Abstract 1493: TAK-475, a Squalene Synthase Inhibitor, Improves Lipid Profile in Hyperlipidemic Subjects
TAK-475 decreases LDL-C by inhibiting squalene synthase; this contrasts with statins, which act on HMG-CoA reductase. Preliminary data showed that TAK-475 is safe and improves lipid profiles in animals and healthy volunteers. This phase II randomized, double-blind, placebo and actively controlled, parallel-group study was conducted to assess TAK-475 effects in hyperlipidemic subjects. After dietary run in, screened subjects with LDL-C levels remaining elevated (≥130 mg/dL and ≤210 mg/dL, with mean TG levels ≤350 mg/dL) were randomized (n=321) to blinded treatments consisting of once daily oral administration of TAK-475 (25, 50, or 100 mg), atorvastatin (10 mg), or placebo for 8 weeks, with a subsequent 2-week follow up. The primary efficacy parameter was fasting LDL-C; total cholesterol (TC), TG, VLDL-C, HDL-C, apolipoproteins B and A1, and lipoprotein(a) were also measured. Safety was assessed through evaluations of adverse events, laboratory results, vital signs, physical exams, and ECGs. Baseline LDL-C levels were similar in all groups. At end of treatment, mean LDL-C levels decreased significantly (p<0.001) vs placebo for all TAK-475 doses and for atorvastatin. Statistically significant (p<0.05) changes in secondary lipid parameters were also seen; at the 50 and 100 mg doses, TAK-475 increased HDL-C more than did atorvastatin. Overall, the tolerability and safety profile of TAK-475 was similar to that of atorvastatin and placebo. The incidence, type, and severity of AEs were comparable among groups. No patients died, and no major safety issues were identified. TAK-475 was shown to be an effective and well-tolerated lipid-lowering agent that provided clinically significant changes in major lipid parameters. These data provide evidence to support continued investigation of TAK-475 for use as monotherapy. Moreover, its novel mechanism of action suggests potential use in combination therapy for hyperlipidemic patients.