Early FDA Review Mostly Favorable for Alirocumab

Deborah Brauser

June 08, 2015

BETHESDA, MD — The US Food and Drug Administration (FDA) has noted that the proprotein convertase subtilisin kexin 9 (PCSK9) inhibitor alirocumab (Praluent, Sanofi/Regeneron) is both effective and well-tolerated in lowering LDL cholesterol in patients at risk for CV events, according to early briefing documents released by the Endocrinologic and Metabolic Drugs Advisory Committee[1]. However, the organization also noted several questions that should be discussed at an upcoming review panel.

Interestingly, this week will be unusually busy, as alirocumab goes before the panel tomorrow, followed by the PCSK9 inhibitor evolocumab (Repatha, Amgen) on Wednesday. Although official committee voting on each agent won't occur until after their respective all-day meetings, approval for alirocumab is favored in the documents—prior to information on hard outcomes.

The reviewers write that alirocumab has been shown in 10 phase 3 trials to provide significant reductions in LDL cholesterol in patients whose LDL cholesterol cannot be controlled with existing treatment. However, full results from the large ODYSSEY-Outcomes study, which has not been completed, are not expected to be released until 2018. In his introductory memo, FDA deputy director Dr James P Smith writes that the organization has used LDL cholesterol "as a surrogate for CV risk reduction for several lipid-altering drugs to support traditional approval" for more than 20 years.

However, "regardless of how confident we may be in the 'LDL hypothesis,' we must remember that LDL cholesterol remains a surrogate and not a clinical outcome that reflects how patients feel, function, or survive." Still, Smith noted that the FDA has emphasized its willingness to consider approval based on this measure. The main question could come down to which patients the drug should be indicated for: "What population(s), if any, does the LDL-cholesterol–lowering benefits of alirocumab exceed its risks to support approval?" asked Smith.

The manufacturer wrote in its application that the drug could be a treatment option for a wide mix of patients, including those with heterozygous familial hypercholesterolemia or who have high CV risk yet are not well controlled—either because they cannot tolerate statins or are already receiving a maximally tolerated dose.

Also scheduled for discussion during tomorrow's meeting is how to interpret safety data with respect to possible adverse events involving diabetes, liver, muscle, and neurocognition.

As reported last week by heartwire from Medscape, many clinicians have "guarded enthusiasm" when it comes to the new PCSK9 inhibitors. Although many said they hope both alirocumab and evolocumab will be approved, several also voiced concern that all of this may be premature before the release of findings on outcomes.

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