Abstract 675: Addition of TAK-475 to Atorvastatin Provides Incremental Lipid Benefits
Recent outcome trials with statins demonstrated the benefit of reducing LDL-C to <100 mg/dL in high risk and to <70 mg/dL in very high risk patients; however, many patients cannot achieve these goals with a statin alone. TAK-475, a novel squalene synthase inhibitor, decreases LDL-C by inhibiting the cholesterol biosynthesis pathway at a step distal to HMG-CoA reductase inhibitors (statins). We evaluated the effects of adding TAK-475 to stable atorvastatin therapy in patients with primary hypercholesterolemia. In a 6-week, double-blind, proof of concept study, screened patients with LDL-C >100 mg/dL and TG <400 mg/dL received 4 weeks of stable atorvastatin treatment (10 or 20 mg); 172 patients with LDL-C remaining >100 mg/dL were randomized to the addition of oral, once daily TAK-475 (100 mg) or placebo. The primary efficacy endpoint was % change from baseline for LDL-C. Secondary efficacy variables were total cholesterol (TC), VLDL-C, HDL-C, TG, apo B, and apo A1. Standard safety parameters were assessed. Demographics and baseline characteristics were similar in the two groups. At randomization, mean direct LDL-C was 129.9 mg/dL in the TAK-475 group and 121.6 mg/dL in the placebo group. At the final visit, the mean change from baseline for LDL-C was -19.1% for TAK-475, compared with 0.7% for placebo (p<0.001). Significant decreases (p<0.05) with TAK-475 vs placebo were also seen for TC, TG, and apo B. HDL-C increased slightly in both groups. TAK-475 was well tolerated; most side effects were mild or moderate and not considered related to study drug. There were no deaths or related serious adverse events. No subject experienced ALT >3 x ULN or CPK >10 x ULN. The addition of TAK-475 to stable atorvastatin therapy resulted in significant reductions in LDL-C, TC, TG, and apo B; was well tolerated; and provided incremental improvements over the statin alone. These results demonstrate the potential benefit of TAK-475 in combination with a statin for treatment of hypercholesterolemia.