Breakthroughs in Cholesterol Treatment

The Centers for Disease Control and Prevention report that 73.5 million adults in the United States have high low-density lipoprotein cholesterol (LDL-C), with fewer than 1 in 3 adults having the condition under control. Cholesterol is major risk factor for cardiovascular disease (CVD) with increasing prevalence.

Statins have been the main therapeutic intervention for lowering LDL-C for decades. The clinical efficacy and safety of statin-lowering therapies have been well established in clinical trials showing a reduction in the risk of cardiovascular morbidity and mortality. However, there are individuals for whom statin monotherapy or in combination with other lipid-lowering therapies cannot reach their LDL-C target, even at maximally tolerated doses. There are also individuals who are intolerant to statins due to side effects, such as myalgia and increased risk for diabetes, particularly at higher doses.
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Non-Statin Therapies

Guidelines recommend the consideration of non-statin therapies that have demonstrated favorable benefit for the reduction of atherosclerotic CVD. Non-statin therapies for lowering LDL-C include bile acid sequestrants, cholesterol absorption transport inhibitors, niacin, fibrates, and the newest class of specialty drugs proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Several non-statin therapies are in phase 2 and phase 3 clinical trials such as cholesterol ester transfer protein inhibitors and acetyl coenzyme A carboxylase inhibitors.  

The American College of Cardiology recently published a consensus guidance on the use of non-statin therapies to lower cholesterol in high-risk patients. Before initiating non-stating therapies, clinicians need to consider the extent of available scientific evidence for safety and tolerability, potential for drug-drug interactions, efficacy of additional LDL-C lowering in atherosclerotic CVD event reduction, cost, potential to jeopardize adherence to evidence-based therapies, and patient preferences, according to the document.

PCSK9 Inhibitors and Cost

PCSK9 inhibitors have been touted as important breakthrough drugs for individuals who are unable to control their cholesterol with other treatment options, including diet and statins. However, for stakeholders, the hefty price tag of these medications is raising red flags. 

Currently two PCSK9 inhibitors are on the market—Repatha (evolocumab; Amgen) and Praulent (alirocumab; Sanofi/Regneron), which were both approved by the US Food and Drug Administration (FDA) in 2015. List prices for these two drugs are roughly $14,000 per-patient per-year. Pfizer who was developing its investigational PCSK9 inhibitor bococizumab recently announced it will discontinue the program after spending years and considerable money on the drug’s development. Clinical trials involving approximately 27,000 patients showed that they developed antibodies to the drug, which canceled its benefits.

Studies of Repatha and Praulent have shown significant LDL-C reductions of 26% to 67% over 10 to 78 weeks, according to Marian McDonagh, PharmD, and colleagues in study published in Journal of Managed Care & Specialty Pharmacy. A recent JAMA study of 968 patients followed over 18 months randomized to statin monotherapy, or a statin plus Repatha found that the cholesterol-reducing benefits of Repatha do not subside or plateau over time. Stephen J Nicholls, MBBS, PhD, and colleagues found that the Repatha arm achieved significantly greater reductions in LDL-C compared with the statin arm (36 vs 93, respectively), and some got their level down to 10.

Implications for Stakeholders

The good news for PCK9 inhibitors is their effectiveness; the bad news for stakeholders is the cost implications and how to best manage this specialty drug class. 

“In this cost-conscious era of health care, clinicians, payers, and the public are already questioning how to best manage this costly new drug class,” wrote Dr McDonagh and colleagues.

Several studies have assessed the cost-effectiveness of these PCSK9 inhibitors. Dhruv S Kazi, MD, MSc, MS, and colleagues created a simulation model to evaluate the cost-effectiveness of the approved PCSK9 inhibitors in eligible patients based on the FDA-approved labels. Reporting in JAMA the researchers concluded that PCSK9 inhibitors did not meet generally acceptable cost-effectiveness threshold of $100,000 per quality adjusted life year (QALY) and was estimated to increases US health care costs by billions. “Reducing annual drug prices from more than $14 000 to $4536 would be necessary to meet a $100 000 per QALY threshold,” they wrote.

Another critical issue is that broad use of these drugs could bankrupt the health care system, according to a Forbes article. This has not happened yet, as payers are putting heavy restrictions on their use and a majority of prescriptions are being rejected. This has left patients struggling to get access to these medicines. “Unfortunately, insurance policies called ‘utilization management criteria’ and paperwork have all but closed the door for them—even those patients who fit the FDA prescribing information,” commented Raymond Jordan, Amgen senior vice president, in an article published on Fierce Pharma.

What’s employers take on this drug class? Stanton R Mehr explored this issue in a recent article in American Health & Drug Benefits. He found that employers are carefully monitoring the use of these drugs to determine the degree of financial impact. Furthermore, he noted that employers are looking at utilization management options for the drugs themselves, along with policy considerations that can limit the associated risk.

“Will the PCSK9 inhibitors class be the last straw—the line in the sand? Based on the approved indications, the aggressiveness of pricing, and marketing approaches by the drug manufacturers, the discussion may suggest it is yet another class of specialty agents adding to the growing cost of health benefits, and not the tidal wave that strips the beach bare,” he concluded.