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Randomized Controlled Trial
. 2023 Apr 25;81(16):1553-1564.
doi: 10.1016/j.jacc.2023.02.018. Epub 2023 Mar 6.

Phase 2b Randomized Trial of the Oral PCSK9 Inhibitor MK-0616

Christie M Ballantyne  1 , Puja Banka  2 , Gustavo Mendez  3 , Raymundo Garcia  4 , Julio Rosenstock  5 , Anthony Rodgers  2 , Geraldine Mendizabal  2 , Yale Mitchel  2 , Alberico L Catapano  6
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Free article
Randomized Controlled Trial

Phase 2b Randomized Trial of the Oral PCSK9 Inhibitor MK-0616

Christie M Ballantyne et al. J Am Coll Cardiol. .
Free article

Abstract

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).

Keywords: PCSK9; atherosclerotic cardiovascular disease; lipid-lowering medications; low-density lipoprotein cholesterol; macrocyclic peptides.

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Conflict of interest statement

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.

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