FDA Closely Watching Alirocumab for Adverse Neurocognitive Signal

March 10, 2014

PARIS, FRANCE and TARRYTOWN, NY – The US Food and Drug Administration (FDA) has asked Sanofi and Regeneron, the two companies who have partnered to develop alirocumab, the human monoclonal antibody for proprotein convertase subtilisin/kexin type 9 (PCSK9), to monitor patients taking the drug for possible neurocognitive adverse events[1].

The suggestion there might be a signal of harm with the LDL-cholesterol–lowering drug appears to be news to Sanofi and Regeneron. Dr Leonard Schleifer, the president and chief executive officer of Regeneron, told the Wall Street Journal they are not aware of any adverse clinical signal with alirocumab. In regulatory filings, the companies both stated they did not know of any adverse neurocognitive adverse outcomes associated with use of their drug.

News that the FDA was concerned over possible adverse outcomes with the PCSK9 inhibitor first emerged in annual reports published in February (Regeneron) and March (Sanofi). In their filings, Sanofi and Regeneron stated they had been informed the FDA is aware of neurocognitive adverse events in the PCSK9 class.

Both companies stated, however, they "do not know the circumstances under which the FDA became aware of these adverse events or whether these adverse events were observed with a drug candidate tested as monotherapy or in combination with a statin or other cholesterol-lowering agent."

Sanofi/Regeneron have been asked by the FDA to study the potential for cognitive harm in long-term phase 3 trials, including ODYSSEY-OUTCOMES , their large-scale study of alirocumab in patients with acute coronary syndrome (ACS).

In this study, which will include approximately 18 000 ACS patients, alirocumab will be compared with evidence-based medical therapy to determine whether alirocumab can further reduce the risk of cardiovascular events, including coronary heart disease death, MI, stroke, and coronary revascularization.

If there is the detection of an adverse cognitive signal or any signal of adverse clinical outcomes, "the further development of alirocumab may be delayed or fail or its commercial value diminished, which could severely harm our future prospects," the companies state in their annual reports.

Monoclonal antibodies such as alirocumab are a busy research area, with several pharmaceutical companies developing drugs. Pfizer and Amgen are also working on PCSK9 inhibitors, known as bococizumab and evolocumab, respectively, which are in various stages of development.

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