Background

Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder characterised by extremely high concentrations of LDL cholesterol, leading to early-onset atherosclerosis. Lomitapide is an orally administered microsomal triglyceride transfer protein (MTP) inhibitor that effectively lowers LDL cholesterol and is approved for adults with HoFH. We aimed to investigate the efficacy and safety of lomitapide in paediatric patients with HoFH receiving standard-of-care lipid-lowering therapy.

Methods

APH-19 is an open-label, single-arm, phase 3 trial performed at 12 study centres in Germany, Israel, Italy, Saudi Arabia, Spain, and Tunisia. A 6-week run-in period was followed by a 24-week efficacy phase and an 80-week safety phase. Patients aged 5–17 years, on stable lipid-lowering therapy, with HoFH diagnosed using the criteria from the 2014 European Atherosclerosis Society Consensus Panel on HoFH were titrated to maximum tolerated doses of oral lomitapide, starting at 2 mg (patients aged 5–15 years) or 5 mg (patients aged 16–17 years). The primary endpoint was the percentage change from baseline to week 24 in LDL cholesterol, which was assessed in patients who had received at least one dose of lomitapide, and who had a baseline and at least one post-baseline measurement. The secondary outcomes were the percentage change from baseline at week 24 in total cholesterol, non-HDL cholesterol, VLDL cholesterol, apolipoprotein B, triglycerides, and lipoprotein(a). Safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04681170.

Findings

Between Dec 20, 2020, and Oct 16, 2022, 43 patients were included and treated (24 [56%] were female and 19 [44%] were male, and median age was 10·7 years [7·0–14·0]). Mean change from baseline in LDL cholesterol at week 24 was –53·5% (95% CI –61·6 to –45·4, p<0·0001). Mean percentage reductions were observed at week 24 for non-HDL cholesterol (–53·9%, 95% CI –61·7 to –46·1, p<0·0001), total cholesterol (–50·0%, 95% CI –57·6 to –42·4, p<0·0001), VLDL cholesterol (–50·2%, –59·1 to –41·2, p<0·0001), apolipoprotein B (–52·4%, –60·3 to –44·5, p<0·0001), triglycerides was –49·9% (–58·8 to –41·0, p<0·0001), and lipoprotein(a) (–11·3%, –32·9 to 10·3 [in 21 patients with measurements in mg/dL]; –23·6%, –38·2 to –9·0 [in 22 patients with measurements in nmol/L]; p=0·0070 combined). Adverse events were mostly mild, and gastrointestinal and hepatic in nature. Adverse events of special interest were reported for five (12%) patients (gastrointestinal in two patients and hepatic in three). One serious treatment-emergent adverse event was reported (also classed as an adverse event of special interest): an increase in hepatic enzymes, resulting in two dose interruptions, two dose reductions, and a repeated dose escalation.

Interpretation

Lomitapide provided a significant, clinically meaningful LDL cholesterol reduction and has the potential to be an efficient, LDL receptor-independent option for paediatric patients with HoFH.

Funding

Amryt Pharmaceuticals.

中文翻译：

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洛米他派治疗纯合子家族性高胆固醇血症 （APH-19） 儿科患者：一项开放标签、多中心、3 期研究的疗效阶段结果

 背景

纯合子家族性高胆固醇血症 （HoFH） 是一种罕见的遗传性疾病，其特征是低密度脂蛋白胆固醇浓度极高，导致早发性动脉粥样硬化。Lomitapide 是一种口服微粒体甘油三酯转运蛋白 （MTP） 抑制剂，可有效降低 LDL 胆固醇，并被批准用于 HoFH 成人患者。我们旨在研究洛美他那特在接受标准降脂治疗的 HoFH 儿科患者中的疗效和安全性。

 方法

APH-19 是一项开放标签、单臂、3 期试验，在德国、以色列、意大利、沙特阿拉伯、西班牙和突尼斯的 12 个研究中心进行。6 周的磨合期之后是 24 周的疗效阶段和 80 周的安全阶段。使用 2014 年欧洲动脉粥样硬化学会 HoFH 共识小组的标准诊断为 HoFH 的 5-17 岁患者，接受稳定的降脂治疗，从 2 毫克（5-15 岁患者）或 5 毫克（16-17 岁患者）开始。主要终点是 LDL 胆固醇从基线到第 24 周的百分比变化，该变化在接受至少一剂 lomitapide 以及有基线和至少一次基线后测量的患者中进行评估。次要结局是第 24 周时总胆固醇、非 HDL 胆固醇、VLDL 胆固醇、载脂蛋白 B、甘油三酯和脂蛋白 （a） 相对于基线的百分比变化。在接受至少一剂研究药物的患者中评估安全性。这项研究已在 ClinicalTrials.gov， NCT04681170 注册。

 发现

在 2020 年 12 月 20 日至 2022 年 10 月 16 日期间，纳入并治疗了 43 名患者 （24 名 [56%] 为女性，19 名 [44%] 为男性，中位年龄为 10·7 岁 [7·0–14·0]）。第 24 周时 LDL 胆固醇相对于基线的平均变化为 -53·5%（95% CI -61·6 至 -45·4，p<0·0001）。在第 24 周时观察到非高密度脂蛋白胆固醇（-53·9%，95% CI -61·7 至 -46·1，p<0·0001）、总胆固醇（-50·0%，95% CI -57·6 至 -42·4，p<0·0001）、VLDL 胆固醇（-50·2%，-59·1 至 -41·2，p<0·0001）、载脂蛋白 B（-52·4%，-60·3 至 -44·5、 p<0·0001）、甘油三酯为 -49·9%（-58·8 至 -41·0，p<0·0001）和脂蛋白 （a）（-11·3%，-32·9 至 10·3 [在 21 名测量以 mg/dL 为单位的患者中];-23·6%，-38·2 至 -9·0 [在 22 名测量以 nmol/L 为单位的患者中];p=0·0070 组合）。不良事件大多是轻微的，本质上是胃肠道和肝脏的。5 例 （12%） 患者报告了特别关注的不良事件 （2 例患者为胃肠道，3 例为肝脏）。报告了 1 例严重的治疗中出现的不良事件（也被归类为特别关注的不良事件）：肝酶增加，导致 2 次剂量中断、2 次剂量减少和一次重复剂量递增。

 解释

Lomitapide 提供了显着的、具有临床意义的 LDL 胆固醇降低，并有可能成为 HoFH 儿科患者的一种有效的、不依赖 LDL 受体的选择。

 资金

 Amryt 制药公司。