Cerliponase Alfa

1 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 )

2 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 fibers or opaque particles. These naturally occurring particles are cerliponase alfa. These particles are removed via the 0.2 micron inline filter without having a detectable effect on the purity or strength of BRINEURA. Intraventricular Electrolytes may contain particles, which appear during the thaw period; however, these dissolve when the solution reaches room temperature. 2.5 Storage Instructions for the Thawed Product and Product in Syringe Storage of Thawed Product Use thawed BRINEURA and Intraventricular Electrolytes immediately. If thawed BRINEURA and Intraventricular Electrolytes is not used immediately, store in the refrigerator at 2°C to 8°C (36°F to 46°F) for no more than 24 hours. Discard the thawed product after 24 hours if refrigerated. Storage of Product in Syringe Use product held in labeled syringes immediately. If product held in labeled syringe is not used immediately, store in the refrigerator at 2°C to 8°C (36°F to 46°F) for no more than 4 hours prior to infusion. Discard the product held in labeled syringe after 4 hours if refrigerated. 2.6 Administration Instructions for Intraventricular Infusion Intraventricular Infusion of BRINEURA Figure 1 represents the intraventricular infusion system set up. Use aseptic technique during the infusion. Follow the steps below to proceed with the intraventricular infusion. Figure 1 1. Use aseptic technique when preparing the BRINEURA syringe for infusion. Label one sterile syringe "BRINEURA" and attach the syringe needle. 2. Confirm required dose and volume based on patient age per Table 1. Remove the green flip-off caps from one or both BRINEURA vials. Each BRINEURA vial contains 150 mg or 5 mL. Use the "BRINEURA" labeled syringe to withdraw the volume of BRINEURA solution from the vial per the required dose (see Table 1 ). Intermediate volumes that fall between 1 mL increments should be drawn up in the syringe to the nearest whole number, specifically 3.3 mL to 4 mL and 6.7 mL to 7 mL. Do not dilute BRINEURA. Do not mix BRINEURA with any other drug. Discard any unused portion left in the vial. 3. Label the infusion line "intraventricular infusion only" (see Figure 1 ). 4. Attach the syringe containing BRINEURA to the extension line (see Figure 2 ). Then connect the extension line to the infusion set with a 0.2 micron inline filter (see Figure 1 ). Figure 2 5. Prime the infusion components with BRINEURA. 6. Inspect scalp for signs of intraventricular access device reservoir leakage or failure and for potential infections [see Warnings and Precautions (5.2 , 5.3) ]. 7. Prepare the scalp for intraventricular infusion per institution standard of care. 8. Insert port needle into intraventricular access device reservoir (see Figure 3 ). Figure 3 9. Connect a separate empty sterile single-use luer lock syringe, no larger than 3 mL (not provided) to the port needle. Withdraw 0.5 mL to 1 mL of CSF to check patency of intraventricular access device (see Figure 4 ) and send specimen for culture. Do not return CSF to intraventricular access device. Routinely send CSF samples for infection monitoring [see Warnings and Precautions (5.2) ]. Figure 4 10. Attach the infusion set with 0.2 micron inline filter to the port needle (see Figure 1 ). Secure the components per institution standard of care. 11. Place the syringe containing BRINEURA into the syringe pump and program the pump to deliver at an infusion rate of 1.25 or 2.5 mL per hour (Table 1). Set the pump volume limit to deliver the exact volume that corresponds to the dose of BRINEURA solution appropriate for the patient's age (Table 1). Set the occlusion alarm setting to alert at pressure ≤ 281 mm Hg. See syringe pump operating manual for details. Do not deliver as a bolus or manually. 12. Administer pre-medication 30 to 60 minutes prior to the start of infusion . 13. Monitor vital signs (blood pressure, heart rate) prior to the start of infusion, periodically during infusion, and post-infusion [see Warnings and Precautions (5.4) ]. 14. Initiate infusion of BRINEURA at a rate of 1.25 or 2.5 mL per hour (Table 1). 15. Periodically inspect the infusion system during the infusion for signs of leakage or delivery failure [see Warnings and Precautions (5.3) ] . 16. When the BRINEURA infusion is complete, detach and remove the syringe from the pump and disconnect from the tubing (see Figure 5 ). Discard the syringe containing any residual drug. Proceed to Step 16 for Intraventricular Electrolytes infusion. Figure 5 Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Intraventricular Infusion of Intraventricular Electrolytes Administer the Intraventricular Electrolytes provided after BRINEURA infusion is complete. 17. Use aseptic technique when preparing the Intraventricular Electrolytes syringe for infusion. Label one sterile syringe "Intraventricular Electrolytes" and attach the syringe needle. Remove the yellow flip-off cap from the Intraventricular Electrolytes Injection vial. Withdraw 2 mL of Intraventricular Electrolytes. Discard the remaining unused portion. 18. Attach the syringe to the extension line (see Figure 6 ). Figure 6 19. Place the syringe containing Intraventricular Electrolytes into the syringe pump and program pump to deliver at an infusion rate of 1.25 or 2.5 mL per hour (Table 1). Set the pump volume limit to deliver 2 mL. Set the occlusion alarm setting to alert at pressure ≤ 281 mm Hg. See syringe pump operating manual for details. Do not deliver as a bolus or manually. 20. Initiate infusion of Intraventricular Electrolytes at a rate of 2.5 mL per hour. 21. Periodically inspect the infusion system during the infusion for signs of leakage or delivery failure. 22. When the Intraventricular Electrolytes infusion is complete, detach and remove the empty syringe from the pump and disconnect from the infusion line. 23. Remove the port needle. Apply gentle pressure and bandage the infusion site per institution standard of care. Dispose of the infusion components, needles, unused solutions and other waste materials in accordance with local requirements. Figure 6

6 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, supraventricular extrasystoles, possible left ventricular hypertrophy, intermittent 2 nd degree AV Block (type 2 Mobitz), incomplete right bundle branch block, and prominent Q wave. 8 (100) 6 (100) 14 (100) Decreased CSF protein 8 (100) 4 (67) 12 (86) Increased body temperature Increased body temperature includes: increased body temperature and pyrexia. 6 (75) 6 (100) 12 (86) Seizures Seizures include: atonic, febrile convulsion, generalized tonic-clonic, partial, partial with secondary generalization, petit mal epilepsy, myoclonic and status epilepticus. 4 (50) 4 (67) 8 (57) 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.) 3 (36) 2 (33) 5 (36) Vomiting 2 (25) 3 (50) 5 (36) Hypersensitivity Hypersensitivity includes only the term of hypersensitivity 4 (50) 0 4 (29) Hematoma 2 (25) 0 2 (14) Increased CSF protein 1 (13) 0 1 (7) Pleocytosis 1 (13) 0 1 (7) Irritability 0 1 (17) 1 (7) Headache 1 (13) 0 1 (7) 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of BRINEURA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders : Anaphylactic reaction characterized by acute pyrexia, respiratory distress (bronchospasm, hypoxemia, perioral cyanosis), tachycardia, hypotension, diarrhea, and rash [see Warnings and Precautions (5.1) ] . Infections and infestations : Bacterial meningitis [see Warnings and Precautions (5.2) ] .

12.3 Pharmacokinetics Patients 3 years of age and older The pharmacokinetics of cerliponase alfa were evaluated in patients with CLN2 disease who received intraventricular infusions of 30 mg (0.1 times the maximum approved recommended dosage), 100 mg (approximately 0.3 times the maximum approved recommended dosage), and 300 mg over approximately 4.5 hours once every other week. Cerliponase alfa CSF exposure following the initial single dose administration of BRINEURA increased less than proportionally across doses of 30 mg, 100 mg, and 300 mg. There was no apparent accumulation of cerliponase alfa in CSF or plasma when BRINEURA was administered at a dose of 300 mg once every other week. Cerliponase alfa pharmacokinetics have high inter-subject and intra-subject variability. Following intraventricular infusions of 300 mg of BRINEURA at Day 1, Week 5, and Week 13, the pharmacokinetic parameters in CSF and plasma were assessed in 14 patients and are summarized in Table 4. Table 4: Pharmacokinetic Parameters of Cerliponase Alfa Following Intraventricular Infusion (approximately 4.5 hours in duration) of BRINEURA 300 mg Every Two Weeks in Patients ≥ 3 years Parameter Median [Min, Max] Day 1 Week 5 Week 13 N 13 14 13 T max T max expressed as time since start of ~4.5 hour infusion. , hr 4.5 [4.3, 5.8] 4.3 [3.8, 4.5] 4.3 [4.0, 4.5] C max , mcg/mL 1260 [359, 4380] 1630 [376, 4670] 1390 [1110, 2340] CSF AUC 0-t , mcg-hr/mL 9290 [3660, 19000] 12400 [4620, 26200] 10500 [7000, 18200] V ss , mL 245 [78.4, 909] 196 [85.4, 665] 186 [131, 257] CL, mL/hr 32.3 [15.8, 81.9] 24.2 [11.4, 64.9] 28.7 [16.5, 42.9] t 1/2 , hr 6.2 [5.5, 16.3] 7.4 [3.3, 9.5] 7.7 [5.1, 9.4] N 12 12 9 Plasma V ss , CL, and t 1/2 were not estimated due to insufficient plasma pharmacokinetic data T max , hr 12.0 [4.3, 24.5] 12.0 [7.5, 24.2] 12.3 [4.3, 75.9] C max , mcg/mL 1.3 [0.2, 3.9] 1.9 [0.2, 4.3] 1.0 [0.03, 2.6] AUC 0-t , mcg-hr/mL 16.2 [1.1, 69.9] 40.1 [11.1, 78.9] 9.5 [0.2, 51.6] N 11 12 9 CSF/Plasma Ratio C max 1200 [305, 4530] 809 [202, 9370] 1320 [541, 51200] AUC 0-t 393 [115, 1910] 340 [126, 1780] 1330 [167, 38900] The estimated CSF volume of distribution of cerliponase alfa following intraventricular infusion of 300 mg of BRINEURA (median V ss = 245 mL) exceeds the typical CSF volume (100 mL). Pediatric patients less than 3 years Pediatric CLN2 patients ages 1 to < 2 years (n=2) and 2 to < 3 years (n=6) were administered cerliponase alfa according to the recommended dosing regimen based on age for up to 144 weeks. CSF exposure with 300 mg cerliponase alfa was within the range characterized to be safe and effective in pivotal Trial 1. Plasma exposure in younger patients trended higher than the range characterized in the pivotal study. The pharmacokinetic parameters summarized by age at time of visit and dose are shown in Table 5. Table 5: Pharmacokinetic Parameters of Cerliponase Alfa by Age at Visit and Dose Following Intraventricular Infusion of BRINEURA Every Two Weeks in Pediatric Patients < 3 years Age at Visit Dose (mg) Parameter Median [Min, Max] 1 to < 2 years 200 CSF N 3 C max , mcg/mL 511 [163, 987] AUC 0-t , mcg-hr/mL 2720 [1100, 5050] Plasma N 2 C max , mcg/mL 10.4 [9.46, 11.3] AUC 0-t , mcg-hr/mL 91.8 [72.7, 111] 300 CSF N 2 C max , mcg/mL 566 [496, 636] AUC 0-t , mcg-hr/mL 8030 [8030, 8030] N=1 due to less than 3 evaluable datapoints for determination of AUC 0-t Plasma N 2 C max , mcg/mL 14.1 [11.2, 17.0] AUC 0-t , mcg-hr/mL 145 [82.7, 206] 2 to < 3 years 300 CSF N 6 C max , mcg/mL 896 [508, 1790] AUC 0-t , mcg-hr/mL 4100 [2380, 6720] N=5 due to less than 3 evaluable datapoints for determination of AUC 0-t Plasma N 6 C max , mcg/mL 14.9 [9.08, 35.3] AUC 0-t , mcg-hr/mL 163 [91.5, 320] Cerliponase alfa is a protein and is expected to be degraded through peptide hydrolysis.