Douglas G Johns, Yuddy Almonte, Merck & Co., Inc., Kenilworth, NJ; An Bautmans, MSD (Europe) Inc., Brussels, Belgium; Louis-Charles Campeau, Mark T Cancilla, Merck & Co., Inc., Kenilworth, NJ; Justin Chapman, Merck Sharp & Dohme (UK) Ltd., London, United Kingdom; Inne Crevecoeur, MSD (Europe) Inc., Brussels, Belgium; Erik D Guetschow, Eunkyung A Kauh, Eseng Lai, Christine L Lanning, Anita YH Lee, Li Li, Yale B Mitchel, S. Aubrey Stoch, Merck & Co., Inc., Kenilworth, NJ; Kristien Van Dyck, MSD (Europe) Inc., Brussels, Belgium; Frederic P Vanhoutte, Bram Volckaert, SGS Belgium NV, Antwerpen, Belgium; Dennis G Wolford, Harold B Wood, Andy Xu, Tian Zhao, Susan Zhou, Puja Banka, Merck & Co., Inc., Kenilworth, NJ
 

D.G. Johns: Employment; Significant; Merck & Co., Inc.. Stock Shareholder; Modest; Merck & Co., Inc. Y. Almonte:Employment; Significant; Merck & Co., Inc.. Stock Shareholder; Modest; Merck & Co., Inc. A. Bautmans: Employment; Significant; MSD. L. Campeau: Employment; Significant; Merck & Co., Inc.. Stock Shareholder; Modest; Merck & Co., Inc. M.T. Cancilla:Employment; Significant; Merck & Co., Inc.. Stock Shareholder; Modest; Merck & Co., Inc. J. Chapman: Employment; Significant; Merck Sharp & Dohme (UK) Ltd.. Stock Shareholder; Modest; Merck & Co., Inc. I. Crevecoeur: Other; Significant; MSD (Europe) Inc. E.D. Guetschow: Other; Significant; Merck & Co., Inc. E.A. Kauh: Employment; Significant; Merck & Co., Inc.. Stock Shareholder; Modest; Merck & Co., Inc. E. Lai: Employment; Significant; Merck & Co., Inc.. Stock Shareholder; Modest; Merck & Co., Inc. C.L. Lanning: Employment; Significant; Merck & Co., Inc. A.Y. Lee: Employment; Significant; Merck & Co., Inc.. Stock Shareholder; Modest; Merck & Co., Inc. L. Li: Employment; Significant; Merck & Co., Inc.. Stock Shareholder; Modest; Merck & Co., Inc. Y.B. Mitchel: Employment; Significant; Merck & Co., Inc.. Stock Shareholder; Modest; Merck & Co., Inc. S. Stoch:Employment; Significant; Merck & Co., Inc.. Stock Shareholder; Modest; Merck & Co., Inc. K. Van Dyck: Employment; Significant; MSD (Europe) Inc.. Stock Shareholder; Modest; Merck & Co., Inc. F.P. Vanhoutte: Research Grant; Modest; Merck & Co., Inc. B. Volckaert: Other Research Support; Modest; Merck Sharp & Dohme Corp. D.G. Wolford: Employment; Significant; Merck & Co., Inc.. Stock Shareholder; Modest; Merck & Co., Inc. H.B. Wood: Employment; Significant; Merck & Co., Inc.. Stock Shareholder; Modest; Merck & Co., Inc. A. Xu: Employment; Significant; Merck & Co., Inc. T. Zhao: Employment; Significant; Merck & Co., Inc.. Stock Shareholder; Modest; Merck & Co., Inc. S. Zhou: Employment; Significant; Merck & Co., Inc.. Stock Shareholder; Modest; Merck & Co., Inc. P. Banka: Employment; Significant; Merck & Co.. Stock Shareholder; Modest; Merck & Co..
 

Background: Atherosclerotic cardiovascular disease (ASCVD) is a leading global cause of morbidity and mortality. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition provides an efficacious and safe means of reducing LDL-C and risk of ASCVD. However, development of an oral PCSK9 inhibitor (PCSK9i) has proven to be challenging, due to the difficulty in identifying potent molecules which are also orally bioavailable. We report the first human data for an orally bioavailable PCSK9i, MK-0616, a cyclic peptide identified through mRNA display-based screening structure-guided medicinal peptide chemistry, with nonclinical pharmacokinetic and safety properties which supported characterization in clinical trials. Methods: In a single ascending dose study, healthy male volunteers aged 18-50 years were randomized 3:1 to receive single doses of MK-0616 (10-300 mg) or placebo. In a multiple dose study, hypercholesterolemic but otherwise healthy male and female participants aged 18-65 years with baseline LDL-C 60-160 mg/dL while on statin treatment for at least 3 months were randomized 3:1 to receive MK-0616 or placebo for 14 days. Results: A total of 60 participants were randomized in the single and 40 in the multiple dose study. MK-0616 was well tolerated at doses up to 300 mg with no deaths, serious adverse events, or clinically meaningful trends in laboratory safety tests, vital signs, or ECGs as a function of study intervention. MK-0616 exhibited a dose dependent increase in plasma exposure and > 90% mean maximum reduction of free plasma PCSK9 levels from baseline at all dose levels studied. In the multiple dose study, baseline mean LDL-C was ∼87 mg/dL and 85% of participants were receiving moderate or high-intensity statins. At 14 days of treatment, participants receiving MK-0616 exhibited LDL-C reductions similar to that reported for anti-PCSK9 monoclonal antibodies (>50% LDL-C reduction from baseline). By contrast, placebo-treated participants exhibited <5% LDL-C reduction from baseline. Conclusions: MK-0616 represents the first oral PCSK9i with clinical data supporting its potential to be a powerful oral cholesterol lowering agent for the treatment of hypercholesterolemia and coronary heart disease. An oral PCSK9i would provide greater convenience and patient access and these data support further development of MK-0616 in a range of hypercholesterolemic patients.