High Hopes for Inclisiran. Will the Third Time be the Charm for PCSK9 Inhibition?

Cholesterol is one of the primary causal risk factors for developing atherosclerotic cardiovascular disease (ASCVD) and one of seven critical metrics the American Heart Association (AHA) has used to define cardiovascular health in adults and children, according to AHA’s Heart Disease and Stroke Statistics - 2020 Update.  

“High cholesterol is of significance because it can increase one’s risk of ... heart attack or stroke, especially in patients with other risk factors, such as smoking, diabetes, hypertension and/or a family history of heart disease,” says David Calabrese, RPh, M.H.P., senior vice president and chief pharmacy officer at OptumRx and a member of the Managed Healthcare Executive® editorial advisory board. 

Despite a variety of available treatment options, some patients fail to respond to common treatments, notes Calabrese, so alternatives must be considered. 

Hyperlipidemia’s consequences for American health and healthcare are comparable to those from hypertension, says Elliot Marino, Pharm.D., BCPS, a CompleteRx pharmacist in Olean, New York. “Patients need to be tested regularly, and the impact on their health may not be noticed for decades, making it very difficult to realize benefits to treatment,” says Marino.

Statins are, of course, the front-line therapy for hyperlipidemia. Repatha (evolocumab, Amgen) and Praluent (alirocumab, Sanofi and Regeneron) are currently the only FDA-approved medications in a relatively new drug class know as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. PCSK9 is a protein that binds to and prevents LDL receptors in the liver from clearing circulating LDL cholesterol. PCSK9 inhibitors prevent this binding, thereby increasing the number of LDL receptors available to clear LDL from the bloodstream. 

But PCSK9 inhibitors have had a difficult time catching on. The 2018 cholesterol guidelines from the AHA, the American College of Cardiology and other groups position them as third-line therapies after statins and Zetia (ezetimibe). What’s more, the guidelines say the cost of PCSK9 inhibitors would need reduced by 70% to 85% to meet conventional cost-effectiveness standards. Amgen and Sanofi dropped the price of their products by about 60% in late 2018 to just under $6,000 per year, but use is still far below the companies’ expectations when they launched their PCSK9 inhibitors in 2015. Sanofi CEO Paul Hudson announced late last year that the company was leaving the U.S. cardiovascular market, so Regeneron is now marketing Praluent on its own. 

A study published last year in the Journal of the American Heart Association looked a lipid-lowering prescribing data from Jan. 1, 2015, to March 31, 2017, for 2.2 million people with dyslipidemia (which includes high triglycerides and high LDL) and about 940,000 with coronary artery or coronary heart disease. Just 362 (.02%) people with dyslipidemia had been prescribed a PCSK9 inhibitor, and 1,952 (.21%) people with coronary artery disease or coronary heart disease had been prescribed a PCSK9 inhibitor. 

A Few Newcomers

The bumpy ride of the PCSK9 inhibitors has, understandably, made drugmakers wary of jumping into the market for medications for hyperlipidemia, despite the many people affected. Still, there are a handful of newcomers. Nexletol (bempedoic acid, Esperion) was approved by the FDA in February 2020 as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional lowering of LDL. Nexletol is a first-in-class ATP citrate lyase (ACL) inhibitor that lowers LDL levels by inhibiting cholesterol synthesis in the liver. Studies show that compared to placebo, Nexletol reduced LDL levels by an average of 18% when used with moderate or high intensity statins. 

Evinacumab (Regeneron) is an angiopoietin-like 3 protein (ANGPTL3) antagonist currently being investigated to treat homozygous familial hypercholesterolemia. ANGPTL3 acts as an inhibitor of lipoprotein lipase and endothelial lipase and appears to play a central role in lipoprotein metabolism. In a phase 3 trial, evinacumab resulted in a 49% reduction in cholesterol compared to placebo. 

Inclisiran (Novartis) may be the most intriguing candidate because like Repatha and Praluent, it is a PCSK9 inhibitor - although it works by another mechanism, RNA interference, that keeps PCSK9 from being made in the liver. Results published in the April 16, 2020, issue of the New England Journal of Medicine show that the new drug lowered LDL levels by about 50% in patients who still have high cholesterol despite taking statin therapy at the highest tolerated dose. Novartis has submitted inclisiran for FDA approval. If approved and launched, which seems likely, it will have one major advantage over Repatha and Praluent: Inclisiran only needs to be injected twice a year to be effective, whereas Repatha and Praluent need to be injected at least once a month. On the plus side for Repatha and Praluent, patients can inject themselves; a clinician needs to inject inclisiran.

“Given that there are several existing treatments for high cholesterol on the market today, including several oral generic statins with extensive outcomes data, these new products are likely to be used as second- or third-line agents in patients who have failed to achieve optimal benefit or have contraindications or intolerances to first-line therapy,” says Calabrese. 

One thing to watch for is research showing that these new agents  influence cardiovascular disease - that they treat the disease and not just a number. 

“Cardiovascular outcomes trials typically take years to complete but will significantly impact how these drugs are used in clinical practice down the road,” says Calabrese.   

Erin Johanek, Pharm.D., is a pharmacist at Southwest General Health Center in Middleburg Heights, Ohio.