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Mipomersen, an apolipoprotein B synthesis inhibitor administered as a subcutaneous injection once a week, has been approved for treatment of homozygous familial hypercholesterolemia, with a plan that addresses the risk of hepatoxicity associated with treatment.
On Jan. 29, the Food and Drug Administration announced the approval of mipomersen as an adjunct to lipid-lowering medications and diet to reduce LDL cholesterol, apolipoprotein B (apo B), total cholesterol, and non-HDL cholesterol in patients with homozygous familial hypercholesterolemia (HoFH). Because the disease affects fewer than 200,000 people in the United States, it was approved as an orphan drug and will be marketed as Kynamro by Genzyme Corp., which developed the drug with Isis Pharmaceuticals.
This follows the approval of lomitapide (Juxtapid), a microsomal triglyceride transfer protein (MTP) inhibitor approved in December, to reduce LDL cholesterol, total cholesterol, apolipoprotein B, and non-HDL cholesterol in patients with HoFH.
Approval of mipomersen was based on a study of 51 patients with HoFH, according to the FDA announcement. Patients in the study, aged 12-53 years (mean 32 years), had a mean LDL cholesterol level at baseline of 400-439 mg/dL; over 26 weeks, those levels dropped by a mean of almost 25% among those on mipomersen, compared with about 3% in those on placebo, a statistically significant difference. There were also significant reductions in apo B, total cholesterol, and non-HDL cholesterol. The most common adverse reactions in the clinical trial included injection site reactions, flu-like symptoms, nausea, headache, and elevations in serum transaminases,
The label includes a boxed warning regarding the risk of hepatoxicity with treatment, because of elevations in serum transaminases associated with treatment. The warning also states that treatment has been associated with hepatic steatosis, with or without concomitant increases in transaminases, which "may be a risk factor for progressive liver disease, including steatohepatitis and cirrhosis."
The approval comes with a Risk Evaluation and Mitigation Strategy (REMS) with "elements to assure safe use," aimed at educating prescribers about the hepatoxicity risks, the need to monitor patients, and restrict access to the drug to patients with a clinical or laboratory diagnosis of HoFH, according to the FDA. Requirements include certification of prescribers and pharmacies to prescribe and dispense the drug, and a prescription authorization form for each new prescription.
The company is also required to conduct postmarketing studies, including a patient registry to evaluate long-term safety, and an enhanced pharmacovigilance program to monitor malignancies, immune-mediated reactions, and hepatic abnormalities in treated patients.
Mipomersen is the first systemic "antisense" drug to be marketed, according to the Genzyme statement announcing the approval. In the prescribing information, it is described as an "antisense oligonucleotide targeted to human messenger ribonucleic 399 acid (mRNA) for apo B-100, the principal apolipoprotein of LDL and its metabolic 400 precursor, [very-low-density lipoprotein]."
Genzyme has priced mipomersen at about $3,300 per week, according to a company spokesperson. The company has a program to help with reimbursement, including out-of-pocket costs for those who qualify,
In October, an FDA advisory panel voted to support approval of mipomersen for the approved indication, but panelists voting on both sides expressed concerns about the drug’s safety profile, mainly the potential for drug-induced liver injury.