KEBILIDI

1 INDICATIONS AND USAGE KEBILIDI (eladocagene exuparvovec-tneq) is an adeno-associated virus (AAV) vector-based gene therapy indicated for the treatment of adult and pediatric patients with aromatic L-amino acid decarboxylase (AADC) deficiency. This indication is approved under accelerated approval based on the change from baseline in gross motor milestone achievement at 48 weeks post treatment [see Clinical Studies ( 14 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial. KEBILIDI is an adeno-associated virus (AAV) vector-based gene therapy indicated for the treatment of adult and pediatric patients with aromatic L amino acid decarboxylase (AADC) deficiency. This indication is approved under accelerated approval based on change from baseline in gross motor milestone achievement at 48 weeks post-treatment. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial. ( 1 , 14 )

2 DOSAGE AND ADMINISTRATION For single-dose intraputaminal infusion only. For single-dose intraputaminal infusion only. Recommended dose: 1.8×10 11 vector genomes (vg). ( 2.2 ) Brain imaging for stereotactic planning and intraoperative navigation should be done prior to the procedure. ( 2.4 ) Post stereotactic registration, mark the entry point on the skull. Surgical access through the skull bone and dura should be performed. ( 2.4 ) Administer a total dose of 1.8×10 11 vg (0.32 mL total volume) delivered as four 0.08 mL (0.45×10 11 vg) infusions (two sites per putamen-anterior and posterior) at a rate of 0.003 mL/minute (0.18 mL/hour) for a total of 27 minutes per site, administered in a single stereotactic surgery using a cannula that is FDA-authorized for intraparenchymal infusion. ( 2.2 , 2.4 ) 2.1 Important Dosing Information Confirm patient has AADC deficiency due to biallelic mutations in the DDC gene. Strictly observe aseptic technique during preparation and administration of KEBILIDI. KEBILIDI should be administered in a medical center which specializes in stereotactic neurosurgery. Administer KEBILIDI only using an FDA-authorized cannula for intraparenchymal infusion (i.e., ClearPoint SmartFlow Neuro Cannula Part Number NGS-NC-01-EE or NGS-NC-02-EE). Use of the syringe (i.e., connecting the syringe to the syringe pump and priming of the cannula) should begin within 6 hours of starting product thaw KEBILIDI is intended to be administered with an infusion pump capable of infusing at a rate of 0.003 mL/min. 2.2 Recommended Dose KEBILIDI is administered as four intraputaminal infusions in a single stereotactic neurosurgical procedure as per the recommended dose shown in Table 1 . Table 1: Recommended Dose of KEBILIDI Total Recommended Dose 1.8x10 11 vg (0.32 mL) Total number of infusions 4 Volume (dose) per infusion 0.08 mL (0.45x10 11 vg) Location of infusions 2 in anterior putamen, 2 in posterior putamen Infusion rate at each target point 0.003 mL/min Dose duration for infusion at each target point 27 minutes 2.3 Preparation Thawing KEBILIDI Vial Coordinate timing of KEBILIDI thaw and infusion. KEBILIDI should be used within 6 hours of starting product thaw. Infusion of KEBILIDI takes 4 hours. The maximum time from thaw to completion of infusion should be no more than 10 hours. Thaw the KEBILIDI vial upright at room temperature before use. The contents of the vial will thaw in approximately 15 minutes at room temperature. Do not thaw or warm the vial any other way. Gently invert the vial 3 times. Do not shake the vial. Inspect the fully thawed KEBILIDI vial after mixing. KEBILIDI should be inspected visually for particulate matter, and discoloration prior to administration. KEBILIDI is clear to slightly opaque. The color of KEBILIDI should be a colorless to faint white suspension Do not use if particulates, or discoloration are visible in the suspension. Preparing KEBILIDI in Syringe Gather supplies listed in Table 2 for preparation: Table 2: Supplies for KEBILIDI Preparation Abbreviations: PC=Polycarbonate; PP=Polypropylene Component Material of Construction 1mL lubricated sterile Luer-lock syringe with elastomer plunger Or 5mL lubricated sterile Luer-lock syringe with elastomer plunger Silicone, PC; Silicone, PP Silicone, PP 18 or 19 G sterile needle with 5µm filter Stainless steel, PC hub; Stainless steel, PP hub Sterile Luer-lock syringe cap - Plastic bag for delivery into surgical unit - Secondary container for delivery into surgical unit - Prepare KEBILIDI using sterile techniques under aseptic conditions, proper engineering controls (e.g., biological safety cabinets or isolator) as per the institutional policies. Open the syringe and label it as the product-filled syringe. Attach the filter needle to the syringe. Draw the full volume of the vial of KEBILIDI into the syringe. Invert the vial and syringe and partially withdraw or angle the needle as necessary to maximize recovery of product. Draw air into the syri…

5 WARNINGS AND PRECAUTIONS Procedural complications: Monitor patients for procedural complications for neurosurgery, including events of respiratory and cardiac arrest after administration of KEBILIDI. ( 5.1 ) Dyskinesia: Monitor patients for dyskinesia after treatment with KEBILIDI. The use of dopamine antagonists can be used to control dyskinesia symptoms. ( 5.2 ) 5.1 Procedural Complications Procedural complications have been reported after neurosurgery required for KEBILIDI administration. These events included respiratory and cardiac arrest which occurred within 24 hours of the neurosurgical procedure and during post-surgical care [see Adverse Reactions (6) ] . KEBILIDI administration has the potential risk for additional procedure related adverse events including cerebrospinal fluid (CSF) leak, intracranial bleeding, neuroinflammation, acute infarction, and infection. Monitor patients for procedure related adverse events with KEBILIDI administration, including continuous cardiorespiratory monitoring during hospitalization. 5.2 Dyskinesia Dyskinesia was reported after administration of KEBILIDI. All events were reported within 3 months of administration and 2 events required hospitalization [see Adverse Reactions (6) ] . Monitor patients for signs and symptoms of dyskinesia after KEBILIDI treatment which may include involuntary movements of face, arm, leg, or entire body. These may present as fidgeting, writhing, wriggling, head bobbing or body swaying. The use of dopamine antagonists may be considered to control dyskinesia symptoms.

4 CONTRAINDICATIONS KEBILIDI is contraindicated in patients who have not achieved skull maturity assessed by neuroimaging. Skull maturity is needed for stereotactic neurosurgical administration of KEBILIDI. Patients who have not achieved skull maturity assessed by neuroimaging. ( 4 )

8.1 Pregnancy Risk Summary There are no clinical data from the use of KEBILIDI in pregnant women. Animal reproductive and developmental toxicity studies have not been conducted with KEBILIDI. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥15%) were dyskinesia, pyrexia, hypotension, anemia, salivary hypersecretion, hypokalemia, hypophosphatemia, insomnia, hypomagnesemia, and procedural complications. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact PTC Therapeutics, Inc at toll-free phone 1 866 562 4620 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. The safety data described in this section reflects exposure to KEBILIDI in 13 pediatric patients with genetically confirmed AADC deficiency who received a single dose of 1.8×10 11 vg. The median duration of follow-up was 72 weeks (range 23 to 109 weeks) [see Clinical Studies ( 14 )] . The most common adverse reactions (incidence ≥15%) are summarized in Table 3 . Table 3: Adverse Reactions in ≥15% of Patients in Study 1 * Procedural complications included respiratory and cardiac arrest. Adverse Reaction Patients Treated with KEBILIDI N=13 (%) Dyskinesia 10 (77%) Pyrexia 5 (38%) Hypotension 4 (31%) Anemia 4 (31%) Salivary hypersecretion 3 (23%) Hypokalemia 3 (23%) Hypophosphatemia 3 (23%) Insomnia 3 (23%) Hypomagnesemia 2 (15%) Procedural complications * 2 (15%) Other clinically significant adverse reaction includes worsening in duration and frequency of oculogyric crises during hospitalization following administration of KEBILIDI reported in one patient.