Etelcalcetide

A synthetic eight-residue peptide calcimimetic built on an all-D-amino-acid backbone, FDA approved since 2017 as an intravenous injection given at the end of hemodialysis, that sensitizes the parathyroid calcium-sensing receptor and lowers parathyroid hormone in secondary hyperparathyroidism.

Also referenced as: Etelcalcetide hydrochloride, Parsabiv, AMG 416, AMG-416, AMG416, Velcalcetide, KAI-4169, KAI 4169, ONO-5163, ONO 5163

Also appears in: Other

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What is Etelcalcetide?

Etelcalcetide is a synthetic peptide calcimimetic: a linear chain of seven D-amino acids (an N-acetyl-D-cysteine, two D-alanines, and four D-arginines, the last as a C-terminal amide) with a single L-cysteine attached to the D-cysteine through a disulfide bond, giving a molecule of about 1,048 Da (1047.5 g/mol as the free base). The all-D backbone is deliberate; it makes the peptide resistant to proteolysis and is the reason it survives long enough in circulation to be dosed three times a week. Developed by KAI Pharmaceuticals as KAI-4169, then by Amgen as AMG 416 (its first United States Adopted Name was velcalcetide), it is marketed as Parsabiv and was approved by the FDA on February 7, 2017 for secondary hyperparathyroidism in adults with chronic kidney disease on hemodialysis.

It acts on the parathyroid axis, but in the opposite direction from the PTH analogs. Teriparatide and abaloparatide add PTH-receptor signaling to build bone; etelcalcetide suppresses the parathyroid gland’s own PTH output, which in dialysis patients has become chronically excessive. Outside the clinic it appears mainly in laboratory-reagent catalogs as a calcium-sensing receptor tool compound rather than as a research-market staple.

How it works

Etelcalcetide is a positive allosteric activator of the calcium-sensing receptor (CaSR), the class C G-protein-coupled receptor on parathyroid chief cells that normally senses extracellular calcium and shuts off PTH secretion when calcium is adequate. The drug makes the receptor respond as though calcium were higher than it is.

• Covalent but reversible receptor engagement — the peptide’s cysteine forms a disulfide bond with cysteine 482 in the extracellular domain of the human CaSR. Pigs, whose CaSR carries a tyrosine at that position, show no pharmacodynamic response, and a single tyrosine-to-cysteine substitution restores full activity; mass spectrometry confirmed the peptide–receptor disulfide, and the degree of bond formation tracked the degree of receptor activation. Despite the covalent link, the effect in vivo is readily reversible through disulfide exchange (Alexander et al., Molecular Pharmacology, 2015, 88(5):853–865)
• Receptor activation with or without ambient calcium — unlike cinacalcet, which only amplifies the response to calcium already present, AMG 416 activated the human CaSR in vitro both in the presence and absence of physiologic extracellular calcium. In normal and renally compromised rats it produced dose-dependent falls in PTH and serum calcium regardless of baseline PTH, and in 5/6-nephrectomized rats it reduced vascular calcification and attenuated parathyroid hyperplasia (Walter et al., Journal of Pharmacology and Experimental Therapeutics, 2013, 346(2):229–240)
• Pharmacokinetics tied to the dialysis session — in healthy kidneys the peptide is cleared renally; in dialysis patients clearance depends on the dialyzer, roughly 60% of a radiolabeled dose leaving in dialysate, and the effective half-life is 3 to 5 days. The drug also exchanges reversibly onto serum albumin, forming a 67 kDa conjugate too large to dialyze that releases peptide back into plasma after a session. These properties are why it is given intravenously at the end of hemodialysis rather than before it (Wu et al., Journal of Clinical Pharmacology, 2018, 58(6):717–726)
• Downstream effects on bone turnover — because PTH drives bone remodeling, suppressing it lowers turnover: in a 36-week open-label study, PTH fell 67% while bone formation rate on biopsy decreased and areal bone density at the spine and hip increased (Khairallah et al., Clinical Journal of the American Society of Nephrology, 2023, 18(11):1456–1465)

Research status

Etelcalcetide has a complete Phase 3 program in its approved population, a regulatory record that includes one rejection before approval, and no evidence base outside secondary hyperparathyroidism.

Early clinical work. A single-dose, dose-escalation study in healthy men showed dose-dependent falls in PTH, FGF23, and ionized calcium with a terminal half-life of 18 to 20 hours in people with working kidneys (Martin et al., Nephrology Dialysis Transplantation, 2014, 29(2):385–392). A single-dose study in 28 hemodialysis patients at 5 to 60 mg then established dose-dependent reductions in PTH and FGF23 in the target population (Martin et al., Kidney International, 2014, 85(1):191–197). A randomized, double-blind, placebo-controlled Phase 2 study gave 5 or 10 mg three times weekly at the end of dialysis for up to four weeks and found mean PTH reductions of 33% and 49%, respectively; it was designed to pick a safe starting dose rather than to titrate to a PTH target (Bell et al., Current Medical Research and Opinion, 2015, 31(5):943–952).

Placebo-controlled Phase 3 trials (NCT01785849, NCT01788046). Two parallel 26-week trials randomized 1,023 hemodialysis patients with moderate to severe secondary hyperparathyroidism (mean baseline PTH about 850 pg/mL) to etelcalcetide or placebo given after each session. The primary endpoint, a greater than 30% reduction in mean PTH during weeks 20 to 27, was met by 74.0% versus 8.3% in trial A and 75.3% versus 9.6% in trial B (both P < .001); roughly half of treated patients reached a PTH of 300 pg/mL or lower versus about 5% on placebo. Muscle spasms, nausea, and vomiting were more common on etelcalcetide (Block et al., JAMA, 2017, 317(2):146–155). The approved label reports the same primary result as 77% and 79% versus 11%, using the label’s analysis population.

Head-to-head against cinacalcet (NCT01896232). A double-blind, double-dummy trial randomized 683 patients with PTH above 500 pg/mL to intravenous etelcalcetide plus oral placebo or oral cinacalcet plus intravenous placebo for 26 weeks. Etelcalcetide was noninferior and then superior on the primary endpoint: 68.2% versus 57.7% achieved a greater than 30% PTH reduction (difference −10.5%; P for superiority = .004), and 52.4% versus 40.2% achieved a greater than 50% reduction. The trade-off was more hypocalcemia: decreased blood calcium was reported in 68.9% versus 59.8% (Block et al., JAMA, 2017, 317(2):156–164).

One-year extension (NCT01785875). A 52-week single-arm extension enrolling patients from the two placebo-controlled trials and a cinacalcet-switch study found no new safety signals; decreased blood calcium was reported in 43.3% and symptomatic hypocalcemia in 3.7%, and about 68% maintained a greater than 30% PTH reduction (Bushinsky et al., Nephrology Dialysis Transplantation, 2020, 35(10):1769–1778). A pooled analysis of the placebo-controlled trials found the drug effective across baseline PTH severity strata (Cunningham et al., Kidney International Reports, 2019, 4(7):987–994).

Japan. A separate Japanese program under the code ONO-5163 included a 12-week placebo-controlled Phase 3 trial (Fukagawa et al., Nephrology Dialysis Transplantation, 2017, 32(10):1723–1730), and a post-marketing surveillance of 1,226 patients followed for up to 52 weeks reported hypocalcemia-related adverse drug reactions in 8.7% and no new safety concerns (Yokoyama et al., Clinical and Experimental Nephrology, 2021, 25(1):66–79).

Bone. Effects on the skeleton were not part of the registration program. The investigator-initiated Parsabiv-MBD study (NCT03960437) enrolled 22 patients, of whom 13 completed 36 weeks and 5 had paired biopsies; it reported gains in spine, femoral neck, and total hip areal BMD (3%, 7%, and 3%), a 10% rise in trabecular bone score, and reduced bone formation rate, with no change in bone material properties (Khairallah et al., Clinical Journal of the American Society of Nephrology, 2023, 18(11):1456–1465). It is small, uncontrolled, and hypothesis-generating. No trial has tested etelcalcetide for fracture outcomes, and none has studied it in people without kidney failure.

Regulatory record. Amgen submitted the NDA in August 2015 and the FDA accepted it in November 2015 with a target action date of August 24, 2016; on that date the agency issued a Complete Response Letter, the reasons for which the sponsor did not disclose, and approval followed on February 7, 2017 without new trials. The European Commission authorized Parsabiv on November 11, 2016 (still authorized; EPAR last updated August 2026), and Japan approved it on December 19, 2016. Drugs@FDA lists only labeling supplements since approval (2018, 2019, 2021) and none in 2024 through 2026; the current U.S. label carries a revision date of January 2025, remains adult-only, and the product is not discontinued. A Phase 1 single-dose pediatric study (NCT02833857) in 11 children on hemodialysis has been published (Sohn et al., Pediatric Nephrology, 2021, 36(1):133–142), and a Phase 3 pediatric trial (NCT03633708) is still recruiting with an estimated primary completion in January 2029. There is no registered human program in any indication other than secondary hyperparathyroidism.

Common dosage forms

• Single-dose vials (approved product) — a sterile, preservative-free solution at 5 mg/mL, supplied in 2.5 mg/0.5 mL, 5 mg/1 mL, and 10 mg/2 mL vials, stored refrigerated and protected from light. It is administered as an intravenous bolus into the venous line of the dialysis circuit at the end of a hemodialysis session, by the dialysis unit, not self-administered.
• Prefilled syringe (Japan) — a prefilled-syringe presentation was approved in Japan in June 2020 and launched that December, alongside the original vial.
• No oral, pen, or subcutaneous format exists — this distinguishes it from cinacalcet (an oral tablet) and from the PTH analogs (subcutaneous pens).
• Laboratory reagent — etelcalcetide hydrochloride is listed by reagent suppliers as lyophilized powder or solid for in vitro calcium-sensing receptor work. It is not a common listing in the consumer-facing research-peptide market.

Key considerations

• FDA Approved, narrowly. An FDA-approved drug product containing etelcalcetide exists, so the status is FDA Approved; the approval covers secondary hyperparathyroidism in adults with chronic kidney disease on hemodialysis and nothing else. The label states the drug has not been studied in parathyroid carcinoma, primary hyperparathyroidism, or chronic kidney disease not on hemodialysis and is not recommended in those settings. Its pharmacokinetics assume dialyzer clearance, so the exposure profile in a person with working kidneys is simply different.
• Hypocalcemia is the defining safety issue. Lowering PTH lowers serum calcium, and in the placebo-controlled trials decreased blood calcium was the most common adverse reaction (64% versus 10%). The label warns that severe hypocalcemia can cause QT-interval prolongation, ventricular arrhythmia, and seizures, lists worsening heart failure and upper gastrointestinal bleeding as separate warnings, and flags adynamic bone disease from chronic oversuppression of PTH. In the head-to-head trial, the better PTH control versus cinacalcet came with a higher hypocalcemia rate.
• It lowers PTH; it does not replace it. The parathyroid-axis grouping can mislead. Teriparatide and abaloparatide are PTH-receptor agonists used to stimulate bone formation; etelcalcetide acts upstream on the parathyroid gland to reduce PTH secretion and lowers bone turnover. The two classes are pharmacological opposites, and the bone-density gains seen in the small Parsabiv-MBD study came from relieving hyperparathyroidism in dialysis patients, not from an anabolic effect that would translate to anyone else.
• Evidence covers biochemistry, not hard outcomes. Every registration endpoint was a PTH threshold. No trial has shown that etelcalcetide reduces fractures, cardiovascular events, or mortality; the authors of both JAMA trials said further studies were needed for clinical outcomes, and those studies have not been done. The one bone study had 13 completers and no control group.
• Naming and categorization. The same molecule has been called KAI-4169, AMG 416, velcalcetide, and ONO-5163; Parsabiv is the brand in the United States, Europe, and Japan. “Calcimimetic” is the precise class term; it is not itself a hormone or hormone analog. Its clinical relatives are cinacalcet (an oral small molecule approved in the U.S., Europe, and Japan), evocalcet (an oral calcimimetic approved in Japan in 2018), and upacicalcet (a second intravenous calcimimetic for dialysis patients, approved in Japan in 2021).