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Feb 03, 2014
 |  BioCentury  |  Regulation

Lipid advice in Europe

Why companies will need EMA advice on CV requirements for lipid disorders

A lack of clarity about requirements for cardiovascular safety and outcomes data in updated EMA guidance means companies developing lipid-modulating therapies will need to seek individual advice from the European regulator as early as possible in development.

Although companies developing LDL-lowering molecules still can use LDL reduction as a primary endpoint, the new guidance does nothing to clear up ambiguity in 2004 guidelines about what the threshold is for ruling out a detrimental effect on CV morbidity and mortality.

For non-LDL-lowering therapies - such as compounds designed to lower triglycerides or raise HDL - the new guidance is more stringent in that it now requires companies to demonstrate a CV outcomes benefit.

Moreover, the agency says it will determine case-by-case whether those data are required before or after approval.

Cardiovascular outcomes data are not expected to be required for statins because there is enough evidence that they reduce CV events.

The guidance

Under EMA's 2004 guidance on the development of therapies for lipid disorders, a relative reduction in LDL was an acceptable surrogate primary endpoint for LDL-targeted therapies. But the guidance was less clear for therapies modifying lipids other than LDL.

The 2004 guidance stated: "Measurements of lipid disorders other than LDL-cholesterol such as changes in triglycerides and HDL-cholesterol may become primary efficacy measures, if considered relevant to the target population, provided that no detrimental effects on other lipid parameters are observed."

The updated guideline, published in January, reiterates that relative reduction in LDL is still the accepted primary endpoint for LDL-lowering therapies (see "Featured Links," A23).

LDL reduction endpoints thus should be sufficient for therapeutic classes like proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Three are in large Phase III programs: Amgen Inc.'s evolocumab; Pfizer Inc.'s bococizumab; and alirocumab from Regeneron Pharmaceuticals Inc. and Sanofi.

But the updated guidance appears to raise the bar for therapies that modify other lipids: "For medicinal products modifying parameters other than LDL-C,...

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