FDA Approves Alirocumab, First of Cholesterol-Fighting PCSK9 Inhibitors to Hit US Market

The FDA today approved alirocumab, the first in the much-anticipated class of anti-cholesterol drugs called PCSK9 inhibitors, which have both cardiologists and managed care plans awaiting their arrival.

Alirocumab, to be marketed by Sanofi and Regeneron as Praluent, beat rival evolocumab to the finish line in the United States, although evolocumab, marketed by Amgen as Repatha, was the first to gain approval on Tuesday in Europe. Alirocumab also gained a recommendation for approval in Europe today. FDA must act on the evolocumab application by August 27, 2015.

Alirocumab received approval for use in addition to diet and maximally tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia (HeFH) or patients with clinical atherosclerotic cardiovascular disease such as heart attacks or strokes, who require additional lowering of low-density lipoprotein (LDL) or "bad" cholesterol.

HeFH is an inherited condition that causes high levels of LDL cholesterol. A high level of LDL cholesterol in the blood is linked to cardiovascular disease. In approving alirocumab for treating patients with known heart disease, FDA cited it as the number one cause of death for Americans, both men and women. It cited CDC statistics that about 610,000 people die of heart disease in the United States every year— or 1 of every 4 deaths.

“Praluent provides another treatment option for patients with HeFH or with known cardiovascular disease who have not been able to lower their LDL cholesterol enough on statins,” said John Jenkins, MD, director of the Office of New Drugs, Center for Drug Evaluation and Research. “The FDA strongly supports continued work to provide new and innovative options for the treatment and prevention of cardiovascular disease.”

Late-day reports were listing alirocumab's price at $40 per day at both the 75 mg and 150 mg doses, well above estimates. However, insurers are expected to negotiate discounts, especially once evolocumab is approved.

Alirocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme that when blocked results in dramatically lower levels of low-density lipoprotein (LDL) cholesterol. PCSK9 stymies the liver from effectively eliminating LDL cholesterol on its own. When it was found that persons who lacked this enzyme had abnormally low cholesterol levels, researchers immediately recognized the therapeutic potential and began looking for ways to block PCSK9.

The therapy’s ability to lower cholesterol was outlined in December 2014 at the American Heart Association annual meeting, when phase 3 results from the ODYSSEY trial showed that patients receiving alirocumab lowered their LDL cholesterol between 48.6% and 60.4% compared with 4.3% and 0.5% for placebo. Similarly dramatic results have been reported for evolocumab.

There have been some concerns about cognitive effects of PCSK9s, and FDA has required that this be evaluated in clinical trials. These concerns were discussed in March at the meeting of the American College of Cardiology (ACC), when results were presented that showed evolocumab also reduced the likelihood of a cardiovascular event, in addition to its cholesterol-fighting powers.

Both alirocumab and evolocumab are injectable therapies that have been studied at once-monthly and twice-monthly dosing. Besides possible cognitive effects, there have been concerns that long-term cardiovascular data are not yet available. That fact led to some division on the FDA advisory committees that approved the drugs on June 9 and 10; this meant that while approval was all but certain, the precise indications remained unclear.

Advocates for the PCSK9 inhibitor class see its use not only for patients with hypercholesterolemia, but also for those who have been unable to tolerate statin therapy. This is where pharmacy benefit managers have raised concerns, because they foresee comparatively inexpensive drugs being replaced with a costly new class—and an unclear timetable for how long patients would stay on this new drug.

That is why the question of who gets access to the drug class is so important: estimates have ranged from as low as 200,000 to as high as 2.3 million patients could be treated with a PCSK9 inhibitor, as more are in the pipeline. With costs of the drugs pegged between $7000 and $12,000 per year, one estimate from Prime Therapeutics said the arrival of this class could add as much as $6.71 per member per month to the cost of each person under commercial insurance.

The enthusiasm for this drug class in some quarters has been tempered by those who want to see long-term data. “Because more robust outcomes data, which could show whether these drugs reduce incidence of death and heart attacks, will not be available until 2017, the FDA has approved (alirocumab) for limited groups of patients at very high risk,” said ACC President Kim Allan Williams Sr, MD, FACC.

“The ACC eagerly awaits the results of the clinical trials that are in progress. 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.”

After the experience with the hepatitis C cure Sovaldi, pricing of the PCSK9 inhibitors has been as anticipated as the drug itself. This week, the Institute for Clinical and Economic Review received a grant to evaluate how drugs are priced, and the group said PCSK9s will be first on its list. Express Scripts’ Chief Medical Officer Steve Miller, MD, has been discussing the arrival of this class and its potential impact for months, including an interview with Evidence-Based Diabetes Management.

The European Commission gave a broad indication on Tuesday for evolocumab, including not only treatment for adults with hypercholesterolemia but also those patients taking a maximally tolerated statin or other lipid-lowering therapy who have still not brought LDL cholesterol levels to goal. Also, European regulators approved evolocumab for those unable to tolerate statins or in combination with statins for adults, and in adolescents as young as 13 years old with certain rare conditions.

The fight to be first in the US market has been fierce. Sanofi and Regeneron gained an earlier approval deadline over Amgen by spending $67.5 million for BioMarin to transfer a voucher for a development of a drug for a rare pediatric disease. Alirocumab was eligible because of its indication for hypercholesterolemia, but the market value of approval is not limited to patients with that indication.