GAITHERSBURG, MD. (FRONTLINE MEDICAL NEWS) – The benefit-risk profile of the PCSK9 inhibitor evolocumab, injected subcutaneously once or twice a month, supports its approval for treating hypercholesterolemia in certain high-risk populations, a Food and Drug Administration advisory panel has agreed.

At a meeting on June 10, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 15-0 that evolocumab should be approved for treating patients aged 12 years and older and adults with homozygous familial hypercholesterolemia (HoFH), based on its impact on lowering low-density lipoprotein cholesterol (LDL-C) in patients and what is currently known about its safety profile.

In a separate vote on other populations included in the indication proposed by Amgen, the panel voted 11-4 to recommend approval for treating other types of patients but limited it to patients at higher CVD risk and elevated LDL-C levels, particularly those with heterozygous FH. There also was support for approval for other higher-risk patients, such as those at high risk for CVD and high LDL-C levels and those with high LDL-C levels on maximum statin doses, but there was not support for approval for lower-risk groups, such as those with mixed hyperlipidemia.

Amgen has proposed that evolocumab be approved for patients with HoFH, as well as adults with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia.

With these votes, it is likely that evolocumab will be approved this year since the FDA usually follows the recommendations of its advisory panels. Evolocumab and another PCSK9 inhibitor, alirocumab – which the majority of the panel recommended for approval the day before – will be the first in this new class of lipid-lowering agents to be approved in the United States. The recommended doses for adults with primary hyperlipidemia and mixed dyslipidemia are 140 mg every 2 weeks or 420 mg once a month; 420 mg every 2 or 4 weeks is recommended for those with HoFH.

PCSK9 inhibitors 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 (LDL-R). Inactivation of PCSK9 results in an increase of LDL-R available to clear LDL-C, reducing LDL-C levels.

The data presented by Amgen include four 12-week, phase III double-blind randomized studies comparing the two doses of evolocumab to placebo and/or ezetimibe in about 3,100 patients. The four studies involved patients with HoFH, patients at high CV risk on background statin therapy, patients on monotherapy with diet as background therapy, and patients intolerant to statins who were on no or low-dose statin. The primary efficacy endpoint was reduction n LDL-C at 10-12 weeks.

Both dosing regimens resulted in significantly lower LDL-C levels from baseline, compared with placebo and ezetimibe. Treatment with the two doses resulted in “consistent, clinically equivalent” LDL-C reductions in patients with primary hyperlipidemia and those with mixed dyslipidemia, with reductions of 55%-75% compared with placebo and 35%-45% compared with ezetimibe. Effects were maintained over 2 years in an open-label extension study in different subgroups, including gender and region, according to Amgen.

In a phase III study of 49 patients with HoFH treated with 420 mg once a month or placebo, evolocumab was associated with LDL-C reductions of about 31%, compared with placebo. In phase II and III studies of almost 5,000 patients who received evolocumab, the overall incidence of adverse events was similar to the comparators, and adverse events in long-term studies were similar to those seen in the initial studies, according to Amgen. To date, no major safety issues have been associated with evolocumab, including in patients with very low LDL-C levels (below 25 mg/dL or 40 mg/dL), compared with levels of 40 mg/dL or greater, according to the company.

Adverse events of interest include neurocognitive events and glycemic changes, recently reported with statins. The incidence of new-onset diabetes was low and similar between those on evolocumab and comparators, although there was a “small imbalance” in glycemic changes in patients on evolocumab, a risk that cannot be ruled out and will be monitored in ongoing studies, including the CV outcomes study, according to Amgen. In phase II and III studies, over a median exposure of about 3 months, the rate of neurocognitive adverse events was low and there was no association between low and very low LDL-C levels and neurocognitive events. Most adverse events were rash and eczema and were mild to moderate.

Although the panel agreed there was no major safety signal of concern in the studies, which was reassuring, the members said that safety issues should continue to be followed and that whether very low levels of LDL-C may be associated with adverse events remained an open question and needed to be studied on a long-term basis, including in the CV outcomes study. The concern was raised that, if LDL-C levels dropped to low levels, some clinicians might reduce or withdraw the statin.

As with alirocumab, the panel was asked to discuss whether the impact on LDL-C with evolocumab was sufficient to demonstrate an effect on clinical outcomes; historically, the FDA has considered reductions in LDL-C sufficient to establish the effectiveness of a lipid-lowering drug and does not require that benefit be shown in a CV outcomes trial before approval, “provided the reduction is sufficiently robust” and the product does not have any safety issues that raise concerns about the benefit-risk profile, according to the FDA. Although several panelists said that, while the drug targets LDL-C via a mechanism that is fairly close to the statin target, which provided more confidence in using LDL-C as a surrogate for CV benefit, they said this question can only be answered definitely with the CV outcomes trial.

The CV outcomes study, the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), has been fully enrolled, with about 27,500 patients, and is expected to be completed no later than 2017, according to Amgen. The study also will provide safety data in more than 5,000 patients with LDL-C levels below 40 mg/dL.

The FDA usually follows the recommendations of its advisory panels. The FDA panelists had no potential conflicts of interest. A decision is expected by Aug. 27. If approved, Amgen plans to market evolocumab as Repatha.