PCSK9 inhibitors: What you should know

Proprotein convertase subtilisin/kexin type 9, also known as PCSK9, provides instructions for the body to produce a protein that helps regulate the amount of cholesterol in the bloodstream and appears to control the number of LDL receptors, according to the National Institutes of Health.

Recently, inhibitors of PCSK9 have been developed as potential therapies to reduce LDL levels in patients with elevated cholesterol or inherited cholesterol disorders. Clinical trial data have documented significant LDL reductions in patients with hypercholesterolemia and familial hypercholesterolemia in combination with statins or administered alone, with minimal side effects.

Cardiology Today presents six things you should know about PCSK9 and PCSK9 inhibitors.

1. PCSK9 was discovered in 2003.

In 2003, researchers in France discovered PCSK9 while examining families with extremely high cholesterol and early heart attacks, according to the American Heart Association. Families that shared a mutation in PCSK9, which caused their bodies to produce an excess of the PCSK9 protein, had much less LDL cholesterol removed than people without the mutation.

2. PCSK9 in the bloodstream binds to LDL receptor, along with LDL, and does not destroy receptor.

In 2006, researchers found that PCSK9 in the bloodstream binds to the LDL receptor along with LDL without destroying the receptor. It then targets PCSK9 “like a traffic cop, directing the receptor for destruction, rather than recycling it,” according to Evan A. Stein, MD, PhD. Read more

3. PCSK9 inhibitors undergoing testing in clinical trials.

The various PCSK9 inhibitors undergoing testing in clinical trials include, evolocumab (Repatha, Amgen), alirocumab (Praluent, Sanofi/Regeneron Pharmaceuticals) and bococizumab (Pfizer). Additional candidates are in development. Read more

4. PCSK9 inhibitors reduce mortality and MI.

In a systemic review and meta-analysis including trials of PCSK9 inhibitors, the novel cholesterol-lowering agents were associated with reductions in mortality and MI.

Eliano Pio Navarese, MD, PhD, and colleagues additionally found that increases in serum kinase level were reduced in patients assigned PCSK9 antibodies and that serious adverse events did not increase with administration of PCSK9 antibodies. Read more

5. FDA advisory committee backs approval of evolocumab.

In June, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 15-0 that the benefits of evolocumab outweigh the risks in patients with homozygous familial hypercholesterolemia (HoFH). They additionally voted 11-4 that its benefits outweigh its risks in at least one patient population other than HoFH. Read more

6. FDA advisory committee recommends that alirocumab should be approved.

Also in June, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13-3 that the benefits of LDL lowering via alirocumab exceed its risk, and recommended approval for certain patient populations. All panel members who voted yes indicated that they would recommend approval for treatment of patients with heterozygous familial hypercholesterolemia. Several also said they would support approval for patients at high CV risk whose hypercholesterolemia has not been adequately controlled by maximally tolerated statin therapy. Read more