Statins have been the first-line drugs for lowering cholesterol since the late 1980s. According to the American Heart Association, they have been shown to prevent repeat heart attacks in individuals who have already experienced one as well as first heart attacks in a wide range of at-risk individuals. In about 1 in 5 individuals, however, a statin is not sufficient to lower cholesterol to target levels. Additionally, some people cannot tolerate a statin because of side effects like muscle pain, liver damage, or the development of diabetes.
Proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors are monoclonal antibodies that target and inactivate a specific protein in the liver, dramatically reducing the amount of harmful LDL cholesterol circulating in the bloodstream. At present, two injectable fully human monoclonal antibody PCSK9 inhibitors have been approved by the US Food and Drug Administration—alirocumab (Praluent; Sanofi/Regeneron Pharmaceuticals) and evolocumab (Repatha; Amgen). Both of these agents are indicated as an adjunct to diet and maximally tolerated statin therapy for treatment of adults with heterozygous familial hypercholesterolemia (FH) or clinical atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of low-density lipoprotein (LDL) cholesterol.
Repatha and Praluent were both launched in 2015 with list prices of more than $14,000 per year. Not long after the products launched, the Institute for Clinical and Economic Review (ICER) declared that both PCSK9 inhibitors represented a “low” long-term value for patients at those prices. The group suggested the list prices should have been roughly half of what the manufacturers set. Rebates and discounts on the drugs have resulted in annual net prices below $14,000, but the drugs’ costs remain above ICER’s benchmarks.
Given the perception that PCSK9 inhibitors are relatively costly, payer acceptance of these drugs has been limited.
Barriers to Access
Jerome D Cohen, MD (St Louis University, St Louis, MO), and colleagues conducted a survey on behalf of the National Lipid Association to understand the barriers to PCSK9 inhibitor prescription approval. The study authors noted that such barriers can impede optimal cardiovascular (CV) risk management, and greater understanding was needed so that “healthcare systems and processes can be structured to deliver appropriately targeted, high-quality care to patients who will benefit from additional lipid-lowering therapy with these agents.”
According to their study results, published in the Journal of Clinical Lipidology (2017; doi:10.1016/j.jacl.2017.04.120), a key issue with PCSK9 inhibitor use comes when health care teams apply for approval. Beyond the drug not being on formulary, payers may apply LDL cholesterol thresholds to enable PCSK9 inhibitor use that are higher than the thresholds preferred by many health care teams, they reported.
Two additional studies exploring barriers to access for PCSK9 inhibitors and the potential consequences of denying coverage for high-risk patients were presented at the American College of Cardiology’s 67th Annual Scientific Session. The first study found only 35% of 3472 commercially insured and Medicare patients requesting access to a PSCK9 inhibitor were approved by their health plan in 2016. Among the 65% of patients who were denied access, the rate of acute CV events was higher than the rate in the overall patient population requesting a PCSK9 inhibitor. Acute CV events were defined as heart attack, ischemic stroke, hospitalization for unstable angina or coronary revascularizations.
“Based on the rejection and event rates observed in the 2016 data, we estimate that among appropriate patients prescribed PCSK9 inhibitors, over 110,000 acute cardiovascular events could have occurred in patients rejected access to a PCSK9 inhibitor,” said Seth Baum, MD, president of the American Society for Preventive Cardiology and lead study investigator. “A particular concern is that, among patients who are at an increased risk of subsequent acute cardiovascular events, two out of three were denied access to a PCSK9 inhibitor in 2016.”
Another study presented showed commercial payer utilization management criteria may fail to identify and prioritize patients at the greatest risk for further heart attacks, strokes, or with the greatest need for coronary revascularizations.
Are Payers Changing Their Tune?
A new report from Institute for Patient Access suggests that insurers may be opening up to the cholesterol-lowering drugs, however. They accepted nearly three-fourths of claims for the drugs in 2017, a marked improvement from prior years. Claims for PCSK9 inhibitors had an initial rejection rate of 46% and a final rejection rate of 26% market wide. The drugs fared even better with Medicare than commercial managed care organizations, with final rejection rates of 15% and 46%, respectively. Together, the data paint a rosier outlook for PCSK9 inhibitors. This shift may be the result of a few factors, namely steps by the drugs’ manufacturers to bring down costs, as well as new cardiovascular outcomes data lending stronger support to the use of the drugs.
To improve placement of their PCSK9 products on formulary lists and insurance plans, the drug companies have turned to value-based deals with insurers. As of early 2017, four payers had such contracts in place for Repatha and two for Praluent.
In May, Regeneron and Sanofi agreed with pharmacy benefit manager Express Scripts Holding Co to lower Praluent’s price to between $4500 and $8000 in exchange for easier access for patients covered by their largest plan.
In October, Amgen announced that it would lower the cost of Repatha by roughly 60%, with a new list price of $5850 per year. “Amgen is taking an important step forward to help payers be better positioned to provide breakthrough medicines and help people achieve better outcomes,” Express Scripts’ Chief Medical Officer Steve Miller commented in a statement.
In their Journal of Clinical Lipidology article, Dr Cohen and colleagues suggested that barriers to payer acceptance of PCSK9 inhibitors could only be addressed with additional evidence demonstrating to payers that lower LDL thresholds are clinically indicated and lead to improved outcomes.
Cardiologists have been wary of the pricey drugs as well. Shortly after the release of the two PCSK9 inhibitors, a survey by the Leerink brokerage firm found that cardiologists would be more likely to prescribe the drugs if clinical trials showed cardiovascular risks decrease by at least 20%.
The drugs’ manufacturers have since run additional clinical trials to measure the extent to which their medicines lower the risk of heart attacks and strokes.
Results from the Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk (FOURIER) trial demonstrated that addition of evolocumab to statin therapy significantly reduced CV event rates by 15% to 20% in patients with ASCVD (Marc S. Sabatine et al; N Engl J Med. 2017; 376:1713-1722).
Similarly, the newly published results from the ODYSSEY OUTCOMES trial showed that, among patients who had a previous acute coronary syndrome and who were receiving high-intensity statin therapy, the addition of alirocumab significantly reduced rates of recurrent ischemic cardiovascular events vs placebo (Gregory G. Schwartz et al; N Engl J Med. 2018;379:2097-2107).
In these two trials, aggressive LDL-C lowering with PCSK9 inhibitors was accompanied by a favorable safety profile.
These additional data are likely to not only change prescribing behavior but also influence the position taken by payers.