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Enlicitide chloride

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(Redirected from Enlicitide)

Enlicitide chloride
Enlicitide decanoate
Enlicitide decanoate
Clinical data
Trade namesLipfendra
Other namesMK-0616, enlicitide decanoate (USAN US)
AHFS/Drugs.comlipfendra
License data
ATC code
  • None
Legal status
Legal status
Identifiers
  • [6-6-[[(11S,17S,20S,23S,27S,39S,42S,63S,66R)-47-fluoro-20-[(1R)-1-hydroxyethyl]-17-[(4-methoxyphenyl)methyl]-11,63-dimethyl-10,16,19,22,30,40,58,61,64,67,70-undecaoxo-28-oxa-1,9,15,18,21,24,31,41,51,62,65,68-dodecazanonacyclo[37.18.11.23,6.124,42.133,37.144,51.011,15.023,27.045,50]triheptaconta-3(73),4,6(72),33,35,37(71),44(69),45(50),46,48-decaen-66-yl]methylamino]-6-oxohexyl]-trimethylazanium chloride
CAS Number
PubChem CID
IUPHAR/BPS
UNII
ChEMBL
Chemical and physical data
FormulaC82H110ClFN14O15
Molar mass1586.31 g·mol−1
3D model (JSmol)
  • C[C@H]1C(=O)N[C@H](CNC(=O)CCCCC[N+](C)(C)C)C(=O)N[C@H]2Cc3cccc(c3)CNC(=O)CO[C@H]4CCN5[C@]4([H])C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc6ccc(cc6)OC)C(=O)N7CCC[C@@]7(C)C(=O)NCCc8ccc(cc8)CN(CCCCCCn9cc(C[C@@H](C5=O)NC2=O)c%10cc(ccc%109)F)C(=O)CCC(=O)N1.[Cl-]

  • C[C@H]1C(=O)N[C@@H](C(=O)N[C@H]2CC3=CC(=CC=C3)CNC(=O)CO[C@H]4CCN5[C@@H]4C(=O)N[C@H](C(=O)N[C@H](C(=O)N6CCC[C@]6(C(=O)NCCC7=CC=C(CN(CCCCCCN8C=C(C[C@@H](C5=O)NC2=O)C9=C8C=CC(=C9)F)C(=O)CCC(=O)N1)C=C7)C)CC1=CC=C(C=C1)OC)[C@@H](C)O)CNC(=O)CCCCC[N+](C)(C)C.CCCCCCCCCC(=O)[O-]
  • InChI=1S/C82H109FN14O15.ClH/c1-51-74(103)91-65(47-86-68(99)19-11-10-14-40-97(4,5)6)76(105)88-62-43-56-17-15-18-57(41-56)46-85-70(101)50-112-67-33-39-95-73(67)78(107)92-72(52(2)98)77(106)90-63(42-54-24-27-60(111-7)28-25-54)80(109)96-38-16-34-82(96,3)81(110)84-35-32-53-20-22-55(23-21-53)48-94(71(102)31-30-69(100)87-51)37-13-9-8-12-36-93-49-58(44-64(79(95)108)89-75(62)104)61-45-59(83)26-29-66(61)93;/h15,17-18,20-29,41,45,49,51-52,62-65,67,72-73,98H,8-14,16,19,30-40,42-44,46-48,50H2,1-7H3,(H8-,84,85,86,87,88,89,90,91,92,99,100,101,103,104,105,106,107,110);1H/t51-,52+,62-,63-,64-,65+,67-,72-,73-,82-;/m0./s1
  • Key:CLOLWQCFULXMAR-QQCDJELVSA-N

  • InChI=1S/C82H109FN14O15.C10H20O2/c1-51-74(103)91-65(47-86-68(99)19-11-10-14-40-97(4,5)6)76(105)88-62-43-56-17-15-18-57(41-56)46-85-70(101)50-112-67-33-39-95-73(67)78(107)92-72(52(2)98)77(106)90-63(42-54-24-27-60(111-7)28-25-54)80(109)96-38-16-34-82(96,3)81(110)84-35-32-53-20-22-55(23-21-53)48-94(71(102)31-30-69(100)87-51)37-13-9-8-12-36-93-49-58(44-64(79(95)108)89-75(62)104)61-45-59(83)26-29-66(61)93;1-2-3-4-5-6-7-8-9-10(11)12/h15,17-18,20-29,41,45,49,51-52,62-65,67,72-73,98H,8-14,16,19,30-40,42-44,46-48,50H2,1-7H3,(H8-,84,85,86,87,88,89,90,91,92,99,100,101,103,104,105,106,107,110);2-9H2,1H3,(H,11,12)/t51-,52+,62-,63-,64-,65+,67-,72-,73-,82-;/m0./s1
  • Key:ZMLCOVYFOZPADV-QQCDJELVSA-N

Enlicitide chloride, sold under the brand name Lipfendra as the salt enlicitide decanoate, is a medication used for the treatment of hypercholesterolaemia (high cholesterol).[1] It is an orally available macrocyclic peptide and a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor.[1][2][3]

Enlicitide decanoate was approved for medical use in the United States in July 2026.[4][5][6]

Medical uses

[edit]

Enlicitide decanoate is indicated as an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol in adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia.[1][5] The recommended dose is one 20-mg tablet taken daily in the morning on an empty stomach with water, black coffee, or plain tea. The patient is asked to wait at least 30 minutes before eating or drinking other beverages. The tablet may be taken with other medications, and there are no contraindications.[1]

Pharmacology

[edit]

Enlicitide interacts with the LDL receptor binding domain of PCSK9 and inhibits its interaction with the receptor with an IC50 of 2.5 ±0.1 nM.[7]

History

[edit]

Development

[edit]

Merck developed the drug, applied for US Food and Drug Administration (FDA) approval in 2026,[8] and received approval from the FDA in July 2026.[6]

Clinical trials

[edit]

Early phase I clinical trials evaluated the chloride salt of MK-0616, enlicitide chloride.[9][10][11]

A double-blind, placebo-controlled phase I clinical trial demonstrated that oral administration of enlicitide chloride in 60 healthy males at doses of 10, 35, 100, 200, and 300 mg reduced free plasma levels of PCSK9 by more than 93%.[7] In a separate phase I study with statin-treated participants, daily doses of 10 and 20 mg reduced LDL levels at 14 days by 58.2 and 60.5%, respectively.[7][12]

A phase IIB study of eight weeks evaluated efficacy and safety of MK-0616 formulated with sodium decanoate, a permeation enhancer, in patients with hypercholesterolemia. Daily oral doses of 6, 12, 18, or 30 mg reduced LDL by 41.2, 55.7, 59.1, and 60.9% at the end point. Essentially complete efficacy was reached after two weeks. Adverse events were comparable to placebo at all doses throughout the study period.[7][13]

In August 2023, Merck launched the phase III CORALreef Lipids clinical trial (NCT05952856[14]) to evaluate the efficacy and safety of enlicitide decanoate (the decanoate salt of MK-0616) in adults with hypercholesterolemia.[15][16] The study included 2,912 participants and was completed on 28 July 2025 with results announced on 2 September 2025[17][8] and published on 4 February 2026.[18][19]

Also in August 2023, the company launched the CORALreef HeFH trial (NCT05952869) to evaluate the efficacy, safety, and tolerability of enlicitide decanoate in adults with heterozygous familial hypercholesterolemia.[14][20] The results were published on 13 January 2026.[21]

The efficacy and safety of enlicitide were demonstrated in these two randomized, double-blind, placebo-controlled trials (NCT05952856 [CORALreef Lipids] and NCT05952869 [CORALreef HeFH]) in a total of 3,207 adults with severe hypercholesterolemia, including those with and without heterozygous familial hypercholesterolemia, who were already taking maximally tolerated statin therapy.[5] The primary endpoint for both trials was the percent change from baseline to Week 24 in LDL-C, compared to placebo.[5] The trials showed enlicitide lowered LDL cholesterol by about 56% to 60% in participants undergoing concurrent lipid-lowering therapy over 24 to 52 weeks. Other lipid parameters also improved, including non-HDL cholesterol, apolipoprotein B, and lipoprotein(a). These results were comparable to those obtained with the injectable monoclonal antibody treatments evolocumab and alirocumab, which also target PCSK9 and have been shown to reduce major adverse cardiovascular events. The safety of oral enlicitide was similar to placebo.[22]

The phase III CORALreef Outcomes trial (NCT06008756) was begun in October 2023 with an estimated primary completion date of 29 November 2029. The primary objective is to evaluate the efficacy of enlicitide decanoate in reducing the incidence of major cardiovascular events in patients at high risk. It was expected to enroll 14,550 patients.[23]

Society and culture

[edit]
[edit]

Enlicitide decanoate was approved for medical use in the United States in July 2026.[4][5][24]

The US Food and Drug Administration granted the application for enlicitide priority review.[5] The approval of Lipfendra was granted to Merck Sharp & Dohme.[5]

Names

[edit]

Enlicitide chloride is the international nonproprietary name.[25]

Enlicitide decanoate is sold under the brand name Lipfendra.[1][26]

References

[edit]
  1. 1 2 3 4 5 6 Prescribing Information for Lipfendra (7/2026), merck.com. Retrieved 18 July 2026.
  2. ↑ Burnett JR, Hooper AJ (2023). "MK-0616: an oral PCSK9 inhibitor for hypercholesterolemia treatment". Expert Opinion on Investigational Drugs. 32 (10): 873–878. doi:10.1080/13543784.2023.2267972. PMID 37815341. S2CID 263802012.
  3. ↑ Siddiqui Z, Frishman W (2025). "New Oral PCSK9 Inhibitor: "MK-0616"". Cardiology in Review. 33 (6): 573–577. doi:10.1097/CRD.0000000000000655. PMID 38285643.
  4. 1 2 "Novel Drug Approvals for 2026". U.S. Food and Drug Administration (FDA). 22 July 2026. Retrieved 24 July 2026.
  5. 1 2 3 4 5 6 7 "FDA Approves First Oral Therapy that Inhibits Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) to Lower Bad Cholesterol in Adults with High Cholesterol". U.S. Food and Drug Administration (FDA). 16 July 2026. Retrieved 18 July 2026. Public Domain This article incorporates text from this source, which is in the public domain.
  6. 1 2 Loftus P (16 July 2026). "FDA Approves First-of-Its-Kind Cholesterol Pill, Ushering In New Wave of Treatment". The Wall Street Journal. Retrieved 16 July 2026.
  7. 1 2 3 4 Ferri N, Marodin G (March 2025). "Emerging oral therapeutic strategies for inhibiting PCSK9". Atherosclerosis Plus. 59: 25–31. doi:10.1016/j.athplu.2024.11.003. PMC 11722601. PMID 39802651.
  8. 1 2 Kolata G (8 November 2025). "New Pill From Merck Could Slash Cholesterol Levels, Trials Show. The drug targets the PCSK9 protein, and could give millions of people a more affordable option to reduce their heart disease risk". The New York Times.
  9. ↑ Clinical trial number NCT06814106 for "A Single- and Multiple-Dose Study of Enlicitide Chloride (MK-0616) in Healthy Chinese Adult Participants (MK 0616-010)" at ClinicalTrials.gov
  10. ↑ Clinical trial number NCT06655311 for "A Study of Enlicitide Chloride (MK-0616) in Healthy Participants and Participants Taking Statins (MK-0616-012)" at ClinicalTrials.gov
  11. ↑ Clinical trial number NCT05070390 for "A Study of Enlicitide Chloride (MK-0616 Oral PCSK9 Inhibitor) in Participants With Moderate Renal Impairment (MK-0616-007)" at ClinicalTrials.gov
  12. ↑ Johns DG, Campeau LC, Banka P, Bautmans A, Bueters T, Bianchi E, et al. (July 2023). "Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the Low Density Lipoprotein Receptor". Circulation. 148 (2): 144–158. doi:10.1161/CIRCULATIONAHA.122.063372. PMC 10325562. PMID 37125593.
  13. ↑ Ballantyne CM, Banka P, Mendez G, Garcia R, Rosenstock J, Rodgers A, et al. (25 April 2023). "Phase 2b Randomized Trial of the Oral PCSK9 Inhibitor MK-0616". Journal of the American College of Cardiology. 81 (16): 1553–1564. doi:10.1016/j.jacc.2023.02.018. PMID 36889610.
  14. 1 2 "Our Pipeline at a glance", 30 April 2026. Merck.com.
  15. ↑ "A Study of MK-0616 (Oral PCSK9 Inhibitor) in Adults With Hypercholesterolemia (MK-0616-013) CORALreef Lipids". ClinicalTrials.gov. May 2024.
  16. ↑ "The MK-0616 Information Center". MK-0616.com. 7 July 2024.
  17. ↑ Tracy D (3 September 2025). "Merck's Oral PCSK9 Inhibitor Demonstrates Efficacy in Hypercholesterolemia". Applied Clinical Trials. Retrieved 9 November 2025.
  18. ↑ Navar AM, Mikhailova E, Catapano AL, Banka P, Blom DJ, Cadena A, et al. (February 2026). "A Placebo-Controlled Trial of the Oral PCSK9 Inhibitor Enlicitide". New England Journal of Medicine. 394 (6): 529–539. doi:10.1056/NEJMoa2511002.
  19. ↑ Boden WE (February 2026). "Exploring a New "Reef" in Dyslipidemic Risk Reduction". New England Journal of Medicine. 394 (6): 597–599. doi:10.1056/NEJMe2516860.
  20. ↑ Clinical trial number NCT05952869 for "A Study of Enlicitide Decanoate (MK-0616 Oral PCSK9 Inhibitor) in Adults With Heterozygous Familial Hypercholesterolemia (MK-0616-017/​CORALreef HeFH)" at ClinicalTrials.gov
  21. ↑ Ballantyne CM, Gellis L, Tardif JC, Banka P, Navar AM, Asprusten EA, et al. (13 January 2026). "Efficacy and Safety of Oral PCSK9 Inhibitor Enlicitide in Adults With Heterozygous Familial Hypercholesterolemia: A Randomized Clinical Trial". Journal of the American Medical Association. 335 (2): 129–139. doi:10.1001/jama.2025.20620. PMC 12598580. PMID 41206969.
  22. ↑ Müller-Kozarez I, Laufs U (10 April 2026). "Phase 3 study results for oral PCSK9 inhibition with enlicitide". Med. 7 (4). 101097. doi:10.1016/j.medj.2026.101097. PMID 41966715.
  23. ↑ Clinical trial number NCT06008756 for "Enlicitide Decanoate (MK-0616 Oral PCSK9 Inhibitor) Cardiovascular Outcomes Study (MK-0616-015) CORALreef Outcomes" at ClinicalTrials.gov
  24. ↑ "FDA Approves First Oral PCSK9 Inhibitor to Lower LDL Cholesterol in Adults with High Cholesterol". U.S. Food and Drug Administration (FDA) (Press release). 17 July 2026. Retrieved 18 July 2026. Public Domain This article incorporates text from this source, which is in the public domain.
  25. ↑ World Health Organization (2023). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 90". WHO Drug Information. 37 (3). hdl:10665/373341.
  26. ↑ "Merck's Lipfendra (enlicitide) is the First and Only Once-Daily Oral PCSK9 Inhibitor Approved by the U.S. FDA to Reduce LDL-C in Adults with Hypercholesterolemia" (Press release). Merck. 16 July 2026. Retrieved 18 July 2026 – via Business Wire.

Further reading

[edit]
[edit]
  • Clinical trial number NCT05952856 for "A Study of Enlicitide Decanoate (MK-0616 Oral PCSK9 Inhibitor) in Adults With Hypercholesterolemia (MK-0616-013) CORALreef Lipids" at ClinicalTrials.gov
  • Clinical trial number NCT05952869 for "A Study of Enlicitide Decanoate (MK-0616 Oral PCSK9 Inhibitor) in Adults With Heterozygous Familial Hypercholesterolemia (MK-0616-017/CORALreef HeFH)" at ClinicalTrials.gov
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