Laroprovstat 30 mg once daily reduced LDL-C by 51% (95% CI, 58%-44%) from baseline after a rosuvastatin run-in, achieving an 80% total reduction in patients with hypercholesterolemia.
RCT
Single-blind
Randomized
Does laroprovstat reduce LDL-C levels in treatment-naive patients with hypercholesterolemia?
Laroprovstat, a novel oral small-molecule PCSK9 inhibitor, significantly reduced LDL-C levels by up to 51% when added to rosuvastatin in treatment-naive patients with hypercholesterolemia, with no safety concerns.
Effect estimate: 51% reduction (95% CI 58%-44%)
BACKGROUND: Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) is an effective therapy for reducing low-density lipoprotein (LDL) cholesterol (LDL-C) in adults with hyperlipidemia, including heterozygous familial hypercholesterolemia, thereby lowering cardiovascular risk. Current PCSK9 inhibitors are injectable therapies; no oral small-molecule PCSK9 inhibitor has yet been approved. METHODS: Laroprovstat (AZD0780) is a novel small-molecule identified through structure-based design that binds to the PCSK9 C-terminal domain. The effects of laroprovstat on LDL receptor expression and LDL-C levels were assessed in vitro and in mice expressing human PCSK9 . 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. 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. 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 increased LDL receptor expression and reduced LDL-C levels in mice expressing human PCSK9 . Laroprovstat displayed dose-proportional pharmacokinetics and a half-life suitable for once-daily dosing (≈40 hours). There was no clinically meaningful change in exposure when dosed with a high-fat meal compared with the fasted state (AUC inf and C max geometric mean reduction of 1.15 90% CI, 1.11–1.19 and 1.06 90% CI, 1.00–1.13, respectively). After a rosuvastatin 20 mg 3-week run-in treatment period, laroprovstat 1 and 30 mg reduced LDL-C by 29% (95% CI, 38%–18%) and 51% (95% CI, 58%–44%) compared with baseline. 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. CONCLUSIONS: Laroprovstat was well tolerated with no safety findings of concern and may be dosed with or without food. In treatment-naive 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. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05384262.
“Laroprovstat dosed with a statin would enable most patients to achieve their [LDL-C] goal and may lead to a reduction of cardiovascular risk and improved cardiovascular outcomes.”
Vega et al. (Fri,) conducted a rct in Hypercholesterolemia. Laroprovstat vs. Placebo was evaluated on Reduction in LDL-C compared with baseline (51% reduction, 95% CI 58%-44%). Laroprovstat 30 mg once daily reduced LDL-C by 51% (95% CI, 58%-44%) from baseline after a rosuvastatin run-in, achieving an 80% total reduction in patients with hypercholesterolemia.