Approve PCSK9 Inhibitor Evolocumab, FDA Panel Recommends

June 10, 2015

GAITHERSBURG, MD ( UPDATED June 11, 2015) — In the second US Food and Drug Administration (FDA) advisory meeting this week, the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) gave its blessing to another investigational proprotein convertase subtilisin kexin 9 (PCSK9) inhibitor for lowering low-density lipoprotein (LDL) cholesterol levels.

The committee members overwhelmingly felt the benefits of lowering LDL cholesterol with evolocumab (Repatha, Amgen) outweighed the potential risks, most notably in patients with heterozygous familial hypercholesterolemia (FH). Regarding the actual vote: 11 EMDAC members said the benefits of LDL lowering with evolocumab outweighed any potential harms, while four committee members weren't convinced about the risk/benefit trade-off at this stage of the drug's development.

In a second vote, the advisory committee dealt with the use of evolocumab in patients with homozygous FH and unanimously felt the benefits of lowering LDL cholesterol with the PCSK9 inhibitor outweighed the risks (15 votes in support of approval, zero opposed). The "unmet need" in this patient population, said panelists, was "enormous," and "patients need everything we can offer them."

With the first vote, the panel members didn't cast their ballot for evolocumab in a specific patient population, although many felt the patients who would benefit the most were those with heterozygous FH and high-risk secondary-prevention patients, including those unable to achieve an adequate degree of LDL lowering despite treatment with statin therapy.

"I was really focused on the very large unmet medical need in patients who are high risk," said panel member Dr Philip Sager (Stanford University School of Medicine, San Francisco, CA) in explaining his "yes" vote. "It's more likely than not this drug will actually be able to reduce cardiovascular outcomes. I do acknowledge the uncertainty in not knowing what the cardiovascular outcomes will actually show, but I was unwilling to wait until 2017 or 2018 to get those results."

Dr Michael Blaha (Johns Hopkins University School of Medicine, Baltimore, MD) also voted yes for approval, saying there was a strong need for PCSK9 inhibition in patients with well-documented heterozygous FH. This appeared to be the consensus for the majority of panel members. The use of evolocumab is "very appropriate," because lowering LDL cholesterol is a valid surrogate end point for an expected cardiovascular benefit in the FH setting, said Blaha.

In addition, Blaha believes there is a need for evolocumab in secondary-prevention patients at high risk for cardiovascular events, such as those with a residually high level of LDL cholesterol or apolipoprotein B because of a less-than-anticipated response to statin therapy.

When it comes to approving evolocumab for statin-intolerant patients only, Blaha said he is not convinced, particularly if the drug were to be used in primary-prevention patients unable to take a statin. This, he said, "would lead to the use of the therapy as routine monotherapy before a cardiovascular-outcomes trial," something he does not support. He also does not want to see evolocumab used in diabetic dyslipidemia or other clinical scenarios in which lifestyle changes or statins are effective.

The FOURIER Trial and CVD Outcomes

One of the major questions before the advisory committee, as hinted at by Sager, was whether or not to recommend approval of evolocumab before the completion of the large-scale clinical-outcomes study. That study, known as Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER), is currently ongoing and is testing the use of evolocumab in combination with statin therapy against placebo (plus statin therapy) in patients with elevated cholesterol levels and existing cardiovascular disease.

The results of the 27,500-patient outcomes study, which completed enrollment just last week, are expected in 2017. The primary end point of the trial is a composite of cardiovascular death, MI, hospitalization for unstable angina, stroke, or coronary revascularization.

For his part, Dr William Hiatt (University of Colorado School of Medicine, Aurora) voted against approving evolocumab outside of homozygous FH, although he might have been more reassured if evolocumab was reviewed as part of the FDA's accelerated approval program.

Instituted in 1992, the accelerated approval program was designed to approve drugs to treat serious conditions on the basis of a surrogate end point. As part of this pathway, pharmaceutical companies are required to complete phase 4 confirmatory studies, and if such trials turn out negative, the FDA has regulations in place to remove the drug from the market. In contrast, Amgen would not be required to show a positive effect on cardiovascular outcomes if evolocumab were approved on the basis of changes in LDL cholesterol.

"Without the [accelerated approval] option, a yes vote means that we're going to expose a large population of patients to a drug that has a very limited safety base and absolutely no clinical evidence of benefit," said Hiatt.

Dr Peter Wilson (Emory University, Atlanta, GA) agreed with Hiatt and also voted no, saying he believes there were inadequate long-term data. He said the evidence presented to the FDA in support of the drug consisted mostly of trials just 24 weeks in duration, and only one study, which tested evolocumab in high-risk cardiovascular patients, went a full year. "I'm particularly concerned if the agency were to approve the drug, there'd be a large number of people [who receive the drug] in whom there'd be very little benefit," said Wilson.

The two other "no" votes against approving evolocumab included Dr Abraham Thomas (New York University Lutheran, Brooklyn) and statistician Dr Martha Nason (National Institutes of Health, Bethesda, MD). Hiatt, Wilson, Thomas, and Nason all favored the approval of evolocumab in patients with homozygous FH.

LDL Cholesterol as a Surrogate Endpoint

During the discussion, the advisory-committee members debated the merits of approving evolocumab based on the 40% to 60% reduction in LDL cholesterol observed in the clinical trials. Many panel members said reductions in LDL cholesterol were "population-" or "context-" dependent and expressed confidence with approving evolocumab because the mechanism for reducing LDL cholesterol with the PCSK9 inhibitors is similar to that of statins, a drug class with conclusive evidence of cardiovascular benefit.

Dr Robert Shamburek (National Heart, Lung, and Blood Institute, Bethesda, MD), similar to others, was cautious about overreaching, but said there is compelling evidence highlighting the association between LDL cholesterol and cardiovascular risk. "I do believe LDL and other lipoproteins are biomarkers, but I also believe that LDL cholesterol, in certain circumstances, is a surrogate for cardiovascular risk."

Blaha noted that LDL as a surrogate marker of risk is likely very different in FH—where patients have been exposed to a lifetime of very high LDL cholesterol levels—compared with in primary prevention patients who have elevated LDL-cholesterol levels. Still, he believes that on the basis of the biology and genetic data, this "all points to PCSK9 inhibition [being] a potentially favorable mechanism of attacking elevated lipoprotein load."

Other EMDAC members agreed with such an assessment, with Dr Yves Rosenberg (National Institutes of Health, Bethesda, MD) saying, "there is not much doubt that any large reduction in LDL cholesterol is related to decreasing cardiovascular risk, provided you don't have any off-target effects."

For Hiatt, the implications of recommending approval of evolocumab are that it would provide tacit support for LDL cholesterol as a surrogate end point "under all conditions." That raises the possibility that new drugs testing very novel mechanisms that do not work through LDL receptors will be approved on the basis of changes in LDL cholesterol, he noted. Niacin, he warned, lowered LDL cholesterol yet failed in two large-scale cardiovascular-outcomes studies.

Evolocumab has been tested in a number of clinical trials, including many that have been reported by heartwire . It has been tested as monotherapy, in combination with statin therapy, and in patients treated with statins and ezetimibe. Regarding patient populations, evolocumab has been tested in patients with heterozygous and homozygous FH, in patients unable to tolerate a statin, and in patients at high-risk for cardiovascular events who are inadequately controlled on statin therapy.

The vote follows on the heels of yesterday's 13 to 3 vote in favor of approving alirocumab (Praluent, Sanofi/Regeneron) for lowering LDL cholesterol in patients with hypercholesterolemia.

Evolocumab, along with alirocumab, are human monoclonal antibodies that target and inactivate hepatic PCSK9, which is involved in the degradation of LDL receptors in the liver. By blocking PCSK9, the monoclonal antibodies make LDL receptors in the liver more available and increase cholesterol-rich LDL clearance from the bloodstream, thereby lowering LDL-cholesterol levels.

A decision by the FDA on approving evolocumab, and in what patients, is expected in late August. One is expected sooner with alirocumab—the official date is July 24, 2015, because Sanofi/Regeneron purchased a priority review voucher for $67.5 million to expedite the review process.

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