Etelcalcetide (formerly velcalcetide, trade name Parsabiv) is a

calcimimetic A calcimimetic is a pharmaceutical drug that mimics the action of calcium on tissues, by allosteric activation of the calcium-sensing receptor that is expressed in various human organ tissues. Calcimimetics are used to treat secondary hyperparathy ...

drug for the treatment of secondary hyperparathyroidism in patients undergoing

hemodialysis Hemodialysis, also spelled haemodialysis, or simply dialysis, is a process of purifying the blood of a person whose kidneys are not working normally. This type of dialysis achieves the extracorporeal removal of waste products such as creatinin ...

. It is administered intravenously at the end of each dialysis session."Amgen Submits New Drug Application For Novel Intravenous Calcimimetic Etelcalcetide (AMG 416)"
/ref> Etelcalcetide functions by binding to and activating the

calcium-sensing receptor The calcium-sensing receptor (CaSR) is a Class C G-protein coupled receptor which senses extracellular levels of calcium ions. It is primarily expressed in the parathyroid gland, the renal tubules of the kidney and the brain. In the parathyroi ...

in the

parathyroid gland Parathyroid glands are small endocrine glands in the neck of humans and other tetrapods. Humans usually have four parathyroid glands, located on the back of the thyroid gland in variable locations. The parathyroid gland produces and secretes pa ...

. Parsabiv is currently owned by

Amgen Amgen Inc. (formerly Applied Molecular Genetics Inc.) is an American multinational biopharmaceutical company headquartered in Thousand Oaks, California. One of the world's largest independent biotechnology companies, Amgen was established in T ...

and Ono Pharmaceuticals in Japan.

Medical uses

Etelcalcetide is used for the treatment of secondary hyperparathyroidism in people with chronic kidney disease (CKD) on hemodialysis. Hyperparathyroidism is the condition of elevated

parathyroid hormone Parathyroid hormone (PTH), also called parathormone or parathyrin, is a peptide hormone secreted by the parathyroid glands that regulates the serum calcium concentration through its effects on bone, kidney, and intestine. PTH influences bone ...

(PTH) levels and is often observed in people with CKD.

Pharmacodynamics

Mechanism of action

Etelcalcetide functions by binding to and activating the

(CaSR) in the parathyroid gland as an allosteric activator, resulting in PTH reduction and suppression.

Pharmacokinetics

Etelcalcetide functions in a first order elimination, with a half life of 19 hours. No interaction studies in humans were conducted. Studies ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology ...

'' showed no affinity of etelcalcetide to

cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

enzymes or common

transport protein A transport protein (variously referred to as a transmembrane pump, transporter, escort protein, acid transport protein, cation transport protein, or anion transport protein) is a protein that serves the function of moving other materials within ...

s. Therefore, no relevant pharmacokinetic interactions are expected.

Side effects

Common side effects (in more than 10% of people) are

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

, vomiting, diarrhoea, muscle spasms, and

hypocalcaemia Hypocalcemia is a medical condition characterized by low calcium levels in the blood serum. The normal range of blood calcium is typically between 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L) while levels less than 2.1 mmo ...

(too low blood calcium levels). In clinical studies, the latter side effect was usually mild to moderate and without symptoms. An increase of the QT interval of more than 60 ms was detected in 1.2% of people receiving etelcalcetide. Due to the lower iPTH levels achieved by the use of this drug, it is possible that adynamic bone disease could occur at levels "below 100 pg/mL"

Contraindications

The drug is contraindicated in people with blood serum calcium levels below the norm.

Chemistry

The substance is a

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

consisting mostly of D-

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...

s instead of the common L-amino acids. More specifically, it is the

disulfide In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...

of ''N''-acetyl-D-

cystein Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, someti ...

yl-D- alanyl-D- arginyl-D-arginyl-D-arginyl-D-alanyl-D-argininamide with L-cysteine.

History

Originally, Etelcalcetide was being developed by KAI Pharmaceuticals. After positive Phase II trials, Amgen acquired KAI for $315 Million. In 2011, KAI entered into agreement with Ono Pharmaceutical for production of Etelcalcetide in Japan, the deal being worth ¥1 Billion. On 25 August 2015 Amgen Inc. announced its submission of a new drug application to the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

for etelcalcetide. The European Medicines Agency approved the drug in November 2016. In February 2017, the FDA approved Parsabiv for the treatment of secondary hyperparathyroidism.

Research

Phase II trials found that Etelcalcetide was able to lower PTH levels in one cohort by -49% vs a 29% increase in the placebo group. In another Phase II study "89% of patients experienced a C30% reduction in PTH and 56% achieved a PTH level of B300 pg/mL." In 2017, two Phase III trials found that using etelcalcetide showed greater symptom reduction compared to placebo. Etelcalcetide was also able to lower PTH levels below 300pg/mL more often. Phase I Pediatric studies are planned for the US and UK for etelcalcetide.