Metabolic and Atherosclerosis Research Center, Cincinnati, OH 45212, USA.
Circulation. 2011 May 10;123(18):1974-85. doi: 10.1161/CIRCULATIONAHA.110.975284. Epub 2011 Apr 25.
Lapaquistat acetate is a squalene synthase inhibitor investigated for the treatment of hypercholesterolemia.
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.
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.
URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00487994, NCT00143663, NCT00143676, NCT00864643, NCT00263081, NCT00286481, NCT00249899, NCT00249912, NCT00813527, NCT00256178, NCT00268697, and NCT00251680.
拉帕曲他酯是一种正在研究用于治疗高胆固醇血症的角鲨烯合酶抑制剂。
本报告总结了拉帕曲他酯临床研究的 2 期和 3 期结果，由于潜在的肝脏安全性问题，该研究在后期阶段被停止。从 12 项研究（n=6151）中汇总了疗效和安全性数据。这些研究是为期 6-96 周的随机、双盲、平行、安慰剂或阳性对照试验，研究对象为血脂异常患者，包括一项大型（n=2121）为期 96 周的安全性研究，患者接受拉帕曲他酯单药治疗或与其他调脂药物联合治疗。所有研究均使用拉帕曲他酯 100 mg/d；5 项研究使用 50 mg；1 项研究使用 25 mg。主要观察指标为低密度脂蛋白胆固醇的百分比变化、次要脂质/代谢参数和总体安全性。拉帕曲他酯 100 mg 单药治疗可使低密度脂蛋白胆固醇降低 21.6%，与他汀类药物联合治疗可降低 18.0%。它还降低了其他心血管风险标志物，如 C 反应蛋白。拉帕曲他酯的总不良事件发生率高于安慰剂，但各事件发生率一般相似。在 100 mg 剂量时，丙氨酸氨基转移酶值升高≥3 倍正常值上限的患者比例较高（疗效研究中，拉帕曲他酯组为 2.0%，安慰剂组为 0.3%；长期研究中，低剂量阿托伐他汀组为 2.7%，安慰剂组为 0.7%）。两名接受拉帕曲他酯 100 mg 治疗的患者符合丙氨酸氨基转移酶升高和总胆红素升高的 Hy Law 标准。
角鲨烯合酶抑制作用的拉帕曲他酯，单独或与他汀类药物联合使用，可有效降低低密度脂蛋白胆固醇，呈剂量依赖性。丙氨酸氨基转移酶升高，加上胆红素升高的罕见增加，提示存在潜在的肝脏安全性问题，导致研究终止。拉帕曲他酯的经验说明了目前在调脂药物开发中面临的挑战。
