FDA advisors vote 9 to 6 to approve mipomersen for homozygous FH

October 18, 2012

Bethesda, MD - The Food and Drug Administration (FDA) Endocrinologic and Metabolic Drugs Advisory Committee tackled another lipid-lowering drug today for the treatment of homozygous familial hypercholesterolemia (FH), voting 9 to 6 in favor of approving mipomersen (Genzyme, Cambridge, MA) as an adjunct to maximally tolerated lipid-lowering medications for the reduction of LDL and total cholesterol levels, as well as the reduction of apolipoprotein B (apoB), apoA, and non-LDL cholesterol.

Yesterday, the same panel voted 13 to 2 in favor of recommending approval of lomitapid e (Aegerion Pharmaceuticals, Cambridge, MA) as an adjunct to a low-fat diet and other lipid-lowering drugs, with or without LDL apheresis, to reduce LDL-cholesterol levels in patients with homozygous FH.

In contrast with lomitapide, an oral agent, mipomersen would be available as a 200-mg once-weekly subcutaneous injection. Mipomersen also differs in its mechanism of action, the drug being a first-in-class antisense oligonucleotide (ASO) inhibitor that targets apoB-100. Today, however, the panel wasn't quite as sold on the benefits of mipomersen, questioning the drug's relatively "modest" reductions in LDL-cholesterol levels, but felt the drug did provide benefit in the extremely rare but difficult-to-treat homozygous-FH population.

Dr Erica Brittain (National Institutes of Health, Bethesda, MD) said she voted yes, "but it was a very close call because of the uncertainty about the risk/benefit [trade-off], and it mainly came down to the fact that there would be patients who would have a dramatic response to mipomersen. It didn't seem fair to not make it available for those patients."

Similarly, Dr Edward Gregg (Centers for Disease Control and Prevention, Atlanta, GA) also voted in favor of mipomersen, given that the risk for major clinical cardiovascular events is extremely high in homozygous-FH patients. On the other hand, it is a small group of patients, and they should be able to be monitored closely. "Within that context, we view the efficacy a bit differently," he said. "Even if a third of the group responded very well, then that's a major success."

The trials leading to approval

In the pooled phase 3 clinical trials, 261 individuals with FH were randomized to treatment with mipomersen. In these four trials, the percent reduction in LDL-cholesterol levels from baseline to week 26 ranged from 24.7% to 36.9%. One study included patients with homozygous FH, while the other three trials included individuals with severe hypercholesterolemia treated with maximum baseline therapy, individuals with heterozygous FH and coronary artery disease on a maximally tolerated statin, and individuals with high cardiovascular disease risk on a maximally tolerated statin, respectively.

In the study that included 34 patients with homozygous FH, the reduction in LDL cholesterol from baseline was 24.7% and the treatment difference compared with placebo was a 21.4% reduction in LDL cholesterol. However, there was a wide variability in treatment response in these patients, which ranged from a 2% increase to an 82% decrease in LDL-cholesterol levels. Panel members felt the treatment response with mipomersen was modest and said there was a need to understand the factors or patients who would respond best to the drug.

The panel members also grappled with the safety of mipomersen, with many concerned about the potential for liver-related adverse effects, including elevations in hepatic transaminases and hepatic steatosis that were observed in the mipomersen-treated patients. Commonly reported adverse events also included cardiac disorders, such as angina and palpitations, which caused some concern given that the drug is designed to lower LDL cholesterol to prevent cardiovascular events. There were also concerns about inflammatory and immunological changes.

Panel chair Dr Abraham Thomas (Henry Ford Hospital, Detroit, MI) said he had a hard time with his decision but voted against approval. Although homozygous FH is a rare disease and patient stories are hard to listen to, the reduction in LDL lowering was less than he would have liked in light of the hepatic concerns.

Noting that five patients had liver biopsies prompted by increases in hepatic fat, "we are actually able to have more information and we're able to see some steatohepatitis," said Thomas. "The fact that it occurred so soon after the initiation of the drug makes me concerned that this isn't something we're going to see in 20 or 30 years, but maybe this is something we're going to see the effects of in five years. And then really, the trade-off between cardiovascular risk and liver disease is narrower than I would have liked."

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