Efficacy and safety of pemafibrate in patients with statin-intolerant hypercholesterolemia: results from a 12-week, randomized, double blind, placebo-controlled, phase 3 trial

Abstract Background Pemafibrate is a selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) that reduces plasma triglyceride (TG) and increases high-density lipoprotein cholesterol (HDL-C) levels. Previous clinical trials have shown that the effects of pemafibrate on low-density lipoprotein cholesterol (LDL-C) levels vary depending on the target patient population. Pemafibrate has the following effects: - 1) Increases LDL-C levels by promoting the catabolism of very low density lipoprotein (VLDL) to LDL. 2) Reduces LDL-C levels by reducing VLDL production and inhibiting cholesterol absorption and synthesis. Based on these contrasting effects, the LDL-C lowering effect of pemafibrate may be observed in patients with hypercholesterolaemia and normal TG levels, as the contribution of VLDL to LDL catabolism is presumed to be limited. Purpose In this study, we aimed to evaluate the efficacy (primarily the LDL-C-lowering effect) and safety of pemafibrate administered for 12 weeks to patients with statin-intolerant hypercholesterolaemia and TG levels 150 mg/dL. Methods This was a Phase 3, multicentre, placebo-controlled, double-blind, parallel-group comparative study. Patients (n=71) with statin-intolerant hypercholesterolaemia and TG levels 150 mg/dL were randomly assigned to receive once-daily extended-release pemafibrate (0.2 mg/day or 0.4 mg/day) or a placebo. Results The mean LDL-C level at baseline was 176.9 mg/dL, and the mean apolipoprotein B (ApoB) level was 116.3 mg/dL. A total of 23.5% of the patients received concomitant ezetimibe therapy. Repeated measures analysis of covariance (ANCOVA) of LDL-C at weeks 4, 8, and 12 showed that the least squares mean percentage changes from baseline in the pemafibrate groups relative to the placebo group were -19.7% and -24.5% for 0.2 mg/day and 0.4 mg/day, respectively. Both values were statistically significant. ANCOVA of ApoB at week 12, using the last observation carried forward (LOCF) method, showed that the least squares mean percentage changes from baseline in the pemafibrate groups relative to the placebo group were -15.9% and -18.3% for 0.2 mg/day and 0.4 mg/day, respectively. Both values were statistically significant (see Fig.1 and 2). No serious adverse events were directly attributed to the investigated drugs. Nine patients discontinued participating in the study: five in the 0.2 mg/day group, four in the 0.4 mg/day group, and none in the placebo group. Although all patients discontinued participating due to adverse events, all of the reported adverse drug reactions were mild in severity. Conclusion Administration of pemafibrate to patients with statin-intolerant hypercholesterolaemia and normal TG levels statistically significantly reduced serum LDL-C and ApoB levels. No major safety concerns were identified, indicating that pemafibrate may serve as a novel treatment option for patients with statin-intolerant hypercholesterolaemia and normal TG levels.