Etelcalcetide, sold under the brand name Parsabiv, is a calcimimetic medication for the treatment of

secondary hyperparathyroidism Secondary hyperparathyroidism is the medical condition of excessive secretion of parathyroid hormone (PTH) by the parathyroid glands in response to hypocalcemia (low blood calcium levels), with resultant hyperplasia of these glands. This disorde ...

in people undergoing

hemodialysis Hemodialysis, American and British English spelling differences#ae and oe, also spelled haemodialysis, or simply ''"'dialysis'"'', is a process of filtering the blood of a person whose kidneys are not working normally. This type of Kidney dialys ...

. 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, pancreatic islets and the br ...

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 par ...

. Parsabiv is currently owned by

Amgen Amgen Inc. (formerly Applied Molecular Genetics Inc.) is an American multinational biopharmaceutical Corporation, company headquartered in Thousand Oaks, California. As one of the world's largest independent biotechnology companies, Amgen has a ...

and Ono Pharmaceuticals in Japan.

Medical uses

Etelcalcetide is used for the treatment of secondary hyperparathyroidism in people with

chronic kidney disease Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...

(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 serum calcium and phosphate through its actions on the bone, kidneys, and small intestine. PTH incre ...

(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 In mathematics and other formal sciences, first-order or first order most often means either: * "linear" (a polynomial of degree at most one), as in first-order approximation and other calculus uses, where it is contrasted with "polynomials of high ...

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'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

'' showed no affinity of etelcalcetide to

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

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 Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific subs ...

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. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

, vomiting, diarrhoea, muscle spasms, and hypocalcaemia (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 The QT interval is a measurement made on an Electrocardiography, electrocardiogram used to assess some of the electrical properties of the heart. It is calculated as the time from the start of the QRS complex, Q wave to the end of the T wave, an ...

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. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

consisting mostly of D-

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

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

disulfide In chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups. In inorg ...

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 enables the formation of disulfide bonds, and often participates in enzymatic reactions as a nucleophile. Cysteine is ...

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. In August 2015 Amgen Inc. announced its submission of a

new drug application The Food and Drug Administration's (FDA) New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing. Some 30% or less of initial ...

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 respo ...

for etelcalcetide. The

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

approved the medication 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.

References

{{Authority control Nephrology procedures Systemic hormonal preparations Peptides