Brineura (cerliponase alfa) clinical study: efficacy results
Brineura (cerliponase alfa) injection for intraventricular use is indicated to slow the loss of ambulation in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase 1 (TPP1) deficiency.
Brineura helped maintain patients’ motor function by slowing the loss of ambulation1
Decline was defined as a sustained 2-point loss or an unreversed score of 0 in the Motor domain of the CLN2 Clinical Rating Scale.1

95% of patients treated with Brineura (21/22) did not show Decline compared to 50% in the natural history cohort (21/42)1
The only Brineura-treated patient deemed to have Decline discontinued from the study after 1 infusion due to inability to continue with study procedures1
Ten Brineura-treated patients experienced 1-point loss on the Motor domain of the CLN2 Clinical Rating Scale while on the 300 mg dose
Brineura is contraindicated in patients with acute intraventricular access device related complications or ventriculoperitoneal shunts. Cardiovascular and hypersensitivity reactions related to Brineura may occur.

Fewer patients treated with Brineura declined vs natural history cohort1
Decline was defined as a sustained 2-point loss or an unreversed score of 0 in the Motor domain of the CLN2 Clinical Rating Scale.1

*94% of Brineura-treated patients (16/17) had no decline in motor function from week 48 through 96.1
Matched-population analysis based on baseline age at time of screening within 3 months, genotype (0, 1, or 2 key mutations), and baseline Motor domain CLN2 score at time of screening1
Brineura-treated patients better maintained motor function over time vs untreated patients1
Cox Proportional Hazards Model adjusted for age, initial motor score, and genotype was used to evaluate time to unreversed 2-point Decline or unreversed score of 0 in the Motor domain.1

Follow-up began at 36 months of age and the first recorded Motor plus Language CLN2 score <6 for the natural history cohort. The Brineura-treated population included all 24 patients, with the exception of the 2 patients whose baseline Motor plus Language CLN2 score was 6.1

Covariates: screening age; screening Motor score; genotype: 0 key mutations (yes/no). In the natural history cohort: “screening age” was the age ( 36 months) when a Motor plus Language CLN2 score <6 was first recorded; “screening Motor score” was the Motor score at the screening age.1

Decline was defined as a sustained 2-point loss or unreversed score of 0 in the Motor domain of the CLN2 Clinical Rating Scale.1

In clinical trials, the most frequently reported adverse reactions ( 8%) were pyrexia, ECG abnormalities, CSF protein decreased, vomiting, seizures, hypersensitivity, CSF protein increased, hematoma, headache, irritability, pleocytosis, device-related infection, bradycardia, feeling jittery, and hypotension.1
Brineura safety profile
The safety of Brineura was evaluated in a clinical study of 24 patients with CLN2 disease.
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References: 1. Brineura [package insert]. Novato, CA: BioMarin Pharmaceutical Inc; 2017.

Brineura® (cerliponase alfa) clinical study: efficacy results

Brineura® (cerliponase alfa) injection for intraventricular use is indicated to slow the loss of ambulation in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase 1 (TPP1) deficiency.
Brineura helped maintain patients’ motor function by slowing the loss of ambulation1
Decline was defined as a sustained 2-point loss or an unreversed score of 0 in the Motor domain of the CLN2 Clinical Rating Scale.1
•
95% of patients treated with Brineura (21/22) did not show Decline compared to 50% in the natural history cohort (21/42)1
–
The only Brineura-treated patient deemed to have Decline discontinued from the study after 1 infusion due to inability to continue with study procedures1
–
Ten Brineura-treated patients experienced 1-point loss on the Motor domain of the CLN2 Clinical Rating Scale while on the 300 mg dose

Brineura is contraindicated in patients with acute intraventricular access device–related complications or ventriculoperitoneal shunts. Cardiovascular and hypersensitivity reactions related to Brineura may occur.

Fewer patients treated with Brineura declined vs natural history cohort1

Decline was defined as a sustained 2-point loss or an unreversed score of 0 in the Motor domain of the CLN2 Clinical Rating Scale.1
*94% of Brineura-treated patients (16/17) had no decline in motor function from week 48 through 96.1
•
Matched-population analysis based on baseline age at time of screening within 3 months, genotype (0, 1, or 2 key mutations), and baseline Motor domain CLN2 score at time of screening1

Brineura-treated patients better maintained motor function over time vs untreated patients1

Cox Proportional Hazards Model adjusted for age, initial motor score, and genotype was used to evaluate time to unreversed 2-point Decline or unreversed score of 0 in the Motor domain.1

Follow-up began at ≥36 months of age and the first recorded Motor plus Language CLN2 score <6 for the natural history cohort. The Brineura-treated population included all 24 patients, with the exception of the 2 patients whose baseline Motor plus Language CLN2 score was 6.1

Covariates: screening age; screening Motor score; genotype: 0 key mutations (yes/no). In the natural history cohort: “screening age” was the age (≥36 months) when a Motor plus Language CLN2 score <6 was first recorded; “screening Motor score” was the Motor score at the screening age.1

Decline was defined as a sustained 2-point loss or unreversed score of 0 in the Motor domain of the CLN2 Clinical Rating Scale.1

In clinical trials, the most frequently reported adverse reactions (≥8%) were pyrexia, ECG abnormalities, CSF protein decreased, vomiting, seizures, hypersensitivity, CSF protein increased, hematoma, headache, irritability, pleocytosis, device-related infection, bradycardia, feeling jittery, and hypotension.1

Brineura safety profile

The safety of Brineura was evaluated in a clinical study of 24 patients with CLN2 disease.
Next section >

Reference: 1. Brineura [package insert]. Novato, CA: BioMarin Pharmaceutical Inc; 2020.

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Brineura safety was evaluated in a clinical study of 24 patients with CLN2 disease
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Indication
Brineura® (cerliponase alfa) injection for intraventricular use is indicated to slow the loss of ambulation in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase 1 (TPP1) deficiency.
Important Safety Information
Contraindications

Brineura is contraindicated in patients with:

  • any sign or symptom of acute, unresolved localized infection on or around the device insertion site (e.g., cellulitis or abscess); or suspected or confirmed CNS infection (e.g., cloudy CSF or positive CSF gram stain, or meningitis)
  • any acute intraventricular access device-related complications (e.g., leakage, extravasation of fluid, or device failure)
  • ventriculoperitoneal shunts
Important Preparation and Administration Information
Brineura must only be administered via the intraventricular route using aseptic technique to reduce the risk of infection. Administer Brineura and the Intraventricular Electrolytes using the provided Administration Kit for use with Brineura components. Prior to each infusion, inspect the scalp for signs of intraventricular access device leakage or failure and for potential infection. Prior to each infusion of Brineura and when clinically indicated, send cerebrospinal fluid (CSF) samples for testing of cell count and culture.
Special Populations

Brineura has not been studied in pregnancy or lactation.

Safety and effectiveness in pediatric patients below 3 years of age have not been established.

WARNINGS AND PRECAUTIONS
Meningitis and Other Intraventricular Access Device-Related Infections
Bacterial meningitis requiring antibiotic treatment and removal of the device was reported during postmarketing use of Brineura. The signs and symptoms of infections may not be readily apparent in patients with CLN2 disease. To reduce the risk of infectious complications, Brineura should be administered by, or under the direction of, a physician experienced in intraventricular administration.
Intraventricular Access Device-Related Complications
During the clinical trial and in postmarketing reports, intraventricular access device-related complications were reported (e.g., device leakage, device failure, extravasation of CSF fluid, or bulging of the scalp around or above the intraventricular access device). In case of intraventricular access device-related complications, discontinue the Brineura infusion and refer to the device manufacturer’s labeling for further instructions.
Material degradation of the intraventricular access device reservoir was reported after approximately 4 years of administration, which may impact the effective and safe use of the device. The intraventricular access device should be replaced prior to 4 years of single-puncture administrations, which equates to approximately 105 administrations of Brineura.
Cardiovascular Adverse Reactions
Monitor vital signs before infusion starts, periodically during infusion, and post-infusion in a healthcare setting. Perform electrocardiogram (ECG) monitoring during infusion in patients with a history of bradycardia, conduction disorder, or with structural heart disease. In patients without cardiac abnormalities, regular 12-lead ECG evaluations should be performed every 6 months.
Hypersensitivity Reactions, Including Anaphylaxis
Hypersensitivity reactions, including anaphylaxis, have been reported in Brineura-treated patients during clinical studies and postmarketing use. In clinical trials, a total of 11 out of 24 patients (46%) experienced hypersensitivity reactions during the infusion or within 24 hours of completion of the infusion.
Due to the potential for anaphylaxis, appropriate medical support should be readily available when Brineura is administered. If a severe hypersensitivity reaction or anaphylaxis occurs, immediately discontinue the infusion and initiate appropriate medical treatment. Observe patients closely during and after the infusion. Inform patients/caregivers of the signs and symptoms of hypersensitivity reactions and anaphylaxis and instruct them to seek immediate medical care should signs and symptoms occur. Consider the risks and benefits of readministration of Brineura following an anaphylactic reaction.
ADVERSE REACTIONS
In clinical trials, the most frequently reported adverse reactions (≥8%) were pyrexia, ECG abnormalities, decreased CSF protein, vomiting, seizures, device-related complications, hypersensitivity, increased CSF protein, hematoma, headache, irritability, pleocytosis, device-related infection, bradycardia, feeling jittery, and hypotension.
Seizures were reported in 12 of 24 patients and included atonic, generalized tonic-clonic, focal, and absence. Seizures were managed with standard anticonvulsive therapies and did not result in discontinuation of Brineura treatment.
Adverse reactions related to the device were observed in 12 of 24 patients. Device-related adverse reactions include infection, delivery system-related complications, and pleocytosis.
Hematoma adverse reactions were reported in 5 patients and presented as hematoma, post-procedural hematoma, traumatic hematoma, and subdural hematoma. Hematomas did not require treatment and did not interfere with Brineura infusion.
Anti-drug antibodies (ADAs) were detected in serum (79%) and CSF (33%) in patients treated with Brineura. No association was found between serum or CSF ADA titers and incidence or severity of hypersensitivity.
To report SUSPECTED ADVERSE REACTIONS, contact BioMarin Pharmaceutical Inc. at 1-866-906-6100, or FDA at 1-800-FDA-1088, or go to www.fda.gov/medwatch.
Please see accompanying full Prescribing Information, or visit www.Brineura.com.
What is Brineura?
Brineura® (cerliponase alfa) is a prescription medication used to slow loss of ability to walk or crawl (ambulation) in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase 1 (TPP1) deficiency.
Who should not take Brineura?
  • Patients with active intraventricular access device-related complications (eg, leakage, device failure, or device-related infection, including meningitis)
  • Patients with any sign or symptom of acute or unresolved localized infection around the device insertion site (eg, cellulitis or abscess) or suspected or confirmed central nervous system (CNS) infection (eg, cloudy cerebrospinal fluid [CSF] or positive CSF gram stain, or meningitis)
  • Patients with shunts used to drain extra fluid around the brain

What is the most important information I should know about Brineura?

Administration: Brineura is only given by infusion into the fluid of the brain (known as an intraventricular injection) and using sterile technique to reduce the risk of infection. An intraventricular access device or port must be in place at least 5 to 7 days prior to the first infusion.

  • Prior to administration, it is important to discuss your child’s medical history with their doctor
  • Tell the doctor if they are sick or taking any medication and if they are allergic to any medicines

Meningitis and other device-related infections: Intraventricular access device-related infections, including meningitis, were observed with Brineura treatment. Infections required treatment with antibiotics and removal of the access device. If any signs of infection or meningitis occur, contact your child’s doctor immediately. The signs and symptoms of infections may not be readily apparent in patients with CLN2 disease.

  • Your child’s doctor should vigilantly be looking for signs and symptoms of infection, including meningitis, during treatment with Brineura
  • Your child’s doctor should inspect the scalp and collect samples of your child’s CSF prior to each infusion of Brineura, to check for infections and that there is no device failure
  • Signs of infection on or around the device insertion site may include redness, tenderness, or discharge
Device-related complications such as device leakage, device failure, extravasation of CSF fluid, or bulging of the scalp around or above the intraventricular access device have occurred. In case of intraventricular access device-related complications, Brineura infusions may be discontinued.
Material degradation of the intraventricular access device reservoir was reported after approximately 4 years of administration, which may impact the effective and safe use of the device. During testing such material degradation was recognized after approximately 105 perforations of the intraventricular access device. The intraventricular access device should be replaced prior to 4 years of single-puncture administrations, which equates to approximately 105 administrations of Brineura.
Cardiovascular side effects: Low blood pressure and/or slow heart rate may occur during and following the infusion of Brineura. Contact your child’s healthcare provider immediately if these reactions occur. As part of the infusion, the healthcare provider will monitor vital signs (blood pressure, heart rate) before infusion starts, periodically during infusion, and post-infusion, and assess the patient’s status after administration to determine if continued observation may be necessary. Additional monitoring is required for patients with a history of cardiac abnormalities. In patients without cardiac abnormalities, regular 12-lead electrocardiogram (ECG) evaluations should be performed every 6 months.
Hypersensitivity reactions including serious and severe allergic reactions (anaphylaxis) may occur. Symptoms of anaphylaxis may include fever, respiratory distress, rash, vomiting, and irritability, and may occur during treatment or within several hours of Brineura infusion. Seek immediate medical care should signs and symptoms of anaphylaxis occur. Your child may receive medication such as antihistamines before Brineura infusions to reduce the risk of reactions.
If anaphylaxis occurs, you and your child’s healthcare providers should consider the risks and benefits of readministration of Brineura. If the decision is made to readminister Brineura after the occurrence of anaphylaxis, the healthcare providers should ensure appropriately trained personnel and equipment for emergency resuscitation (including epinephrine and other emergency medicines) are readily available during infusion and will start the subsequent infusion at approximately one-half the initial infusion rate at which the anaphylactic reaction occurred.

The most common side effects reported during Brineura infusions included:

  • Fever, problems with the electrical activity of the heart, decreased or increased protein in the fluid of the brain, vomiting, seizures, device-related complications, hypersensitivity, collection of blood outside of blood vessels (hematoma), headache, irritability, increased white blood cell count in the fluid of the brain, device-related infection, slow heart rate, feeling jittery, and low blood pressure
The risk information provided here is not comprehensive. Talk to your healthcare provider to learn more or for medical advice about any side effects.
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1–800-FDA-1088.
Please click here to see full Prescribing Information or visit www.Brineura.com.