FDA Advisory Panel Recommends Approval of Alirocumab, Citing Value for Patients With FH

Deborah Brauser

June 09, 2015

GAITHERSBURG, MD — The Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) of the US Food and Drug Administration (FDA) gave the thumbs-up today to recommending, for the first time, approval for a new class of medications: proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors.

They voted 13 to 3 in favor of alirocumab (Praluent, Sanofi/Regeneron) for lowering LDL cholesterol in patients with hypercholesterolemia, citing likely benefit especially for patients with heterozygous familial hypercholesterolemia (HeFH). Other groups predicted to get special benefit include those at high CV risk or who don't tolerate statins. Although there was a lot of debate without consensus about these latter groups, the vote just focused on whether the drug's benefits exceeded its risks to support approval "in one or more patient populations."

The biggest discussion of the day was whether the drug should be approved based only on its effect on LDL-C—even before its CV-outcomes trial has been completed. Many panel members, including chair Dr Robert J Smith (Alpert Medical School of Brown University, Providence, RI), did not agree that LDL-C lowering is sufficient for establishing effectiveness for reducing CV risk. "I just don't think it predicts clinical outcomes. I would need to see the clinical outcomes," he said.

However, Smith was among the "yes" votes today, noting that patients with HeFH really need this drug—a point that came out throughout all discussions. During the public-hearing session, 14 of 16 speakers gave strong approval for the medication, with most sharing stories of how they and/or family members have struggled with this disorder.

Committee member Dr Philip Sager (Stanford University School of Medicine, CA), who also voted yes, told heartwire from Medscape after the meeting that this drug fills an unmet need for these patients, as well as for the other discussed populations.

"I felt that the mechanism of action as well as the genetic data supported that the very large LDL-C reductions are likely to translate to clinical benefit," he said. "And if we were not to make the drug available now and waited several years for the cardiovascular-outcomes study, there would be potential risk for patients who could have benefited going untreated."

Another big discussion throughout the day centered on safety. Overall, the committee agreed that there were no major risk "signals," but many voiced concerns that these could develop into something stronger with broader use. This included events involving glucose control, liver, and unstable angina—especially because there are currently no data on long-term exposure.

"Adverse events of interest" presented by the FDA reviewers included injection-site reactions and allergic events, which were both higher in study patients receiving alirocumab vs placebo. Although there were also 29 total neurocognitive events, Dr Mary Dunne Roberts (FDA) noted that this was too few to determine a definitive association with the drug and that there were too few adjudicated major adverse cardiovascular events (MACE) to determine its effect on CV morbidity or mortality.

Another question brought up was whether alirocumab will increase risk of diabetes, based on concerns whether statin use was associated with diabetes risk in the JUPITER trial. Although there has been no strong evidence so far of this for alirocumab, a representative for Sanofi noted that a CV-outcomes study will need to be done to officially rule this out—and noted that that is one of the things that ODYSSEY-Outcomes will examine. That trial is reported to complete enrollment by the end of this year, with results scheduled to be released by the end of 2017.

"The outcomes trial will probably answer many but not all of these concerns," said Smith. "So ongoing monitoring programs will be needed."

The three "no" votes came from Dr Martha Nason (National Institutes of Health, Bethesda, MD), Dr William R Hiatt (University of Colorado School of Medicine, Aurora), and Dr Peter J Wilson (Atlanta Veterans Administration Medical Center, GA). "I'm certain that I'm uncertain, so I voted conservatively," said Wilson. "We need an outcomes trial."

"This was not an easy decision, especially for the population of FH patients," said Nason. "But for the other populations, I think the safety data are just not there. I'm not fully convinced that LDL is the right surrogate in a new class of drugs." Hiatt agreed and also noted concerns that the sponsor "intentionally targeted" a broad range of patients.

Still, an overwhelming majority were in favor for approval of the drug. An official decision by the FDA on alirocumab is now expected by July 24, an early date because of the purchase of a priority-review voucher by Sanofi/Regeneron[1]. A second PCK9 inhibitor, evolocumab (Repatha, Amgen), goes before the EMDAC tomorrow.

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