CVS Health Seeks Return To LDL Treatment Targets To Control PCSK9s

Pharmacy benefit manager CVS Health Corp. is calling for a return to specific LDL-cholesterol targets in heart society treatment guidelines to enable utilization management programs aimed at restricting use of the new PCSK9 inhibitors.

Sanofi/RegeneronPharmaceuticals Inc.’s eagerly awaited PCSK9 inhibitor Praluent (alirocumab) was approved by FDA on July 24 for heterozygous familial hypercholesterolemia or clinical cardiovascular disease on top of a maximum tolerated dose of statins, with a price tag of $14,600 per year (Also see "Praluent Coverage: Being First May Not Matter As Payers Await Repatha" - Pink Sheet, 3 Aug, 2015.).

Amgen Inc.’s competing PCSK9 inhibitor Repatha (evolocumab) is expected to be approved soon; its user fee goal date is Aug. 27.

Between eight and 10 million people might be eligible for treatment with the new robust LDL-lowering drugs, but the actual figure could well be lower with payer controls.

CVS Health has said it would hold off on reimbursement decisions for Praluent until after Repatha was approved, but in a “Viewpoint” article published in the Journal of the American Medical Association on Aug. 10, a trio of CVS Health executives drew attention to a potential problem in managing utilization of the drugs.

The latest set of cholesterol treatment guidelines, jointly developed by the American Heart Association and American College of Cardiology and released in November 2013, marked a major shift in clinical practice. Whereas previously health care providers treated patients to particular LDL targets, e.g. 70 mg/dL for high-risk patients, the 2013 guidelines instead focused on risk factors to guide treatment .

Due to the expected demand and the ambiguity of treatment guidelines from major cardiology associations, there is potential for broad use of injectable PCSK9 inhibitors for lowering LDL-C, possibly including relatively low-risk people, the article maintains.

“The cost implications for payers and society could be extraordinary; if used broadly, PCSK-9 inhibitors would likely be the most costly class of medications marketed thus far,” co-authors William Shrank, Troyen Brennan and Jane Barlow asserted.

They cite Gilead Inc.’s Sovaldi (sofosbuvir) to underscore their concern. The hepatitis C treatment, which cures most patients with a short course of treatment, “shocked the health care system because of the high cost and relatively large eligible population, up to 3 million infected individuals,” the article notes.

“PCSK-9 inhibitors will be used long-term – generally for the remainder of the lives of treated patients. As a result, most payers, both government and commercial, should begin to consider thoughtful ways to rationalize the use of these medications.”

The CVS Health executives believe that low-cost statins should be promoted instead of PCSK9 inhibitors, but that the current cholesterol treatment guidelines could complicate this strategy.

The guidelines released in 2013 “fundamentally altered the way cholesterol-lowering medications are prescribed and inadvertently limited the ability of payers to employ typical utilization management tools,” they argued.

CVS Health would like to see the guidelines updated and clarified to reflect more recent developments, notably the approval of PCSK9 inhibitors.

The ACC isn’t commenting on when the next guidelines update is due, but in a statement, it noted that “our guidelines are based on current evidence and developed through a lengthy and rigorous process; any changes to them must be supported by evidence.”

In the past, the guidelines have been updated infrequently; the last set was released in 2002 and updated in 2004.

Taming Market Demand

It remains to be seen how the PCSK9 inhibitors are adopted into practice. But determining eligibility for Praluent based on labeling leaves a lot of gray areas. The maximum tolerated dose of background statin therapy is left up to the discretion of prescribing physicians and the issue of how low LDL should go is left unresolved (Also see "Praluent Launch Brings Clinical Practice Challenges" - Pink Sheet, 3 Aug, 2015.).

Outcomes studies of statins have shown that the lower LDL goes, the better the patient fares in terms of cardiovascular events, but there has been uncertainty in the cardiology community about how aggressively to treat cholesterol and what the long-term risks might be for achieving extremely very low cholesterol.

PCSK9 inhibitors are highly effective at driving down cholesterol and have a similar mechanism of action as statins. But unlike statins, which are now largely available as low-cost generics, outcomes data are not available yet to prove a benefit for PCSK9 inhibitors in reducing morbidity or mortality.

The differences in costs between older and newer drugs are substantial, yet the comparative clinical outcomes are “not yet clear,” the authors note.

Rita Redberg, director of women’s cardiovascular services at UCSF and a frequent commentator in debates over cholesterol treatments, noted that drugs get onto the market with the “hope but not the reality of assuring clinical benefits.” Surrogate markers frequently turn out to be meaningless, added Redberg, who was also concerned about how much the PCSK9 class would add to health care spending.

Although the FDA advisory committees noted the lack of outcomes data for the PCSK9 inhibitors during their review of Praluent and Repatha, and urged that use be limited aside from patients with HeFH, “there is likely to be substantial enthusiasm about this class of drugs in the marketplace,” the JAMA article stated.

Foiling Utilization Management

Normally, when evidence is unclear, payers would use utilization management criteria to ensure appropriate use.

“Traditional utilization management techniques, such as step therapy and prior authorization, require patients to first try a lower-cost, evidence-based therapy, and if clinical goals are not met, therapy can be escalated to a more intensive and costly therapy. However, some may argue that such a strategy cannot be supported when the guidelines do not endorse treating to specific targets and titrating therapy based on their effects,” the JAMA article states.

The authors contend that these issues may not have been considered at the time the guidelines were written.

“The dilemma presented by the introduction of the PCSK-9 inhibitors reinforces the need to update guidelines on a regular basis, or at least offer clarification when new data emerge,” they argued.

The guidelines do stress use of statins over other classes of therapies, and urge caution regarding determinations that patients are statin-intolerant, which is another target group for PCSK9 sponsors.

But the CVS Health executives see too much ambiguity. The guidelines advise that “once patients are stratified based on risk, the most effective therapy should be initiated,” with patients at high risk of an event recommended to get high-potency statins for maximal LDL-C lowering.

“Now, a richer set of therapeutic options are available to clinicians treating hyperlipidemia, and the most recent set of guidelines do not provide clarity on how to choose,” the article says. “In particular, the guidelines do not recommend titration of therapy based on LDL-C control. Will clinicians interpret the guidelines to indicate that the highest-risk patients should be prescribed PCSK-9 inhibitors? Perhaps most concerning from a social cost point of view, will relatively low-risk patients be considered for PCSK-9 inhibitors?”

The CVS Health authors acknowledged that cholesterol management studies were not designed specifically to test PCSK9 vs. statins in treating to targets and these studies may need to be done.

The ACC noted that LDL-C levels are incorporated into guidelines for initiating treatment, along with other risk factors, though there aren’t goals for treatment. PCSK9 inhibitors were not available when the current guidelines were published, but the guidelines were written to accommodate new evidence-based treatments, ACC President Kim Allan Williams said in a statement.

Until “more robust” outcomes data are available for the class, the ACC recommends limiting use “to only very high-risk and hard-to-treat patients.”

Other patients should consider lifestyle changes and statins, the ACC advised.

Redberg commented that she sees “no rush” to use PCSK9 inhibitors to lower cholesterol.

“I think use of the PCSK9 drugs should be limited to people with familial hypercholesterolemia until we have data in a few years on the risks and benefits of these drugs for other indications,” she said.