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Of Cholesterol Busters: PCSK9 Inhibitors: A New Class
Of Cholesterol Busters: PCSK9 Inhibitors: A New Class
of Cholesterol Busters
Medically reviewed on Jan 12, 2017 by L. Anderson, PharmD
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Flashback: A Review of Statins
The PCSK9 inhibitors (PSK9i) are a newer class of injectable drugs that have
been shown to dramatically lower LDL cholesterol levels, by up to 60% when
combined with a statin. PCSK9 inhibitors are monoclonal antibodies (MABs), a
type of biologic drug. They bind to and inactivate a protein in the liver called
proprotein convertase subtilisin kexin 9 (PCSK9). PCSK9 itself inactivates the
needed receptors on the liver cell surface that transport LDL into the liver for
metabolism (break down). Without these receptors, more LDL ("bad" cholesterol)
remains in the blood. So, by inactivating PCSK9 via inhibition, more receptors are
available to capture LDL for metabolism and removal from the blood. And, as we
know, lower LDL is better for the heart.
Who Needs a PCSK9 Inhibitor?
There are roughly 37 million adults in the U.S. whose high cholesterol is not
treated, with about 11 million who cannot reach their LDL cholesterol goals, even
though they have been on a first-line treatment like statins. In fact, about 1 in 5
patients on statins cannot lower their cholesterol adequately at all; some due to
serious genetic defects. In addition, some patients stop their statin treatment due
to side effects. PCSK9 inhibitors may be used alone or in combination with
statins to further lower the hardest-to-treat elevated cholesterol levels for patients
who cannot tolerate any statin drug.
Clinical Studies for PCSK9 Inhibitors
Here is a sampling of what we know so far with this new class of drugs. PCSK9
inhibitors are given by subcutaneous (under the skin) injection, via self-
administration with a pen device, one or two times per month. In general, PCSK9
inhibitors have been well-tolerated, but the common cold, itching, flu, injection
site reactions, and serious allergic reactions have been reported. Injection site
reactions are the most common reaction but infrequently lead to discontinuation
of treatment.
More studies of a larger population size are ongoing to fully define outcomes like
prevention of heart attack, stroke, and other cardiovascular disease. These drugs
are monoclonal antibodies (MABs), an expensive drug type, and cost roughly
$14,000 per year in the US. They are also approved in the European Union.
Praluent (alirocumab) by Sanofi/Regeneron
In July 2015, alirocumab (Praluent) by Sanofi and Regeneron was the first
PCSK9 inhibitor to receive an FDA-approval.
The incidence of pre-specified cardiac adverse events like heart attack or stroke
were lower in the alirocumab group (1.7%) compared to placebo (3.3%), but full
cardiovascular outcomes are not known yet.
In the OSLER-1 and OSLER-2 open-label studies, side effects that occurred
with Repatha at a rate of at least 1% included arthralgia (joint pain, 4.6%),
injection site reactions (4.3%), headache (3.6%), limb pain (3.3%), and fatigue
(2.8%). Injection site reactions rarely lead to discontinuation of PCSK9 inhibitors.
Neurocognitive effects like confusion were low (under 1%). Evolocumab was
stopped in 7.2% of 2976 patients. Very low levels of LDL did not appear to affect
rates of side effects. Other side effects include the common cold, upper
respiratory tract infections, and injection site reactions. No clinically important
drug interactions have been identified with Repatha.
PCSK9 Dosing
Some studies are looking at monotherapy with PCSK9 inhibitors, too. While the
levels of cholesterol lowering are dramatic, experts are quick to point out that
ongoing research will determine if ill-effects occur from such large LDL
reductions.
Pfizer stated that unexpected results occurred in looking at the outcomes of six
Phase III studies. Compared to current agents in this class, LDL lowering over
time with bococizumab was not as robust, and a higher level of immunogenicity
and a higher rate of injection-site reactions also occurred. Due to lack of value to
shareholders, especially in the currently marketplace, Pfizer decided to halt the
studies worldwide.
In addition to blocking the PCSK9 receptor to lower LDL, blocking the synthesis
of PCSK9 can lower LDL levels. Synthesis of PCSK9 requires mRNA. Phase I
dose-ranging studies have looked at degradation of the mRNA needed for
PCSK9 development with a compound called ALN-PCS (inclisiran) from Alnylam
Pharmaceuticals/The Medicines Company.
In a Phase I study published in the New England Journal of Medicine in early
2017, inclisiran (ALN-PCS) doses of 300 mg or more (in single or multiple doses)
significantly reduced levels of PCSK9 (~75%) and LDL cholesterol (~50%) for at
least 6 months. The most common adverse events were cough, musculoskeletal
pain, cold/runny nose, headache, back pain, and diarrhea. Further studies to
investigate effectiveness, safety and long-term use, and FDA-approval, will need
to be completed before clinical use.
Everyone should partake in a healthy lifestyle, whether they have high cholesterol
or not. We know you've heard this before, but it really is important:
Quit smoking
Eat a low fat, low salt diet
Exercise 30 to 40 minutes a day on most days of the week
Control your stress, learn to relax
If your cholesterol and LDL levels remains high, even with lifestyle
changes,medications to improve your cholesterol might be needed to help
prevent heart disease and stroke. The statins, PCSK9 inhibitors, and upcoming
investigational agents may offer hope to millions trying to achieve their
cardiovascular goals.
Finished: PCSK9 Inhibitors: A New Class of
Cholesterol Busters
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