Cerliponase

INDICATIONS AND USAGE BRINEURA is indicated to slow the loss of ambulation in pediatric patients with neuronal ceroid lipofuscinosis type 2 (CLN2 disease), also known as tripeptidyl peptidase 1 (TPP1) deficiency. BRINEURA is a hydrolytic lysosomal N-terminal tripeptidyl peptidase indicated to slow the loss of ambulation in pediatric patients with neuronal ceroid lipofuscinosis type 2 (CLN2 disease), also known as tripeptidyl peptidase 1 (TPP1) deficiency. ( 1 )

DOSAGE AND ADMINISTRATION Administration of BRINEURA should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. ( 2.1 ) BRINEURA should be administered by or under the supervision of a physician experienced in intraventricular administration. ( 2.1 ) Premedication of patients with antihistamines with or without antipyretics or corticosteroids is recommended. ( 2.1 ) Prior to each infusion, inspect the scalp for signs of intraventricular access device reservoir leakage, failure, or potential infection. ( 2.1 ) Recommended BRINEURA dosage is 300 mg administered once every other week as an intraventricular infusion. In patients less than 2 years of age, lower doses are recommended. ( 2.2 ) Dosing is not recommended in patients less than 37 weeks post-menstrual age or those weighing less than 2.5 kg. ( 2.2 ) See the full prescribing information for dosage modifications due to hypersensitivity reactions. ( 2.3 ) See the full prescribing information for preparation and administration instructions. ( 2.4 , 2.6 ) 2.1 Recommendations Prior to BRINEURA Treatment Administration of BRINEURA should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Initiate BRINEURA in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment [see Warnings and Precautions (5.1) ] . BRINEURA should be administered by or under the supervision of a physician experienced in intraventricular administration via a surgically implanted intraventricular access device system which consists of the reservoir and catheter components [see Dosage and Administration (2.6) ] . Premedication of patients with antihistamines with or without antipyretics or corticosteroids is recommended 30 to 60 minutes prior to the start of infusion [see Warnings and Precautions (5.1 , 5.5) ] . Aseptic technique must be strictly observed during preparation and administration [see Dosage and Administration (2.6) ] . Prior to each infusion of BRINEURA, inspect the scalp for signs of intraventricular access device reservoir leakage, failure or potential infection [see Warnings and Precautions (5.2 , 5.3) ] . Prior to each infusion of BRINEURA and when clinically indicated, obtain a sample of CSF for cell count and culture [see Warnings and Precautions (5.2) ] . Replace the intraventricular access device reservoir prior to 4 years of single-puncture administrations [see Warnings and Precautions (5.3) ]. 2.2 Recommended Dosage and Administration The recommended dosage of BRINEURA in pediatric patients is provided in Table 1. The dose is administered once every other week by intraventricular infusion. BRINEURA is not recommended in patients less than 37 weeks post-menstrual age (gestational age at birth plus post-natal age) or those weighing less than 2.5 kg [see Use in Specific Populations (8.4) ]. Administer BRINEURA first followed by infusion of the Intraventricular Electrolytes. The complete BRINEURA infusion, including the required infusion of Intraventricular Electrolytes, is approximately 2 to 4.5 hours, depending on the dose and volume administered. See Table 1 for the appropriate volume and infusion rate. For volumes that are not whole numbers, see Dosage and Administration (2.6) . Table 1: BRINEURA Dose, Volume, and Infusion Rate by Age Age groups BRINEURA dose administered every other week Volume of BRINEURA solution Infusion rate Birth to < 6 months 100 mg 3.3 mL 1.25 mL/hr 6 months to < 1 year 150 mg 5 mL 2.5 mL/hr 1 year to < 2 years 200 mg (first 4 doses) 6.7 mL (first 4 doses) 2.5 mL/hr 300 mg (subsequent doses) 10 mL (subsequent doses) 2 years and older 300 mg 10 mL 2.5 mL/hr Missed Dose If one or more doses are missed, restart BRINEURA treatment as soon as possible, maintaining the 2-week interval between infusions thereafter. 2.3 Administration Modifications due to Hypersensitivity Reactions Including Anaphylaxis In the event of a severe hypersensitivity reaction (e.g., anaphylaxis), immediately discontinue BRINEURA administration and initiate appropriate medical treatment. If the decision is made to readminister BRINEURA after the occurrence of anaphylaxis, initiate the subsequent infusion at approximately one-half the infusion rate at which the anaphylactic reaction occurred with appropriate premedication. For additional recommendations in the event of a hypersensitivity reaction, see Warnings and Precautions (5.1) . 2.4 Preparation Instructions for Intraventricular Administration of the Product BRINEURA and the Intraventricular Electrolytes must only be administered by the intraventricular route, using the provided Administration Kit for use with BRINEURA. Each vial of BRINEURA and Intraventricular Electrolytes is intended for a single dose only. BRINEURA is administered into the cerebrospinal fluid (CSF) by infusion via a surgically implanted reservoir and catheter (the "intraventricular access device system"). BRINEURA is intended to be administered via the Codman ® HOLTER RICKHAM Reservoirs (Part Numbers: 82-1625, 82-1621, 82-1616) with the Codman ® Ventricular Catheter (Part Number: 82-1650). The intraventricular access device reservoir and catheter must be implanted prior to the first infusion. It is recommended that the first dose be administered at least 5 to 7 days after device implantation. BRINEURA is intended to be administered with the B Braun Perfusor ® Space Infusion Pump System (Product Code: 8713030U). If an alternative pump must be used, the essential performance requirements for this syringe pump used to deliver BRINEURA are as follows: Delivery rate of 1.25 or 2.5 mL per hr with delivery accuracy of +/- 1 mL per hr Compatible with 20 mL syringes provided in the Administration Kit for use with BRINEURA Occlusion alarm setting to ≤ 281 mm Hg Cleared for intraventricular route of administration Administer BRINEURA and the Intraventricular Electrolytes using the provided Administration Kit for use with BRINEURA components [see How Supplied/Storage and Handling (16) ] . Each infusion consists of 3.3 to 10 mL of BRINEURA followed by 2 mL of Intraventricular Electrolytes. The complete infusion must be administered using an infusion set with a 0.2 micron inline filter. The Intraventricular Electrolytes are used to flush the infusion line, port needle, and intraventricular access device in order to fully administer BRINEURA and to maintain patency of the intraventricular access device. Supplies for Infusion Preparation BRINEURA and Intraventricular Electrolytes Injection vials (package 1 of 2) [see How Supplied/Storage and Handling (16) ] Administration Kit for use with BRINEURA (package 2 of 2) [see How Supplied/Storage and Handling (16) ] Syringe pump (not supplied) Empty sterile single-use luer lock syringe, no larger than 3 mL (not supplied) Inspect the Administration Kit infusion components to ensure the components are in the individual packages and have not been compromised. Thaw BRINEURA and Intraventricular Electrolytes Injection vials at room temperature 20°C to 25°C (68°F to 77°F) for approximately 60 minutes. Do not thaw or warm vials any other way. Do not shake vials. Condensation will occur during thawing period. Do not re-freeze vials or freeze syringes containing BRINEURA or Intraventricular Electrolytes. Inspect fully thawed BRINEURA and Intraventricular Electrolytes Injection vials. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. BRINEURA is a clear to slightly opalescent and colorless to pale yellow solution. Intraventricular Electrolytes is a clear to colorless solution. Do not use if the solutions are discolored or if there is other foreign particulate matter in the solutions. BRINEURA vials may occasionally contain thin translucent fib

WARNINGS AND PRECAUTIONS Meningitis and Other Intraventricular Access Device-Related Infections : Monitor the device insertion site for signs of infection. ( 4 , 5.2 ) Intraventricular Access Device-Related Complications : Consult a neurosurgeon for any complications with the implanted device. In case of device-related complication, discontinue the infusion and refer to the device labeling for further instructions. ( 4 , 5.3 ) Cardiovascular Adverse Reactions : Monitor vital signs before, during, and post-infusion. Monitor Electrocardiogram (ECG) in patients with a history of bradycardia, conduction disorder, or with structural heart disease, during the infusion. In patients without cardiac abnormalities, perform regular 12-lead ECG evaluations every 6 months. ( 2.5 , 5.4 ) Infusion-Associated Reactions (IARs) : If an IAR occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or administering antihistamines and/or antipyretics may ameliorate the symptoms. ( 5.5 ) 5.1 Hypersensitivity Reactions Including Anaphylaxis Life-threatening hypersensitivity reactions including anaphylaxis have been reported in patients treated with enzyme replacement therapies, including BRINEURA . BRINEURA-treated patients have had these reactions occur in clinical studies and postmarketing use [see Adverse Reactions (6) ] . In clinical Trial 1 and Trial 2 to 96 weeks, a total of 11 of 24 (46%) patients experienced hypersensitivity reactions during the infusion or within 24 hours of completion of the infusion. Patients in clinical trials were routinely pre-medicated with antihistamines with or without antipyretics or corticosteroids, prior to infusion of BRINEURA. During postmarketing use, anaphylactic reactions occurred during or within several hours of BRINEURA infusion. Epinephrine was administered in these patients, and they received subsequent BRINEURA infusions without recurrence of anaphylaxis. In Trial 3, hypersensitivity reactions were reported in 5 of 8 (63 %) patients less than 3 years of age at baseline as compared to 0 of 6 patients ≥ 3 years of age at baseline [see Adverse Reactions (6.1) ] . Of the reported hypersensitivity reactions, a single anaphylactic reaction occurred in a subject < 3 years of age. Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Administration of BRINEURA should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Initiate BRINERUA in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. Premedication of patients with antihistamines with or without antipyretics or corticosteroids is recommended 30 to 60 minutes prior to the start of infusion. Observe patients closely during and after the infusion. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue BRINEURA and immediately initiate appropriate medical treatment including use of epinephrine. Inform patients and caregivers of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur. The management of hypersensitivity reactions should be based on the severity of the reaction and may include temporarily interrupting the infusion, and/or treatment with antihistamines, antipyretics, and/or corticosteroids. Consider the risks and benefits of readministration of BRINEURA following an anaphylactic reaction. If the decision is made to readminister BRINEURA after the occurrence of anaphylaxis, ensure appropriately trained personnel and equipment for emergency resuscitation (including epinephrine and other emergency medicines) are readily available during infusion. Initiate subsequent infusion at approximately one-half the initial infusion rate at which the anaphylactic reaction occurred. 5.2 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. Additionally, in clinical trials and during postmarketing use there were reports of other device-related clinical infections which were confirmed by positive CSF cultures, treated with antibiotics and removal of the entire intraventricular access device, and in which patients resumed treatment with BRINEURA after the device was replaced [see Adverse Reactions (6.1) ] . In all cases, antibiotics were administered, the intraventricular access devices were removed and replaced, and patients resumed treatment with 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 supervision of, a physician experienced in intraventricular administration. Prior to each infusion of BRINEURA and when clinically indicated, obtain a sample of CSF for cell count and culture. Do not administer BRINEURA if there are localized signs of infection on or around the device insertion site, such as erythema, tenderness, or discharge or suspected or confirmed CNS infection (e.g., cloudy CSF or positive CSF gram stain, or meningitis) [see Contraindications (4) ] . Healthcare providers should be vigilant for the development of signs and symptoms of infection, including meningitis, during treatment with BRINEURA and monitor the device insertion site for signs of infection. 5.3 Intraventricular Access Device-Related Complications During the clinical trials 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) [see Adverse Reactions (6.1) ] . For any complications with the implanted intraventricular access device, consult with a neurosurgeon to confirm the integrity or performance of the device. In case of intraventricular access device-related complications, discontinue the BRINEURA infusion and refer to the device manufacturer's labeling for further instructions [see Contraindications (4) ] . 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 benchtop 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. 5.4 Cardiovascular Adverse Reactions Monitor vital signs (blood pressure, heart rate) before infusion starts, periodically during infusion, and post-infusion in a healthcare setting [see Dosage and Administration (2.6) ] . Upon completion of the infusion, clinically assess the patient status. Continued observation may be necessary if clinically indicated. Perform electrocardiogram (ECG) monitoring during infusion in patients with a history of bradycardia, conduction disorder, or with structural heart disease, as some patients with CLN2 disease may develop conduction disorders or heart disease. In patients without cardiac abnormalities, regular 12-lead ECG evaluations should be performed every 6 months. In clinical Trial 1 and Trial 2 to 96 weeks, hypotension was reported in 2 of 24 (8%) patients, which occurred during or up to eight hours after BRINEURA infusion. Patients did not require alteration in treatment, and reactions resolved spontaneously or after intravenous fluid administration [see Adverse Reactions (6.1) ] . 5.5 Infusion-Associated Reactions Infusion-associated reactions (IARs) such as vomiting, seizure, rash, pyrexia, hypersensitivity, and anaphylactic reaction have been obse

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) [see Warnings and Precautions (5.2) ] . any acute intraventricular access device-related complication (e.g., leakage, extravasation of fluid, or device failure) [see Warnings and Precautions (5.3) ]. ventriculoperitoneal shunts. Any sign or symptom of acute or 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). ( 4 ) Any acute intraventricular access device-related complication (e.g., leakage, extravasation of fluid, or device failure). ( 4 ) Patients with ventriculoperitoneal shunts. ( 4 )

ADVERSE REACTIONS The following adverse reactions are described below and elsewhere in the labeling: Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions (5.1) ] Meningitis and Other Intraventricular Access Device-Related Infections [see Warnings and Precautions (5.2) ] Intraventricular Access Device-Related Complications [see Warnings and Precautions (5.3) ] Cardiovascular Adverse Reactions [see Warnings and Precautions (5.4) ] Infusion-Associated Reactions [see Warnings and Precautions (5.5) ] Most common adverse reactions (≥8%) are: pyrexia, ECG abnormalities, decreased CSF protein, vomiting, seizures, device-related complications, hypersensitivity, increased CSF protein, hematoma, headache, irritability, pleocytosis, device-related infections, bradycardia, feeling jittery, and hypotension. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact BioMarin at 1-866-906-6100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Trial 1 and Trial 2 The safety of BRINEURA was evaluated in 24 patients with CLN2 disease who received at least one 300 mg dose of BRINEURA given by intraventricular infusion in a clinical trial with extension (Trials 1 and 2) of up to 161 weeks [see Clinical Studies (14) ] . Table 2 summarizes the most common adverse reactions that occurred in BRINEURA-treated patients through 96 weeks. Table 2: Adverse Reactions Reported in ≥ 8% of Symptomatic Pediatric Patients with CLN2 Disease in BRINEURA Trial 1 and Trial 2 at Week 96 Adverse Reaction Patients Treated with BRINEURA n=24 (%) Increased body temperature Increased body temperature includes: increased body temperature and pyrexia 17 (71) ECG abnormalities ECG abnormalities include: non-specific repolarization abnormality, notched QRS, ST segment elevation, biphasic T wave abnormality, supraventricular extrasystoles, bradycardia, sinus tachycardia, and intraventricular conduction delay 17 (71) Decreased CSF protein 17 (71) Vomiting 15 (63) Seizures Seizures include: atonic, generalized tonic-clonic, focal, and absence 12 (50) Device-related complications Device-related complications include device-related infection, delivery system-related complications (needle issues, device leakage, device malfunction, device difficult to use, medical device site irritation, device breakage, etc.) and pleocytosis. 12 (50) Hypersensitivity Hypersensitivity includes only hypersensitivity [see Warnings and Precautions (5.4) ] 9 (38) Increased CSF protein 5 (21) Hematoma 5 (21) Headache 4 (17) Irritability 4 (17) Pleocytosis 4 (17) Device-related infections Device-related infections include: Propionibacterium acnes and Staphylococcus epidermidis 2 (8) Bradycardia 2 (8) Feeling jittery 2 (8) Hypotension 2 (8) Description of Selected Adverse Reactions from Trial 1 and Trial 2 at 96 weeks Seizures Seizures were reported in 12 of 24 (50%) patients. The seizure types reported include atonic, generalized tonic-clonic, focal, and absence. Seizures were managed with standard anti-convulsive therapies and did not result in discontinuation of BRINEURA treatment. Device-Related Complications Adverse reactions related to the device were observed in 12 of 24 (50%) of patients. Device-related adverse reactions include infection, delivery system-related complications, and pleocytosis. Nine out of 24 patients (38%) experienced adverse reactions, which involved complications of the non-implanted delivery system components. Four out of 24 patients (16%) had device-related adverse reactions, which required medical intervention, including two patients (8%) with intraventricular access device-related CNS infections, and one patient (4%) each with leakage of the intraventricular access device and pleocytosis. Device-related infections were diagnosed by increased CSF pleocytosis and microbiology culture and organism identification, without accompanying signs and symptoms of meningitis. Intraventricular access devices were replaced and infections were treated with antibiotics . Device-related complications did not result in discontinuation of BRINEURA treatment. Hematoma Hematoma adverse reactions were reported in 5 of 24 (21%) patients treated with BRINEURA and presented as hematoma, post procedural hematoma, traumatic hematoma and subdural hematoma. Hematomas did not require treatment and did not interfere with BRINEURA infusion. Hypersensitivity Hypersensitivity reactions were reported in 11 out of 24 patients (46%) treated with BRINEURA during or within 24 hours after completion of the BRINEURA infusion, despite pre-medication with antihistamines with or without antipyretics or corticosteroids. The most common manifestations observed concomitantly with hypersensitivity included pyrexia with vomiting, pleocytosis, or irritability, which are not consistent with classic immune mediated hypersensitivity. Symptoms resolved over time or with administration of antipyretics, antihistamines and/or corticosteroids and no patient discontinued treatment with BRINEURA. One patient experienced hypoxia (decreased oxygen saturation less than 88% by pulse oximeter), 8 hours after BRINEURA infusion, followed by a low mean arterial pressure at 15 hours post infusion. Symptoms resolved after oxygen administration, airway repositioning and normal saline infusion. One patient reported decreased oxygen saturation (90% by pulse oximeter), 45 minutes after starting BRINEURA with associated low diastolic blood pressures. Hypoxia resolved after oxygen administration. No treatment was administered for the low diastolic blood pressure, which returned to normal while the patient continued to receive BRINEURA infusion without change to the infusion rate or dose. Trial 3 Trial 3 enrolled 14 patients aged 1 to 6 years at baseline who received BRINEURA at the recommended dose based on the age of the patient, every other week for a median of 142 weeks. Adverse reactions that occurred in at least 5% of patients are described in Table 3. The most frequent adverse reactions reported in patients < 3 years treated with BRINEURA were similar to those observed in patients ≥ 3 years of age except for hypersensitivity reactions, which were reported in 5 of 8 (63%) in patients < 3 years at baseline compared with 0 of 6 in patients ≥ 3 years of age at baseline. The most common manifestations of hypersensitivity were pyrexia and vomiting and the timing and resolution were similar to Trials 1 and 2. Symptoms of severe hypersensitivity reactions (e.g., anaphylaxis) included tachycardia, bronchospasm, rash, diarrhea, hypotension, increased body temperature and vomiting. Drug-related IARs In Trial 3, 12 patients (86%) who received BRINEURA had 83 IARs. Of those, 8 patients were < 3 years of age and 4 were ≥ 3 years of age. The symptoms occurring in more than one patient consisted of vomiting, seizure, rash, pyrexia, hypersensitivity, and abnormal electrocardiogram. Eight (57%) patients had serious IARs: pyrexia, hypersensitivity, anaphylactic reaction, seizure, and pleocytosis. Device-related IARs In Trial 3, 3 patients (21%) who received BRINEURA had 3 IARs related to the intraventricular device. Of those, 2 were < 3 years of age and 1 was ≥ 3 years of age. The events were: device leakage, device breakage, and CSF red blood cell count positive. One (7%) patient had a serious IAR of device leakage. Table 3: Adverse Reactions Reported in ≥ 5% of Pediatric Patients (1 to 6 years of age) with CLN2 Disease treated with BRINEURA in Trial 3 Adverse Reaction Age 1 to 3 years n=8 (%) Age 3 to 6 years n=6 (%) Total n=14 (%) Note: Incidence numbers are based on baseline age group ECG abnormalities ECG abnormalities include: non-specific repolarization abnormality

Mechanism of Action CLN2 disease is a neurodegenerative disease caused by deficiency of the lysosomal enzyme tripeptidyl peptidase-1 (TPP1), which catabolizes polypeptides in the CNS. TPP1 has no known substrate specificity. Deficiency in TPP1 activity results in the accumulation of lysosomal storage materials normally metabolized by this enzyme in the central nervous system (CNS), leading to progressive decline in motor function. Cerliponase alfa (rhTTP1), a proenzyme, is taken up by target cells in the CNS and is translocated to the lysosomes through the Cation Independent Mannose-6-Phosphate Receptor (CI-MPR, also known as M6P/IGF2 receptor). Cerliponase alfa is activated in the lysosome and the activated proteolytic form of rhTPP1 cleaves tripeptides from the N-terminus of proteins.