By Michael H. Crawford, MD, Editor
SYNOPSIS: A Phase IIb study of four doses of MK-0616, an orally administered PCSK9 inhibitor, compared to placebo showed significant reductions in LDL cholesterol levels without any differences in adverse effects over eight weeks.
SOURCE: Ballantyne CM, Banka P, Mendez G, et al. Efficacy and safety of the oral PCSK9 inhibitor MK-0616: A phase 2b randomized controlled trial. J Am Coll Cardiol 2023; Feb 16: S0735-1097(23)00412-6. doi: 10.1016/j.jacc.2023.02.018. [Online ahead of print].
The serial injection of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to result in large reductions in LDL cholesterol and a decrease in atherosclerotic cardiovascular disease (ASCVD) events.1 However, patient acceptance of repeated injections has been challenging. Therefore, there is considerable interest in an orally effective version of a PCSK9 inhibitor.
In a Phase IIb study, Ballantyne et al recently assessed LDL level reductions and the safety of an oral agent, MK-0616, in a diverse population with hypercholesterolemia and a spectrum of ASCVD risk in 63 sites in eight countries. Entry criteria included age 18 years to 80 years, an LDL cholesterol level between 70 mg/dL and 160 mg/dL, and at least a 10-year ASCVD risk of more than 5% by the pooled risk equation. Patients with familial hypercholesterolemia, a fasting triglyceride level > 400 mg/dL, active ASCVD, or moderate or worse renal disease were excluded. All lipid-lowering oral therapies ended 30 days before trial entry — longer for those on an injectable PCSK9 inhibitor.
Enrolled subjects were randomized to receive one of four doses of MK-0616 or matching placebo after fasting overnight in a double-blind fashion for eight weeks. The primary efficacy endpoint was LDL level reduction, and the primary safety endpoint was adverse events and premature discontinuation of the study drug. The authors administered the study drug to 380 subjects (median age = 62 years; 49% were women; mean LDL = 120 mg/dL), 94% of whom completed the eight-week study. Clinically evident ASCVD was present in 39% of subjects, 56% were at least at an intermediate 10-year risk of ASCVD (more than 7.5%), and 5% were at borderline risk (5% to 7.5%).
MK-0616 significantly (P < 0.001) reduced LDL levels at each of the four MK-0616 doses: by 41% (6 mg), by 56% (12 mg), by 59% (18 mg), and by 61% (30 mg) compared to placebo at eight weeks. Researchers also observed significant reductions in ApoB and Lp(a) of similar magnitude. Adverse events were similar in both groups (40% vs. 43%) and did not increase in a dose-dependent manner. No more than two subjects discontinued the study in each group. There were no more than three serious adverse events in any MK-0616 groups, and none were deemed attributable to the study drug. The most common adverse event was COVID-19 infection, followed by gastrointestinal (GI) upset, fatigue, and arthralgias. Standard comprehensive metabolic panel lab tests were not different between the MK-0616 and placebo groups. The authors concluded that in a diverse group of subjects, MK-0616 showed robust, significant dose-dependent reductions in LDL levels of up to 61% compared to placebo and was well tolerated for eight weeks.
COMMENTARY
If this new drug receives FDA approval, it could offer a potent alternative for our statin-reluctant and injection-shy patients who would benefit from LDL cholesterol reduction. MK-0616 lowered LDL levels to a similar extent as the injectable PCSK9-targeted therapies evolocumab and alirocumab, and the small interfering RNA agent inclisiran when they were added to statins (50% to 60%). Also, MK-0616 produced meaningful reductions in ApoB and Lp(a). Safety was similar to placebo, and few patients withdrew from the study.
After COVID, the most common adverse event was GI upset (i.e., nausea, diarrhea, and dyspepsia). Fatigue was next, followed by arthralgias. Limb pains are the most common side effect of statins, so the latter was concerning. However, arthralgias were reported in only about 2% of subjects; like the other adverse events, this was not related to the dose of MK-0616.
The strengths of this study included the diversity of the patients: 40% Hispanic, but only 5% each were Black or Native American. ASCVD was present in 40% of subjects, and more than 50% of participants carried a higher than 7.5% 10-year risk of ASCVD. Also, almost half the patients were women. The weaknesses included the relatively small number of subjects and the short study duration.
Ultimately, MK-0616 may be prescribed to many patients as an add-on to statin therapy. In this role, it likely would be more potent than the currently available add-on therapies, such as bile acid sequestrants (producing a 12% to 18% reduction), ezetimibe (producing a 20% to 25% reduction), and bempedoic acid (producing an 18% reduction). Notably, in the Ballantyne et al study, most patients who were taking all but the lowest dose of MK-0616 achieved an LDL level lower than 70 mg/dL.
REFERENCE
1. Cho KH, Hong YJ. Proprotein convertase subtilisin/kexin type 9 inhibition in cardiovascular disease: Current status and future perspectives. Korean J Intern Med 2020;35:1045-1058.
A Phase IIb study of four doses of MK-0616, an orally administered PCSK9 inhibitor, compared to placebo showed significant reductions in LDL cholesterol levels without any differences in adverse effects over eight weeks.
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