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).

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

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

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 observed in patients treated with BRINEURA [see Adverse Reactions (6.1)].

Premedication of patients with antihistamines with or without antipyretics or corticosteroids is recommended 30 to 60 minutes prior to the start of infusion. If an IAR occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or administering antihistamines and/or antipyretics may ameliorate the symptoms. Closely monitor patients who have experienced IARs when re-administering BRINEURA.

In Trial 3, infusion-associated reactions were reported in 8 of 8 patients less than 3 years of age at baseline as compared to 4 of 6 patients ≥ 3 years of age at baseline.

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.

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)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of BRINEURA have been established to slow the loss of ambulation in pediatric patients with CLN2 disease and the information on this use is discussed throughout the labeling.

BRINEURA is not recommended for use 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 due to physiologic immaturity which may increase risk of serious and clinically significant adverse reactions observed with BRINEURA [see Warnings and Precautions (5)].

Patients less than 3 years of age may be at increased risk for developing hypersensitivity reactions with BRINEURA use compared to patients 3 years of age and older [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

12.1 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.

12.2 Pharmacodynamics

No formal pharmacodynamic studies have been conducted with cerliponase alfa.

12.3 Pharmacokinetics

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies including cerliponase alfa.

In Trials 1 and 2 [see Clinical Studies (14)], 19 of 24 (79%) and 10 of 24 (42%) patients treated with BRINEURA developed anti-drug antibodies (ADAs) in serum and CSF, respectively. Drug-specific neutralizing antibodies (NAb) capable of inhibiting receptor-mediated cellular uptake of cerliponase alfa were detected in the CSF of 3 of 24 (13%) patients at a single visit and were undetectable in all other CSF samples tested in ADA positive patients. In Trial 3 [see Clinical Studies (14)], 14 of 14 (100%) and 3 of 14 (21%, all of the 3 patients were < 3 years of age) patients treated with BRINEURA developed ADAs in serum and CSF, respectively. NAb responses were not detected in the CSF of any ADA positive patients. Overall, patients younger than 3 years of age had higher ADA titers compared to patients 3 years of age and older.

In Trials 1 and 2, patients who experienced moderate to severe hypersensitivity adverse reactions were tested for drug-specific IgE and found to be negative. No association was found between serum ADA titers and incidence or severity of hypersensitivity. In Trial 3, hypersensitivity occurred in higher percentage in BRINEURA-treated patients < 3 years of age at baseline (amongst these patients, one patient experienced anaphylaxis), and higher ADA titers were also observed in this age group compared to patients ≥ 3 years of age at baseline. There was no identified clinically significant effect of ADA on pharmacokinetics or efficacy of BRINEURA. There is insufficient information to characterize the effects of ADA on safety.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, genotoxicity, and fertility studies have not been performed with cerliponase alfa. Based on the mechanism of action, cerliponase alfa is not expected to be tumorigenic.

Descriptive non-randomized comparison

In an unadjusted non-randomized comparison, of the 22 patients treated with BRINEURA and evaluated for efficacy at week 96, 21 (95%) did not decline, and only the patient who terminated early was deemed to have a decline in the Motor domain of the CLN2 Clinical Rating Scale. Results from the natural history cohort demonstrated progressive decline in motor function; of the 42 patients in the natural history cohort, 21 (50%) experienced an unreversed (sustained) 2-category decline or unreversed score of 0 in the Motor domain of the CLN2 Clinical Rating Scale over 96 weeks.

Given the non-randomized study design, a Cox Proportional Hazards Model adjusted for age, initial motor score, and genotype was used to evaluate time to unreversed 2-category decline or unreversed score of 0 in the Motor domain. This model showed a lesser decrease in motor function in the BRINEURA-treated patients when compared to the natural history cohort (see Figure 7).

Motor Domain Scores: Matched Patients Only

To further assess efficacy, the 22 patients from the BRINEURA clinical study with a baseline combined Motor plus Language CLN2 score less than 6 were matched to 42 patients in the natural history cohort. Patients were matched based on the following covariates: 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 screening.

Using the Motor domain of the CLN2 Clinical Rating Scale, decline was defined as having an unreversed 2-category decline or an unreversed score of 0. At 96 weeks, the matched analysis based on 17 pairs demonstrated fewer declines in the Motor domain for BRINEURA-treated patients compared to untreated patients in the natural history cohort (see Table 6).

Trial 3 (NCT02678689) was a Phase 2, open label clinical study designed to enroll symptomatic and presymptomatic CLN2 patients less than 18 years of age. The trial enrolled 14 patients ranging in age from 1 to 6 years at baseline, including 8 patients less than 3 years of age, the median age was 2.7 years. Patients received BRINEURA at the recommended dose every 2 weeks by intraventricular infusion for 144 weeks (1 patient withdrew to receive treatment commercially). Fifty-seven percent of patients were female and 43% were male. All patients were White; for ethnicity, 14% identified as Hispanic/Latino, 86% as non-Hispanic/Latino. The mean baseline CLN2 Motor score was 2.3 (standard deviation (SD) 0.83) with a range from 1 to 3.

Thirteen of the 14 BRINEURA treated patients were matched with up to 3 natural history comparators on the basis of age within 3 months, equal CLN2 Motor score, and genotype (0, 1, or 2 key mutations). None of the BRINEURA treated patients (N=14) had a 2-point decline or score of zero in the Motor scale by Week 169. Among the matched natural history comparators (N=31), 20 subjects (65%) had an unreversed 2-point decline or score of zero by last assessment.

The median time to an unreversed 2-point decline in Motor score or score of 0 was 133 weeks among the natural history comparators and was not reached by last assessment (Week 169) in patients treated with BRINEURA.

In patients below 3 years of age, none (0%) of the BRINEURA treated patients (N=8) had a 2-point decline or score of zero in the Motor score by Week 169. Among the 8 treated patients, 7 were matched to 18 untreated patients from the natural history cohort. Among the matched natural history comparators (N=18), 11 subjects (61%) had an unreversed 2-point decline or score of zero in the Motor score by last assessment. All seven of the treated patients below 3 years of age with a motor score of 3 at baseline remained at a motor score of 3 at the last measured timepoint, which represents grossly normal gait. In this population BRINEURA treated patients showed a delay in disease onset.

Package 1 of 2

Each BRINEURA (cerliponase alfa) Injection vial has a green flip-off cap (plastic) and contains 150 mg cerliponase alfa per 5 mL (30 mg/mL).

Each Intraventricular Electrolytes Injection vial has a yellow flip-off cap (plastic) and contains 5 mL of solution.

Package 2 of 2

The Administration Kit for use with BRINEURA is supplied separately and contains the following single-use, sterile infusion components:

• Two 20-mL syringes
• Two syringe needles (21 G, 25.4 mm)
• One extension line
• One infusion set with 0.2 micron inline filter
• One port needle (22 G, 16 mm)

Storage

BRINEURA (cerliponase alfa) Injection and Intraventricular Electrolytes Injection:
Store upright in a freezer (-25°C to -15°C) in original carton to protect from light.

Administration Kit for use with BRINEURA:
Store in original carton separately from BRINEURA. Do not freeze.