Homozygous Familial Hypercholesterolemia (HoFH) is a rare genetic lipid disorder resulting in an accumulation of low-density lipoprotein (LDL-C) often referred to as bad cholesterol in the blood. Patients diagnosed with HoFH have as much as 3-6 times the normal amount of LDL-C even while using lipid-lowering drug treatments. They are at severely high risk of experiencing a heart attack or stroke in their twenties. And if untreated, patients with HoFH generally die before the age of thirty.
HoFH affects both children and adults and is both serious and life-threatening. It is typically caused by a mutation that affects the structure and function of a cell-surface receptor that normally removes LDL from plasma resulting in impaired or total loss of function in the LDL receptor. An LDL receptor is a protein on the surface of cells that is responsible for binding with and removing LDL from the blood. A loss of LDL receptor function results in accumulation of LDL-C in the blood.
Patients with untreated HoFH have extremely high LDL-C levels, typically between 500 mg/dL and 1,000 mg/dL. These patients are at severely high risk of experiencing premature cardiovascular events, such as heart attack or stroke and cholesterol deposits that form xanthomas, a pooling of cholesterol around tendons in the body to such a degree that the swelling in easily visible.
Current Treatments
Aggressive treatments for HOFH include dietary modifications plus a combination of currently approved lipid-lowering drug therapies such as statins and in many cases plasma-apheresis, a mechanical filtration used to remove lipids from the blood. These treatments are nearly always ineffective in reducing LDL-C to recommended levels. There is a significant unmet medical need for patients with these severe forms of hypercholesterolemia, and patients who do not respond to currently available treatments. A potentially effective route of therapy for homozygous familial hypercholesterolemia would be to reduce LDL production in both the liver and intestine.
Aegerion’s product candidate lomitapide, a potent Microsomal Triglyceride Transfer Protein (MTP) inhibitor, is being studied to treat patients with HoFH by lowering the plasma level of LDL-C level beyond reductions seen with standard therapies.
HoFH affects both children and adults and is one of several disorders included in the designation “familial type 2 hyperlipoproteinemia.” HoFH is generally diagnosed clinically based on levels of plasma LDL-C, family history of hypercholesterolemia, premature cardiovascular disease, and poor response to standard drug therapy.
HoFH patients exhibit marked hypercholesterolemia from birth that persists throughout life. They also exhibit unique yellow-orange cutaneous xanthomas, frequently present at birth, and that develop in almost all patients by age 4. Tendon xanthomas, arcus corneae, and generalized atherosclerosis inevitably develop in HoFH patients during childhood. Death from myocardial infarction typically occurs before age 30.
For patients with HoFH and severe hypercholesterolemia, the primary goals of treatment are to lower the plasma level of LDL-C and prevent coronary artery disease. First-line therapy for these patients is a low-fat diet and maximum doses of oral drug therapies to further reduce LDL-C levels as aggressively as possible.
These drug therapies include statins, cholesterol absorption inhibitors and bile acid sequestrants. Less frequently, other drugs, such as niacin and fibrates, can be added to provide some incremental reductions in LDL-C levels. But patients with homozygous familial hypercholesterolemia generally have a poor response to conventional drug therapy. These high-risk patients who are unable to reach their recommended target lipid levels on drug therapy often are supplemented with apheresis. LDL-apheresis is used to physically remove LDL-C lipoproteins. This procedure can reduce LDL cholesterol levels by more than 50% and may delay the onset of atherosclerosis, but it must be repeated as frequently as every 1 to 2 weeks. In addition, this therapy is not available at all medical centers and provides only temporary LDL reductions.