Recombinant human cerliponase alfa, marketed under the brand name Brineura, is an enzyme replacement therapy used in the treatment of a rare inherited disorder called late infantile neuronal ceroid lipofuscinosis type 2 (CLN2). This disorder is a form of Batten disease, which is a group of rare, inherited neurological disorders that primarily affect children.

Cerliponase alfa works by replacing the deficient enzyme, tripeptidyl peptidase 1 (TPP1), which is responsible for breaking down certain proteins in the cells. In CLN2 disease, mutations in the TPP1 gene lead to a deficiency in this enzyme, causing the accumulation of toxic substances within cells, particularly in the brain's nerve cells.

Recombinant Human Cerliponase Alfa (Brineura) is a recombinant human TPP1 (tripeptidyl peptidase 1 indicated in children with a rare neurodegenerative condition called infantile neuronal ceroid lipofuscinosis type 2 caused by the deficiency of TPP1 enzyme.

Uses:

• Neuronal ceroid lipofuscinosis type 2:
  • In symptomatic pediatric patients with late infantile neuronal ceroid lipofuscinosis type 2 who are under the age of three, the loss of ambulation is postponed (CLN2)

Recombinant human cerliponase alfa Dose in Adults

Not recommended.

Recombinant Human Cerliponase Alfa (Brineura) Dose in Children

Note: Pretreatment should be done with antihistamines +/- antipyretics or corticosteroids 30 minutes or 1 hour before the start of infusion.

Recombinant Human Cerliponase Alfa (Brineura) Dose in the treatment of Neuronal ceroid lipofuscinosis type 2:

• For kids aged 3 years and older, as well as adolescents, with Neuronal ceroid lipofuscinosis type 2, the dose of recombinant human cerliponase alfa is 300 mg (which is 10 mL) every other week.
• This medicine is given through a special device implanted in the brain, called a reservoir, along with an infusion device designed for cerliponase alfa.
• Treatment starts about 5 to 7 days after the device is implanted. After giving cerliponase alfa, another 2 mL of electrolytes (which are included in the administration kit) are also given into the reservoir.
• This therapy requires careful medical attention and expertise because of the way it's given and the special equipment involved.

Pregnancy Risk Category: X

• No studies have been done in animals to see if cerliponase alfa affects reproduction.

Use during breastfeeding:

• It's unclear whether cerliponase alfa can pass into breast milk.
• The manufacturer advises that if a mother is considering breastfeeding while on this therapy, she should weigh the potential risks of exposing her baby to the medication against the benefits of breastfeeding for the baby, as well as the benefits of the treatment for herself.

Dose in Kidney Disease:

• For children aged 3 years and older, as well as adolescents, there are no specific changes to the dosage mentioned in the manufacturer's instructions.

Dose in Liver disease:

• For children aged 3 years and older, as well as adolescents, there are no specific changes to the dosage mentioned in the manufacturer's instructions.

Common Side Effects of Recombinant Human Cerliponase Alfa (Brineura):

• Cardiovascular:
  • ECG Abnormality
• Central Nervous System:
  • Abnormal Proteins In Cerebrospinal Fluid
  • Seizure
  • Abnormal Cerebrospinal Fluid
  • Headache
  • Irritability
• Gastrointestinal:
  • Vomiting
• Hematologic & Oncologic:
  • Hematoma
• Miscellaneous:
  • Fever
• Hypersensitivity:
  • Hypersensitivity Reaction
• Immunologic:
  • Antibody Development

Less Common Side Effects of Recombinant Human Cerliponase Alfa (Brineura):

• Cardiovascular:
  • Bradycardia
  • Hypotension
• Central Nervous System:
  • Jitteriness
• Local:
  • Catheter Infection

Contraindications to Recombinant Human Cerliponase Alfa (Brineura):

• If there is an acute, unresolved localized infection such as cellulitis or an abscess at or near the site where the device is inserted, or if there is a suspected or confirmed infection in the central nervous system (like meningitis, cloudy cerebrospinal fluid, or a positive CSF gram stain), the use of cerliponase alfa should be avoided. Additionally, if there are acute complications related to the intraventricular access device (like leakage, fluid extravasation, or device failure) or if the patient has ventriculoperitoneal shunts, the use of cerliponase alfa is also not recommended.
• The Canadian labeling includes an additional contraindication not found in the U.S. labeling: the use of cerliponase alfa is contraindicated in patients with a severe hypersensitivity to cerliponase or any component of its formulation.

Warnings and precautions

Cardiovascular adverse reactions

• Hypotension, or low blood pressure, has been reported to occur up to 8 hours after the infusion of cerliponase alfa is completed.
• Therefore, it's important to monitor the patient's vital signs during this period.
• Additionally, caution is advised when using cerliponase alfa in patients who have a history of bradycardia (slow heart rate), conduction disorders (problems with the electrical signaling in the heart), or structural heart disease.
• For these patients, monitoring with an electrocardiogram (EKG) during the infusion is recommended to check for any potential heart-related issues.

Complications relating to devices:

• Device-related complications can occur with the use of cerliponase alfa, including leakage from the device, device failure, leakage of cerebrospinal fluid (CSF), and bulging of the scalp near the intraventricular access device.
• It's important to regularly monitor the device for any signs of these issues.
• If any device-related complications are observed, use of cerliponase alfa should be discontinued, and the guidelines provided in the device manufacturer's labeling should be followed for further action.
• Additionally, the material of the intraventricular access device reservoir can degrade over time with prolonged use.
• Therefore, the device should be replaced before reaching 4 years of use or approximately 105 single-puncture administrations to prevent failures and maintain safety.

Device-related infections

• Device-related infections, such as bacterial meningitis and other infections that may require antibiotic treatment and removal of the device, have been noted with the use of cerliponase alfa.
• In cases where infections occurred, patients were typically able to restart treatment after the infections were managed with antibiotics and the intraventricular access device was removed and replaced.
• To prevent and detect these issues, it's recommended to obtain a cerebrospinal fluid (CSF) sample for cell count and culture before each infusion and additionally when clinically necessary.
• This is particularly important because patients with CLN2 disease might not show typical signs and symptoms of infection.
• Monitoring the device insertion site for signs of infection such as redness, tenderness, or discharge is also crucial.
• The use of cerliponase alfa is contraindicated if there are any signs of localized infection at or near the device insertion site, or if there is a suspected or confirmed central nervous system infection, including conditions like meningitis, cloudy CSF, or a positive CSF gram stain.
• This precaution helps to prevent worsening of the infection and potential complications.

Hypersensitivity reactions

• Hypersensitivity reactions to cerliponase alfa can occur, and these reactions may include symptoms such as fever (pyrexia), vomiting, increased white blood cell count in the cerebrospinal fluid (pleocytosis), and irritability.
• These reactions can happen during the infusion and up to 24 hours after it is completed.
• To help reduce the risk of these reactions, it is recommended to pre-treat patients with antihistamines and possibly antipyretics (fever reducers) or corticosteroids about 30 to 60 minutes before starting the infusion.
• This pre-treatment can help manage and mitigate potential allergic reactions associated with the therapy.

Monitoring parameters:

• Vital Signs:
  • Check blood pressure and heart rate before starting the infusion.
  • Monitor these signs periodically during the infusion and after it ends.
• Skin and Device Check:
  • Inspect the skin and device for any signs of infection, leakage, or failure before starting each infusion.
• Cerebrospinal Fluid (CSF) Samples:
  • Collect routine CSF samples before each infusion to check for infections that might not show symptoms.
  • Additional CSF samples may be needed based on clinical signs.
• Heart Monitoring:
  • Perform a 12-lead EKG every 6 months.
  • Monitor with an EKG during infusions if there are known cardiac abnormalities.

How to administer Recombinant Human Cerliponase Alfa (Brineura)?

• Administration Route:
  • Cerliponase alfa is strictly for intraventricular use.
  • It should be administered into the intraventricular space using an infusion pump connected to a surgically implanted reservoir and catheter.
• Before Each Infusion:
  • Inspect the scalp for any signs of leakage or failure of the intraventricular access device.
  • Check for any signs of infection around the device area.
• Infusion Details:
  • Use a 0.2 micron inline filter, which is provided in the administration kit.
  • Infuse the treatment at a rate of 2.5 mL/hour, which totals approximately 4 hours for the complete dose.
• Post-Infusion Procedure:
  • After the cerliponase alfa dose is completed, administer intraventricular electrolytes at the same rate of 2.5 mL/hour. These electrolytes are included in the administration kit.
• Additional Information:
  • Refer to the prescribing information for further details on how to properly administer the intraventricular infusion.

Mechanism of action of Recombinant Human Cerliponase Alfa (Brineura):

• Cerliponase alfa is a proenzyme that becomes active once it's activated.
• It works by cutting off tripeptides from the beginning of proteins.
• This action helps break down the lysosomal storage materials that build up in patients with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2).
• Without this breakdown, these materials accumulate, leading to a decline in motor function over time.
• Intraventricular electrolytes, which are provided in the administration kit, serve an important purpose.
• They're used to flush the infusion line, port needle, and intraventricular access device.
• This flushing helps ensure that cerliponase alfa is fully administered and that the intraventricular access device remains open and working properly.
• Maintaining the patency, or openness, of the device is crucial for effective treatment.

Distribution in Pediatric Patients ≥3 Years:

• Volume of Distribution in Cerebrospinal Fluid (CSF): Median range is 186 to 245 mL.
• With repeated dosing, there's observed decrease in volume over time.

Metabolism:

• Cerliponase alfa is metabolized through peptide hydrolysis.

Elimination Half-life:

• In CSF: Elimination half-life ranges from 6.2 to 7.7 hours.

Time to Peak:

• For Pediatric Patients ≥3 Years:
  • In CSF: Median range is 4.3 to 4.5 hours after the start of infusion.
  • In Plasma: Median range is 12 to 12.3 hours after the start of infusion.

International Brand Names of Recombinant human cerliponase alfa:

• Brineura

Recombinant human cerliponase alfa Brand Names in Pakistan:

No Brands Available in Pakistan.