Repatha, Amgen's PCSK9 Competitor, Gains FDA Approval

The FDA today approved evolocumab, Amgen’s entrant into the PCSK9 inhibitor frenzy, a month after giving the green light to Sanofi-Regeneron’s alirocumab and setting up standoffs with pharmacy benefits managers (PBMs) over what they will pay for these revolutionary but expensive cholesterol-lowering drugs.

Evolocumab, to be sold as Repatha, gained approval for indications similar those FDA gave on July 24, 2015, to alirocumab, being sold as Praluent. Repatha was approved for use in addition to diet and maximally-tolerated stain therapy in adult patients with heterozygous familial hypercholesterolemia (HeFH), homozygous familial hypercholesterolemia (HoFH), or clinical atherosclerotic cardiovascular disease, such as heart attacks or strokes, who require additional lowering of low-density lipoprotein (LDL) cholesterol.

Alirocuamb was approved to treat patients with familial hypercholesterolemia, as well as high-risk patients with demonstrated heart disease whose cholesterol has not been controlled with maximally tolerated statins.

It is expected that managed care plans and PBMs will have highly specific protocols to determine who gains access to the drug, given its price. Amgen announced late in the day that it will list the wholesale price of Repatha at $14,100 a year, just below Sanofi-Regeneron's annual price of $14,600 for Praluent. CVS Health announced August 10, 2015, it would refuse to negotiated prices for the new drug class until after today’s FDA action, when it could work with 2 competitors.

In a press release, Amgen said the wholesale price would be for dosing of 140 mg by injection every 2 weeks. A once-a-month option of 420 mg is expected to be available next year.

With both drugs being priced well above analysts' estimates, PBMs are ready to negotiate. Late yesterday, Express Scripts' Chief Medical Officer Steve Miller, MD, said in a statement that the PBM's pharmacy and therapeutics committee will be reviewing both drugs next month, and will announce decisions on covering 1 or both drugs after that process. "While a drug exclusion remains a possibility, our preference would be that both manufacturers provide our clients with favorable pricing so that it would make sense for our national formulary to cover both products. We would only exclude one if our P&T committee determines that the product we cover is at least clinically equivalent to the one we exclude. And only then would we exclude one of these products if that exclusion would deliver significant savings for our clients and patients."

Until that time, Miller said, the PCSK9 inhibitors will be availble through an medical exception process that ensures "their use is restricted only to those for whom the products are clinically appropriate and in line with FDA recommendations."

FDA regulators did not go as far in approving evolocumab as European regulators have. While the drug was second to be approved here, it beat alirocumab to the finish line overseas in late July. The European Commission allowed broader indications including for those unable to tolerate statins, a key patient group that evolocumab’s sponsors in particular had hoped to target when presenting data on the drug to an FDA advisory committee in June. Amgen will present additional data on the effects of the drug on this population at a conference in London next week.

Like its competitor, evolocumab is an injectable monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme that when blocked results in dramatically lower levels of LDL cholesterol. PCSK9 prevents the liver from effectively eliminating LDL cholesterol on its own. The discovery that persons who lacked this enzyme had abnormally low cholesterol levels triggered wave of research to unleash the therapeutic potential, as pharmaceutical sponsors began looking for ways to block PCSK9.

Evolocumab dazzled attendees at the 2014 meeting of the American College of Cardiology (ACC) with 3 studies that showed the therapy lowering cholesterol between 55% and 62% for various conditions, including heterozygous familial hypercholesterolemia.

The most recent clinical findings for evolocumab were presented at ACC this past March, when Marc Sabatine, MD, MPH, of Brigham and Women’s Hospital outlined preliminary safety data as well as additional results to confirm the drug’s effects on lowering cholesterol. Compared with standard therapy along, patients taking evolocumab saw LDL cholesterol reduced 61%, and the rate of cardiovascular events at 1 year was reduced from 2.18% in the standard therapy group to 0.95% in the evolocumab group. However, these results are only after 11 months, and FDA likely will not expand the drug’s indications until after results from a long-term safety trial of 27,500 patients appear in 2017.

CVS Health Seeks Revised Guidelines

Health plans and formulary managers have been bracing for the arrival of the PCSK9 inhibitor class for nearly a year, having learned difficult lessons after the arrival of Sovaldi, the cure for hepatitis C. When that drug arrived at $84,000, benefits managers and state Medicaid officials were unprepared to absorb the cost while waiting for a competitor to arrive, and all vowed to take a more proactive approach with this new group of cholesterol fighters.

If anything, the PCSK9 inhibitors pose a more difficult long-term cost challenge, because they could, over time, replace low-cost statins with high-cost biologics. Unlike Sovaldi, which would be taken for a defined course of treatment, no similar timeline was offered by researchers who were asked at ACC in March to offer one.

PBMs are sufficiently concerned about the cost of this class that CVS Health Chief Scientific Officer William Shrank, MD, MSHS, published a commentary in JAMA that calls on the ACC and the American Heart Association to update their guidelines, giving cardiologists advice on who should receive these therapies. In his statement last night, Express Scripts' Miller specifically cited the Sovaldi experience as an example of how the PBM had used the arrival of competition to benefit clients, and ultimately, consumers.

Current guidelines, revised in late 2013, do not “provide clarity as to how these expensive new medications could fit in the treatment paradigm, potentially resulting in some scenarios where a prescriber could consider a PCSK9 inhibitor for a low-risk patient.”

The 2013 ACC/AHA guidelines brought forth controversial recommendations that increased the number of patients who might be recommended for statins; at the time, statins were the most popular treatment option available, including high-dose options for patients at elevated risk.

“There is a need for consensus around management strategies for patients with high cholesterol, given that the cost differential between proven older therapies and this new class of drugs is substantial,” Dr Shrank said. “In fact, if used broadly, PCSK9 inhibitors would likely be the most costly class of medications we have seen thus far.”

Estimates have varied widely on how many potential patients could receive the drug, from as low as 200,000 to as high as 2.3 million. While some cardiologists are highly enthusiastic about the arrival of this drug class, others are taking a wait-and-see approach until more long-term data are available. That was evident in the statement from ACC President Kim Allan Williams Sr, MD, FACC, when alirocumab was approved last month.

“The ACC eagerly awaits the results of the clinical trials that are in progress," he said. "In the meantime, we continue to recommend physicians limit prescribing to the very high risk, hard-to-treat groups approved by the FDA and otherwise follow the current guidelines, which recommend lifestyle change and, if needed, statins for most patients with or at risk of heart disease. Improving diet and optimizing exercise are the cornerstones of heart disease management and prevention. Statins are available as low-cost generics, are well tolerated in most patients, and their effectiveness is supported by strong evidence.”