New Treatment on the Horizon – What is a PCSK9 Inhibitor?

Stories and insights from people living with Familial Hypercholesterolemia (FH)
New Treatment on the Horizon – What is a PCSK9 Inhibitor?
by Cat Davis Ahmed

This is a hopeful time in the field of Familial Hypercholesterolemia (FH). Developments in both treatment and in the effort to diagnose people with FH are coming together, creating a “virtuous circle” that I believe will save many lives and help the people I love – and the people you love – live longer, healthier lives.

It’s an exciting time to be a part of the Family Heart Foundation and I’d like to share some of that excitement with you (and invite you to join us).

One of the biggest developments is in a potential new class of treatments called PCSK9 inhibitors. These are new treatments that are in clinical trials right now. They hold a lot of promise for people with FH. They are hard to explain, but, I’ll try!

First let me say that statins and other lipid lowering treatments such as ezetimibe and bile acid sequestrants are the mainstay of FH treatment.  Statins, ezetimibe and bile acid sequestrants have been proven in clinical trials to reduce the incidence of cardiac events.  But, many people with FH need something more, either because we cannot reach an acceptable LDL level on existing treatments, or because we have side effects.  There are already new treatments for homozygous FH (mipomersen and lomitapide) and there is lipoprotein apheresis, but PCSK9 inhibitors, if approved, could be a great new addition to the FH treatment tool kit for both heterozygous and homozygous FH.

You may have heard about PCSK9 inhibitors – or maybe not.  They are a new class of drug and work differently from statins and other therapies.  Several companies have PCSK9 inhibitors in clinical trials right now – Amgen (evolocumab), Sanofi/Regeneron (alirocumab), and Pfizer (bococizumab).

Early results are very promising, both in terms of results and in terms of safety.  People on PCSK9 inhibitors in clinical trials have seen their LDL reduced by 40-60%, depending on various factors.  For some people with FH, that means getting their LDL down below 100 mg/dL for the first time in their lives.

The drug is taken by injection every 2 or every 4 weeks.  The most common side effects reported so far include nasopharyngitis (similar to a simple cold) and mild injection site reactions.  In clinical trials, PCSK9 inhibitors were usually added to statin alone or statin/ezetimibe therapy.  Some results are also available for statin intolerant patients.  PCSK9 inhibitors have shown promising results for both heterozygous and homozygous FH in lowering LDL levels, although the percentage of LDL reduction for homozygous FH was less than for heterozygous FH and depended on the form of the HoFH genetic mutation (whether or not the patient has any LDL receptor activity).  Outcome trials, demonstrating that the lower LDL levels lead to lower rates of cardiovascular disease, will take longer but are also underway.

None of these drugs has been approved for use by the Food and Drug Administration (FDA) yet, so they are not available unless you are in a clinical trial.  The FDA may decide based on LDL lowering effects alone, or they may wait to see the results of outcome trials to see if there is a real reduction in cardiac events (heart attacks, bypass or stenting, or death).  But, if they are approved based on their ability to lower LDL, they could become available as early as this summer.

PCSK9 (proprotein convertase subtilisin/kexin type 9) is an enzyme that affects the LDL receptors we all need to manage the LDL cholesterol produced by our liver and circulating in our bodies.  People with FH often do not start with enough healthy LDL receptors on the surface of their liver cells. We can’t afford to lose any along the way – they are what pulls LDL cholesterol out of our blood and back into our liver cells.  In addition, if the LDL cholesterol can get back into the liver, it tells the liver there is plenty of cholesterol and it can stop making more. So, if the LDL receptors aren’t there to do their job, more LDL continues to circulate in the blood, the liver doesn’t know to slow down or stop, and it keeps on making LDL cholesterol.

LDL receptors are normally recycled in the liver cells up to 100 times, and returned to the cell surface to collect more LDL from the blood, but they don’t last forever.  PCSK9 eventually attaches itself to each LDL receptor and causes it to be targeted for destruction.  This loss of LDL receptors leaves more LDL circulating in the blood.  A PCSK9 inhibitor is a drug that binds to the PCSK9, making it inactive, thereby reducing the amount of PCSK9 that is available to degrade the LDL receptors.  That leaves more LDL receptors available to do their job of removing excess LDL from the blood.

PCSK9 inhibitors were developed as a result of some interesting genetic discoveries.  In France, some families with very high LDL cholesterol and early heart disease were found to have a genetic mutation that caused higher PCSK9 levels.  On the other end of the spectrum, some individuals with extremely low LDL, and a low incidence of cardiac events, were found to have a genetic mutation that lowered their PCSK9 levels.  These two discoveries led scientists to focus on inhibiting the activity of this important enzyme to mimic the effect of the genetic mutation that resulted in low LDL levels.

Do you have a subject you would like me to write about? Please let me know by commenting here.  I will try to translate medical information into language we, as patients, can understand and use.

Cat Davis Ahmed is Director of Outreach for the Family Heart Foundation and a person living well with FH.