If you make them build it they still may not come

This knowledge won’t come cheap, as the system braces for new agents that could add another $42 billion to the nation’s drug bill.

There are at least two sides to every story, including the one involving the PCSK9 inhibitors. Oftentimes, one side of a story can overshadow the other, and that seems to be the case with the new anticholesterol agents evolocumab (Repatha), made by Amgen, and alirocumab (Praluent), a joint effort by Sanofi and Regeneron.

These new lipid fighters are coming onto the market under a cloud of worry and criticism about their exorbitant costs and inadequate outcomes data. They are expected to cost between $5,000 and $12,000 annually per prescription. Other reports have highlighted the lack of safety and cardiovascular outcomes data. The drugs have been evaluated by the FDA for their impact on low-density lipoprotein (LDL), a surrogate outcome, and one-year safety profiles.

By some estimates, 3.5 million Americans might eventually be prescribed a PCSK9 inhibitor. The FDA approved alirocumab on July 24 as a treatment for familial hypercholesterolemia and for people at high risk for a cardiovascular event, such as a heart attack, who need LDL-lowering therapy in addition to whatever diet and aggressive statin therapy can accomplish in that department. But the approved indications and use of alirocumab and its PCSK9 inhibitor colleagues could broaden.

Say that 3.5 million estimate proves to be accurate. The annual tab for PCSK9 inhibitors at their anticipated prices would range from $17.5 billion to $42 billion.

PCSK9 inhibitors ”may present an opportunity to more clearly understand the true potential of low cholesterol in reducing cardiovascular events,” says Elliott Antman, MD, immediate past president of the American Heart Association.

But the other side of the PCSK9 inhibitor story sets costs aside and looks at the phenomenal impact these agents have in lowering LDL cholesterol. “They may present an opportunity to more clearly understand the true potential of low cholesterol in reducing cardiovascular events,” notes Elliott Antman, MD, a professor at Harvard Medical School and the immediate past president of the American Heart Association. When alirocumab and evolocumab are added to existing anticholesterol therapy, they can cut LDL levels by another 60%.

Atorvastatin (Lipitor) alone can reduce LDL by between 39% and 50%, and adding a PCSK9 inhibitor may lower LDL levels much further. The FDA’s advisory panel briefing document shows that with a statin plus evolocumab, it is possible to achieve LDL levels below 50 mg/dL, which is far below 100 mg/dL, the optimum level in the current federal cholesterol guidelines.

Antman notes that in the first year of life, a healthy infant’s cholesterol level is about 30 mg/dL—an indication that human beings can get their LDL levels down to much lower levels—and also that triple digit levels are not normal but the consequence of bad diets and sedentary ways. Moreover, as Antman points out, people with an inherited PCSK9 defect have very low lifelong LDL levels and almost never have vascular disease.

If pushing down LDL levels translates into less cardiovascular disease, then the cost-benefit math of the PCSK9 inhibitors could put the high price of the drugs in a more favorable light, argues Antman. The direct costs of cardiovascular disease are well over $300 billion a year. Add in disability and lost wages, and the dollar figures get much higher. About 200,000 of the heart attacks that Americans have each year are repeat heart attacks, and secondary prevention efforts, including therapy to ratchet down LDL levels to much lower levels, might reduce that number by a lot. The same might be true for stroke.

How low should we go?

Antman is not alone in suggesting a more aggressive approach to cholesterol management. In 2013, the cholesterol guidelines from the American College of Cardiology and the American Heart Association started to move away from absolute cholesterol targets. Instead, they target percentage reductions in LDL, and those percentage reductions may translate into LDL reductions well below 100 mg/dL.

22% reduction in cardiovascular events

The current evidence is that a 40 mg/dL reduction in LDL cholesterol is associated with a 22% reduction in cardiovascular events. In two of the clinical trials of evolocumab, there was an absolute reduction of at least 70 mg/dL in patients with a median LDL of 120 mg/dL. If the relationship between cholesterol reduction and risk reduction is linear, then evolocumab could, in theory, reduce cardiovascular events by 38.5%.

Studies of other agents have also suggested that perhaps we haven’t gone nearly far enough in lowering cholesterol levels. The IMPROVE-IT trial of ezetimibe (Zetia) showed a statistically significant benefit in driving cholesterol lower than the 100 mg/dL benchmark. The study included 18,144 high risk patients taking ezetimibe plus a simvastatin (the treatment group) or a placebo plus simvastatin (the control group). After a year, the mean LDL level in the treatment group was 53.2 mg/dL vs. 69.9 mg/dL in the control group.

The seven-year event (cardiovascular death, heart attack, and so on) rate was 32.7% in the treatment group and 34.7% in the control group, a 2% percentage point difference and a relative difference of about 6%. These results indicate that about 50 patients would need to be treated for seven years to prevent one CVD event.

While the risk difference was statistically significant, IMPROVE-IT has not generated that much excitement. One reason, perhaps, is that the study’s results identify a factor that must be taken into consideration when evaluating new therapies: poor adherence. It is definitely a barrier to achieving lasting cholesterol reductions. In the IMPROVE-IT trial, 42% of patients in each arm discontinued their study regimen before the end of the trial.

All of the stories surrounding the PCSK9 inhibitors present a real management challenge for health insurers and PBMs. The additive power of the PCSK9 inhibitors in driving LDL levels down means they will be attractive to some patients and clinicians.

The high cost of PCSK9 inhibitors means that they may not be the best means, even if very low LDL cholesterol levels—by today’s standards—turn out to be the desired end. Chronis Manolis, RPh, vice president of pharmacy at UPMC Health Plan in Pittsburgh, notes that the current arsenal of statins is often capable of getting patients well below 100 mg/dL.

Clinicians need to pay close attention to adherence, partly because PCSK9 inhibitors are so expensive, says Chronis Manolis, RPh, vice president of pharmacy at UPMC Health Plan.

However, there is considerable play yet in what PCSK9 inhibitors will actually end up costing. As they have with sofosbuvir (Sovaldi) and other new hepatitis C drugs, the national PBMs may have enough clout to negotiate discounts, rebates, and formulary placement so that the actual price to plan sponsors will be considerably lower than the sticker price.

Still, there are unresolved questions about the safety and outcomes of the PCSK9 inhibitors. Multiple phase 3 cardiovascular outcome studies are underway for both evolocumab and alirocumab, but the results will not be available until 2017 or 2018. These large-scale trials in diverse populations are intended to prove longer term safety and clearly demonstrate the impact of these drugs on cardiovascular outcomes, since the initial review relied upon LDL as a surrogate outcome.

Pay attention to adherence

An article last month on the American College of Cardiology’s website acknowledged that definitive safety and outcomes data are not available, so the role that PCSK9 inhibitors will play in cardiovascular disease prevention is hazy right now. The piece went on to say, though, that the excitement surrounding the new medications was warranted because they “may potentially change the paradigm surrounding the treatment and management of patients for years to come.”

Manolis argues for a measured response. While it’s an important development to have an effective medication for cholesterol management, he says clinicians need to pay close attention to adherence, partly because PCSK9 inhibitors are expensive. And it needs to be confirmed that there has been a thorough attempt at statin therapy.“Clinicians shouldn’t bring out the big guns unless they are truly indicated,” he says.

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