Compelling evidence supports a causal role for lipoprotein(a) (Lp(a)) in cardiovascular disease. No pharmacotherapies directly targeting Lp(a) are currently available for clinical use. Here we report the discovery and development of olpasiran, a first-in-class, synthetic, double-stranded, N-acetylgalactosamine-conjugated small interfering RNA (siRNA) designed to directly inhibit LPA messenger RNA translation in hepatocytes and potently reduce plasma Lp(a) concentration. Olpasiran reduced Lp(a) concentrations in transgenic mice and cynomolgus monkeys in a dose-responsive manner, achieving up to over 80% reduction from baseline for 5–8 weeks after administration of a single dose. In a phase 1 dose-escalation trial of olpasiran (ClinicalTrials.gov: NCT03626662), the primary outcome was safety and tolerability, and the secondary outcomes were the change in Lp(a) concentrations and olpasiran pharmacokinetic parameters. Participants tolerated single doses of olpasiran well and experienced a 71–97% reduction in Lp(a) concentration with effects persisting for several months after administration of doses of 9 mg or higher. Serum concentrations of olpasiran increased approximately dose proportionally. Collectively, these results validate the approach of using hepatocyte-targeted siRNA to potently lower Lp(a) in individuals with elevated plasma Lp(a) concentration.

令人信服的证据支持脂蛋白 (a) (Lp(a)) 在心血管疾病中的因果作用。目前没有直接针对 Lp(a) 的药物疗法可用于临床。在这里，我们报告了 olpasiran 的发现和开发，这是一种一流的、合成的、双链的、N-乙酰半乳糖胺缀合的小干扰 RNA (siRNA)，旨在直接抑制LPA肝细胞中的信使 RNA 翻译并有效降低血浆 Lp(a) 浓度。Olpasiran 以剂量反应方式降低转基因小鼠和食蟹猴体内的 Lp(a) 浓度，在单剂量给药后 5-8 周内从基线水平降低 80% 以上。在 olpasiran 的 1 期剂量递增试验（ClinicalTrials.gov：NCT03626662）中，主要结果是安全性和耐受性，次要结果是 Lp(a) 浓度和 olpasiran 药代动力学参数的变化。参与者对单次剂量的 olpasiran 耐受良好，Lp(a) 浓度降低了 71-97%，并且在给予 9 mg 或更高剂量后效果持续数月。olpasiran 的血清浓度增加大约与剂量成正比。总的来说，