Lomitapide, mipomersen: Two novel agents for homozygous familial hypercholesterolemia
Juxtapid (lomitapide—Aegerion); Kynamro (mipomersen—Genzyme)
Two novel agents have recently received FDA approval for the management of patients with homozygous familial hypercholesterolemia: lomitapide (Juxtapid—Aegerion) and mipomersen (Kynamro—Genzyme). Lomitapide capsules were approved as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, to reduce LDL cholesterol, total cholesterol (TC), apolipoprotein B (apo B), and non-HDL cholesterol in patients with homozygous familial hypercholesterolemia. Mipomersen, a once-weekly subcutaneous injection, was approved for use as an adjunct to lipid-lowering medications and diet to reduce LDL cholesterol, apo B, TC, and non-HDL cholesterol in the same patient population.
Familial hypercholesterolemia is one of the most common and severe forms of hypercholesterolemia. It is characterized by high levels of LDL cholesterol as a result of reduced function of the LDL-receptor pathway that removes LDL particles from the circulation into the liver. If left untreated, patients usually develop coronary heart disease at an early age.
The cornerstone of treatment for familial hypercholesterolemia includes diet and lifestyle modifications and pharmacotherapy. Maximal doses of statins are commonly used; however, statins require some residual LDL-receptor function, making them ineffective in some patients. Because some patients fail to respond to conventional drug therapies, LDL apheresis is usually required. The approval of lomitapide and mipomersen now offers patients additional treatment options to manage their condition.
Unique mechanisms of action
Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor. MTP resides in the lumen of the endoplasmic reticulum, thereby preventing the assembly of apo B–containing lipoproteins in enterocytes and hepatocytes. This inhibition leads to a reduction in the synthesis of chylomicrons and very low–density lipoprotein, resulting in a reduction in plasma LDL levels. This is the first MTP inhibitor approved by FDA for any indication.
Mipomersen is an oligonucleotide inhibitor of apo B-100 synthesis that reduces LDL cholesterol by preventing the formation of atherogenic lipids. It decreases the production of apo B, which provides the structural core for all atherogenic lipids, including LDL cholesterol, which carry cholesterol through the bloodstream.
Efficacy, safety data
Approval was based on data from a Phase III, single-arm, open-label trial that evaluated the use of lomitapide in 29 adult patients with homozygous familial hypercholesterolemia. Patients were treated with lomitapide at an initial dose of 5 mg daily and gradually escalated to doses of 10 mg, 20 mg, 40 mg, up to 60 mg, based on tolerability and acceptable liver enzyme levels.
Results from the study showed that when lomitapide was added onto existing lipid-lowering treatment, LDL cholesterol was significantly reduced from a baseline average of 336 mg/dL to 190 mg/dL (40% reduction) at week 26. In 23 patients, LDL cholesterol was reduced by an average of 50% at week 26. Some of the more common adverse events, occurring at an incidence of 28% or more, included diarrhea, nausea, vomiting, dyspepsia, and abdominal pain.
The drug was approved with a boxed warning citing the risk of hepatotoxicity. Because of the risk of liver toxicity, lomitapide will only be available through the restricted Juxtapid Risk Evaluation and Mitigation Strategy (REMS) Program. Under the program, only certified health care providers can prescribe the drug, and only certified pharmacies may dispense the medicine. Additional information about this program can be accessed at or at 855-898-2743.
Approval was based on a randomized, double-blind, placebo-controlled, multicenter trial that enrolled patients aged 12 years to 53 years (n = 51) who were maintaining a regimen of maximally tolerated lipid-lowering medications. Results showed that after 28 weeks of therapy, mipomersen further reduced LDL cholesterol levels by an average of 113 mg/dL, or 25%, from a treated baseline of 439 mg/dL, and further reduced all measured endpoints for atherogenic particles. The most common adverse events reported in the trial, occurring at an incidence of 10% or more, included injection site reactions, flu-like symptoms, nausea, headache, and elevations in serum transaminases.
Mipomersen has similar restrictions as lomitapide, as the drug will only be available through the restricted Kynamro REMS Program because of the risk of hepatotoxicity. Under the program, only certified health care providers can prescribe the drug, and only certified pharmacies may dispense the medicine. Additional information about this program can be accessed at or at 877-596-2676.
Some similarities, some differences
Both of these novel agents have a boxed warning for hepatotoxicity and are only available via restricted distribution programs; however, they differ in several key areas. Lomitapide is an oral capsule taken daily, whereas mipomersen is a once-weekly subcutaneous injection; this difference in mode of administration is sure to play a role in patient preference. Another difference is the safety of these agents if used by women of reproductive potential. Lomitapide is a Pregnancy Category X, whereas mipomersen is a Category B agent.
The potential for drug–drug interactions is also significantly different. Lomitapide interacts with numerous agents such as cytochrome P450 3A4 inhibitors, warfarin, select statins, P-glycoprotein substrates, and bile acid sequestrants, while mipomersen has minimal clinically relevant drug–drug interactions. Pharmacists should consider these differences when selecting between the two new agents.
Drug class: Microsomal triglyceride transfer protein inhibitor
Indication: Homozygous familial hypercholesterolemia
Dosage: Initiate treatment with 5 mg once daily, taken orally 2 hours after the evening meal; then increase to 10 mg daily after at least 2 weeks, and then at a minimum of 4-week intervals to 20 mg, then 40 mg, and finally up to a maximum dose of 60 mg/d.
- Dosage modifications are needed for those taking concomitant weak cytochrome P450 (CYP)3A4 inhibitors and those with renal or hepatic impairment; refer to prescribing information for specific recommendations.
Of note: Lomitapide can cause elevations in transaminases, and the label has a boxed warning describing the risk of hepatotoxicity; liver function tests must be monitored closely before initiating treatment and routinely while receiving the drug.
- The drug is contraindicated for patients who are pregnant (i.e., Category X), are receiving concomitant strong or moderate CYP3A4 inhibitors, and for those with moderate or severe hepatic impairment or active liver disease.
- Other warnings and precautions with lomitapide include reduced absorption of fat-soluble vitamins and serum fatty acids, gastrointestinal adverse events, and numerous drug–drug interactions.
Give patients the FDA-approved Medication Guide and review it with them. Educate patients on proper administration, which includes taking the capsules 2 hours after the evening meal and never doubling doses if one is missed. Emphasize the numerous safety concerns, such as the risk of adverse liver and gastrointestinal effects, and the importance of using proper contraceptives for females who are able to get pregnant.
Drug class: Oligonucleotide inhibitor of apolipoprotein B-100 synthesis
Indication: Homozygous familial hypercholesterolemia
Dosage: 200 mg once weekly, administered as a subcutaneous injection. The injection should be given on the same day each week, but if a dose is missed, the injection should be given at least 3 days from the next weekly dose.
- The injection should be administered into the abdomen, thigh region, or outer area of the upper arm.
Of note: Mipomersen can also cause elevations in transaminases, and the label has a boxed warning describing the risk of hepatotoxicity. Liver function tests must be monitored closely before initiating treatment and routinely while receiving the drug.
- The drug is contraindicated for patients with moderate or severe hepatic impairment, those with active liver disease, and patients with known hypersensitivity to any component of the product.
- Other warnings and precautions with mipomersen include injection site reactions and the potential to cause flu-like symptoms.
Give patients the FDA-approved Medication Guide and review it with them. Educate patients on proper administration, which includes injecting the medication subcutaneously once a week into the abdomen, thigh region, or outer area of the upper arm. Inform patients about potential safety concerns such as liver adverse effects, injection site reactions, and flu-like symptoms.