October 18th, 2012

FDA Panel Recommends Approval of Mipomersen for Homozygous Familial Hypercholesterolemia

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee gave a weak endorsement to mipomersen, an antisense oligonucleotide inhibitor manufactured by Genzyme, for use in homozygous familial hypercholesterolemia (FH). With its relatively close 9-6 vote, and with its comments, the committee expressed concerns about both the efficacy and safety of the drug, but ultimately the severity of homozygous FH led the panel to recommend approval.

“We need a toolkit, we need as many options as possible for these patients,” said one panel member.

On Wednesday the same committee voted 13-2 in favor of  a similar indication for lomitapide capsules, manufactured by Aegerion. On both days, panel members strongly urged the FDA to restrict use of lomitapide and mipomersen to patients with homozygous FH and “avoid the slippery slope” of using the drugs in heterozygous FH or in patients with resistant hypercholesterolemia.

Some panel members voiced concern that the clinical trials with mipomersen excluded patients with apheresis. During the section for public comments, Sidney Wolfe said that the trials were unethical for this reason, since apheresis represents the gold standard of treatment for these patients. One panelist responded that though it was an unfortunate exclusion, it was not unethical. A Genzyme spokesperson reported that a trial is now underway looking at mipomersen on top of apheresis.

The panel agreed that mipomersen was effective in lowering cholesterol but felt the reduction was “modest” and that most patients would not reach LDL levels under 100. As with lopitamide, trials were not powered for clinical endpoints. Panelists wondered about the clinical effect of lowering LDL cholesterol from 400 to 300.

The committee did not appear to be greatly concerned about the possibility of a cancer signal brought up in the FDA review. Several panelists thought that the cancer signal may have reflected an ascertainment bias, and, further, that a young homozygous FH population would be less susceptible to an elevated cancer risk. Most of the cancers observed in the clinical trials occurred in elderly patients who did not have homozygous FH.

The biggest obstacle to mipomersen was the question over liver safety. Committee members wrestled with the issue without reaching a consensus, perhaps reflecting their faith (or hope) that the FDA’s proposed Risk Evaluation and Mitigation Strategy (REMS) will work as intended. The program, similar to the one proposed by the FDA for lomitapide, would “educate prescribers about the approved indication for use of mipomersen, the potential risk of hepatotoxicity associated with the use of mipomersen, and the need to monitor patients during treatment with mipomersen as per product labeling.” The REMS would require special certification for health care professionals and pharmacies that prescribe and dispense the drug.

3 Responses to “FDA Panel Recommends Approval of Mipomersen for Homozygous Familial Hypercholesterolemia”

  1. Leon Hyman, Ms M.D. says:

    Adding Zetia to simvastatin and lowering the ldl to 240 didn’t alter outcomes. The panel seemed desperate to try and do something about familial hyper cholesterolemia.

  2. Joel Wolkowicz, MDCM says:

    I hope prescription will indeed be restricted as described above.

  3. Uffe Ravnskov, MD, PhD says:

    A relevant question is, whether cholesterol lowering is the right way to treat people with FH, because several cohort studies of people with FH have shown that the risk of CHD is the same, whether their cholesterol is only a little higher than normal or it is 2-3 times higher (1-7). Another striking observation is that even in homozygous FH, the cerebral arteries are not more atherosclerotic than in normal people (8,9).

    Then what causes atherosclerosis in FH? This is a relevant question, and there is a likely answer. For instance, in a study of 61 people with FH Sugrue et al. found that plasma fibrinogen and factor VIII were significantly higher in the 32 patients with CHD than in the 29 patients without, whereas there were no significant differences in serum lipid concentrations (1). In a more recent study of 1940 people with FH Jansen et al. found that G20210A polymorphism in the prothrombin gene was strongly associated with CHD risk (10).

    Evidently some of the people with FH have inherited other genetic aberrations of more importance than hypercholesterolemia. Hypercoagulability may explain why atherosclerosis in FH is located mainly to the arteries that are exposed to mechanical forces, such as the arteries of the heart and the legs, while premature atherosclerosis is absent in the arteries of the brain. Maybe it would be a better idea to measure these factors in all people with FH and in case they are elevated, treat them with warfarin.

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    5. Kroon AA et al. J Intern Med 1995;238:451-9.
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    7. Jansen AC et al. Arterioscler Thromb Vasc Biol 2005;25:1475-81.
    8. Postiglione A et al. Atherosclerosis 1991;90:23-30.

    9. Rodriguez G et al. Stroke 1994;25:831-6.
    10. Jansen AC et al. Arterioscler Thromb Vasc Biol 2005;25:1475-81.