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FDA approves evolocumab as LDL-lowering therapy in certain patients
The FDA has approved evolocumab, a PCSK9 inhibitor, for lowering LDL in adults with heterozygous or homozygous familial hypercholesterolemia or clinical atherosclerotic CVD, according to a press release from the agency.
Evolocumab (Repatha, Amgen) is intended for use in addition to diet and maximally tolerated statin therapy in patients with heterozygous familial hypercholesterolemia (HeFH) or atherosclerotic CVD, and in addition to diet and other LDL-lowering therapies for patients with homozygous familial hypercholesterolemia (HoFH), according to an Amgen press release.
The approval follows results from several placebo-controlled trials, including one 52-week study and eight 12-week trials involving patients with primary hyperlipidemia. In phase 3 studies, researchers observed an LDL reduction of 54% to 77% compared with placebo among patients with HeFH or clinical atherosclerotic CVD, and a 30% reduction compared with placebo among patients with HoFH, according to the company release.
“Repatha provides another treatment option in this new class of drugs for patients with familial hypercholesterolemia or with known CVD who have not been able to lower their LDL cholesterol enough with statins,” John Jenkins, MD, director of the Office of New Drugs at the FDA’s Center for Drug Evaluation and Research, said in the FDA release.
The most commonly observed adverse events among patients treated with evolocumab in clinical trials included reactions at the injection site, back pain, nasopharyngitis, upper respiratory tract infection and influenza. The effect of the drug on CV-related morbidity and mortality has yet to be determined, according to the company release.
Evolocumab is the second PCSK9 inhibitor to be approved in the United States, after alirocumab (Praluent, Sanofi/Regeneron) received approval in July as an LDL-lowering therapy for patients with HeFH or clinical atherosclerotic CVD. The drug received marketing authorization from the European Commission in July for the treatment of adult patients with primary hypercholesterolemia or mixed dyslipidemia, either alone or in combination with other lipid-lowering therapies, and for patients aged 12 years or older with HoFH, in combination with other lipid-lowering agents.
Disclosure: Jenkins is director of the Office of New Drugs at the FDA’s Center for Drug Evaluation and Research.Perspective
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The FDA approval of evolocumab, another anti-PCSK9 monoclonal antibody along with alirocumab, is good news for those of us who believe in the causality of atherogenic lipoproteins. Our belief in the “LDL hypothesis” is based on more than 100 years of research, demonstrating that LDL cholesterol is causal for CVD and lowering LDL is associated with a reduction in major adverse CV events.
The second part of this hypothesis is “the lower the LDL, the better.” Therefore, having anti-PCSK9 monoclonal antibodies clinically available provides a potent weapon in our lipid-lowering armamentarium to address the unmet medical needs for patients with refractory dyslipidemia despite maximally tolerated statin therapy. The patients with refractory dyslipidemia include those with clinical atherosclerotic CVD or those with familial hypercholesterolemia with LDL above desirable levels despite maximally tolerated lipid lowering therapy.
These biologic therapies are very effective in lowering LDL by more than 50% and appear to be well-tolerated. Ongoing CV outcome trials will further test the clinical value of these agents in achieving LDL levels below 50 mg/dL on CV outcomes.
The FDA should be congratulated on maintaining a regulatory path for LDL-lowering therapies that balances the need for encouraging innovation while also requiring these novel therapies to ultimately validate their clinical value with proven outcome benefits.
Perspective
Back to TopThe 2013 prevention guidelines focused on 'proven' agents to reduce MI and stroke. With the publication of the IMPROVE-IT trial, one can now say that ezetimibe is a second-line option after statin therapy. The guideline writers did believe that lower is better with proven and safe therapies. Now, we have two different classes (statin and cholesterol absorption inhibitor) to choose from. The dilemma many clinicians will face is whether to first add fenofibrate and/or niacin to further lower LDL and non-HDL before prescribing the very effective but expensive PCSK9 inhibitor in order to further lower lipids. We anxiously await the ongoing clinical outcome studies in order to determine the true incremental clinical benefit of this exciting class of medication as well as its long-term safety.
Perspective
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It’s good to now have two of these drugs on the market. You always want to have alternatives, and you never know when a patient will have a problem with a drug, so having a second drug approved gives us more choices.
It’s also important to understand that the strategy of the two companies in developing the drugs is slightly different: Alirocumab is going to be essentially marketed at a low dose, with the option to titrate to a higher dose. Evolocumab is really marketed only at the single dose, with the view that maximal LDL-lowering is desirable in these patients. So it’s two different dosing strategies, and that represents options for physicians and patients.
Otherwise, the drugs are really pretty similar. The maximum dose of both drugs is similar in efficacy and durability, both drugs are well-tolerated with a low incidence of injection site reactions, and both drugs represent a huge advance in terms of the ability to treat patients to low levels of LDL cholesterol — which, despite our misguided guidelines, most of us still think is the right thing to do.