Regulators in the USA and Europe have given the green light to Sanofi and Regeneron's alirocumab, making it the first proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to be approved on both sides of the Atlantic. In the USA, the cholesterol-lowering drug is approved for use in patients with heterozygous familial hypercholesterolaemia and in patients with clinical atherosclerotic cardiovascular disease who require additional lowering of low-density lipoprotein (LDL) cholesterol. In the European Union (EU), the label explicitly includes statin-intolerant patients.

The European Medicines Agency (EMA) also recently approved Amgen's PCSK9-targeting antibody, evolocumab, for use in the EU. As Nature Reviews Drug Discovery went to press, analysts expected the US Food and Drug Administration (FDA) to approve evolocumab by the end of August.

Each antibody is predicted to earn over $US2 billion by 2020, according to consensus global sales forecasts from Thomson Reuters Cortellis. The drugs are also set to provide a proof of principle for high-volume use of antibodies in a chronic-disease market, although there is pushback at their cost (over $14,000 per year for alirocumab in the USA).

PCSK9 binds the LDL receptor on the surface of liver cells, resulting in reduced removal of LDL cholesterol from the blood. By blocking PCSK9, these receptors are free to clear LDL cholesterol from the blood, lowering LDL cholesterol levels. Work on the class began after researchers found a gain-of-function PCSK9 mutation that was associated with hypercholesterolaemia, in 2003. When they subsequently found a loss-of-function mutation that was associated with decreased LDL cholesterol levels and lower risk of coronary artery disease, interest increased. The relatively fast development of the class provides a compelling example of the benefits of genetic validation of drug targets (Nat. Rev. Drug Discov. 12, 581–594; 2013).

Pfizer's PCSK9 inhibitor bococizumab is in Phase III trials, with top-line results expected next year. Pfizer is also developing a small-molecule PCSK9 inhibitor, which it plans to advance into clinical trials later this year, and a vaccine against PCSK9, which it plans to advance into clinical trials next year.