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

By now you've heard of statins, also known as HMG-CoA reductase inhibitors.
Statins are the cornerstone of treatment to help regulate cholesterol production.
Available since the late 1980's, statins include well-known blockbusters like
atorvastatin (Lipitor), simvastatin (Zocor), and rosuvastatin (Crestor). Statins
work so well because they inhibit an enzyme involved in the making of
cholesterol in the liver and boost the number of low density lipoprotein receptors
(LDL-R) to help clear the body of LDL ("bad cholesterol). However,
asresearchers have reported in Annals of Internal Medicine, a new class of
drugs may change the face of lowering LDL cholesterol.

What Are PCSK9 Inhibitors?

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

Several PCSK9 studies were published in the New England Journal of

Medicine(NEJM) in March 2015. The studies show that two
agents, evolocumab (Repatha) or alirocumab (Praluent), when combined with
statins, lower cholesterol better than the statin alone. After one year, those
patients who were taking both the PCSK9 inhibitor and the statin together had
LDL levels that were at least 60 percent lowerthan the group taking only statins.
LDL levels dropped dramatically. Larger studies are ongoing to evaluate PCSK9
inhibitors on the ability to lower outcomes like heart attack or stroke, but early
results suggest cardiovascular events could be lowered by half.

PCSK9 Inhibitors: Just the Basic Facts

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 selfadministration 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.
Clinical studies included ODYSSEY, an 18-month, phase 3 trial of 2,341 high-risk
patients with high cholesterol on statin therapy. LDL was reduced over 60 percent
after 24 weeks, and remained low over 78 weeks. Ongoing trials with Praluent
are assessing cardiovascular outcomes like heart attack or stroke.

Praluent Side Effects

Praluent was evaluated in five placebo-controlled trials involving 2,476 patients.
All patients had HeFH or were otherwise at high risk for heart attack or stroke,
and were taking maximally tolerated doses of a statin. Participants taking
Praluent had an LDL reduction from 36 to 59 percent compared to placebo. The
most common side effects have included nasopharyngitis (common cold),
injection site reactions, and influenza. Serious allergic reactions were also
reported. There are no known drug interactions with Praluent.
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.

Repatha (evolocumab) by Amgen

Repatha (evolocumab) was FDA-approved in August of 2015. Repatha injection
is indicated for use in addition to diet and maximally-tolerated statin therapy in
adult patients with heterozygous familial hypercholesterolemia (HeFH),
homozygous familial hypercholesterolemia (HoFH), or clinical atherosclerotic
cardiovascular disease (ASCVD), such as a heart attack or stroke, who require
additional lowering of LDL cholesterol. In Phase 3 clinical trials, Repatha lowered
LDL by roughly 60% across all study groups in 12 week and 52-week studies;

Repatha reduced LDL cholesterol levels by 61% (from a median of 120 mg/dL to
48 mg/dL over 12 weeks. In HoFH, Repatha reduced LDL by 31%.

Side Effects with Repatha

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
The recommended dose of Repatha(evolocumab):

140 mg subcutaneously (abdomen, thigh, or upper arm) every two weeks

or 420 mg once monthly for primary hyperlipidemia with established clinical
atherosclerotic CVD or heterozygous familial hypercholesterolemia (HeFH).

For homozygous familial hypercholesterolemia (HoFH), the approved dose

is 420 mg subcutaneously once monthly or 420 mg every two weeks.

The initial dose of Praluent (alirocumab):

75 mg subcutaneously once every two weeks; most patients will achieve

adequate LDL lowering with this dose.

LDL plasma levels should be measured within 4 to 8 weeks of initiating or

changing the dose and an increase in dosage to 150 mg can be initiated if LDL
lowering is inadequate.

If a dose is missed, administer the injection within 7 days from the missed dose
and then resume your original schedule. If the missed dose is not given within 7
days, you should wait until the next dose on the original schedule.

Ongoing PCSKi Questions

Analysts predict that Repatha and Praluent could each generate annual sales of
over $1 billion by 2020. Managed care experts suggest this new class of
drug could add considerable costs to statin therapy - which primarily exist in
generic - and very affordable form - now. However, treatment targets the highestrisk patients who cannot reach adequate LDL levels with statins.
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.

Bococizumab Studies Halted

In November 2016, Pfizer discontinued the global development of bococizumab,
their investigational PCSK inhibitor, as well as the two ongoing cardiovascular
outcome studies, SPIRE-1 and SPIRE-2.
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.

Alternate Mechanisms: PCSK9

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.

Lifestyle is Still an Important Adjunct

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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