Juxtapid获准治疗纯合子家族性高胆固醇血症

圣路易斯(MD Consult)——2012年12月24日，Aegerion 制药公司宣布，美国食品药品管理局(FDA)已批准了Juxtapid(lomitapide)作为低脂饮食和其他降血脂治疗的辅助药物，用于降低纯合子家族性高胆固醇血症(HoFH)患者低密度脂蛋白胆固醇(LDL-C)、总胆固醇、载脂蛋白B和非高密度脂蛋白胆固醇(非-HDL)。Juxtapid是一种微粒体甘油三酯转运蛋白抑制剂。

FDA批准Juxtapid是基于一项关键性3期研究结果。该研究评价了29例HoFH患者服用Juxtapid降低LDL-C水平的有效性和安全性，是一项为期78周的国际多中心、单组、开放性研究，其结果发表于《柳叶刀》杂志。在这项研究中，Juxtapid初始治疗剂量为每天5 mg，基于耐受性和可接受的肝酶水平，剂量逐渐增加至10 mg、20 mg、40 mg和 60 mg。

在现有降血脂治疗的Juxtapid添加治疗中，意向治疗患者平均LDL-C水平由基线时的336 mg/dL 显著降至26周时的190 mg/dl(降低40%)，其中提前终止治疗患者采取末期观察推进法评估。23例完成26周研究患者LDL-C水平平均降低50%。在26周后的安全性评价阶段，允许调整同期降脂治疗。在长期治疗阶段，LDL-C平均降低幅度仍能维持。

该研究最常见不良反应是胃肠道反应，在29例患者中有27例(93%)报告出现胃肠道反应。28%的患者报告的不良反应包括腹泻、恶心、呕吐、消化不良和腹痛。其他常见不良反应有体重下降、腹部不适、腹胀、便秘、胃肠气胀、胸痛、流感、鼻咽炎和疲乏。还观察到肝酶水平和肝脏脂肪升高。

由于肝脏毒性风险，根据风险评估和降低策略，Juxtapid的使用将受到限制。在治疗开始之前，应检测肝脏转氨酶、碱性磷酸酶和总胆红素水平，并应定期监测丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)。治疗期间，如果ALT或AST水平≥ 3倍正常值最高上限，应调整Juxtapid剂量。一旦出现有临床意义的肝脏毒性，应停止使用Juxtapid。

考虑到Juxtapid作用于小肠，可能会减少脂溶性营养成分的吸收。接受Juxtapid治疗的患者应每天服用含有400 IU的维生素E和至少200 mg亚油酸、210 mg α-亚麻酸、110 mg EPA以及80 mg DHA的补充剂。

Juxtapid用于非HoFH高脂血症患者的安全性和有效性尚未确定。

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ST LOUIS (MD Consult) - On December 24, 2012, Aegerion Pharmaceuticals announced that the US Food and Drug Administration (FDA) has approved Juxtapid (lomitapide) as an adjunct to a low-fat diet and other lipid-lowering treatments, to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol, apolipoprotein B, and non-high-density-lipoprotein cholesterol (non-HDL) in patients with homozygous familial hypercholesterolemia (HoFH). Juxtapid is a microsomal triglyceride transfer protein inhibitor.

The FDA approval of Juxtapid was granted on the basis of results from a pivotal phase 3 study, which evaluated the safety and effectiveness of the medicine to reduce LDL-C levels in 29 adult patients with HoFH. The study was a multinational, single-arm, open-label, 78-week trial that was published in The Lancet. In the study, treatment with Juxtapid was initiated at 5 mg daily and the dose was gradually escalated to 10 mg, 20 mg, 40 mg, up to 60 mg, on the basis of tolerability and acceptable liver enzymes levels.

When added to existing lipid-lowering therapy, the use of Juxtapid significantly reduced LDL-C from a baseline average of 336 mg/dL to 190 mg/dL (40% reduction) at Week 26 in the intent-to-treat population with last observation carried forward for the patients who discontinued prematurely. LDL-C was reduced by an average of 50% for the 23 patients who completed the study through Week 26. After Week 26, during the safety phase of the study, adjustments to concomitant lipid-lowering treatments were allowed. Average reductions in LDL-C were sustained during chronic therapy.

The most common adverse reactions in the trial were gastrointestinal, reported by 27 (93%) of 29 patients. Adverse reactions, which were reported by 28% of patients in the trial, included diarrhea, nausea, vomiting, dyspepsia, and abdominal pain. Other common adverse reactions included weight loss, abdominal discomfort, abdominal distension, constipation, flatulence, chest pain, influenza, nasopharyngitis, and fatigue. Elevations in liver enzyme levels and hepatic fat were also observed.

Because of the risk of hepatotoxicity, Juxtapid is available only through a restricted program under a Risk Evaluation and Mitigation Strategy. Liver transaminases, alkaline phosphatase, and total bilirubin levels should be measured before initiating treatment, and alanine transaminase (ALT) and aspartate transaminase (AST) levels should be monitored regularly. During treatment, the dose of Juxtapid should be adjusted if the ALT or AST levels are ≥ 3 times the upper limit of normal. Juxtapid should be discontinued in the presence of clinically significant liver toxicity.

Given its mechanism of action in the small intestine, Juxtapid may reduce the absorption of fat-soluble nutrients. Patients treated with Juxtapid should take daily supplements that contain 400 international units of vitamin E and at least 200 mg linoleic acid, 210 mg alpha-linolenic acid, 110 mg eicosapentaenoic acid, and 80 mg docosahexaenoic acid.

The safety and effectiveness of Juxtapid have not been established in patients with hypercholesterolemia who do not have HoFH.