Mipomersen is a novel antisense Oligonucleotide Inhibitor that is indicated for the treatment of familial homozygous hypercholesterolemia who have an inadequate response to statins and PCSK-9 inhibitor therapy (Evolocumab).

Mipomersen Uses:

• Homozygous familial hypercholesterolemia:

  • It is used in the treatment of dyslipidemia as an adjunct to diet, exercise, and other lipid lowering drugs.
  • In patients with homozygous familial hypercholesterolemia, it reduces:
    • low-density lipoprotein cholesterol (LDL-C),
    • total cholesterol (TC),
    • apolipoprotein B (apo B), and
    • non-high-density lipoprotein cholesterol (non-HDL-C)

  • Guideline recommendations:

    • Mipomersen may be especially useful in patients with familial homozygous hypercholesterolemia who are not responsive to PCSK9 inhibitor therapy (Evolocumab).
    • In addition, it may be also be considered in patients with baseline LDL-C exceeding 190 mg/dL and ASCVD who have an inadequate response to statins with or without ezetimibe and PCSK9 inhibitors (evolocumab).

Mipomersen Dose in Adults:

Mipomersen Dose in the treatment of Homozygous familial hypercholesterolemia (HoFH):

• 200 mg subQ once a week.

Note: The maximal LDL-C reduction is seen after about 6 months.

• Missed dose:

  • If a dose is missed, the next dose should be administered at least three days before the next weekly dose.

Dose in Children:

Not indicated

Pregnancy Risk Factor B

• Animal reproduction studies have not shown adverse fetal outcomes.
• Effective contraception should be used during treatment for females in their reproductive years.

Mipomersen use during breastfeeding:

• It is unknown if the drug will be excreted into breastmilk.
• Manufacturers recommend that you weigh the risks to the child from drug exposure and the benefits for the mother.

Mipomersen Dose in Kidney Disease:

• The drug has not been studied in patients with kidney disease.
• The manufacturer has not recommended any dose adjustment in patients with kidney disease.
• The drug should not be administered in patients with severe renal impairment, those with clinically significant proteinuria, or patients who are on hemodialysis.

Mipomersen Dose in Liver disease:

• The drug has not been studied in patients with liver disease.
• The manufacturer has not recommended any dose adjustment in patients with liver disease.
• It should, however, be avoided in patients with moderate to severe liver disease, those with active liver disease, or those patients with persistently unexplained elevated liver enzymes.

Common Side Effects of Mipomersen:

• Central Nervous System:

  • Fatigue
  • Headache

• Dermatologic:

  • Skin Discoloration At Injection Site

• Gastrointestinal:

  • Nausea

• Hepatic:

  • Increased Serum ALT

• Immunologic:

  • Antibody Development

• Local:

  • Injection Site Reaction
  • Erythema At Injection Site
  • Pain At Injection Site
  • Hematoma At Injection Site
  • Itching At Injection Site
  • Swelling At Injection Site

• Respiratory:

  • Flu-Like Symptoms

Less Common Side Effects of Mipomersen:

• Cardiovascular:

  • Hypertension
  • Peripheral Edema
  • Angina Pectoris
  • Palpitations

• Central Nervous System:

  • Chills
  • Insomnia

• Gastrointestinal:

  • Vomiting
  • Abdominal Pain

• Genitourinary:

  • Proteinuria

• Hematologic & Oncologic:

  • Neoplasms

• Hepatic:

  • Increased Serum AST
  • Liver Steatosis
  • Abnormal Hepatic Function Tests
  • Increased Liver Enzymes

• Hypersensitivity:

  • Recall Skin Sensitization

• Neuromuscular & Skeletal:

  • Limb Pain
  • Musculoskeletal Pain

• Miscellaneous:

  • Fever

Contraindications to Mipomersen:

• Hypersensitivity to any drug or component of the formula
• Moderate or severe hepatic impairment (Child Puugh class B orC);
• Active liver disease
• Unexplained persistently high liver enzymes

Warnings and precautions

• Hepatotoxicity: [US Boxed Warning]

  • It is possible for liver damage to occur from its use, manifesting as high levels of liver enzymes.
  • Patients with elevated liver enzymes were most common in clinical trials (ALT > 3x the upper limit of normal).
  • However, concomitant elevations bilirubin or coagulopathy were not observed.
  • Also, hepatic fat was increased either with or without liver enzyme elevations. 
  • Hepatic Steatosis could be a risk factor in progressive liver disease, including cirrhosis or steatohepatitis.
  • Before treatment is initiated, it is important to monitor liver functions (ALT,AST, Total bilirubin and alkalinephosphatase).
  • This should also be done at regular intervals. Transaminitis that exceeds three times the normal upper limit of normal may cause treatment to be stopped.
  • If clinically significant liver damage occurs, treatment may be stopped.
  • Patients should be warned to limit or avoid alcohol intake. Alcohol can cause liver injury and increase hepatic fatty accumulation.
  • The use of concomitant hepatotoxic drug such as isotretinoin, amiodarone, acetaminophen exceeding 4 g/day for >=3 days/week should be avoided.
  • Concomitant use of other lipid-lowering drugs is not recommended, as it may lead to hepatic Steatosis.

• Hypersensitivity

  • Angioedema, rash and urticaria can all be signs of allergic reactions.

• Influenza-like symptoms:

  • Studies showed that 30% of patients experienced influenza-like symptoms within 2 days of receiving the injection.

• Injection site reactions:

  • It is possible for injection site reactions to manifest as tenderness, pain, swelling, itching, swelling, or erythema.
  • To minimize the possibility of these reactions, use a properly administered injection technique.

• Hepatic impairment

  • It has not been tested in patients suffering from liver disease.
  • It should not be used in patients suffering from moderate or severe liver disease (Child Classes B and C), active liver disease and people with persistently elevated liver enzymes that are unrelated.

• Renal impairment

  • Patients with kidney impairment have not been tested. Patients with kidney disease, including dialysis patients, should not use it.
  • Patients with severe renal impairment, patients with clinically significant proteinuria, or those on hemodialysis should avoid it.

Mipomersen: Drug Interaction

Monitoring parameters:

• Before inititiating the treatment, measure ALT, AST, total bilirubin, and alkaline phosphatase, then every month for the first year, followed by every three months after the first year, or frequently if clinically indicated.
• Measure Lipid levels (total cholesterol, LDL-C, HDL-C, and triglycerides every three months for the first year.

How to administer Mipomersen?

• It is available for SubQ administration only.
• Intravenous and Intramuscular administration should be avoided.
• The syringe should be stored in a refrigerator.
• It should be kept at room temperature for at least 30 minutes before administering it.
• The injection should not be co-administered or mixed with other medicines.
• If the contents of the injection become cloudy or particulate matter is visible, it should not be administered.
• The injection should be adminstered in the anterior abdomen, upper thighs or outer arms.
• The injection site should be rotated. Furthermore, administration into skin that is infected, bruised, inflamed, tattooed, scarred, or in areas affected by psoriasis should be avoided.
• The drug should be administered on the same day each week.

Mechanism of action of Mipomersen:

• Mipomersen acts as an oligonucleotide inhibitor of apo B100 synthesis and inhibits lipid bosynthesis. 
• ApoB is LDL-C's main component and very low density lipoprotein, VLDL (precursor to LDL)-C. Mipomersen is a sequence-specific binding agent to the messenger Ribonucleic Acid (mRNA), of apoB.
• This results in degradation (RNaseH-mediated) or disruption, thereby reducing the formation of apoB.

Protein binding:

• More than 90% of the drug is protein-bound.

Metabolism:

• It is metabolized by endonucleases in tissues to form shorter oligonucleotides that are then further available for metabolism by exonucleases

Bioavailability:

• 54% to 78%, however, bioavailability is dose-dependent)

Half-life elimination:

• About 1 to 2 months

Time to peak:

• 3 to 4 hours

Excretion:

• Less than 4% of the drug is excreted in Urine within 24 hours after the dose.

International Brand Names of Mipomersen:

• Kynamro

Mipomersen Brand Names in Pakistan:

No Brands Available in Pakistan.