Rare Disease Report

Current and Emerging Treatments for Homozygous Familial Hypercholesterolemia

DECEMBER 16, 2014
Christina Loguidice

Homozygous familial hypercholesterolemia (HoFH) is an exceedingly rare, life-threatening autosomal dominant disorder characterized by markedly elevated low-density lipoprotein cholesterol (LDL) levels (>500 mg/dL), extensive xanthomas, and marked premature and progressive atherosclerotic cardiovascular disease (CVD) if left untreated. The condition has been reported to affect approximately 1 in 1 million individuals worldwide; however, it is more common in certain populations, including persons of South African, Lebanese, French Canadian, and Finnish descent, and researchers speculate that the condition might be underdiagnosed.
Patients with HoFH inherit 2 mutated genes from their parents, with mutations in the LDL receptor being the most common. Mutations in the alleles of three other genes have also been observed in some individuals: apolipoprotein B (ApoB), proprotein convertase subtilisin/kexin 9 (PCSK-9), and the autosomal recessive hypercholesterolemia adaptor protein (LDLRAP1). Researchers surmise that some genetic mutations contributing to HoFH have yet to be identified.
Treatment guidelines for HoFH generally recommend reducing LDL cholesterol levels by 50% or more, with LDL goals often being stricter in individuals with a history of CVD or at high risk of another cardiovascular condition. To achieve this goal, HoFH treatments may include dietary modification; use of lipid-lowering agents, such as statins, ezetimibe, and bile acid sequestrants; and LDL apheresis, which filters LDL and apolipoprotein particles from the blood, but is costly and time-consuming. Despite such treatments, LDL targets are difficult for many patients with HoFH to achieve, leading to poor outcomes and necessitating liver transplantation in some patients. This has prompted the search for new and more effective treatments for this patient population.

Mipomersen Sodium (Kynamro)

On January 29, 2013, the US Food and Drug Administration (FDA) approved mipomersen injection as an addition to lipid-lowering medications and diet to treat HoFH. Mipomersen, which is an oligonucleotide inhibitor of apolipoprotein B-100 synthesis, helps reduce LDL levels, apolipoprotein B, total cholesterol, and non-high density lipoprotein (non-HDL) cholesterol levels. The safety and effectiveness of mipomersen were evaluated in a clinical trial of 51 patients with HoFH. On average, levels of LDL cholesterol fell by about 25% during the first 26 weeks in those receiving the drug; however, the this agent has not been evaluated as an adjunct to LDL apheresis and is not recommended in this setting. Mipomersen is administered as a once weekly injection.

Lomitapide (Juxtapid)

On December 12, 2012, the FDA approved lomitapide to reduce LDL cholesterol levels, total cholesterol, apolipoprotein B, and non-HDL cholesterol levels in patients with HoFH. Juxtapid is intended for use in combination with a low-fat diet and other lipid-lowering treatments. The safety and effectiveness of lomitapide were evaluated in a clinical trial of 29 patients with HoFH. On average, patients’ LDL cholesterol levels fell by approximately 50% during the first 26 weeks among those who tolerated the drug. Lomitapide is taken as a capsule once daily without food and at least 2 hours after the evening meal. Supplements that contain fat-soluble vitamins and essential fatty acids should be taken daily while a patient is on this treatment.
Of note, mipomersen and lomitapide carry a Boxed Warning regarding a serious risk of liver toxicity. Both of these agents are associated with liver enzyme abnormalities and accumulation of fat in the liver, which could potentially lead to progressive liver disease with chronic use.
Several other treatments are being explored as potential treatments for HoFH, including PCSK9 inhibition, infusion of apolipoprotein A1 mimetic peptides, and mesenchymal stem cell transplantation. Of these, PCSK9 inhibitors are the furthest along in development.

PCSK9 Inhibition  

PCSK9 inhibitors target the PCSK9 protein, which binds to LDL receptors and results in their degradation, making fewer available on liver cells and removing excess LDL cholesterol from the blood. Two PCSK9 inhibitors are currently being evaluated as possible treatments for HoFH: evolocumab, also known as AMG-145, and alirocumab, also known as REGN727/SAR236553. Both agents have shown promising results in clinical trials, but it remains unclear whether PCSK9 inhibition will be effective in patients with HoFH who have minimal or no LDL-receptor function. Nevertheless, there is speculation that these agents will reach the market within a year.

Did you know…

  • Even at maximal statin doses, most patients with HoFH only modestly lower their LDL cholesterol levels, generally by 10% to 25%.
  • Familial hypercholesterolemia is the first genetic disorder shown to cause myocardial infarction.
  • Individuals with familial hypercholesterolemia have a 20 times higher risk of heart disease than those without the condition.

Image of cholesterol courtesy wikimedia commons.

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