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The Food and Drug Administration has approved evolocumab for lowering LDL cholesterol in some high-risk populations, making this the second biologic lipid-lowering therapy to be approved in the United States.
Evolocumab, a PCSK9 inhibitor, is self-injected subcutaneously once or twice a month, and will be marketed as Repatha by Amgen. It is approved for use in addition to diet and maximally tolerated statin therapy in adults with heterozygous familial hypercholesterolemia (HeFH), homozygous familial hypercholesterolemia (HoFH), or clinical atherosclerotic cardiovascular disease, “who require additional lowering of LDL cholesterol,” according to the FDA statement announcing approval.
“Repatha provides another treatment option in this new class of drugs for patients with familial hypercholesterolemia or with known cardiovascular disease who have not been able to lower their LDL cholesterol enough with statins,” Dr. John Jenkins, director of the office of new drugs, in the FDA’s Center for Drug Evaluation and Research, said in the statement.
In studies, evolocumab lowered low-density lipoprotein cholesterol (LDL-C) by approximately 55%-75%, compared with placebo, and by 35%-45%, compared with ezetimibe after 10-12 weeks, in patients with primary hyperlipidemia and those with mixed dyslipidemia. In a phase III study of 49 patients with HoFH, evolocumab reduced LDL-C by about 31%, compared with placebo.
Nasopharyngitis, upper respiratory tract infection, flu, back pain, and reactions such as redness, pain, or bruising at the injection site are among the adverse events associated with evolocumab, according to the FDA. Allergic reactions, such as rash and hives, have been reported in patients treated with evolocumab, who should “stop using Repatha and get medical help if they experience symptoms of a serious allergic reaction,” the statement said.
In July, the FDA approved the first PCSK9 inhibitor, alirocumab (Praluent), as an “adjunct to diet and maximally tolerated statin therapy” for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease, “who require additional lowering” of LDL-C. Alirocumab was not approved for HoFH.
Evolocumab and alirocumab are human monoclonal antibodies that lower LDL-C by binding to and inactivating proprotein convertase subtilisin kexin type 9 (PCSK9), which regulates the LDL receptor. When PCSK9 is inhibited, more LDL receptors are available to remove LDL-C from the bloodstream.
The prescribing information for alirocumab includes a “Limitations of Use” statement that says the effects of treatment on cardiovascular morbidity and mortality has not been determined, an issue discussed at the FDA advisory panel meetings held in June where the drugs were reviewed. Cardiovascular outcomes trials for both alirocumab and evolocumab are underway. The FDA statement notes that many clinical trials “have demonstrated that statins lower the risk of having a heart attack or stroke,” and refers to the ongoing study that is evaluating the effect of adding evolocumab to statins for reducing cardiovascular risk.
That study, the CV outcomes trial for evolocumab – FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) – is fully enrolled and is expected to be completed by 2017, according to Amgen.
Although long-term outcome data about the drug’s impact on cardiovascular events, CVD-related mortality, and all-cause mortality are still being collected, an FDA advisory panel voted unanimously in June to approve evolocumab to treat patients aged 12 years and older with HoFH. The panel also voted 11-4 to approve the drug for other high-risk populations, including HeFH and other groups at high risk for CVD with elevated LDL-C.
Dr. Robert Smith
At the hearing, the panel chair, Dr. Robert Smith, professor of medicine at Brown University, Providence, R.I., said that evolocumab “is addressing an unmet need in a very-severe clinical situation with a new class of drugs that has promise.” Evolocumab, he said, “is worth the risks that accompany uncertainty about its ultimate effects on outcome.” Another panelist, Dr. Michael Blaha, director of clinical research at the Ciccarone Center for Prevention of Heart Disease, Johns Hopkins University, Baltimore, said at the hearing that he strongly supported approval for patients with well-documented HeFH, for whom lowering LDL-C is a “valid surrogate for expected cardiovascular benefit.”
In an interview, Dr. Stephen L. Kopecky of the Mayo Clinic, Rochester, Minn., agreed. Although those taking evolocumab may experience some of the same side effects seen with statins, “no one believes the outcomes won’t be good,” he said.
Dr. Seth S. Martin, a cardiologist at Johns Hopkins Hospital, said that as a clinician and a public health researcher, he is optimistic about the data. Although longterm clinical trials are needed to detect safety signals, evolocumab represents “a triumph of translational medicine,” he said in an interview.
