MK-0616, an Oral PCSK9 Inhibitor, Shows Promise in Phase 2 Trial


New research from a phase 2b trial presented at ACC 2023 suggests an oral PCSK9 inhibitor could help reduce LDL-C by 60% in patients with or at-risk for atherosclerotic cardiovascular disease.

Christie Ballantyne, MD

Christie Ballantyne, MD
Courtesy: Baylor College of Medicine

An oral PCSK9 inhibitor could be the next major addition to the providers’ armamentarium of lipid-lowering, according to the results of a phase 2b trial.

Presented at the American College of Cardiology’s (ACC) 2023 Annual Scientific Session Together With the World Congress of Cardiology, results of the study demonstrate use of the oral PCSK9 inhibitor MK-0616 was associated with reductions in LDL-C exceeding 55% in 3 of the 4 doses examined in the trial.1

“This is a highly effective compound that was well tolerated,” said lead investigator Christie M. Ballantyne, MD, director of the Center for Metabolic Disease Prevention at Baylor College of Medicine.2 “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.”

One of the most significant advances in lipid management in the 21st century, PCSK9 inhibitors ushered in a new era of LDL-C lowering. However, as with all injectable agents, some patients opt against use despite the proven efficacy of agents within the class.

Sponsored by Merck, the trial presented by Ballantyne at ACC 2023 was a randomized, double-blind, placebo-controlled, multicenter trial designed with the intent of evaluating the efficacy and safety of 4 different doses of MK-0616 in patients with hypercholesterolemia. Conducted in 63 sites in 83 countries, a total of 668 patients underwent screening for inclusion.1

Of these, 381 underwent randomization and 380 were treated and included in both the efficacy and safety analyses. Overall, 77, 76, 76, 76, and 75 participants treated with MK0616 6 mg, MK-0616 12 mg, MK-0616 18 mg, MK-0616 30 mg, and placebo therapy, respectively.1

For inclusion in the trial patients had to meet 1 of the 3 following criteria1:

  • Clinical atherosclerotic cardiovascular disease (ASCVD)
  • Intermediate of high risk for ASCVD
  • Borderline risk for ASCVD

The primary efficacy outcome of interest for the trial was the change in LDL-C from baseline to week 8, with the primary safety outcome of the trial assessed through 12 weeks.1

Investigators noted baseline characteristics were generally balance between the treatment groups. The overall study cohort had a median age of 62 years, 49% of participants were female, and the mean LDL-C was 119.5 (SD, 34.8) mg/dL. Investigators pointed out 38.6% of patients had clinical ASCVD and 56.4% were considered as intermediate/high risk for ASCVD.1

Upon analysis, results revealed the differences in least squares means for percent change from baseline in LDL-C at Week 8 were -41.2%, -55.7%, -59.1%, and -60.9% for 6 mg, 12 mg, 18 mg, and 30 mg groups, respectively, when compared against placebo therapy (P for all <.001). Analysis of secondary endpoints revealed changes in ApoB and non-HDL-C in support of the findings from the primary efficacy endpoint. Safety analyses demonstrated there were no adverse events that increased in incidence in a dose-dependent manner.1

“I was told early on that developing an oral PCSK9 inhibitor is impossible,” Ballantyne added.2 “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.”


  1. Ballantyne CM, Banka P, Mendez G, et al. Efficacy and safety of the oral PCSK9 inhibitor MK-0616: A phase 2B randomized controlled trial. Journal of the American College of Cardiology. March 2023. doi:10.1016/j.jacc.2023.02.018
  2. Oral PCSK9 inhibitor substantially reduces cholesterol in phase 2 trial. American College of Cardiology. Published March 6, 2023. Accessed March 7, 2023.
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