Lapaquistat Acetate Development of a Squalene Synthase Inhibitor for the Treatment of Hypercholesterolemia

Article

关键词: C-REACTIVE PROTEIN;    DENSITY-LIPOPROTEIN CHOLESTEROL;    MODERATE HYPERCHOLESTEROLEMIA;    STATIN THERAPY;    HYS LAW;    EZETIMIBE;    PLASMA;    HEPATOTOXICITY;    DYSLIPIDEMIA;    EFFICACY;   

DOI  :  10.1161/CIRCULATIONAHA.110.975284

来源: SCIE

【 摘 要 】

Background-Lapaquistat acetate is a squalene synthase inhibitor investigated for the treatment of hypercholesterolemia. Methods and Results-This report summarizes the phase 2 and 3 results from the lapaquistat clinical program, which was halted at an advanced stage as a result of potential hepatic safety issues. Efficacy and safety data were pooled from 12 studies (n=6151). These were 6- to 96-week randomized, double-blind, parallel, placebo-or active-controlled trials with lapaquistat monotherapy or coadministration with other lipid-altering drugs in dyslipidemic patients, including a large (n=2121) 96-week safety study. All studies included lapaquistat 100 mg daily; 5 included 50 mg; and 1 included 25 mg. The main outcome measures were the percent change in low-density lipoprotein cholesterol, secondary lipid/metabolic parameters, and overall safety. Lapaquistat 100 mg significantly decreased low-density lipoprotein cholesterol by 21.6% in monotherapy and by 18.0% in combination with a statin. It also reduced other cardiovascular risk markers, such as C-reactive protein. Total adverse events were higher for lapaquistat than placebo, although individual events were generally similar. At 100 mg, there was an increase in alanine aminotransferase value >= 3 times the upper limit of normal on >= 2 consecutive visits (2.0% versus 0.3% for placebo in the pooled efficacy studies; 2.7% versus 0.7% for low-dose atorvastatin in the long-term study). Two patients receiving lapaquistat 100 mg met the Hy Law criteria of alanine aminotransferase elevation plus increased total bilirubin. Conclusions-Squalene synthase inhibition with lapaquistat acetate, alone or in combination with statins, effectively lowered low-density lipoprotein cholesterol in a dose-dependent manner. Elevations in alanine aminotransferase, combined with a rare increase in bilirubin, presented potential hepatic safety issues, resulting in termination of development. The lapaquistat experience illustrates the current challenges in lipid-altering drug development.

【 授权许可】

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