Novel oral small-molecule PCSK9 inhibitor shows promise in hypercholesterolemia

In the treatment of hypercholesterolemia, the investigational oral small-molecule PCSK9 inhibitor laroprovstat appears well tolerated and may help reduce low-density lipoprotein cholesterol (LDL-C) levels when used in combination with rosuvastatin, according to a phase I study.

In the study, researchers first examined the effects of laroprovstat on LDL receptor expression and LDL-C levels in vitro and in mice expressing human PCSK9. Then, they assessed the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of laroprovstat in healthy participants with LDL-C ≥70 and ≤190 mg/dL after single ascending doses. Finally, outcomes with laroprovstat at 1 or 30 mg were compared against placebo in participants with LDL-C ≥100 and ≤190 mg/dL, with treatment administered once daily for 28 days after a rosuvastatin 20 mg run-in treatment period.

In vitro analyses showed that laroprovstat did not inhibit the PCSK9–LDL receptor interaction but stabilized the PCSK9 C-terminal domain, preventing lysosomal trafficking and degradation of LDL receptor. The drug also promoted LDL receptor expression and reduced LDL-C levels in mice expressing human PCSK9.

Laroprovstat had dose-proportional pharmacokinetics and a half-life suitable for once-daily dosing (≈40 hours). Notably, exposure did not meaningfully change when dosed with a high-fat meal as opposed with the fasted state.

After a 3-week run-in rosuvastatin 20 mg treatment period, LDL-C levels decreased by 29 percent with laroprovstat 1 mg and by 51 percent with laroprovstat 30 mg. Combined rosuvastatin and laroprovstat treatment resulted in a total approximate LDL-C reduction of 70 percent and 80 percent for laroprovstat 1 and 30 mg, respectively.