Novel cholesterol lowering drugs: Can phase 2/3 clinical trial safety assessments predict cardiovascular event outcome trial efficacy?

Setting: Prior to a cardiovascular outcomes trial (CVOT), novel cholesterol-lowering therapies undergo phase 2/3 studies for their lipid and atherosclerotic effects and safety (non-CVOTs). Since the occurrence of major adverse cardiovascular events (MACE) is part of the safety assessment, nominal reductions or increases may be observed prior to definitive testing of the effect in a CVOT. Study objective: To investigate if the observed MACE treatment effect in non-CVOT lipid-lowering registration studies holds value in predicting the outcome in a CVOT trial, typically reported later than the initial lipid-lowering studies. Design/participants/interventions: We reviewed recent development programs for cholesterol-lowering drugs that had completed non-CVOT and CVOT studies. MACE data were compared for phase 2/3 non-CVOT versus pivotal CVOT results. Main outcome measures: Our primary outcome was a qualitative comparison for directionally concordant consistency in MACE risk ratio treatment effects (harm, neutrality, or benefit). Correlation analysis was also performed. Results: Seven drugs were reviewed in 3 cholesterol-lowering classes: CETP inhibitors, bempedoic acid, and PCSK9 inhibitors. Concordance in non-CVOT vs CVOT results was seen in 6 of 7 drugs. One drug (dalcetrapib) had a trend for benefit observed, albeit with very small numbers, in early development, but showed a neutral CVOT. There was a moderate correlation between the risk reductions or increases from the non-CVOTs and CVOTs: Conclusion: Within the limitations of the drugs studied and the variability in MACE definitions, there is value in the results of non-CVOTs to predict the CVOT outcome.