Merck's IMPROVE-IT bolsters case for PCSK9 inhibitors, but sets bar for outcomes

The long-awaited results from the IMPROVE-IT cardiovascular outcomes trial have been hailed as opening the gates for next-generation cholesterol drugs to gain approval on the basis of LDL reductions alone. That may be true. But the results also set a bar for CV outcomes that newcomers will have to beat to keep payers from limiting access to patients who don't do well on inexpensive current therapies.

The most advanced players, which have PCSK9 inhibitors in registration, already have outcomes studies under way, but there is likely to be an 18-month gap between approval and availability of the study results.

The reliability of LDL-C lowering as a surrogate endpoint came into question when several trials combining statins with other agents that also lowered LDL failed to show additional cardiovascular benefit. These results led to speculation about whether it is possible to improve CV outcomes by any means of reducing LDL apart from statins themselves.

Data from the IMPROVE-IT trial of Merck & Co. Inc.'s Zetia ezetimibe presented at the American Heart Association meeting last week confirmed that a non-statin that lowers LDL, when added to statin therapy, can further improve cardiovascular outcomes. By extension, IMPROVE-IT demonstrated that LDL lowering may be an appropriate surrogate endpoint for non-statins.

Zetia is a cholesterol absorption inhibitor that inhibits the Niemann-Pick C1-like protein (NPC1L1). Adding it to simvastatin met the primary composite endpoint by significantly reducing the risk of cardiovascular events by 6.4% compared to simvastatin alone in the intent-to-treat population.

That number increased to 7.6% for the on-treatment population, for whom the incremental CV risk reduction per absolute amount of LDL lowered approached that seen in previous statin trials.

Doctors who spoke to BioCentury said IMPROVE-IT made them more likely to use these agents before CV

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