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The FDA granted approval to alirocumab (Praluent) for heterozygous familial hypercholesterolemia (FH) and for patients with clinical atherosclerotic cardiovascular disease, making it the first in the new class of lipid-lowering PCSK9 inhibitors.
The approval was for use in addition to diet and maximally-tolerated statin therapy in adults who require additional LDL cholesterol lowering.
Notably left out of the indications listed in the announcement was statin-intolerant patients without established clinical atherosclerotic cardiovascular disease, such as a prior heart attack or stroke.
"I think that seems like a very prudent group of patients to treat,” Christopher Cannon, MD, of Brigham and Women’s Hospital in Boston and a lead investigator on the pivotal trials, told ľֱ, noting that about 85% of patients in the clinical trial program fit in the secondary prevention bucket.
, of Massachusetts General Hospital in Boston, agreed that "it's not surprising as a first step that it get approved with this indication," but he added, "I don't envision this is the only indication it will get."
, although the European Commission still has to give the final okay as it did for a second PCSK9 inhibitor evolocumab on Tuesday.
That approval was broader, including also primary hypercholesterolemia or mixed dyslipidemia alone or with other lipid-lowering therapy for patients unable to tolerate a statin and approval down to age 12 for homozygous familial hypercholesterolemia.
"It's not unreasonable to take a conservative approach," given that studies for adolescents and children haven't been done, Januzzi told ľֱ. "It's not an efficacy issue, it's a safety issue. The FDA tends to be more risk-averse."
“We see this all the time where there are differences in labels across the Atlantic,” agreed Steven Nissen, MD, chief of cardiology at the Cleveland Clinic and an investigator on evolocumab and bococizumab. "I personally have treated some adolescents with really high severe heterozygous FH. The earlier you intervene the better. I tend to agree with the Europeans on this."
The injectable monoclonal antibody will be an important option for familial hypercholesterolemia (FH), suggested , of California’s Stanford University and chief medical advisor for the non-profit FH Foundation.
"The approval of PCSK9 inhibitors is exciting both clinically and scientifically,” he said in a prepared statement. “Patients with familial hypercholesterolemia and other very high risk conditions that cannot achieve optimal LDL levels with current therapies are going to be the direct beneficiaries of this revolutionary genetic approach to drug discovery.”
In terms of the large primary prevention population without FH, “I can understand why the FDA may have shied away from statin intolerance,” said Howard S. Weintraub, MD, clinical director of the NYU Center for the Prevention of Cardiovascular Disease in New York City.
"It is something difficult to define and they may have just wanted to avoid it. However, we all know, that what the FDA approves may not necessarily be what the managed [care] payers approve.”
The wholesale acquisition price for alirocumab on the U.S. market will be $1,120 every 28 days for both the 75 mg and 150 mg doses, Sanofi-Aventis and Regeneron Pharmaceuticals announced.
That price point makes alirocumab "the lowest priced patient-administered monoclonal antibody therapy on an annualized basis,” they said in a press release, pointing out that “the companies carefully considered the potential medical value that Praluent offers patients in determining the wholesale acquisition cost.”
Market research has suggested the price tag could be in the $7,000 to $12,000 per year range. The actual cost announced comes in well above the top of that range at about $14,600 per year ($40 per day), although health system and payer negotiations are likely to trim things a bit as has been the case with the expensive hepatitis C medications, noted , president of the Institute for Clinical and Economic Review (ICER), an independent nonprofit research institute in Boston focused on comparative effectiveness and cost effectiveness.
The companies noted that they "will provide patient assistance to uninsured or underinsured patients, including providing free medicine to eligible patients, and can help identify coverage options for out-of-pocket costs ... as well as reimbursement services, including co-pay support for eligible patients and information about insurance eligibility support."
Another question is whether payers will be as liberal as the FDA in accepting clinicians’ determination of who needs "additional LDL cholesterol lowering," Weintraub noted.
"The issue is in patients with existing cardiovascular disease, at what level of LDL will they permit the addition of a PCSK9 inhibitor?" he said in an email to ľֱ. "Will they use LDL levels as in IMPROVE-IT? This will be an interesting issue."
The FDA approval for alirocumab is widely expected to be followed closely by approval of evolocumab (Repatha) by Aug. 27.
The decision followed last month’s 13-3 FDA advisory committee recommendation for approval for alirocumab and an 11-4 vote in favor of evolocumab approval.
The five placebo-controlled clinical trials with alirocumab showed average LDL cholesterol reductions 36% to 59% over placebo.
The most common side effects have included itching, swelling, pain, or bruising where injection is given, nasopharyngitis, and flu. Some cases of allergic reactions, such as hypersensitivity vasculitis and hypersensitivity reactions requiring hospitalization, have also been reported with the drug.
From the American Heart Association: