GAITHERSBURG, MD. (FRONTLINE MEDICAL NEWS)The majority of a Food and Drug Administration Advisory panel has supported the approval of alirocumab, a biologic lipid-lowering drug injected subcutaneously twice a month, as a long-term treatment for hypercholesterolemia, but support for the different patient populations included in the proposed indication varied.

At a meeting on June 9, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13-3 that the manufacturer had “sufficiently established that the LDL cholesterol–lowering benefit of alirocumab exceeds its risks,” and to “support approval in one or more patient populations,” the question posed to the panel. However, those voting in favor of approval said the optimal benefit would be in patients with familial hypercholesterolemia; there was also support among some panelists for patients who are truly statin intolerant and those who cannot get to goal on statin therapy alone and are at a high cardiovascular risk.

The proposed indication for the PCSK9-inhibitor is for treating adults with primary hypercholesterolemia (nonfamilial and heterozygous familial) or mixed dyslipidemia, including patients with type 2 diabetes, to reduce LDL cholesterol, total cholesterol, non-HDL cholesterol, apolipoprotein B, triglycerides, and lipoprotein A, and to increase HDL cholesterol and apolipoprotein A-1 (Apo A-1) – either in combination with a statin or as monotherapy, including in patients who cannot tolerate statins. The proposed dose is 75 mg administered subcutaneously every 2 weeks (or a starting dose of 150 mg every 2 weeks for patients who need more than a 60% reduction in LDL-C.

Dr. Brendan Everett, director of the cardiology inpatient service at Brigham and Women’s Hospital, Boston, voted for approval, because of the drug’s potential benefits for patients with heterozygous FH, but added that he would restrict approval to these patients, and did not support approval in other patients, such as those with mixed dyslipidemia.

Alirocumab was compared with placebo or ezetimibe in 10 phase III studies of about 5,100 patients, including those at high CV risk and statin-intolerant patients.

The percent reduction in LDL cholesterol at 24 weeks, from baseline, was the primary endpoint. Summarizing the FDA’s view on the safety and efficacy of alirocumab, Dr. Julie Golden, a medical reviewer in the FDA’s division of metabolism and endocrinology products, said that the agency agrees with the manufacturer, that alirocumab is associated with “substantial and persistent” cholesterol-lowering effects, compared with controls, in all patient populations studied. However, any conclusions about CV benefits are “premature,” she said.

Panelists said that in the studies, there were “weak” safety signals for neurocognitive effects, diabetes, and abnormal liver enzymes, but they were somewhat reassured by the absence of any “highly concerning” adverse events in the studies. Panelists said there was little or no evidence that low levels of LDL cholesterol are harmful, but that did not provide assurance of safety of low levels. Several panelists raised the concern that statins may be reduced or stopped in patients whose LDL cholesterol levels dropped to very low levels while on alirocumab, instead of stopping treatment with alirocumab.

Over 20 years, the FDA has accepted reductions in LDL cholesterol as a surrogate for CV risk reduction to support approval of lipid-lowering drugs, but once approved, CV outcomes trials are not required. One of the panelists voting against approval was Dr. Peter Wilson , professor of medicine and public health, Emory University, who said that cardiovascular outcomes data were needed to support approval. “I no longer think we are in an LDL-surrogate era,” he noted.

The alirocumab CV outcomes study – the ODYSSEY Outcomes trial – is enrolling 18,000 patients with recent acute coronary syndrome who are on high intensity statin treatment and are randomized to alirocumab or placebo; MACE is the primary endpoint. The company expects that enrollment in the outcomes study will be completed this year and results will be available in 2017; it will represent 50,000 patient years of experience (vs. 5,000 patient years with the phase III trials) and will include further evaluation of the risks associated with treatment.

The FDA usually follows the recommendations of its advisory panels. The FDA panelists had no potential conflicts of interest.

If approved, Sanofi and Regeneron plan to market alirocumab as Praluent; a decision is expected by July 24th.

On June 10 , the panel will review evolocumab, another PCSK9-inhibitor. If approved, these will be the first drugs in this new class of lipid-lowering agents to be approved in the United States. They are human monoclonal antibodies that bind to proprotein convertase subtilisin kexin type 9 (PCSK9), a serine protease that is involved in the regulation of LDL receptor (LDR-R). Inactivation of PCSK9 results in an increase of LDL-R available to clear LDL-C, reducing LDL-C levels.


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