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STAT

An MUSC blog
Keyword: ldl-c

photo fo pill bottle and paperworkThe FDA approved alirocumab (Praluent; Sanofi and Regeneron Pharmaceuticals) for patients with heterozygous familial hypercholesterolemia (HeFH) and for patients with clinical atherosclerotic cardiovascular disease, according to a press release from the FDA July 24.

HeFH is an inherited disease that causes high levels of low-density lipoprotein (LDL) cholesterol in patients. Alirocumab is designed to lower this “bad” cholesterol and is an injectable monoclonal antibody and is the first in its class of PCSK9 inhibitors.

"This new class of medications can significantly and effectively lower LDL cholesterol in very high-risk patients who could not otherwise achieve acceptable LDL cholesterol levels,” said MUSC Health cardiologist Pamela B. Morris, M.D., who is the principal investigator for multiple trials of PCSK9 inhibitors at MUSC. “Long-term outcomes trials in progress will determine if this dramatic reduction in LDL-C results in a reduction in cardiovascular events," says Morris. (To learn more about PCSK9 inhibitors, their mechanism of action, and clinical trials with these inhibitors at MUSC, click here.)

This new drug is most successful when combined with a healthy diet and maximum-tolerated statin therapy. It is not indicated, however, for statin-intolerant patients without established clinical atherosclerotic cardiovascular disease.

Clinical trials for this drug in children have not yet been performed, so it is only prescribed to patients 12 years of age and older.

The side effects of this drug include itching, swelling, pain, or bruising at the injection site, nasopharyngitis, and the flu. There have also been reported cases of allergic reactions to this drug, causing hypersensitivity vasculitis and hypersensitivity reactions requiring hospitalization.

It is expected the FDA will approve a second PCSK9 inhibitor called evolocumab (Repatha; Amgen) by August 27.

Statins can lower low-density lipoprotein cholesterol (LDL-C) levels by 25%-50%, but for many patients that is not enough to reach target levels, leaving them at residual risk for cardiovascular events. Some patients experience muscle aches when taking statins and must discontinue therapy or take a suboptimal dose. The search has been on for agents that can provide additional benefit in patients already taking statins or that can provide an alternative therapeutic option for those who do not tolerate them, but with largely disappointing results.

That is why the dramatic reduction in LDL-C levels achieved by proprotein convertase subtilisin–kexin type 9 (PC3K9) inhibitors are being met with such excitement. The interim results of the Osler-1 and -2 trials (NCT01439880 and NCT01854918) and the Odyssey Long Term trial (NCT01507831) were published online on March 15 in the New England Journal of Medicine (Osler: http://dx.doi.org/10.1056/NEJMoa1500858; Odyssey: http://dx.doi.org/10.1056/NEJMoa1501031). The results showed a more than 60% decrease in LDL-C levels (from a median of 119-120 mg/dL to 48 mg/dL; P<.001) and a significant decrease in cardiovascular events in patients taking the PC3K9 inhibitor evolocumab (Amgen; Osler) or alirocumab (Sanofi/Regeneron; Odyssey) in addition to standard therapy vs those receiving standard therapy alone. Those decreases were maintained over time.  The FDA has scheduled a target action date for evolocumab and alirocumab for August and July, respectively, and could approve both for certain indications as early as September of this year.

“PCSK9 inhibitors are the most exciting thing going on right now in the field of lipids. They are rocking the lipid world,” says MUSC Health cardiologist Pamela B. Morris, M.D., who is the principal investigator for the MUSC site of two trials of these inhibitors: GAUSS III, which is testing the efficacy of evolocumab in patients who have been verified as being statin intolerant, and FOURIER (NCT01764633), which is seeking to definitively establish whether the dramatic decreases in LDL-C seen with evolocumab indeed reduce the risk for cardiovascular events long term in patients already receiving statin therapy.

Side effects of PCSK9 inhibitors include  minor injection-site reactions and a few cases of memory deficit that were at first thought to due to excessively low LDL-C levels; the Osler interim results showed that this was not the case.

PCSK9 inhibitors are monoclonal antibodies that must be subcutaneously injected, and it is still being assessed whether better efficacy and patient adherence can be achieved with a smaller dose every two weeks or a larger dose once a month.

If approved, PCSK9 inhibitors will offer a promising new treatment option for patients who could not take statins or who did not reach target LDL-C levels despite taking the highest dose of statins they could tolerate.

How They Work: The body clears LDL-C via LDL receptors on the surface of liver cells, which bind to LDL-C and target it for degradation. Depending of the body’s needs, the LDL receptor is then itself degraded or is recycled (as many as 200 times) to clear more LDL-C. PCSK9 binds to the LDL-C/LDL receptor complex and targets the receptors for degradation rather than recycling. When PCSK9 levels are decreased, more LDL-C receptors are recycled to the cell surface to clear LDL-C. Indeed, patients with a loss-of-function PCSK9 mutation tend to have very low levels of LDL-C and very low rates of cardiovascular disease, an observation that helped spark interest in PCSK9 inhibitors. 

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