetic for treatment of secondary hyperparathyroidism in patients with chronic kidney disease on hemodialysis. J Clin Pharmacol. 2018; 58(6):717-726.
Alexander ST, Hunter T, Walter S, Dong J, Maclean D, Baruch A, et al. Critical cysteine residues in both the calcium-sensing receptor and the allosteric activator AMG 416 underlie the mechanism of action. Mol Pharmacol. 2015; 88(5):853-65.
Martin KJ, Bell G, Pickthorn K, Huang S, Vick A, Hodsman P, et al. Velcalcetide (AMG 416), a novel peptide agonist of the calcium-sensing receptor, reduces serum parathyroid hormone and FGF23 levels in healthy male subjects. Nephrol Dial Transplant. 2014; 29(2):385-92.
Subramanian R, Zhu X, Kerr SJ, Esmay JD, Louie SW, Edson KZ, et al. Nonclinical pharmacokinetics, disposition, and drug-drug interaction potential of a novel d-amino acid peptide agonist of the calcium-sensing receptor AMG 416 (Etelcalcetide). Drug Metab Dispos. 2016; 44(8):1319-31.
Martin KJ, Pickthorn K, Huang S, Block GA, Vick A, Mount PF, et al. AMG 416 (velcalcetide) is a novel peptide for the treatment of secondary hyperparathyroidism in a single-dose study in hemodialysis patients. Kidney Int. 2014; 85(1):191-7.
Bell G, Huang S, Martin KJ, Block GA. A randomized, double-blind, phase 2 study evaluating the safety and efficacy of AMG 416 for the treatment of secondary hyperparathyroidism in hemodialysis patients. Curr Med Res Opin. 2015; 31(5):943-52.
Bushinsky DA, Block GA, Martin KJ, Bell G, Huang S, Sun Y, et al. Treatment of secondary hyperparathyroidism: results of a phase 2 trial evaluating an intravenous peptide agonist of the calcium-sensing receptor. Am J Nephrol. 2015; 42(5):379-88.
Fukagawa M, Yokoyama K, Shigematsu T, Akiba T, Fujii A, Kuramoto T, et al. A phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, for secondary hyperparathyroidism in Japanese haemodialysis patients. Nephrol Dial Transplant. 2017; 32(10):1723-1730.
Block GA, Bushinsky DA, Cunningham J, Drueke TB, Ketteler M, Kewalramani R, et al. Effect of etelcalcetide vs placebo on serum parathyroid hormone in patients receiving hemodialysis with secondary hyperparathyroidism: two randomized clinical trials. JAMA. 2017; 317(2):146-155.
Block GA, Bushinsky DA, Cheng S, Cunningham J, Dehmel B, Drueke TB, et al. Effect of etelcalcetide vs cinacalcet on serum parathyroid hormone in patients receiving hemodialysis with secondary hyperparathyroidism: A randomized clinical trial. JAMA. 2017; 317(2):156-164.
Pereira L, Meng C, Marques D, Frazão JM. Old and new calcimimetics for treatment of secondary hyperparathyroidism: impact on biochemical and relevant clinical outcomes. Clin Kidney J. 2018; 11(1):80-88.
Cunningham J, Block GA, Chertow GM, Cooper K, Evenepoel P, Iles J, et al. Etelcalcetide is effective at all levels of severity of secondary hyperparathyroidism in hemodialysis patients. Kidney Int Rep. 2019; 4(7):987-994