Dr. Ahmed
Drug: Lomitapide
Brand Names: Juxtapid, Lojuxta
Manufacturer: Aegerion Pharmaceuticals [Ref]
Date of Approval: 2012
Primary Indication: Homozygous Familial Hypercholesterolemia
Lomitapide (Juxtapid) is an oral medicine, taken once daily, that has been approved for the treatment of patients with Homozygous Familial Hypercholesterolemia.
Homozygous Familial Hypercholesterolemia (HoFH) is an autosomal recessive disorder that manifests early in childhood.
It is a severe form of lipid disorder that is associated with early (in childhood) cardiovascular diseases such as angina and myocardial infarction.
On the other hand, Heterozygous Familial Hypercholesterolemia (HeFH) is a relatively milder form of the disease manifesting in adult life.
The table below summarizes the key differences between the homozygous and the heterozygous variants of Familial Hypercholesterolemias:
Characteristic |
HoFH |
HeFH |
| Inheritance pattern | Autosomal recessive | Autosomal dominant |
| Cholesterol levels | LDL cholesterol usually >400 mg/dl | LDL cholesterol usually >190 mg/dl |
| Onset of symptoms | Symptoms appear in childhood | Symptoms appear in adult life |
| Severity of symptoms | Severe | Less severe |
| Treatment | Requires aggressive treatment, such as LDL apheresis or liver transplant | Can be managed with medications |
| Prognosis | Higher risk of heart disease and other complications | Lower risk of complications |
Drugs approved for the treatment of Homozygous Familial Hypercholesterolemia:
Statins don’t work here. Only a few drugs have been approved and are effective in lowering LDL cholesterol and the risk of cardiovascular diseases. These include:
- Mipomersen (Kynamro)
- Lomitapide (Juxtapid)
- Evolocumab (Repatha) and Alirocumab (Praluent)
A summary of the above three drugs approved for the treatment of Homozygous Familial Hypercholesterolemia is given in the table below:
Characteristic |
Mipomersen |
Lomitapide |
Evolocumab/Alirocumab |
| Drug class | Antisense oligonucleotide | Microsomal triglyceride transfer protein inhibitor | PCSK9 inhibitor |
| Mechanism of action | Reduces production of apolipoprotein B | Inhibits assembly and secretion of LDL cholesterol | Blocks PCSK9 protein, increasing the number of LDL receptors in the liver |
| Administration | Subcutaneous injection once a week | Oral capsule once a day | Subcutaneous injection every two to four weeks |
| Common side effects | Injection site reactions, flu-like symptoms, liver problems | Nausea, diarrhea, vomiting, liver problems | Injection site reactions, flu-like symptoms |
| Approved indications | HoFH | HeFH | HoFH, HeFH, and other high-risk patients with elevated LDL cholesterol levels |
| Use with other drugs | Yes | Yes | Yes |
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Lomitapide (Juxtapid) for the treatment of Hyperlipidemia:
Among the available drugs for the treatment of HoFH (Homozygous Familial Hypercholesterolemia), Lomitapide is the only medicine that is available in an oral capsule formulation.
It has a different mechanism of action than statins and other lipid-lowering drugs. Lomitapide blocks the assembly of apo-B-containing lipoproteins and the secretion of LDL by inhibiting the key protein, MTP (microsomal triglyceride transfer protein).
Lomitapide blocks the production of VLDl in the liver cells and chylomicrons in the intestine. Chylomicrons are large particles containing various lipid particles including triglycerides. Blocking the assembly and transport of chylomicrons by Lomitapide can result in diarrhea.
Diarrhea is especially bothersome in patients who are taking high amounts of fats in their diet. It is essential, not only to reduce the side effects of Lomitapide but also to lower plasma lipids by reducing dietary fats to less than at least 20% of the total calorie intake per day.
Another important side effect, based on the mechanism of action of Lomitapide, is the deposition of more and more fats in the liver which can damage the liver.
A larger number of patients developed subclinical and clinical hepatitis manifesting as abnormal liver functions (LFTs).
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Efficacy of Lomitapide (Juxtapid) in HoFH:
Lomitapide has been studied in patients who were diagnosed with HoFH. The drug lowers the plasma LDL by up to 50% from the baseline.
It may reduce the need to undergo lipid apheresis which is a kind of procedure in which the lipids (LDL and apolipoprotein B – ApoB particles) in the blood are removed by the mechanism of filtration.
Study 1:
In one study conducted on 75 patients diagnosed with HoFH, Lomitapide administration significantly lowered plasma LDL levels.
The study was conducted for a median duration of 19 months. The following results were obtained:
| LDL-C Reduction | 60% reduction from baseline |
| LDL-C Achieving Target Levels |
|
| LDL Apheresis | 36.8% of patients discontinued |
| Adverse Events | GI side effects in 40% of patients |
| Transaminitis | 13% |
| Hepatic Steatosis | Modest increase observed |
| Liver Stiffness | Remained within the normal range in 30 patients |
| Cardiovascular Events | Lower incidence after 2 years of treatment |
Case reports:
Lomitapide is one of the options for patients with HoFH where lipid apheresis is not available. A report of two patients in Saudi Arabia who were started on Lomitapide treatment resulted in 87% and 45% reduction in the plasma LDL levels.
However, one patient had to discontinue the treatment because of the non-availability of the drug while the other patient died at the age of 26 during a cardiac surgical intervention.
Another small study:
In another small study, comprising 12 patients diagnosed with HoFH, Lomitapide resulted in an LDL reduction of about 28%, however, GI side effects were very common and the primary reason for discontinuing the drug.
The table below summarizes the findings of the study:
Findings |
Results |
| Number of patients | 12 |
| Age | Mean age: 44 ± 18 years |
| Age at HoFH diagnosis | 2 to 59 years |
| Medications | All patients on statin and ezetimibe |
| 5 patients received LDL apheresis | |
| LDL-C reduction with lomitapide | 38% |
Meta-analysis:
A meta-analysis of 18 studies and case reports evaluated the efficacy and safety of Lomitapide in patients with HoFH [Ref].
The results of the meta-analysis are summarized in the table below:
Study |
Sample size |
Age range |
Lomitapide dose |
LDL-C reduction |
Apo B reduction |
AEs |
| Sperlongano et al. | 2 | Not specified | Not specified | 78% (patient 1), 86% (patient 2) | Not specified | Mild GI symptoms |
| Roeters et al. | 4 | Adult | maximum 1.0 mg/kg/d | 35-73% | Not specified | Mild GI symptoms in 3 patients, elevated ALT levels in 1 patient |
| Mahzari et al. | 2 | Not specified | Not specified | 55% | Not specified | No severe AEs |
| Suppressa et al. | 1 | 28 years old | Up to 30 mg/d | Not specified | Not specified | No CVD complications |
| Cuchel et al. | 6 | 18-40 years old | 0.03-1.0 mg/kg/d | 50.9% | 55.6% | Elevated ALT levels and hepatic fat accumulation |
| Stefanutti et al. | 7 | Adult | 5-60 mg/d | >50% (3 patients) | Not specified | Mild GI symptoms |
Note: AEs = adverse events; LDL-C = low-density lipoprotein cholesterol; Apo B = apolipoprotein B; CVD = cardiovascular disease; LA = lipoprotein apheresis; LLT = lipid-lowering therapy
HOFH in Children: Results of the above meta-analysis:
Study |
Patients |
Age Range |
Lomitapide Dose |
LDL-C Reduction |
Apo B Reduction |
Severe AEs |
| Cuchel et al. | 6 | 18-40 | 0.03-1.0 mg/kg/d | 50.9% | 55.6% | Elevated ALT levels and hepatic fat accumulation |
| Stefanutti et al. | 7 | N/A | 5-60 mg/d | >50% reduction in 3 patients | N/A | N/A |
| Ben-omran et al. | 11 | 11.6 ± 1.1 years | 24.5 ± 4.3 mg/d | 6 patients reached LDL <135 mg/dL | N/A | GI side effects and raised ALT |
| Mahzari et al. | 2 | N/A | N/A | 87% | N/A | N/A |
| Kolovou et al. | 1 | 8 years | 2.5-40 mg/d | N/A | N/A | No side effects reported |
| Chacra et al. | 1 | 7.6 years | 20 mg/d | 37% | N/A | Diarrhea, progression of atherosclerosis |
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In Summary:
Although there are availability issues and the drug is very expensive, Lomitapide is one of the key drugs that can significantly lower the LDL cholesterol levels in patients with HoFH (homozygous familial hypercholesterolemia).
Statins in combination with Ezetimibe, lipid apheresis, and PCSK-9 inhibitors are currently being used but most patients respond only partially to these treatments.
In addition, Lipid apheresis is an effective way of lowering LDL cholesterol but its effects last only for two weeks.
PCSK9 inhibitors (Evolocumab and Alirocumab) are other drugs but these are too costly, administered as injections, and not available everywhere.
Lomitapide, especially in combination with Evonocumab, can change the treatment guidelines worldwide in patients with HoFH if it is made available and the costs are lowered.
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