Design and baseline data of AZURE-LDL, a phase 3 study assessing the effect of the oral PCSK9 inhibitor laroprovstat on LDL cholesterol in patients with, or at risk for, ASCVD

Background/Introduction It is well established that LDL cholesterol (LDLc) is causal for atherosclerotic cardiovascular disease (ASCVD) and that the magnitude of LDLc lowering with lipid-lowering therapy (LLT) is directly related to ASCVD risk reduction. However, many patients with or at risk for ASCVD events fail to achieve guideline-directed LDLc goals with conventional oral medication. The use of injectable PCSK9 inhibitors has been limited due to factors including access, cost and acceptability. Laroprovstat (LARO) is a novel oral PCSK9 inhibitor that was well-tolerated and achieved substantial LDLc reductions when added to statin therapy in a Phase 2 study, without food interactions. Purpose To present design and preliminary baseline data for the evaluation of efficacy and safety of LARO vs placebo added to background oral LLT for reducing LDLc in patients with a prior ASCVD event or at high risk for a first ASCVD event. Methods AZURE-LDL is a fully enrolled, Phase 3, randomised, double-blind, placebo-controlled trial in participants ≥18 years with either a prior ASCVD event and LDLc ≥1.4 mmol/L, or at high cardiovascular risk without a prior ASCVD event and with LDLc ≥1.8 mmol/L; all on maximally tolerated statin therapy, with or without ezetimibe or bempedoic acid (Figure). The primary outcome is the relative change from baseline in LDLc at 12 weeks. Participants are being followed for one year with secondary endpoints including relative change in LDLc from baseline at 52 weeks. Results Based on preliminary data, 3053 participants were randomised and dosed between June and December 2025. Baseline characteristics are shown in the Table. The cohort comprises participants with a prior ASCVD event (59.4%) or those at high risk of experiencing a first ASCVD event. Overall 95.3% received any statin, and 79.1% received high-intensity statin therapy. Ezetimibe and bempedoic acid were used by 28.1% and 2.4% of participants respectively. Mean baseline LDLc was 2.30 mmol/L despite maximally tolerated oral LLT. The trial is ongoing with final results anticipated in 2027. Conclusion(s) In AZURE-LDL, 3053 participants were randomised and dosed with LARO or placebo. Participants had either a prior ASCVD event or were at high risk for a first ASCVD event and had not achieved guideline-directed LDLc goals on conventional oral LLT. Baseline lipid values on maximally tolerated oral LLT underscore a large therapeutic gap. This trial will determine whether that gap can be addressed with oral combination therapy, including LARO as a safe, well-tolerated and highly effective PCSK9 inhibitor.