Familial hypercholesterolemia is characterized by extremely high total and LDL cholesterol levels, premature vascular disease, and tendon xanthomas. In most cases, this is due to a genetic mutation of the LDL receptor, rarely mutations of the apoprotein B100 or PCSK9 genes.
There are three pharmaceutical products available in the United States that reduce PCSK9 activity: alirocumab, evolocumab, and inclisiran.
These highly effective agents help the body pull excess cholesterol from the blood, but unlike statins, which are available as oral agents, PCSK9 inhibitors can only be administered as shots, creating barriers to their use.
Now, a new study from investigators at University Hospitals (UH) and Case Western Reserve University School of Medicine describes an orally administered small-molecule drug that reduces PCSK9 levels and lowers cholesterol in animal models by 70%. Published in Cell Reports, the findings represent a previously unrecognized strategy for managing cholesterol and may also impact cancer treatments.
“Cholesterol lowering is one of the most important therapies we have to prolong life and protect people from heart disease, which is still the number one cause of morbidity and mortality in the Western world,” said Jonathan S. Stamler, MD, senior author, President, Harrington Discovery Institute at UH, Robert S. and Sylvia K. Reitman Family Foundation Distinguished Professor of Cardiovascular Innovation, and Professor of Medicine and Biochemistry at UH and Case Western Reserve School of Medicine.
Central to cholesterol regulation are LDL receptors, which sit at the surface of liver cells and remove cholesterol from the blood, thereby lowering serum levels. PCSK9 in the bloodstream controls the number of LDL receptors by marking them for degradation. Therefore, agents that inhibit PCSK9 increase the number of LDL receptors that remove cholesterol.
Nitric oxide is a molecule that is known to prevent heart attacks by dilating blood vessels. In the new study, Stamler and colleagues show that nitric oxide can also target and inhibit PCSK9, thus lowering cholesterol. They identify a small molecule drug that functions to increase nitric oxide inactivation of PCSK9. Mice treated with the drug display a 70% reduction in LDL “bad” cholesterol.
Beyond cholesterol to cancer
In addition to impacting the field of cholesterol metabolism, the findings may impact patients with cancer, as emerging evidence suggests targeting PCSK9 can improve the efficacy of cancer immunotherapies.
“PCSK9 not only targets LDL receptors for degradation, it also mediates the degradation of MHC 1 on lymphocytes, which is used for recognition of cancer cells,” said Stamler. “PCSK9 is effectively preventing your lymphocytes from recognizing cancer cells. So, if you inhibit PCSK9, you can boost the body’s cancer surveillance. There may be an opportunity one day to apply these new drugs to that need.”
In the United States, there are currently two FDA-approved monoclonal antibodies that inhibit the action of PCSK9: alirocumab and evolocumab. Recently the European Union and FDA have approved inclisiran a small interfering mRNA that inhibits the intracellular synthesis of PCSK9.
FDA has approved alirocumab for adults with an established or high risk of cardiovascular disease and adults with familial hypercholesterolemia.
- To reduce the risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease.
- As an adjunct to diet, alone or in combination with other LDL-C lowering therapies, for treating adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia, to reduce LDL C.
- As an adjunct to diet and other LDL-C lowering therapies in adults with homozygous familial hypercholesterolemia to reduce LDL-C.
FDA has approved evolocumab for adults with an established or high risk of cardiovascular disease and adults and pediatric patients older than 10 years of age with familial hypercholesterolemia.
- To reduce the risk of myocardial infarction, stroke, and coronary revascularization in adults with established cardiovascular disease.
- As an adjunct to diet, alone or combined with other LDL-C lowering therapies for treating adults with primary hyperlipidemia including heterozygous familial hypercholesterolemia to reduce LDL-C.
- As an adjunct to diet and other LDL-C-lowering therapies in pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia, to reduce LDL-C
- As an adjunct to other LDL-C-lowering therapies in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia, to reduce LDL-C
FDA has approved inclisiran for adults
- As an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia who require additional lowering of LDL-C
- As an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-C.
Mechanism of Action
Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as an important regulator of cholesterol metabolism. Increased activity is associated with higher LDL cholesterol levels, while certain gain of function mutations cause autosomal dominant familial hypercholesterolemia with very high cholesterol levels, premature atherosclerotic vascular disease, and the development of tendon xanthomas. Those with reduced PCSK9 activity, whether due to genetic polymorphism or administration of monoclonal antibodies to PCSK9, have lower cholesterol levels and a reduced risk of cardiovascular disease.
Normal Cholesterol Metabolism
LDL cholesterol is normally cleared from the circulation as apoprotein B100 on the surface of LDL binds to LDL receptors on hepatic and extrahepatic tissues. LDL bound to its receptors undergoes a process of endocytosis. The endocytic vesicle fuses with lysosomes, increasing the intracellular concentration of free cholesterol. As the intracellular concentration of cholesterol increases, three events occur.
- Decrease activity of HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis
- Activation of ACAT, an enzyme that increases the storage of cholesterol as a cholesterol ester
- Reduced expression of LDL receptors on the cell surface
In this highly integrated system, as the cell takes up more cholesterol by this normal LDL-receptor pathway, de novo production of cholesterol decreases, and less is taken up by the LDL receptors. When LDL levels are particularly high or undergo modification, such as glycation or oxidation, they are more apt to be taken up by the scavenger pathway on endothelial cells, leading to the development of atherosclerotic plaques and vascular disease.
An important concept to recognize is that LDL receptors continually recycle back to the cell surface, where they can bind and clear more LDL cholesterol. PCSK9, a product of hepatocytes, is secreted into the plasma, where it binds to the LDL receptors facilitating lysosomal degradation of LDL receptors. Thus, PCSK9 reduces the expression of LDL receptors on the cell membrane, thereby decreasing the clearance of LDL cholesterol.
Statins decrease HMG-CoA reductase activity, reducing cholesterol synthesis. Reduced intracellular cholesterol leads to increased recycling and the expression of LDL receptors on the cell surface. This, in turn, allows for increased clearance of LDL cholesterol by this non-atherogenic receptor-mediated pathway, leaving less LDL to be taken up by the scavenger pathway. However, statins also increase the activity of PCSK9. While statins effectively decrease cholesterol levels, their efficacy is diminished by this increase in PCSK9 activity.
Familial hypercholesterolemia is characterized by extremely high total and LDL cholesterol levels, premature vascular disease, and tendon xanthomas. In most cases, it is due to a genetic mutation of the LDL receptor, rarely a mutation of the apoprotein B100 gene. In 2003, researchers found a family in France with the familial hypercholesterolemia phenotype without an identifiable mutation of the LDL receptor or apoprotein B100. Affected family members were discovered to have a gain of function mutation of a serine protease, proprotein convertase subtilisin/kexin type 9 (PCSK9). Transgenic mice overexpressing PCSK9 have reduced LDL-R function and elevated LDL cholesterol, while PCSK9 knockout mice have increased LDL-R activity and low LDL cholesterol levels. A longitudinal epidemiologic study found subjects with loss of function mutations in PCSK9 had a modest reduction in LDL cholesterol but a more significant decrease in coronary heart disease.
Understanding these basic principles of cholesterol metabolism led to the hypothesis that measures to reduce PCSK9 activity would lower LDL cholesterol levels and possibly reduce the risk of cardiovascular disease. Three pharmaceutical products are available in the United States that reduce PCSK9 activity: alirocumab, evolocumab, and inclisiran. Alirocumab and evolocumab are fully-humanized monoclonal antibodies injected subcutaneously at intervals of every 2 to 4 weeks that are highly effective in lowering total and LDL cholesterol. Whether used as monotherapy or in combination with a statin, they typically reduce LDL cholesterol levels by 50% to 60%. The effect is sustained as long as treatment continues. Inclisiran is a small interfering mRNA that inhibits the intracellular synthesis of PCSK9. When administered to patients on maximally tolerated statin inclisiran reduces LDL cholesterol by 50%.
- Supplied in 75 mg or 150 mg single-dose prefilled pen or syringe.
- The recommended starting dose is 75 mg once every two weeks, administered subcutaneously.
- An alternative starting dose is 300 mg once every four weeks.
- If the LDL-C response is inadequate, the dosage may be adjusted to the maximum dosage of 150 mg administered every two weeks.
- There is currently no pediatric dosing for this drug.
- Supplied as a 140 mg/mL single-use prefilled syringe or autoinjector and 420 mg/3.5 mL solution in a single-use infusor with a prefilled cartridge.
- For adults, the dosing is 140 mg every two weeks or 420 mg once monthly administered subcutaneously.
- 420 mg dose can be administered over 5 minutes using the single-use infusor or by giving three 140 mg injections consecutively within 30 minutes.
- For children 10 years of age and older with heterozygous familial hypercholesterolemia, the dosing is 140 mg subcutaneously every two weeks or 420 mg subcutaneously once a month.
- For adults and children, 10 years of age and older with homozygous familial hypercholesterolemia the dosing is 420 mg subcutaneously once a month but can be increased to 420 mg every 2 weeks if a clinically meaningful response is not achieved in 12 weeks.
- Supplied in 284mg/1.5 mL prefilled syringe.
- The recommended dose is 284 mg subcutaneous injection initially, again at 3 months, and then every 6 months.
No dose adjustment is necessary for patients with mild or moderately impaired hepatic or renal function. For both alirocumab, evolocumab, and inclisiran no data are available in patients with severe hepatic. For alirocumab, no data are available in patients with severe renal impairment, and for inclisiran no data in those with end-stage renal disease.
- Decreases LDL cholesterol by 45 to 70%
- Decreases apoprotein B by 40 to 50%
- Decreases lipoprotein (a) by 30 to 40%
- Decreases triglyceride by 8 to 10%
- Increases HDL-cholesterol by 8 to 10%
- Increases apoprotein A1 by 4 to 5%
Both short and long-term studies have shown a significant reduction in cardiovascular events with both alirocumab and evolocumab.
Cardiovascular outcomes trials for inclisiran are currently being conducted but at the present time, there are no published results.
- Intravascular ultrasound evidence of plaque regression in patients on PCSK9 inhibitors (GLAGOV study).
- Evolocumab versus placebo x 76 weeks:
- Decreased plaque volume and plaque regression in a more significant percentage of treated subjects than with placebo
- Evolocumab versus placebo x 76 weeks:
- FOURIER (evolocumab): Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk.
- Studied 27,564 subjects ages greater than or equal to 40 to less than or equal to 85 with clinically evident cardiovascular disease at high risk for a recurrent event with LDL-C greater than or equal to 70 mg/dL or non-HDL-C greater than or equal to 100 mg/dL and triglycerides less than or equal to 400 mg/dL
- Fifteen percent reduction in the primary endpoint, composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization, hazard ratio, 0.85; 95% CI, 0.79 to 0.92
- Twenty percent reduction in the secondary endpoint of cardiovascular death, MI, or stroke, hazard ratio, 0.80; 95% CI, 0.73 to 0.88
- ODYSSEY (alirocumab): Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab.
- Studied 18,924 subjects 40 years of age or older, hospitalized with an acute coronary syndrome 1 to 12 months before randomization, and had an LDL-C of at least 70 mg/dL, a non-HDL-C of at least 100 mg/dL, or an apolipoprotein B level of at least 80 mg/dL.
- Fifteen percent reduction in the primary endpoint, composite of death from coronary heart disease, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization, hazard ratio, 0.85; 95% CI, 0.78 to 0.93
- Fifteen percent reduction in the secondary endpoint, any coronary heart disease event, major coronary heart disease events, any cardiovascular event, and a composite of death from any cause, nonfatal myocardial infarction, or nonfatal ischemic stroke, hazard ratio, 0.85; 95% CI, 0.73 to 0.98
- The absolute benefit was greater among patients with a baseline LDL level greater than or equal to 100 mg/dL.
- Expensive: Monthly cost based on the Red Book wholesale acquisition cost: alirocumab and Evolocumab $450 – $500; inclisiran $6,500
- Requires prior authorization
- Generally recommended for patients with established or at high risk for cardiovascular disease who cannot achieve adequate lowering of LDL cholesterol with maximally tolerated statin ± ezetimibe or who are statin-intolerant
The American College of Cardiology, American Heart Association, and the National Lipid Association 2018 published guidelines on the use of PCSK9 inhibitors in adults
PCSK9 inhibitors are recommended for the following groups:
- In patients with cardiovascular disease at very high risk whose LDL-C level remains ≥70 mg/dL (≥1.8 mmol/L) on a maximally tolerated statin and ezetimibe therapy, adding a PCSK9 inhibitor is reasonable.
- In patients with severe primary hypercholesterolemia (LDL-C level ≥190 mg/dL [≥4.9 mmol/L]), without calculating 10-year ASCVD risk, if the LDL-C level on statin plus ezetimibe remains ≥100 mg/dL (≥2.6 mmol/L) and the patient has multiple factors that increase subsequent risk of ASCVD events, a PCSK9 inhibitor may be considered.
- In patients 30 to 75 years of age with heterozygous FH and an LDL-C level of 100 mg/dL or higher (≥2.6 mmol/L) while taking maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor may be a considered.
- In patients 40 to 75 years of age with a baseline LDL-C level of 220 mg/dL or higher (≥5.7 mmol/L) who achieve an on-treatment LDL-C level of 130 mg/dL or higher (≥3.4 mmol/L) while receiving maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor may be considered.
The specific details of these guidelines formulated by the ACC and NLA are cited in the references at the end of this article.
Treatment with small interfering RNAs (inclisiran) designed to target PCSK9 messenger RNA is under investigation in clinical trials as an alternative mechanism to reduce PCSK9 activity and LDL cholesterol levels.
Adverse side effects can include:
- Injection-site reactions, generally mild
- No increased signal for hepatotoxicity
- No increase in muscle-related complaints or increase in muscle enzymes compared to ezetimibe
- No clinically significant drug-drug interactions
- No increased risk of cognitive impairment
Alirocumab and evolocumab are contraindicated in patients with a history of hypersensitivity reactions to either of the agents. Caution is advised in giving evolocumab to patients with latex hypersensitivity. Neither of these agents currently has any significant drug-drug interactions listed. No contraindications are listed for inclisiran.
reference link : https://www.ncbi.nlm.nih.gov/books/NBK448100/
More information: Colin T. Stomberski et al, A multienzyme S-nitrosylation cascade regulates cholesterol homeostasis, Cell Reports (2022). DOI: 10.1016/j.celrep.2022.111538