Background and Aims

Available PCSK9 inhibitors have demonstrated significant reductions in LDL-C but their injectable route of administration and access barriers have resulted in limited utilization. This study evaluated the efficacy and safety of MK-0616, an oral PCSK9 macrocyclic peptide inhibitor, in participants with hypercholesterolemia.

Methods

This Phase 2b, double-blind, placebo-controlled, multicenter study randomized 381 (380 treated) adult participants with a wide range of ASCVD risk to MK-0616 (6, 12, 18, or 30 mg QD) or matching placebo (1:1:1:1:1 ratio). The primary endpoints included percent change from baseline in LDL-C at Week 8 and the proportion of participants with adverse events (AE) and study intervention discontinuations due to AEs over the 8-week treatment period and additional 8-week follow-up period. Secondary efficacy endpoints included percent change in ApoB and non-HDL-C.

Results

Median age was 62 years and 49% of participants were female. All MK-0616 doses demonstrated statistically significant (p<0.001) differences in LS mean percent change in LDL-C from baseline to Week 8 vs. placebo (Figure). Secondary efficacy endpoints were consistent with the primary endpoint. The proportion of participants with AEs was similar between the MK-0616 arms (39.5% to 43.4%) and placebo (44.0%); ≤2 participants in any treatment arm discontinued intervention due to AEs.

Conclusions

MK-0616 demonstrated statistically significant and robust, dose-dependent placebo-adjusted reductions in LDL-C at Week 8 from baseline and was well tolerated over 8 weeks of treatment and an additional 8 weeks of follow-up. (Ballantyne et al. J Am Coll Cardiol. 2023: S0735-1097(23)00412-6.)

Figure: LDL-C Reduction with MK-0616 vs. Placebo after 8 weeks of Treatment