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  • Oral PCSK9 Inhibitor MK-0616 Significantly Reduces LDL-C vs. Placebo at 8 Weeks: Randomized Trial

    Using varying dosage levels, the oral PCSK9 inhibitor MK-0616 significantly and clinically reduced low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia and a wide range of atherosclerotic cardiovascular disease (ASCVD) risk and background statin therapy compared to placebo after 8 weeks, new randomized trial results show.

    Christie M. Ballantyne, MD, of Baylor College of Medicine, Houston, presented these findings during a Late-Breaking Clinical Trials session Monday at the American College of Cardiology Scientific Sessions 2023 in New Orleans. A manuscript reporting these results was simultaneously published online in the Journal of the American College of Cardiology.

    “I was told early on that developing an oral PCSK9 inhibitor is impossible,” Ballantyne said in a news release announcing the results. “But the technology keeps advancing. It’s very exciting to see the tremendous advances in understanding the pathways and finding ways to make a challenging target like PCSK9 treatable with a once-daily pill.”

    MK-0616 is an oral PCSK9 macrocyclic peptide inhibitor that is being developed to treat hypercholesterolemia. While injectable PCK9 inhibitors have shown the ability to reduce LDL-C and the risk of ASCVD events, an oral medication might be easier to dose and access and be preferred by patients, Ballantyne and colleagues wrote in the manuscript.

    During his presentation Monday, Ballantyne explained that the large, diffuse, flat surface of the PCSK9/LDL receptor makes the interaction between PCSK9s and LDL receptors difficult to disrupt with “typical small molecules.” However, macrocyclic peptides can bind with PCSK9s with an affinity similar to that of monoclonal antibodies at 1/100th the molecular weight, he said.

    Early studies showed that MK-0616 led to a substantial (>90%) reduction in free PCSK9, and multiple doses over 2 weeks decreased LDL-C plasma by >60%.

    The phase 2b study presented Monday was designed to evaluate the performance of MK-0616 in a larger, more diverse population of patients with hypercholesterolemia. The study was funded by the drug’s manufacturer, Merck & Co., Inc.

    The trial screened 668 subjects from eight centers globally and randomized 381; all but one of the randomized subjects were included in the efficacy and safety analyses. The patients were divided into the following dosage groups: 77 received 6-mg doses of MK-0616, 76 received 12-mg doses, 76 received 18-mg doses, 76 received 30-mg doses, and 75 received a placebo. Most participants (358, 94.2%) completed both the 8-week treatment period and 8-week safety follow-up.

    The study’s primary hypothesis was at least one of the four doses of MK-0616 would be superior to placebo for the primary efficacy endpoint of percent change in LDL-C from baseline to 8 weeks. The primary safety endpoints were adverse events and premature stoppage of the drug.

    At baseline, the subjects’ median age was 62 years, 49% were female, and their mean LDL-C level was 119.5 ± 34.8 mg/dL. More than half (56.4%) of the participants were considered to be at intermediate or high risk for developing ASCVD, and 38.6% had clinical ASCVD. About 60% were on statin therapy.

    At 8 weeks, the placebo arm’s mean LDL-C had risen from 121.3 ± 28.0 mg/dL to 124.0 ± 34.6 mg/dL (1.2% least-squares mean change; 95% confidence interval [CI]: -4.1%, 6.5%).

    The three MK-0616 dosage arms all showed marked reductions in LDL-C from baseline to 2 weeks, with a persistent effect achieved from then through the 8-week treatment period, Ballantyne said Monday.

    The 6-mg dose led to a 40% least-squares mean change from baseline to 8 weeks (95% CI: -45.2%, -34.8%), with LDL-C falling from 116.5 ± 37.0 mg/dL to 69.6 ± 29.2 mg/dL. The difference in least-squares mean between the 6-mg dose and placebo was -41.2% (95% CI: -47.8%, -34.7%; p<0.001).

    For the other two dosage levels, the differences were even larger from baseline to 8 weeks, with the least-squares mean change being even greater between them and placebo: 12 mg (-55.7%), 18 mg (-59.1%) and 30 mg (-60.9%).

    The proportion of adverse events was similar in all arms (6-mg 44.2%, 12-mg 39.5%, 18-mg 43.4%, 30-mg 42.1%, placebo 44.0%). The same was true of the proportion of participants who stopped taking MK-0616 prematurely, with no more than two subjects in each group discontinuing the drug.

    Serious adverse events were rare, with no more than three in any of the groups, and none of these were considered to be related to the drug. One person in the 18-mg group died after a motor vehicle accident, which was considered unrelated to the drug.

    Ballantyne concluded that the study’s data support the further development of MK-0616.

    “This is a highly effective compound that was well tolerated,” Ballantyne said. “MK-0616 could offer another potential option. Between this and statins and the other therapies we have, we should be able to basically treat almost everybody in terms of LDL cholesterol.”


    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 Mar 6 (Article in press).

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