Phase 2b Randomized Trial of the Oral PCSK9 Inhibitor MK-0616.
Level 2 - randomized trial
Individual double-blind randomized controlled trial
PubMed 36889610 · doi:10.1016/j.jacc.2023.02.018
What was done
This phase 2b, multicenter, double-blind, placebo-controlled trial evaluated the efficacy and safety of MK-0616, an oral macrocyclic peptide PCSK9 inhibitor, in adults with hypercholesterolemia across a range of atherosclerotic cardiovascular disease risks. A total of 381 participants were randomized (1:1:1:1:1) to receive MK-0616 once daily (6 mg, 12 mg, 18 mg, or 30 mg) or matching placebo for 8 weeks, followed by an additional 8 weeks of safety follow-up. Primary endpoints were percentage change from baseline in LDL-C at Week 8, incidence of adverse events (AEs), and discontinuations due to AEs.
What was found
Among 380 treated participants (median age 62 years, 49% female), all MK-0616 doses produced statistically significant (P < 0.001) dose-dependent reductions in least squares mean LDL-C at Week 8 versus placebo: -41.2% (6 mg), -55.7% (12 mg), -59.1% (18 mg), and -60.9% (30 mg). AEs occurred in 39.5% to 43.4% of participants across MK-0616 arms versus 44.0% with placebo. Discontinuations due to AEs occurred in 2 or fewer participants in any treatment group.
Why it matters
MK-0616 demonstrates that an oral peptide PCSK9 inhibitor can achieve LDL-C reductions of up to ~61%, comparable to injectable monoclonal antibodies, potentially offering a more accessible and convenient oral treatment option for hypercholesterolemia.
Limits
The active treatment period was brief (8 weeks), and the sample size (n = 380 treated) was designed to evaluate surrogate lipid endpoints rather than major adverse cardiovascular events, long-term durability, or rare adverse effects.
Cited by
- supports Enlicitide (MK-0616) is an oral PCSK9 inhibitor developed by Merck.