Mipomersen Approved in US for Homozygous FH


January 30, 2013

BETHESDA, Maryland — The US FDA has approved mipomersen sodium (Kynamro, Genzyme, Cambridge MA), a once-weekly subcutaneous injection, as an adjunct to maximally tolerated lipid-lowering medications and diet for the treatment of patients with homozygous familial hypercholesterolemia (HoFH) [1].

The decision follows a recommendation from the FDA's Endocrinologic and Metabolic Drugs Advisory Committee, which voted 9 to 6 in favor of approval of mipomersen for this indication in October.

Those who voted against approval did so because of uncertainty as to the risk/benefit trade-off for mipomersen; there were concerns about the variability in LDL lowering seen in the clinical trial of mipomersen in HoFH, as well as worries about malignancies, immune-mediated reactions, and hepatic abnormalities in a range of trials, including the risk of liver toxicity, for which the product carries a boxed warning.

For these reasons, the European Medicines Agency (EMA) last month recommended against approval of mipomersen for the treatment of homozygous and severe heterozygous FH; it also said it did not believe that the cardiovascular benefit of the agent, in terms of reducing cholesterol levels, outweighs its cardiovascular risk: cardiac side effects such as angina and palpitations were also seen in clinical trials.

The FDA is requiring a risk evaluation and mitigation strategy (REMS) for mipomersen in the US, to ensure safe use, and four postmarketing studies must be conducted: an enhanced pharmacovigilance program to monitor reports of malignancy, immune-mediated reactions, and hepatic abnormalities in patients treated with the agent; a long-term registry of patients with HoFH to determine the long-term safety of mipomersen; the development of a sensitive assay that binds double-stranded (ds) DNA; and a study to assess for the presence of antibodies to ds-DNA in patients treated with mipomersen.

Another agent for homozygous familial hypercholesterolemia (FH), lomitapide (Juxtapid, Aegerion Pharmaceuticals), has also recently been approved by the FDA. Lomitapide also carries a boxed warning regarding hepatotoxicity and is available only through a REMS. Aegerion has made a commitment to the FDA to conduct a postapproval, observational cohort study.

Orphan Drug Approval for Homozygous Familial Hypercholesterolemia

HoFH is an extremely rare, difficult-to-treat, inherited disorder that affects about one in a million people in the US, whereby the body is unable to remove LDL cholesterol from the blood. Those with HoFH often suffer MI and death before the age of 30. Because HoFH is so rare, mipomersen is approved as an orphan drug, meaning it was developed to treat a disorder affecting fewer than 200 000 people.

Mipomersen is a first-in-class antisense oligonucleotide (ASO) inhibitor that targets apolipoprotein B-100, and its addition to maximally tolerated lipid-lowering therapy is intended to further reduce LDL-C, as well as other lipids, including apolipoprotein B, total cholesterol, and non-HDL-C.

The FDA approval is based on the largest clinical trial of mipomersen conducted to date in the HoFH patient population, says Genzyme: 34 patients who were already on maximal lipid-lowering therapy were treated with mipomersen and experienced further reductions in LDL-C levels of an average of 113 mg/dL, or 25%, from a treated baseline of 439 mg/dL, compared with the 17 patients treated with placebo. But there was a wide variability in treatment response to mipomersen in this trial, ranging from a 2% increase to an 82% decrease in LDL levels, and this issue was raised during the FDA advisory committee meeting.

Safety data for mipomersen are based on pooled results from four phase 3 trials in which 261 patients received mipomersen for a median of 25 weeks, including the HoFH trial. Treatment was discontinued by 18% of those on mipomersen and 2% of patients on placebo due to adverse reactions.

Genzyme to Resubmit European Application for Hofh Only

Ingrid Mitchell, a spokesperson for Genzyme, told heartwire that the new drug application (NDA) for mipomersen in the US was for homozygous FH only, whereas in the EU the development program was built "looking at a broader patient population," and the marketing application, submitted in July 2011 and subsequently rejected, was for homozygous and severe heterozygous FH.

"What we know now is, given the powerful nature of the drug, it is not something that will be used for a broader patient population, but the benefit/risk really makes sense in the most severe patient population. In the EU, we’re diligently working through the reexamination process . . . seeking an indication in homozygous FH for mipomersen. We expect to have a [European] decision in the second quarter of this year."

There is also a study ongoing in the US, FOCUS FH, she notes, which was designed with the FDA "to provide support for potentially broadening the indication to include severe heterozygous FH. We continue to work toward that goal."