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 Strategies (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.