Efficacy of enlicitide, an oral PCSK9 inhibitor, across baseline Lp(a) strata in an analysis of two phase 3 trials

Background Lipoprotein(a) [Lp(a)] is a genetically determined and likely causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Enlicitide, an oral, once-daily, macrocyclic peptide PCSK9 inhibitor (PCSK9i), demonstrated ~60% placebo-corrected LDL-C and ~28% Lp(a) lowering in Phase 3 studies, similar to injectable monoclonal antibody PCSK9i's. Purpose To assess LDL-C and Lp(a) lowering with enlicitide 20 mg vs. placebo across baseline Lp(a) strata in pooled data from the phase 3, randomised, double-blind, placebo-controlled CORALreef Lipids and CORALreef HeFH studies. Methods Participant-level data were pooled. Participants included adults with/ without a history of major ASCVD events on stable lipid lowering therapy. Baseline Lp(a) was analysed as a continuous variable and by predefined strata (<125 nmol/L; ≥125 nmol/L) and quartiles. Results Of 3212 randomised participants, 40% were female, 55% had history of a major ASCVD event, 97% were receiving statins and 30% cholesterol-absorption inhibitors. Among 3187 participants with baseline Lp(a) values, median (IQR) baseline Lp(a) was 39.6 nmol/L (13.7–150.2); 28.9% had a baseline Lp(a) of ≥ 125nmol/L. Baseline median (IQR) Lp(a) levels were 108.6 (37.1, 197.7) nmol/L in Black or African American participants, 37.0 (14.7, 124.3) nmol/L in Asian, 36.1 (11.8, 154.6) nmol/L in White, and 36.1 (11.8, 154.6) nmol/L in Multiple race participants, and 32.8 (10.7, 131.3) in Hispanic and 42.6 (14.8, 154.3) in non-Hispanic participants. Placebo-corrected % Lp(a) reductions at Week 24 are shown in the Figure. Lp(a) reductions were observed across all racial/ethnic groups with the largest reduction in the Asian race (p<0.001 for all). Placebo-corrected %Lp(a) reduction with enlicitide was significant across all baseline Lp(a) levels (p<0.001 for all), with the largest % reductions in those with a baseline Lp(a) of 13.7 to 150.2 nmol/L. By comparison, absolute differences in median change from baseline vs. placebo in nmol/L(95% CI) were -45.8 (-52.6, -39.2) and -8.4 (-9.5, -7.4) for participants with Lp(a) ≥125 nmol/L and <125 nmol/L at baseline, respectively (p<0.001 for both). Absolute difference in medians (95% CI) vs. placebo by baseline Lp(a) quartiles, were greatest for those with highest baseline Lp(a): -0.7 (-1.1, -0.4) for Q1, -9.5 (-10.7, -8.4) for Q2, -30.4 (-33.6, -27.3) for Q3, and -46.8 (-54.4, -39.4) for Q4 (p<0.001 for all). Conclusions In this pooled analysis of phase 3 trials, baseline Lp(a) levels varied by race. Treatment with enlicitide resulted in significant Lp(a) reductions across all baseline Lp(a) levels and across racial and ethnic subgroups with the largest % reductions in those with Lp(a) levels between 13.7 and 150.2 nmol, and largest absolute reductions in those with Lp(a) levels ≥125 nmol/L and ≥ 39.6 nmol/L. Placebo corrected %LDL-C reduction with enlicitide was >60% and consistent across the full range of baseline Lp(a) levels.