ORLANDO (EGMN) – Lomitapide is a powerful lipid-lowering agent with a potentially serious drawback, according to interim results of an ongoing phase III study in patients with homozygous familial hypercholesterolemia.

Lomitapide is first in a new class of investigational lipid-lowering drugs known as microsomal triglyceride transfer protein inhibitors. These agents reduce LDL cholesterol levels by inhibiting apolipoprotein B lipidation, a novel mechanism that results in reduced secretion of atherogenic apo B–containing lipoproteins, Dr. Marina Cuchel explained at the annual scientific sessions of the American Heart Association.

Homozygous familial hypercholesterolemia is a rare but daunting therapeutic challenge. Affected patients have extraordinarily severe dyslipidemia from birth that often is resistant to lipid-lowering drugs. They typically develop clinical cardiovascular disease before reaching adulthood.

For example, the 14 participants in the phase III open-label lomitapide study who have been on the drug for at least 6 months had a baseline mean LDL cholesterol level of 351 mg/dL, a total cholesterol level of 444 mg/dL, a non-HDL cholesterol level of 404 mg/dL, and an apo B level of 278 – and that’s while on maximum tolerated doses of statins and other standard lipid-lowering drugs as well as apheresis and a low-fat diet. At a mean age of only 33 years, 12 of the 14 (86%) had cardiovascular disease.

At week 26 of the phase III study, patients on lomitapide at a median dose of 40 mg/day – which appeared to be the most effective dose – along with concomitant maximal background lipid-lowering therapies, showed a mean 57% reduction in LDL from baseline. Ten of the 14 patients had an LDL level below 165 mg/dL, including 6 with an LDL level of less than 100 mg/dL, reported Dr. Cuchel of University of Pennsylvania Institute for Translational Medicine, Philadelphia.

In addition, total cholesterol was down by 53% from baseline, non-HDL cholesterol by 56%, and apo B by 53%. Triglycerides dropped from a mean baseline of 112 to 57 mg/dL, while HDL decreased from 40 to 32 mg/dL.

The most common side effects associated with lomitapide were mild to moderate diarrhea, abdominal discomfort, and nausea and vomiting. To date, three patients have dropped out of the study because of GI side effects before reaching the 6-month mark on lomitapide.

Two of 14 patients developed transient elevations in liver function tests of at least five times the upper limit of normal. Both responded to temporary reductions in lomitapide dosing.

Potentially, the most problematic adverse effect associated with lomitapide is accumulation of liver fat. Hepatic fat content climbed from a mean baseline of 1.3% to 7.9% after 26 weeks on the investigational drug.

The long-term clinical implications of this adverse effect remain unclear. It appears to be intrinsic to inhibition of microsomal triglyceride transfer protein. Encouragingly, however, in the six patients who have been on lomitapide for 1 year or longer, liver fat content stabilized or retreated from its 6-month high to a mean value of 3.7% at 56 weeks, Dr. Cuchel continued.

To date, the phase III study has enrolled 22 of a planned 25 subjects. The trial is funded by the U.S. Food and Drug Administration’s Office of Orphan Drug Development and Aegerion Pharmaceuticals Inc. Dr. Cuchel indicated she has no relevant financial conflicts of interest in connection with the study.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

奥兰多(EGMN)——据一项对纯合子家族性高胆固醇血症患者进行的III期研究(尚在进行中)中期结果显示，lomitapide是一种强效降脂药物，但有潜在严重不良反应。

 

Marina Cuthel博士在美国心脏学会科学年会上解释说， lomitapide是一类新型研究用降脂药——微粒体甘油三酯转运蛋白抑制剂中的首个药物。这类药物通过抑制载脂蛋白B的酯化，可降低低密度脂蛋白(LDL)胆固醇，这是减少含有载脂蛋白B(致动脉粥样硬化的危险因子)的脂蛋白分泌的新机制。

 

纯合子家族性高胆固醇血症是一种罕见病，有较高的治疗难度。受累患者自出生起就存在极为严重的脂代谢紊乱，降脂药对该病常常无效。患者通常在成年以前就发生临床心血管疾病。

 

例如，在对lomitapide进行的这项III期开标签研究中，14名受试者坚持服用该药至少6个月，其基线平均LDL胆固醇水平为351 mg/dl，总胆固醇水平为444 mg/dl，非高密度脂蛋白(HDL)胆固醇水平为404 mg/dl，载脂蛋白B水平为278，这些指标水平是患者服用最大耐受剂量的他汀类药物、其他标准降脂药以及析离术加低脂饮食控制的水平。在平均年龄仅为33岁时，14人中就有12人(86%)发生了心血管疾病。

 

宾夕法尼亚大学费城转化医学研究所Cuchel博士报告指出，在这项III期研究进行到26 w时，服用lomitapide(中位剂量为40 mg/day，可能为最有效剂量)并联用最主要的基础降脂药治疗的患者，其LDL水平较基值平均下降57%。14例患者中有10例LDL水平低于165 mg/dl，其中6例LDL水平低于100 mg/dl。

 

另外，总胆固醇较基值降低53%，非HDL胆固醇降低56%，载脂蛋白 B降低53%。甘油三酯自平均基值112 mg/dl降至57 mg/dl，而HDL自40 mg/dl降至32 mg/dl。

 

Lomitapide相关的最常见的副作用为轻度至中度腹泻、腹部不适、恶心和呕吐。迄今，有3例患者因胃肠道副反应未完成6个月的lomitapide治疗期而退出研究。

 

14例患者中有2例肝功能检测结果超出正常范围上限至少5倍，呈暂时性。暂时减少lomitapide剂量对这2例患者的肝功能恢复有效。

 

Lomitapide相关的最难处置的不良反应为肝脏脂肪积聚。服用研究药26w后，肝脏脂肪含量由平均基值1.3%攀升至7.9%。

 

Cuchel继续阐释到，此不良反应的长期临床影响尚不清楚，可能是抑制微粒体甘油三酯转运蛋白的固有现象。然而鼓舞人心的是，6例服用lomitapide达1年或1年以上的患者肝脏脂肪含量稳定，或至56w时由6个月的高水平回落至平均值3.7%。

 

至今，这项III期研究已募集22例受试者，拟定名额为25例。该试验得到美国食品药品管理局孤儿药研发办公室和Aegerion制药公司的资助。Cuchel博士表示，其本人没有与研究相关的经济利益冲突。

 

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