Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is an established strategy for lowering low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk. Investigators evaluated laroprovstat (AZD0780), a novel oral small-molecule PCSK9 inhibitor, in preclinical studies and early-phase clinical trials assessing safety, pharmacokinetics, and LDL-C lowering efficacy. The early-phase study was published in the Circulation.
Clinical evaluation included healthy participants with LDL-C levels between 70 and 190 mg/dL receiving single ascending doses, as well as participants with hypercholesterolemia receiving once-daily laroprovstat at 1 mg or 30 mg versus placebo for 28 days following a rosuvastatin 20 mg run-in period.
Findings
- Laroprovstat increased LDL receptor expression and reduced LDL-C levels in mice expressing human PCSK9.
- The drug demonstrated dose-proportional pharmacokinetics with an approximate half-life of 40 hours, supporting once-daily administration.
- Administration with a high-fat meal did not meaningfully alter drug exposure compared with fasting conditions.
- After rosuvastatin run-in therapy, laroprovstat 1 mg reduced LDL-C by 29% (95% CI 38%–18%) relative to baseline.
- Laroprovstat 30 mg reduced LDL-C by 51% (95% CI 58%–44%) relative to baseline.
- Combined rosuvastatin and laroprovstat treatment produced total LDL-C reductions of approximately 70% with 1 mg dosing and 80% with 30 mg dosing.
- Laroprovstat was generally well tolerated, with no major safety concerns identified during the study period.
In this early-phase evaluation, the investigational oral PCSK9 inhibitor laroprovstat demonstrated substantial LDL-C reductions when combined with rosuvastatin, along with favorable pharmacokinetic characteristics and short-term tolerability.
