First Oral PCSK9 Inhibitor Laroprovstat shows Up to 80 Percent LDL Reduction in Phase 1 Trial
Sweden: Laroprovstat, the first oral small-molecule PCSK9 inhibitor under clinical development, demonstrated substantial LDL cholesterol–lowering effects in a phase 1 study involving treatment-naive participants with hypercholesterolemia, results published in Circulation by Rick B. Vega and colleagues have revealed.
The findings indicate a major advance in lipid-lowering therapy, with the oral agent achieving reductions in LDL cholesterol of up to 80% when combined with statin therapy. This could potentially shift treatment paradigms away from injectable biologics toward more convenient oral options.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are already established as effective agents for reducing low-density lipoprotein cholesterol (LDL-C) and lowering cardiovascular risk, particularly in patients with hyperlipidemia and familial hypercholesterolemia. However, currently available therapies are injectable monoclonal antibodies. Laroprovstat (AZD0780) represents a novel approach as the first orally available small-molecule targeting PCSK9.
Unlike conventional agents that block the PCSK9–LDL receptor interaction or reduce PCSK9 levels, laroprovstat works through a distinct mechanism. It binds to the C-terminal domain of PCSK9, stabilizing its structure and preventing lysosomal degradation of LDL receptors. This preserves LDL receptor function, enhancing clearance of LDL cholesterol from the bloodstream.
The following were the key findings:
- Preclinical studies showed that laroprovstat increased LDL receptor expression and lowered LDL-C levels in animal models expressing human PCSK9. These results supported its advancement into clinical trials in humans.
- The phase 1 program included both healthy volunteers and participants with elevated LDL cholesterol levels.
- In single ascending dose studies, laroprovstat demonstrated dose-proportional pharmacokinetics and a half-life of about 40 hours, supporting once-daily dosing.
- Food had minimal effect on drug exposure, indicating it can be taken with or without meals.
- In a 28-day randomized, placebo-controlled study after a rosuvastatin run-in period, laroprovstat significantly reduced LDL-C levels.
- LDL cholesterol decreased by 29% at 1 mg and 51% at 30 mg compared with baseline.
- When combined with rosuvastatin, total LDL-C reduction reached approximately 70% with 1 mg and about 80% with 30 mg doses.
- The treatment was well-tolerated overall.
- No safety concerns or clinically significant adverse effects were observed during the study period.
The study highlights several clinically relevant advantages. The combination of laroprovstat with statin therapy achieved rapid and robust LDL-C lowering, suggesting that most patients could potentially reach guideline-recommended lipid targets using a simplified regimen. The oral route of administration also addresses a major limitation of current PCSK9 therapies, which require injections and may affect long-term adherence.
Overall, these early-phase findings support further clinical development of laroprovstat as a first-in-class oral PCSK9 inhibitor. If confirmed in larger trials, it could offer a more convenient and widely accessible option for intensive lipid lowering and cardiovascular risk reduction.
Reference:
https://doi.org/10.1161/CIRCULATIONAHA.125.075973
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