Laroprovstat, the First Oral Small-Molecule PCSK9 Inhibitor for the Treatment of Hypercholesterolemia: Results From a Randomized, Single-Blind, Placebo-Controlled Phase 1 Trial in Treatment-Naïve Patients.

Current PCSK9 inhibitors are injectable therapies; no oral small-molecule PCSK9 inhibitor has yet been approved.

目前的PCSK9抑制剂是注射疗法；尚未批准任何口服小分子PCSK9抑制剂。

Methods

Laroprovstat (AZD0780) is a novel small-molecule identified through structure-based design that binds to the PCSK9 C-terminal domain.

Laroprovstat (AZD0780) 是一种通过基于结构的设计识别出的新型小分子药物，它能够与PCSK9的C末端结构域结合。

The effects of laroprovstat on LDL receptor expression and LDL-C levels were assessed in vitro and in mice expressing human PCSK9.

在体外和表达人类PCSK9的小鼠中评估了laroprovstat对LDL受体表达和LDL-C水平的影响。

Safety, tolerability, and pharmacokinetic and pharmacodynamic properties of laroprovstat were assessed in healthy participants with LDL-C ≥70 and ≤190 mg/dL after single ascending doses.

在LDL-C水平≥70且≤190 mg/dL的健康参与者中评估了laroprovstat的安全性、耐受性以及药代动力学和药效学特性，这些参与者在单次递增剂量后接受评估。

Laroprovstat was also assessed in participants with LDL-C ≥100 and ≤190 mg/dL at doses of 1 mg or 30 mg versus placebo administered once daily for 28 days after a rosuvastatin 20 mg run-in treatment period.

在经过20 mg rosuvastatin预处理期后，对LDL-C水平≥100且≤190 mg/dL的参与者进行了每日一次1 mg或30 mg laroprovstat与安慰剂的比较，为期28天。

Results

Laroprovstat does not inhibit the PCSK9-LDL receptor interaction but stabilizes the PCSK9 C-terminal domain, preventing lysosomal trafficking and degradation of LDL receptor.

Laroprovstat 不抑制PCSK9-LDL受体相互作用，但稳定PCSK9 C末端结构域，阻止LDL受体的溶酶体转运和降解。

Laroprovstat increased LDL receptor expression and reduced LDL-C levels in mice expressing human PCSK9.

Laroprovstat增加了表达人类PCSK9的小鼠的LDL受体表达，并降低了LDL-C水平。

Laroprovstat displayed dose-proportional pharmacokinetics and a half-life suitable for once-daily dosing (≈40 hours).

Laroprovstat显示出剂量成比例的药代动力学特性，并且其半衰期适合每日一次给药（约40小时）。

There was no clinically meaningful change in exposure when dosed with a high-fat meal compared with the fasted state (area under the plasma concentration-time curveinf and Cmax geometric mean reduction of 1.15 [90% CI, 1.11-1.19] and 1.06 [90% CI, 1.00-1.13], respectively).

与空腹状态相比，高脂餐后Laroprovstat的暴露量没有临床上显著的变化（血浆浓度-时间曲线下面积和Cmax几何平均值分别减少了1.15 [90% CI, 1.11-1.19]和1.06 [90% CI, 1.00-1.13]）。

After a rosuvastatin 20 mg 3-week run-in treatment period, laroprovstat 1 and 30 mg reduced LDL-C by 29% (95% CI, 18%-38%) and 51% (95% CI, 44%-58%) compared with baseline.

在20 mg瑞舒伐他汀为期3周的导入治疗后，1 mg和30 mg的laroprovstat分别使LDL-C降低了29%（95% CI，18%-38%）和51%（95% CI，44%-58%）与基线相比。

Combined rosuvastatin and laroprovstat treatment resulted in a total approximate reduction in LDL-C of 70% and 80% for laroprovstat 1 and 30 mg, respectively.

联合使用瑞舒伐他汀和laroprovstat治疗后，LDL-C的总降低幅度分别约为70%和80%，对应于laroprovstat 1 mg和30 mg。

Conclusions

Laroprovstat was well tolerated with no safety findings of concern and may be dosed with or without food.

Laroprovstat 耐受性良好，未发现具有关注的安全问题，可以空腹或餐后服用。

In treatment-naïve participants with hypercholesterolemia, combined rosuvastatin 20 mg and laroprovstat 30 mg treatment led to an 80% LDL-C reduction, supporting further development of laroprovstat as the first oral small-molecule PCSK9 inhibitor in patients with hypercholesterolemia.

在未接受治疗的高胆固醇血症参与者中，联合使用20毫克瑞舒伐他汀和30毫克laroprovstat治疗可使低密度脂蛋白胆固醇（LDL-C）降低80%，支持将laroprovstat作为首个口服小分子PCSK9抑制剂在高胆固醇血症患者中的进一步开发。

registration

URL: https://www.clinicaltrials.gov; Unique identifier: NCT05384262.

网址: https://www.clinicaltrials.gov; 唯一标识符: NCT05384262.