PMID- 36889610
OWN - NLM
STAT- MEDLINE
DCOM- 20230719
LR  - 20230719
IS  - 1558-3597 (Electronic)
IS  - 0735-1097 (Linking)
VI  - 81
IP  - 16
DP  - 2023 Apr 25
TI  - Phase 2b Randomized Trial of the Oral PCSK9 Inhibitor MK-0616.
PG  - 1553-1564
LID - S0735-1097(23)00412-6 [pii]
LID - 10.1016/j.jacc.2023.02.018 [doi]
AB  - BACKGROUND: MK-0616 is an oral macrocyclic peptide inhibitor of proprotein 
      convertase subtilisin/kexin type 9 (PCSK9) in development for the treatment of 
      hypercholesterolemia. OBJECTIVES: This Phase 2b, randomized, double-blind, 
      placebo-controlled, multicenter trial aimed to evaluate the efficacy and safety 
      of MK-0616 in participants with hypercholesterolemia. METHODS: This trial was 
      planned to include 375 adult participants with a wide range of atherosclerotic 
      cardiovascular disease risk. Participants were assigned randomly (1:1:1:1:1 
      ratio) to MK-0616 (6, 12, 18, or 30 mg once daily) or matching placebo. The 
      primary endpoints included percentage change from baseline in low-density 
      lipoprotein cholesterol (LDL-C) at Week 8 and the proportion of participants with 
      adverse events (AEs) and study intervention discontinuations due to AEs; 
      participants were monitored for AEs for an additional 8 weeks after the 8-week 
      treatment period. RESULTS: Of the 381 participants randomized, 49% were female, 
      and the median age was 62 years. Among 380 treated participants, all doses of 
      MK-0616 demonstrated statistically significant (P < 0.001) differences in least 
      squares mean percentage change in LDL-C from baseline to Week 8 vs placebo: 
      -41.2% (6 mg), -55.7% (12 mg), -59.1% (18 mg), and -60.9% (30 mg). AEs occurred 
      in a similar proportion of participants in the MK-0616 arms (39.5% to 43.4%) as 
      placebo (44.0%). Discontinuations due to AEs occurred in 2 or fewer participants 
      in any treatment group. CONCLUSIONS: MK-0616 demonstrated statistically 
      significant and robust, dose-dependent placebo-adjusted reductions in LDL-C at 
      Week 8 of up to 60.9% from baseline and was well tolerated during 8 weeks of 
      treatment and an additional 8 weeks of follow-up. (A Study of the Efficacy and 
      Safety of MK-0616 [Oral PCSK9 Inhibitor] in Adults With Hypercholesterolemia 
      [MK-0616-008]; NCT05261126).
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Ballantyne, Christie M
AU  - Ballantyne CM
AD  - Baylor College of Medicine, Houston, Texas, USA. Electronic address: cmb@bcm.edu.
FAU - Banka, Puja
AU  - Banka P
AD  - Merck & Co, Inc, Rahway, New Jersey, USA.
FAU - Mendez, Gustavo
AU  - Mendez G
AD  - Hospital Angeles Xalapa, Xalapa, Veracruz, Mexico.
FAU - Garcia, Raymundo
AU  - Garcia R
AD  - Unidad Biomedica Avanzada Monterrey, Monterrey, Nuevo Leon, Mexico.
FAU - Rosenstock, Julio
AU  - Rosenstock J
AD  - Velocity Clinical Research at Medical City, Dallas, Texas, USA.
FAU - Rodgers, Anthony
AU  - Rodgers A
AD  - Merck & Co, Inc, Rahway, New Jersey, USA.
FAU - Mendizabal, Geraldine
AU  - Mendizabal G
AD  - Merck & Co, Inc, Rahway, New Jersey, USA.
FAU - Mitchel, Yale
AU  - Mitchel Y
AD  - Merck & Co, Inc, Rahway, New Jersey, USA.
FAU - Catapano, Alberico L
AU  - Catapano AL
AD  - University of Milan, Milan, Italy; IRCCS Multimedica, Milan, Italy.
LA  - eng
SI  - ClinicalTrials.gov/NCT05261126
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20230306
PL  - United States
TA  - J Am Coll Cardiol
JT  - Journal of the American College of Cardiology
JID - 8301365
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Cholesterol, LDL)
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - EC 3.4.21.- (PCSK9 protein, human)
RN  - EC 3.4.21.- (Proprotein Convertase 9)
RN  - EC 3.4.21.- (Proprotein Convertases)
RN  - EC 3.4.21.- (Serine Endopeptidases)
RN  - 0 (MK-0616)
SB  - IM
CIN - Nat Rev Cardiol. 2023 May;20(5):286. PMID: 36944789
CIN - J Am Coll Cardiol. 2023 Apr 25;81(16):1565-1568. PMID: 37076210
MH  - Adult
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Antibodies, Monoclonal/therapeutic use
MH  - Antibodies, Monoclonal, Humanized/therapeutic use
MH  - Cholesterol, LDL
MH  - Double-Blind Method
MH  - *Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
MH  - *Hypercholesterolemia/drug therapy
MH  - Proprotein Convertase 9
MH  - Proprotein Convertases/therapeutic use
MH  - Serine Endopeptidases/therapeutic use
MH  - Treatment Outcome
OTO - NOTNLM
OT  - PCSK9
OT  - atherosclerotic cardiovascular disease
OT  - lipid-lowering medications
OT  - low-density lipoprotein cholesterol
OT  - macrocyclic peptides
COIS- Funding Support and Author Disclosures Funding for this research was provided by 
      Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, New Jersey, 
      USA. Academic advisors and representatives of the funder participated in the 
      study design. Data collected by the investigators and their site personnel were 
      analyzed and interpreted by senior academic authors and representatives of the 
      funder. The funder provided results and methodologic details and participated in 
      the preparation, review, and approval of the manuscript. Dr Ballantyne has 
      received grant/research support through his institution from Abbott Diagnostic, 
      Akcea, Amgen, Arrowhead, Esperion, Ionis, Merck, New Amsterdam, Novartis, Novo 
      Nordisk, Regeneron, and Roche Diagnostic; and has been a consultant for 89Bio, 
      Abbott Diagnostics, Alnylam Pharmaceuticals, Althera, Amarin, Amgen, Arrowhead, 
      AstraZeneca, Denka Seiken, Esperion, Genentech, Gilead, Illumina, Ionis, Matinas 
      BioPharma Inc, Merck, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, 
      and Roche Diagnostic. Dr Mendez has received lecture fees or research grants from 
      Amgen, MSD, Bayer, Merck, Novartis, Tricida, and Servier. Dr Rosenstock has 
      served on scientific advisory boards and received honorarium or consulting fees 
      from Applied Therapeutics, Boehringer Ingelheim, Eli Lilly, Hanmi, Novo Nordisk, 
      Oramed, Sanofi, Structure Therapeutics, Terns Pharma, and Zealand; has received 
      grants/research support from Applied Therapeutics, AstraZeneca, Boehringer 
      Ingelheim, Eli Lilly, Hanmi, Merck, Oramed, Novartis, Novo Nordisk, Pfizer, and 
      Sanofi; and has received honorarium for lectures sponsored by Boehringer 
      Ingelheim, Eli Lilly, Novo Nordisk and Sanofi. Dr Catapano's work is supported in 
      part by Ministero della Salute Ricerca Corrente; and he has received honoraria, 
      lecture fees, or research grants from Aegerion, Amgen, Amryt, AstraZeneca, Bayer, 
      Daiichi-Sankyo, Eli Lilly, Genzyme, Ionis Pharmaceutical, Kowa, Mediolanum, 
      Medscape, Menarini, Merck, Mylan, Novartis, PeerVoice, Pfizer, Recordati, 
      Regeneron, Sanofi, Sigma-Tau, and The Corpus. Dr Banka, Mr Rodgers, Dr 
      Mendizabal, and Dr Mitchel are employees of Merck Sharp & Dohme LLC, a subsidiary 
      of Merck & Co, Inc, Rahway, New Jersey, USA and may own stock or stock options in 
      Merck & Co, Inc, Rahway, New Jersey, USA. Dr Garcia has reported that he has no 
      relationships relevant to the contents of this paper to disclose.
EDAT- 2023/03/09 06:00
MHDA- 2023/04/21 06:41
CRDT- 2023/03/08 19:33
PHST- 2023/01/17 00:00 [received]
PHST- 2023/02/14 00:00 [revised]
PHST- 2023/02/15 00:00 [accepted]
PHST- 2023/04/21 06:41 [medline]
PHST- 2023/03/09 06:00 [pubmed]
PHST- 2023/03/08 19:33 [entrez]
AID - S0735-1097(23)00412-6 [pii]
AID - 10.1016/j.jacc.2023.02.018 [doi]
PST - ppublish
SO  - J Am Coll Cardiol. 2023 Apr 25;81(16):1553-1564. doi: 10.1016/j.jacc.2023.02.018. 
      Epub 2023 Mar 6.