fbpx

The Antibody That Could Eliminate Heart Disease: PCKS9 Inhibitor.

[additional-authors]
August 17, 2015

Recently, the FDA approved a new cholesterol lowering drug, alirocumab.  Known as Praluent, the injectable drug significantly lowers LDL cholesterol in people with familial hypercholesterolemia, or those with a history of heart disease who can’t reduce their LDL levels enough with existing statin drugs. Another drug, evolocumab (Repatha) received approval in Europe, and is awaiting evaluation by the FDA.  The injectable antibodies are the first in a new class of drugs called PCSK9 inhibitors.

We all have a gene called proprotein convertase subtilisin/kexin type 9 (PCSK9) which directly affects the number of “bad cholesterol” low-density lipoprotein (LDL) receptors in the body. LDL receptors regulate the amount of circulating LDL cholesterol that enters the bloodstream. Most LDL receptors are found on the surface of the liver.  Whereas statins such as Crestor or Lipitor work by binding up cholesterol made in the liver, PCSK-9 inhibitors work by making the liver more efficient at getting rid of LDL.

The antibody was conceived through studying a French family who had exceptionally high levels of LDL and greater than average rates of heart disease. It was discovered that they had aberrations in PCSK9.  Jonathan Cohen and Helen Hobbs at the University of Texas, Southwestern Medical Center in Dallas wondered whether those with lower levels of PCSK9 would show the opposite effect of the French family and benefit from decreased levels of LDL in the blood.  The investigators were involved in a large heart disease study involving 15,000 participants, and decided to look for the PCSK9 mutations among their participants. They sequenced the genes of patients with the highest and lowest levels of LDL cholesterol and found 33 people whose LDL levels were about 40% lower than average and who shared mutations that silenced PCSK9. Effectively, these patients benefited from LDL levels similar to those using statins!  The PCSK9 mutations associated with the lowest LDL appeared predominantly in African-American participants. Patients with one copy of the mutation showed an 88% lower risk of heart disease.

Evolocumab:  4,465 patients were followed for 11.1 months. The drug resulted in a 61% reduction in LDL, from 120 mg/dl to 48 mg/dl. Overall there was a similar rate of serious adverse events (7.5% in each group) but there was a small increase in neurocognitive events (0.9% versus 0.3%). These events did not appear to be related to the reduction in LDL.  Investigators cautioned the cardiovascular outcomes of the drug cannot be fully determined until the completion of the ongoing 27,500 patient FOURIER trial.

Alirocumab:  ODYSSEY studied 2,341 patients.  Treatment with injection of alirocumab every two weeks resulted in a 62% reduction compared to placebo. Similar number of adverse events in both groups but alirocumab was linked to an increase in some adverse events, including  injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitive events (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%).  In a 78 week post hoc analysis of major adverse cardiovascular events, investigators reported event rate of 1.7% in the alirocumab group versus 3.3% in the placebo group (HR 0.52, CI 0.31-0.90, p=0.02).

The wholesale cost of the drug will be about $1,200 per month. The cost for patients will depend on their insurance plan. In comparison, statins cost between $500 and $700 a year for name-brand versions and $48 a year for generics.

Neil Stone and Donald Lloyd-Jones, both of whom served as co-authors of the recent cholesterol guidelines, write in an editorial that the reduction in cardiovascular events with both drugs ”whet our appetites for further results that show cardiovascular benefit and documented safety.”  They express hope that, like statins, the beneficial effect will continue to grow over time.  But, they state, “It would be premature to endorse these drugs for widespread use before the ongoing randomized trials… are available.”

For now, the antibodies should only be prescribed to people with familial hypercholesterolemia, or those who have failed to reduce their LDL levels sufficiently using statins. For many, the new drugs will be used in combination with statins and a heart-healthy diet. There is anticipation among the medical community that patients outside of these groups, who have family histories of heart disease or other risk factors, such as hypertension or diabetes, will start asking about the medications. For them, doctors will have to weigh how well they are doing on statins before considering adding a PCSK9 inhibitor. 

Did you enjoy this article?
You'll love our roundtable.

Editor's Picks

Latest Articles

Print Issue: Got College? | Mar 29, 2024

With the alarming rise in antisemitism across many college campuses, choosing where to apply has become more complicated for Jewish high school seniors. Some are even looking at Israel.

More news and opinions than at a
Shabbat dinner, right in your inbox.

More news and opinions than at a Shabbat dinner, right in your inbox.

More news and opinions than at a Shabbat dinner, right in your inbox.