BETHESDA, MD 30 January 2013—FDA on Tuesday approved the marketing of mipomersen sodium injection, or Kynamro, as add-on therapy to lipid-lowering medications and diet for the treatment of homozygous familial hypercholesterolemia.
Isis Pharmaceuticals Inc., which developed mipomersen sodium, declared the drug the first systemic antisense medication to reach the market.
The labeling (PDF) for mipomersen sodium describes the active substance as a strand of 20 nucleotides that is complementary to the coding region in the messenger RNA for apolipoprotein B-100. By binding to that coding region, mipomersen inhibits the synthesis of apolipoprotein B-100, which is the main apolipoprotein in low-density-lipoprotein (LDL) cholesterol and very-low-density-lipoprotein cholesterol.
In the 26-week placebo-controlled study of the drug in 51 patients with homozygous familial hypercholesterolemia, the labeling reports, serum LDL cholesterol concentration decreased by an average of 25% in the 34 patients who received mipomersen sodium 200 mg/wk. Serum concentrations of apolipoprotein B, total cholesterol, and non-high-density-lipoprotein cholesterol also decreased. These patients received the drug by subcutaneous injection in addition to other lipid-lowering medications. None of the patients underwent LDL apheresis.
FDA said the most common adverse events in that study were injection-site reactions, influenza-like symptoms, nausea, headache, and elevations in serum transaminase concentrations.
The boxed warning in the labeling alerts health care professionals to patients' risk for hepatotoxicity as a consequence of the drug's ability to increase serum transaminase concentrations and hepatic fat. The warning also states that the drug is available only through a "restricted program."
According to the drug's medication guide (PDF), the most important information for patients to know about Kynamro is that it is available only through certified pharmacies enrolled in the product's risk evaluation and mitigation strategy (REMS) program. Also, prescribers must be enrolled in that program.
Genzyme Corporation, which will market Kynamro, and Isis said one of the goals of the REMS is to restrict drug access to patients with a clinical or laboratory diagnosis of homozygous familial cholesterolemia.
The labeling recommends a dosage of 200 mg of mipomersen sodium once weekly by subcutaneous injection.
The labeling also provides a schedule for conducting liver-related tests and recommendations for monitoring patients whose alanine transaminase or aspartate transaminase concentration is three times the upper limit of the normal range or greater.
Use of the drug is contraindicated in patients with moderate or severe hepatic impairment or active liver disease.
Because the greatest effect on LDL cholesterol levels during the clinical studies occurred after about six months, the labeling recommends that health care providers assess patients at that time point to determine whether the lipid-lowering effect of the drug warrants the potential risk of hepatotoxicity.
Genzyme will supply Kynamro in single-use vials and ready-to-use syringes designed to provide 1 mL of 200-mg/mL mipomersen sodium injection, which is colorless to slightly yellow.
The vials and syringes must be refrigerated at 2–8 °C until roughly 30 minutes before administration. If refrigeration is not available, the labeling states, the drug containers may be stored at 30 °C or less, away from sources of heat, for up to 14 days. Until use, the vials and syringes should be protected from light and kept in their original carton.
Genzyme has not announced when it plans to make its new product available.