Etelcalcetide

Etelcalcetide (formerly velcalcetide, trade name Parsabiv) is a calcimimetic drug for the treatment of secondary hyperparathyroidism in patients undergoing hemodialysis. It is administered intravenously at the end of each dialysis session.[1][2] Etelcalcetide functions by binding to and activating the calcium-sensing receptor in the parathyroid gland.[1] Parsabiv is currently owned by Amgen and Ono Pharmaceuticals in Japan.[3][4]

Etelcalcetide
Clinical data
Trade namesParsabiv
Other namesVelcalcetide, telcalcetide, AMG-416, KAI-4169, ONO-5163
AHFS/Drugs.comUK Drug Information
License data
Routes of
administration		Intravenous injection
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life3–5 days in dialysis patients
Excretion60% in dialysate, 7% in urine and faeces
Identifiers
IUPAC name
  • (6R,9R,12R,15R,18R,21R,24S,29R)-24-Acetamido-1,29-diamino-12,15,18-tris(3-carbamimidamidopropyl)-6-carbamoyl-1-imino-9,21-dimethyl-8,11,14,17,20,23-hexaoxo-26,27-dithia-2,7,10,13,16,19,22-heptaazatria contan-30-oic acid
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC38H73N21O10S2
Molar mass1048.26 g·mol−1
3D model (JSmol)
SMILES
  • C[C@H](C(=O)N[C@H](CCCNC(=N)N)C(=O)N)NC(=O)[C@@H](CCCNC(=N)N)NC(=O)[C@@H](CCCNC(=N)N)NC(=O)[C@@H](CCCNC(=N)N)NC(=O)[C@@H](C)NC(=O)[C@@H](CSSC[C@@H](C(=O)O)N)NC(=O)C
InChI
  • InChI=1S/C38H73N21O10S2/c1-18(28(62)56-22(27(40)61)8-4-12-49-35(41)42)53-30(64)23(9-5-13-50-36(43)44)58-32(66)25(11-7-15-52-38(47)48)59-31(65)24(10-6-14-51-37(45)46)57-29(63)19(2)54-33(67)26(55-20(3)60)17-71-70-16-21(39)34(68)69/h18-19,21-26H,4-17,39H2,1-3H3,(H2,40,61)(H,53,64)(H,54,67)(H,55,60)(H,56,62)(H,57,63)(H,58,66)(H,59,65)(H,68,69)(H4,41,42,49)(H4,43,44,50)(H4,45,46,51)(H4,47,48,52)/t18-,19-,21+,22-,23-,24-,25-,26-/m1/s1
  • Key:ANIAZGVDEUQPRI-ZJQCGQFWSA-N

Medical uses

Etelcalcetide is used for the treatment of secondary hyperparathyroidism in people with chronic kidney disease (CKD) on hemodialysis.[5] Hyperparathyroidism is the condition of elevated parathyroid hormone (PTH) levels and is often observed in people with CKD.[6]

Pharmacodynamics

Mechanism of action

Etelcalcetide functions by binding to and activating the calcium-sensing receptor (CaSR) in the parathyroid gland as an allosteric activator, resulting in PTH reduction and suppression.[1]

Pharmacokinetics

Etelcalcetide functions in a first order elimination, with a half life of 19 hours.[4]

No interaction studies in humans were conducted. Studies in vitro showed no affinity of etelcalcetide to cytochrome P450 enzymes or common transport proteins. Therefore, no relevant pharmacokinetic interactions are expected.[5][7]

Side effects

Common side effects (in more than 10% of people) are nausea, 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 of more than 60 ms was detected in 1.2% of people receiving etelcalcetide.[5][7]

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"[4]

Contraindications

The drug is contraindicated in people with blood serum calcium levels below the norm.[5][7]

Chemistry

The substance is a peptide consisting mostly of D-amino acids instead of the common L-amino acids. More specifically, it is the disulfide of N-acetyl-D-cysteinyl-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-D-argininamide with L-cysteine.[8]

History

Originally, Etelcalcetide was being developed by KAI Pharmaceuticals. After positive Phase II trials, Amgen acquired KAI for $315 Million.[9]

In 2011, KAI entered into agreement with Ono Pharmaceutical for production of Etelcalcetide in Japan, the deal being worth ¥1 Billion.[4]

On 25 August 2015 Amgen Inc. announced its submission of a new drug application to the Food and Drug Administration for etelcalcetide.[1] The European Medicines Agency approved the drug in November 2016.[5]

In February 2017, the FDA approved Parsabiv for the treatment of secondary hyperparathyroidism.[10]

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.[4] In another Phase II study "89% of patients experienced a C30% reduction in PTH and 56% achieved a PTH level of B300 pg/mL."[4]

In 2017, two Phase III trials found that using etelcalcetide showed greater symptom reduction compared to placebo.[11] Etelcalcetide was also able to lower PTH levels below 300pg/mL more often.[11]

Phase I Pediatric studies are planned for the US and UK for etelcalcetide.[4]

References
  1. "Amgen Submits New Drug Application For Novel Intravenous Calcimimetic Etelcalcetide (AMG 416)"
  2. Martin KJ, Bell G, Pickthorn K, Huang S, Vick A, Hodsman P, Peacock M (February 2014). "Velcalcetide (AMG 416), a novel peptide agonist of the calcium-sensing receptor, reduces serum parathyroid hormone and FGF23 levels in healthy male subjects". Nephrology, Dialysis, Transplantation. 29 (2): 385–92. doi:10.1093/ndt/gft417. PMC 3910343. PMID 24235081.
  3. "Parsabiv New FDA Drug Approval | CenterWatch". www.centerwatch.com. Retrieved 2017-10-30.
  4. Blair HA (December 2016). "Etelcalcetide: First Global Approval". Drugs. 76 (18): 1787–1792. doi:10.1007/s40265-016-0671-3. PMID 27900648. S2CID 45000617.
  5. "Parsabiv: EPAR – Product Information" (PDF). European Medicines Agency. 24 November 2016.
  6. Wu Q, Lai X, Zhu Z, Hong Z, Dong X, Wang T, et al. (August 2015). "Evidence for Chronic Kidney Disease-Mineral and Bone Disorder Associated With Metabolic Pathway Changes". Medicine. 94 (32): e1273. doi:10.1097/MD.0000000000001273. PMC 4616673. PMID 26266360.
  7. Haberfeld, H, ed. (2016). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  8. "Etelcalcetide". ChemSpider. Retrieved 7 January 2016.
  9. "Amgen - Investors - Press Release". investors.amgen.com. Retrieved 2017-10-30.
  10. "Parsabiv (etelcalcetide) Injection". www.accessdata.fda.gov. Retrieved 2017-10-30.
  11. "Drug and Device News". P & T. 42 (4): 223–265. April 2017. PMC 5358678. PMID 28381913.

Further reading
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