Background

Familial hypercholesterolemia is characterized by an elevated level of low-density lipoprotein (LDL) cholesterol and an increased risk of premature atherosclerotic cardiovascular disease. Monoclonal antibodies directed against proprotein convertase subtilisin–kexin type 9 (PCSK9) have been shown to reduce LDL cholesterol levels by more than 50% but require administration every 2 to 4 weeks. In a phase 2 trial, a twice-yearly injection of inclisiran, a small interfering RNA, was shown to inhibit hepatic synthesis of PCSK9 in adults with heterozygous familial hypercholesterolemia.

Methods

In this phase 3, double-blind trial, we randomly assigned, in a 1:1 ratio, 482 adults who had heterozygous familial hypercholesterolemia to receive subcutaneous injections of inclisiran sodium (at a dose of 300 mg) or matching placebo on days 1, 90, 270, and 450. The two primary end points were the percent change from baseline in the LDL cholesterol level on day 510 and the time-adjusted percent change from baseline in the LDL cholesterol level between day 90 and day 540.

Results

The median age of the patients was 56 years, and 47% were men; the mean baseline level of LDL cholesterol was 153 mg per deciliter. At day 510, the percent change in the LDL cholesterol level was a reduction of 39.7% (95% confidence interval [CI], −43.7 to −35.7) in the inclisiran group and an increase of 8.2% (95% CI, 4.3 to 12.2) in the placebo group, for a between-group difference of −47.9 percentage points (95% CI, −53.5 to −42.3; P<0.001). The time-averaged percent change in the LDL cholesterol level between day 90 and day 540 was a reduction of 38.1% (95% CI, −41.1 to −35.1) in the inclisiran group and an increase of 6.2% (95% CI, 3.3 to 9.2) in the placebo group, for a between-group difference of −44.3 percentage points (95% CI, −48.5 to −40.1; P<0.001). There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia. Adverse events and serious adverse events were similar in the two groups.

Conclusions

Among adults with heterozygous familial hypercholesterolemia, those who received inclisiran had significantly lower levels of LDL cholesterol than those who received placebo, with an infrequent dosing regimen and an acceptable safety profile. (Funded by the Medicines Company; ORION-9 ClinicalTrials.gov number, NCT03397121.)

中文翻译：

---

Inclisiran 治疗杂合子家族性高胆固醇血症

背景

家族性高胆固醇血症的特征是低密度脂蛋白 (LDL) 胆固醇水平升高和过早发生动脉粥样硬化性心血管疾病的风险增加。针对前蛋白转化酶枯草杆菌蛋白酶-kexin 9 型 (PCSK9) 的单克隆抗体已被证明可将 LDL 胆固醇水平降低 50% 以上，但需要每 2 至 4 周给药一次。在一项 2 期试验中，每年两次注射 inclisiran（一种小干扰 RNA）被证明可以抑制杂合子家族性高胆固醇血症成人的肝脏合成 PCSK9。

方法

在这项 3 期双盲试验中，我们以 1:1 的比例随机分配 482 名患有杂合子家族性高胆固醇血症的成年人在第 1 天接受皮下注射 inclisiran 钠（剂量为 300 mg）或匹配的安慰剂， 90、270 和 450。两个主要终点是第 510 天 LDL 胆固醇水平相对于基线的百分比变化，以及第 90 天和第 540 天之间 LDL 胆固醇水平相对于基线的时间调整百分比变化。

结果

患者的中位年龄为 56 岁，其中 47% 为男性；低密度脂蛋白胆固醇的平均基线水平为 153 毫克/分升。在第 510 天，inclisiran 组 LDL 胆固醇水平的百分比变化降低了 39.7%（95% CI，-43.7 至 -35.7），增加了 8.2%（95% CI，4.3 至12.2）在安慰剂组中，组间差异为 -47.9 个百分点（95% CI，-53.5 至 -42.3；P<0.001）。在第 90 天和第 540 天之间 LDL 胆固醇水平的时间平均百分比变化是 inclisiran 组降低了 38.1%（95% CI，-41.1 至 -35.1），增加了 6.2%（95% CI，3.3至 9.2），组间差异为 -44.3 个百分点（95% CI，-48.5 至 -40.1；P<0.001）。在所有基因型的家族性高胆固醇血症中，低密度脂蛋白胆固醇水平都显着降低。两组的不良事件和严重不良事件相似。

结论

在杂合子家族性高胆固醇血症成人中，接受 inclisiran 治疗的患者的 LDL 胆固醇水平显着低于接受安慰剂治疗的患者，且给药方案不频繁且安全性可接受。（由 Medicines Company 资助；ORION-9 ClinicalTrials.gov 编号，NCT03397121。）