What are the PCSK9 Inhibitors for Cholesterol Treatment?

PCSK9 inhibitors: A Newer Class for LDL Lowering

A newer class of drugs may change the face of lowering LDL cholesterol, especailly for hard-to-treat patients that don't fully respond to statins. These drugs are known as the Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors, and include:

• Praluent (evolocumab)
• Repatha (alirocumab)
• Leqvio (inclisiran)

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)
• rosuvastatin (Crestor)

Statins work so well because they block an enzyme involved in the production of cholesterol in the liver and boost the number of low density lipoprotein (LDL) receptors to help clear the body of LDL (also known as "bad cholesterol"). How do the new PCSK9 inhibitors work?

What are PCSK9 Inhibitors and How Do They Work?

The PCSK9 inhibitors are a class of injectable drugs approved in 2015 that have been shown to dramatically lower LDL cholesterol levels -- by up to 60% in some reports -- when combined with a statin.

Praluent and Repatha may be used alone (with diet) OR as an add-on drug (with drugs like a statin) plus diet. These 2 agents can reduce the risk of heart attack, stroke, and other heart complications in adults with heart disease.

Leqvio is only indicated by the FDA to be used in combination with a statin and diet at this time, and it is not known if it will lower the risk of cardiovascular morbidity and mortality.

Mechanism of Action

Although all three drugs inhibit a protein called PCSK9 (proprotein convertase subtilisin kexin 9), they work by different mechanisms.

• Repatha and Praluent are monoclonal antibodies that bind to PCSK9 in the liver and prevent it from binding to LDL receptors.
• Leqvio blocks the PCSK9 protein by interfering with the translation of PCSK9 messenger RNA. It inhibits the intracellular synthesis of PCSK9.
• It's important to block PCSK9 because it inactivates the needed receptors on the liver cell surface that transport LDL into the liver for metabolism (break down).
• Ultimately, these agents all have the same action, that is to free LDL receptors on liver cells to allow LDL to be removed from the blood. In short - by blocking PCSK9, more receptors are available to capture your "bad" cholesterol for break down and removal from the blood.

And, as we know, lower LDL is better for the heart, and can protect against heart disease, heart attacks and stroke in some cases.

Who Needs a PCSK9 Inhibitor?

About 1 in 5 patients on statins cannot lower their cholesterol adequately at all, sometimes due to a serious genetic defect called familial hypercholesterolemia (FH). In addition, some patients stop their statin treatment due to side effects, like intolerable or dangerous muscle aches, muscle or liver damage, or the development of type 2 diabetes.

The PCSK9 inhibitors Praleunt and Repatha are used:

• in combination with maximally tolerated doses of statins to further lower the hardest-to-treat elevated cholesterol levels for adult patients with heterozygous familial hypercholesterolemia (HeFH) or heart disease, who require additional lowering of LDL-cholesterol.
• as an adjunct to diet, alone or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe), for the treatment of adults with primary hyperlipidemia to reduce low-density lipoprotein cholesterol (LDL-C).
• for cardiovascular risk reduction, which means they may help you avoid a heart attack or stroke.
• in conjunction with other LDL-lowering agents when used for Homozygous Familial Hypercholesterolemia (HoFH), a dangerous and rare form of high LDL that is passed down through families.

Clinical Studies for PCSK9 Inhibitors

Clinical studies for Repatha (evolocumab) and Praluent (alirocumab) have shown that when these medicines are combined with maximally tolerated doses of statins (such as atorvastatin or rosuvastatin), they can lower LDL better than just using the statin alone.

After one year, those patients who were taking both the PCSK9 inhibitor and the statin together had LDL levels that were close to 60 percent lower than the group taking only statins. LDL levels dropped dramatically.

For example, in a study with almost 1,553 patients taking maximum dose of statins, Praluent 150 mg was given every 2 weeks and compared to patients using a placebo (inactive injection) every 2 weeks.

• After 24 weeks, the LDL cholesterol levels dropped by 58% more than the LDL levels for patients in the placebo group (also receiving statins).
• This was a statistically significant effect, meaning it did not occur just by chance.

In Repatha studies where patients received 140 mg every 2 week or placebo (in addition to statin treatment), LDL cholesterol was reduced by 71% compared to the placebo group.

• Repatha was also studied when given as a once a month dose of 420 mg and compared to a placebo, also given once a month. The LDL cholesterol levels dropped by 63% compared to placebo.

In the Phase 3 studies, Leqvio lowered LDL-C reduction up to 52% compared to a placebo (an inactive agent) in a 17 month timeframe.

• Over 80% of patients in the Leqvio group achieved the recommended LDL-C target of <70 mg/dL compared to 18% of patients treated with a placebo. It is not known if Leqvio can prevent heart attacks or strokes, but studies are ongoing for this use.

PCSK9 Inhibitors: Administration and Costs

• Repatha and Praluent are given by subcutaneous (under the skin) injection, via self-administration with a pen device or syringe, one or two times per month.
• Leqvio should be administered by a healthcare professional only, and is administered as a subcutaneous injection initially and at 3 months, then every 6 months thereafter.

Side effects: In general, PCSK9 inhibitors (Repatha and Praluent) have been well-tolerated, but the common cold, itching, flu, injection site reactions, and serious allergic reactions have been reported. Common side effects with Leqvio (≥ 3%) include: joint pain, urinary tract infection, diarrhea, chest cold, pain in the arms and legs, and shortness of breath.

Costs:

• The cash price for Praluent runs about $500 per month (coupon cash price without insurance) in the US, but this is variable based on the pharmacy you go to and your dose.
• The cash price for Repatha averages about $550 per month using a coupon.
• Leqvio costs about $3,400 cash price (using a discount coupon), but your doctor will administer the injection every 6 months.
• The prices in general are very high for what most people can afford without insurance. Check with the manufacturers of these medicines as you may be eligible for a CoPay Card that could save you money.
• Contact your insurance company or pharmacist to learn more about how pricing might affect you for a PCSK9 inhibitor. Ask if one is preferred on your insurance formulary.

Praluent (alirocumab) by Regeneron

In July 2015, alirocumab (Praluent) was the first PCSK9 inhibitor to receive an FDA-approval. Praluent is used:

• As an adjunct to diet, alone or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe), for the treatment of adults with primary hyperlipidemia (including heterozygous familial hypercholesterolemia, HeFH) to reduce low-density lipoprotein cholesterol (LDL-C).
• To reduce the risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease.
• Along with other LDL-lowering treatments in adults with a type of serious and rare high cholesterol called homozygous familial hypercholesterolemia (HoFH), who need additional lowering of LDL-C. HoFH is a genetic disease that can be inherited in families.

Clinical studies include ODYSSEY and ODYSSEY OUTCOMES.

• ODYSSEY was an 18-month, phase 3 trial of 2,341 high-risk patients with high cholesterol on statin therapy. LDL was reduced over 60% after 24 weeks, and remained low over 78 weeks.
• 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%).
• Full cardiovascular outcomes (the effect of Praluent on heart problems such as heart attacks, stroke, or death) have now been reported and updated in the label.

ODYSSEY OUTCOMES: Praluent Cardiovascular Outcomes

In April 2019 the FDA approved labeling for Praluent based on data from the ODYSSEY OUTCOMES trial, which was published in the New England Journal of Medicine in November 2018. Praluent is now approved to reduce the risk of myocardial infarction (heart attack), stroke, and unstable angina (chest discomfort caused by poor blood flow to the heart) requiring hospitalization in adults with established cardiovascular disease.

Results from the ODYSSEY OUTCOMES trial (Schwartz and colleagues) with 18,924 patients showed that among patients with a history of acute coronary syndrome 1 to 12 months earlier, the risk of recurrent ischemic cardiovascular events (such as angina, heart attack or stroke) was significantly lower among those who received alirocumab than among those who received placebo. Doses were adjusted to keep LDL levels at 25 to 50 mg per deciliter (mg/dL). About 90% of patients were on high-intensity statins prior to randomization. The mean LDL-C value at baseline was 92.4 mg/dL.

Patients who received Praluent in the trial experienced a 15% reduced risk for major CV events.

• Specifically, in patients receiving high-intensity statin therapy, plus either alirocumab or placebo, the primary end point was a composite of time to death from coronary heart disease, nonfatal myocardial infarction (nonfatal heart attack), fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization.
• After a median follow-up of 2.8 years, the primary end point occurred in 903 patients (9.5%) in the alirocumab group and in 1052 patients (11.1%) in the placebo group, a statistically significant effect (p=0.0003). A greater effect was seen in patients with higher LDL (>100 mg/dL) at baseline.
• Secondary end points of death from the individual components of the composite primary endpoint, or all-cause mortality, were not statistically significant.
• Side effects were similar in the two groups, except more local injection-site reactions were seen in the alirocumab group (3.8%) compared to the placebo group (2.1%).

Praluent Side Effects

Praluent (alirocumab) was evaluated in five placebo-controlled trials involving 2,476 patients for the original FDA approval. 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% compared to placebo.

The most common side effects (occuring in at least 5% of patient) have included:

• nasopharyngitis (common cold)
• injection site reactions (erythema/redness, itching, swelling, pain/tenderness)
• influenza (flu-like symptoms).

Allergic reactions (itching, rash, hives) were also reported in 8.6% of patients. Serious allergic reactions, including hypersensitivity vasculitis and hypersensitivity reactions requiring hospitalization, have also been seen.

In patients with established heart disease, common side effects include chest pain, the common cold and muscle aches.

For a full list of side effects with Praluent, visit here.

Repatha (evolocumab) by Amgen

Repatha (evolocumab) was first FDA-approved in August of 2015.

Repatha injection is used:

• In adults with cardiovascular (heart) disease to reduce the risk of heart attack, stroke and the need for certain types of heart surgery (coronary revascularization).
• With a cholesterol-lowering diet alone, or with diet and other cholesterol-lowering therapies (such as statins), to treat high blood cholesterol levels known as primary hyperlipidemia, including Heterozygous Familial Hypercholesterolemia (HeFH) and to reduce low density lipoprotein (LDL-C), also known as "bad cholesterol".
• In addition to diet and other LDL-lowering therapies in children 10 years and older with HeFH, to reduce LDL-C.
• In addition to other LDL-lowering therapies in adults and children 10 years of age and older with Homozygous Familial Hypercholesterolemia (HoFH), to reduce LDL-C.

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%.

Cardiovascular Outcomes with Repatha

In December 2017, the FDA approved additional product labeling for Repatha (evolocumab) as the first PCSK9 inhibitor to prevent heart attacks, strokes and coronary revascularizations in adults with established cardiovascular disease.

In the Repatha cardiovascular outcomes study (FOURIER) 27,564 patients who had stable atherosclerotic cardiovascular disease (ASCVD) on statin therapy were evaluated.

Patients who received Repatha had their LCL-C lowered by 59% to a median of 30 mg/dL.

• After a median of 26 months of patient follow-up, Repatha significantly reduced the primary composite endpoint of cardiovascular (heart) death, myocardial infarction (heart attack), stroke, hospitalization for angina (severe chest pain), or revascularization (9.8% of patients in the Repatha group compared to 11.3% of the placebo group).
• The secondary endpoint of time to first occurrence of cardiovascular death, myocardial infarction, or stroke was also significantly reduced from 7.4% to 5.9%.

Repatha significantly reduced the risk of heart attack (27%), stroke (21%), and coronary revascularization (22%).

Side Effects with Repatha

Common side effects with Repatha in clinical trials include:

• symptoms of the common cold (nasopharyngitis)
• upper respiratory tract infections
• flu-like symptoms or influenza
• back pain
• injection site reactions (include: redness, pain, bruising)

In the cardiovascular outcomes trials, diabetes mellitus was also reported as a side effect.

To see a detailed list of side effects visit here.

PCSK9 Dosing

Both Repatha and Praluent are given as subcutaneous injections under the skin. You can be taught to do this so you can administer doses at home.

Repatha: The recommended dose of Repatha (evolocumab):

• 140 mg subcutaneously (under the skin) in the abdomen, thigh, or upper arm every two weeks OR 420 mg once monthly for adults with established cardiovascular disease or primary hyperlipidemia (including heterozygous familial hypercholesterolemia).
• In children 10 years of age and older with HeFH, give either 140 mg every 2 weeks OR 420 mg once monthly administered subcutaneously.
• For homozygous familial hypercholesterolemia (HoFH) in adults and children 10 years and older, the initial recommended dose is 420 mg injected subcutaneously once monthly. The dosage can be increased to 420 mg every 2 weeks if a clinically meaningful response is not achieved in 12 weeks. Patients on lipid apheresis may initiate treatment with 420 mg every 2 weeks to correspond with their apheresis schedule. Administer Repatha after the apheresis session is complete.
• For the 420 mg dose, Repatha can be given over 5 minutes by using the on-body infusor with prefilled cartridge (Pushtronex System) OR by giving 3 injections consecutively within 30 minutes using either the prefilled autoinjector or the prefilled syringe.

Praluent: The initial adult dose of Praluent (alirocumab) in patients with established cardiovascular disease or with primary hyperlipidemia, including HeFH :

• 75 mg subcutaneously once every two weeks OR or 300 mg subcutaneously once every 4 weeks. For patients receiving Praluent 300 mg every 4 weeks, measure LDL-C just prior to the next scheduled dose, because LDL-C can vary between doses in some patients
• If the LDL-C response is inadequate, the dosage may be adjusted to 150 mg administered every 2 weeks.
• The recommended dose of Praluent in patients with HeFH undergoing LDL apheresis or HoFH is 150 mg once every 2 weeks. Praluent can be given without regard to timing of apheresis.
• Assess LDL-C when clinically appropriate. The LDL-lowering effect of Praluent may be measured as early as 4 weeks after initiation.

Leqvio (inclisiran): First-in-Class siRNA Oligonucelotide

Approved in Dec. 2021, Leqvio (inclisiran) is a small interfering ribonucleic acid (siRNA) oligonucelotide that inhibits liver synthesis of the protein PCSK9 (proprotein convertase subtilisin kexin type 9). It works by preventing the formation of a protein (PCSK9) that keeps blood cholesterol levels high.

• Leqvio is used in combination with diet and a statin (another type of cholesterol-lowering medicine) when the maximum dose of the statin does not lower cholesterol levels enough.
• It is used for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH), an inherited condition that causes high levels of LDL-C, and / or in those with known cardiovascular (heart) disease.
• Leqvio is manufactured by Novartis.

All Phase 3 studies were published in the New England Journal of Medicine. When studies were evaluated at 17 months, Leqvio showed that levels of LDL cholesterol were reduced by up to 52% when compared to people taking a placebo (an inactive treatment). Over 80% of people taking Leqvio reached LDL levels of < 70 mg/dL, the recommended study target. It is not known if Leqvio can prevent heart attacks or strokes, but this is under study in the Orion-4 cardiovascular outcomes trial.

Leqvio is given by a healthcare provider as a subcutaneous (under the skin) injection initially (the first dose), then once at 3 months, and then once every 6 months (twice a year) thereafter. It is injected into the abdomen, upper arm, or thigh only by a healthcare professional.

Common side effects (≥ 3%) include injection site reaction, joint pain, urinary tract infection, diarrhea, chest cold, pain in the arms and legs, and shortness of breath.

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, limit or stop electronic screen time one hour before bed
• If you take medications, adhere to your treatment plan and take your medication as directed.

If your cholesterol and LDL levels remains high, even with lifestyle changes, medications to improve your cholesterol might be added to help prevent heart disease and stroke. The statins, PCSK9 inhibitors, and other upcoming investigational agents may offer hope to millions trying to achieve their heart health goals.