Etranacogene Dezaparvovec

1 INDICATIONS AND USAGE HEMGENIX is an adeno-associated virus vector-based gene therapy indicated for treatment of adults with Hemophilia B (congenital Factor IX deficiency) who: Currently use Factor IX prophylaxis therapy, or Have current or historical life-threatening hemorrhage, or Have repeated, serious spontaneous bleeding episodes. HEMGENIX is an adeno-associated virus vector-based gene therapy indicated for the treatment of adults with Hemophilia B (congenital Factor IX deficiency) who: Currently use Factor IX prophylaxis therapy, or Have current or historical life-threatening hemorrhage, or Have repeated, serious spontaneous bleeding episodes.

2 DOSAGE AND ADMINISTRATION For single-use intravenous infusion only. For patient selection: Perform Factor IX inhibitor titer testing. In case of a positive test result for human Factor IX inhibitors, perform a re-test within approximately 2 weeks. If both the initial test and re-test results are positive, do not administer HEMGENIX to this patient. Perform liver health assessments, including: Enzyme testing [alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bilirubin)], Hepatic ultrasound and elastography. In case of radiological liver abnormalities and/or sustained liver enzyme elevations, consider a consultation with hepatologist to assess eligibility for HEMGENIX [see Warnings and Precautions (5.2) ] . For single-use intravenous infusion only. ( 2 ) Perform baseline testing to select patients, including testing for Factor IX inhibitor presence and liver health tests. ( 2.1 ) The recommended dose of HEMGENIX is 2 × 10 13 genome copies (gc) per kg of body weight. ( 2.1 ) Administer HEMGENIX as an intravenous infusion after dilution with 0.9% normal saline at a constant infusion rate of 500 ml/hour (8 mL/min). ( 2.1 ) 2.1 Dose The recommended dose of HEMGENIX is 2 × 10 13 genome copies (gc) per kilogram (kg) of body weight (or 2 mL/kg body weight) administered as an intravenous infusion after dilution with 0.9% sodium chloride solution (normal saline) [see Dosage and Administration (2.2) ] . Calculate the dose as follows: HEMGENIX dose (in mL) = patient body weight (in kilogram) × 2 The multiplication factor 2 represents the per kilogram dose (2 × 10 13 gc/kg) divided by the amount of genome copies per mL of the HEMGENIX solution (1 × 10 13 gc/mL). Number of HEMGENIX vials needed = HEMGENIX dose (in mL) divided by 10 (round up to next whole number of vials). The division factor 10 represents the extractable volume of HEMGENIX from each vial (10 mL). The total volume of the patient's HEMGENIX dose to be diluted may be less than the total volume of vials needed. Example calculation for 72 kg patient Patient Weight HEMGENIX dose (mL) (body weight multiplied by 2) Number of Vials needed [HEMGENIX dose (mL) divided by 10, then rounded up] 72 kg 144 mL 15 HEMGENIX can be administered only once. 2.2 Preparation The vials are for single-dose only. General precautions Prepare HEMGENIX using sterile technique under aseptic conditions, proper engineering controls (e.g., biological safety cabinet or isolator) and according to institutional policies. Do not expose HEMGENIX to the light of an ultraviolet radiation disinfection lamp. Confirm that the patient's identity matches with the patient-specific identifier number on the outer carton. Verify the required dose of HEMGENIX based on the patient's body weight. Confirm that the carton contains sufficient number of vials to prepare the diluted HEMGENIX patient-specific infusion bag. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Required supplies and materials: Normal saline infusion bag(s)* of 500 mL (1 to 2 bags based on patient's body weight) Labels** for the infusion bag(s) of 500 mL IV Infusion line/drip chamber* primed with 0.9% normal saline Infusion bag connector(s) 20 mL or larger Luer-lock syringes* 20 G Needles* or vial adaptors* 70% isopropyl alcohol Sharps disposal container The following Table shows the supplies and materials compatible with HEMGENIX: Component* Material of Construction MABS = Methyl methacrylate acrylonitrile butadiene styrene; PE = Polyethylene; PP = Polypropylene; PVC = Polyvinyl chloride; TOTM = Trioctyltrimellitate, Acrylonitrile butadiene styrene (ABS) Normal saline infusion bag (0.9% normal saline) PE/PP copolymer (PVC-free) (Stability after dilution was established using PE/PP copolymer, PVC-free infusion bags with 0.9% normal saline.) 20 G Needle Stainless Steel Vial adapter PP, Silicone; PP, stainless; MABS, acrylic silicone; ABS Luer-lock syringe PP, Silicone IV Infusion line/drip chamber PVC/TOTM, PP/styrene-ethylene-butylene-styrene **Information to be included on the infusion bag label: Product name: Diluted Hemgenix Patient identifier Expiration date/time (24 h from the vial removal from refrigerator) Storage condition: Room Temperature [15-25 °C (59-77 °F] protected from light. Contains genetically modified organisms Number of infusion bag: 1 of 2 bags / 2 of 2 bags Preparation of 0.9% normal saline infusion bags Prior to dilution, spike the infusion bag(s) of 0.9% normal saline solution with applicable connector. Connect a luer-lock syringe at the mixing adapter site of the applicable connector. Withdraw the volume equal to the calculated HEMGENIX dose (in mL) from the 500 mL infusion bag(s) of 0.9% normal saline solution. The volume to be withdrawn and number of infusion bag(s) needed will vary based on the patient body weight: Patient body weight Number of 500 mL 0.9% normal saline infusion bag(s) required Volume of saline solution to withdraw Less than 120 kg body weight One Equal to the total HEMGENIX dose (in mL) from one bag Equal to or more than 120 kg body weight Two Equal to the total HEMGENIX dose (in mL). Remove half of the dose equivalent volume from each of the two bags. HEMGENIX injection to the 0.9% normal saline infusion bags Dilute HEMGENIX with 0.9% normal saline solution only prior to administration. 4. Prior to dilution, inspect each of the HEMGENIX single-dose vials. If particulates, cloudiness, or discoloration is visible, DO NOT use the vial(s). 5. Gently swirl the vials 3 times (about 10 seconds) to homogenize the HEMGENIX suspension. To avoid foaming, DO NOT shake the HEMGENIX vial(s). 6. Remove the plastic flip-off cap from the vials and disinfect the rubber stopper with a sterilizing agent (for example sterile 70% isopropyl alcohol). 7. Withdraw HEMGENIX from each vial using a 20 G needle/vial adapter and syringe. Use recommended 20 mL luer-lock or larger syringe that is suitable for volume measuring and a needle. DO NOT use filter needles during preparation of HEMGENIX. Use a new needle/vial adapter and syringe for each HEMGENIX vial. Dispose of the needle and syringe in an appropriate container. 8. Slowly add the required HEMGENIX dose from the syringe(s) directly to the 0.9% normal saline solution in the infusion bag(s) (from step #3) to bring the total volume in each infusion bag back to 500 mL. DO NOT add HEMGENIX into the airspace of the bag to avoid foaming throughout this process. 9. Repeat steps 7 and 8 with additional needles/vial adaptors and syringes to inject the total calculated HEMGENIX volume to the infusion bag(s) required for the patient dose. 10. Gently invert the infusion bag(s) at least 3 times (about 10 seconds) to mix the solution and ensure even distribution of the diluted product. To avoid foaming, DO NOT shake the diluted HEMGENIX infusion bag(s). 11. Label the infusion bag(s). 12. Connect the infusion bag(s) to an infusion tube pre-filled with sterile 0.9% normal saline solution to reduce the risk of spillage and/or aerosol formation. 13. Transport the diluted HEMGENIX infusion bag(s) in the transport container/bag protected from light to the administration site, avoiding any shaking or excessive agitation. 2.3 Administration Required supplies and materials for administration: Winged intravenous needle or catheter set* Infusion pump 0.2 mcm in-line filter* Antiseptic skin preps 70% isopropyl alcohol wipes Gauze and tape, or transparent dressing Sharps disposal container Virucidal agent to treat spill/spill kit The following Table shows the supplies and materials compatible for infusion of HEMGENIX: Component* Material of Construction DEHP = Di(2-ethylhexyl)phthalate; DEHT = Di(2-ethylhexyl)terephthalate; MABS = Methyl methacrylate acrylonitrile butadiene styrene; PES = Polyether sulfone; PVC = Polyvinyl chloride Winged IV needle or catheter set PVC/TOTM, MABS 0.2 mcm in-line filter PES Catheter PVC/DEHT, Stainless steel Administer HEMGENIX as a single-dose intravenous infusion through a peripheral venous catheter : Visually inspect diluted HEMGENIX prior to administration. The diluted HEMGENIX should be clear and colorless. DO NOT use if particulates, cloudiness, or discoloration are visible. Use the diluted HEMGENIX within 24 hours after the dose preparation [see How supplied/Storage and Handling (16.2) ] . Use an integrated (in-line) 0.2 mcm filter made out of PES. Subsequently, connect the pre-filled IV infusion line/drip chamber to the main intravenous line which has been primed with sterile 0.9% normal saline solution prior to use. Infuse diluted HEMGENIX at a constant infusion rate of 500 mL/hour (8 mL/min). DO NOT administer HEMGENIX as an intravenous push or bolus. DO NOT infuse the diluted HEMGENIX solution in the same intravenous line with any other products. DO NOT use a central line or port. In the event of an infusion reaction during administration [see Warnings and Precautions (5.1) ] : The rate of infusion may be reduced or stopped, to manage the infusion reaction. If the infusion is stopped, restart at a slower rate when the infusion reaction is resolved. If the infusion rate needs to be reduced, or stopped and restarted, HEMGENIX should be infused within 24 hours after the dose preparation [see How supplied/Storage and handling (16.2) ] . After the entire content of the bag(s) is infused, flush the IV infusion line/drip chamber at the same infusion rate with 0.9% normal saline solution to ensure all HEMGENIX is delivered. Treat spills of HEMGENIX with a virucidal agent with proven activity against non-enveloped viruses. Dispose of unused product and disposable materials that may have come in contact with HEMGENIX in accordance with local biosafety guidelines applicable for handling and disposal of the pharmaceutical waste. Monitoring Post-Administration Conduct the following tests after HEMGENIX administration [see Warnings and Precautions (5.2 , 5.3 , 5.4) ] : Perform regular liver enzyme testing to monitor for liver enzyme elevations which may indicate immune-mediated hepatotoxicity: Monitor ALT and AST (transaminase) levels by testing weekly for 3 months following administration of HEMGENIX. Continue to monitor transaminases in all patients who developed liver enzyme elevations until liver enzymes return to baseline. In the event of ALT increase to above normal limits or to twice the patient`s baseline in the first 3 months post-dose, consider implementing a course of corticosteroids. For patients with clinically relevant ALT increases who need corticosteroid treatment, administer the recommended starting dose of 60 mg/day of oral prednisolone or prednisone, with a subsequent taper in response to normalization of the ALT levels (see Table 1 ): Table 1. Prednisolone Treatment Applied in Clinical Studies With HEMGENIX: Timeline Medications equivalent to prednisolone may also be used. A combined immunosuppressant regimen or the use of other products can be considered in case of prednisolone treatment failure or contraindication. Prednisolone Oral Dose (mg/day) Week 1 60 Week 2 40 Week 3 30 Week 4 30 Maintenance dose until ALT level returns to baseline level 20 Taper dose after ALT baseline level has been reached Reduce daily dose by 5 mg/week In the clinical studies, the mean duration of corticosteroid use for elevated transaminases was 81.4 days [Standard Deviation (SD) 28.6] and ranged from 51 to 130 days [see Warnings and Precautions (5.2) ] . Monitor Factor IX activity (e.g., weekly for 3 months). Monitor patients regularly for their Factor IX activity, in particular when exogenous Factor IX is administered. It may take several weeks before improved hemostatic control becomes apparent after HEMGENIX infusion; therefore, continued hemostatic support with exogenous human Factor IX may be needed during the first weeks after HEMGENIX infusion [see Clinical Pharmacology (12.3) ] . The use of different assays may impact the test results; therefore, use the same assay and reagents to monitor patients over time, if feasible [see Monitoring Laboratory Tests (5.5) ] . Use of exogenous Factor IX concentrates before and after HEMGENIX administration may impede assessment of endogenous, HEMGENIX-derived Factor IX activity. Perform regular alpha-fetoprotein (AFP) level testing and abdominal ultrasound (e.g., annually) in patients with preexisting risk factors for hepatocellular carcinoma (e.g., in patients with cirrhosis, advanced hepatic fibrosis, hepatitis B or C, non-alcoholic fatty liver disease (NAFLD), chronic alcohol consumption, non-alcoholic steatohepatitis (NASH), and advanced age). Monitor patients for human Factor IX inhibitors. Post-dose inhibitor testing should be performed if bleeding is not controlled, or plasma Factor IX activity levels decrease [see Warnings and Precautions (5.5) ] .

6 ADVERSE REACTIONS The most common adverse reactions (incidence ≥5%) reported in clinical studies were ALT elevations, headache, blood creatine kinase elevations, flu-like symptoms, infusion-related reactions, fatigue, malaise, and AST elevations. The following adverse reactions are discussed in greater detail in other sections of the label: Infusion related reactions [see Warnings and Precautions (5.1) ] . Hepatotoxicity [see Warnings and Precautions (5.2) ] . Immune-mediated neutralization of the AAV5 vector capsid [see Warnings and Precautions (5.3) ] . The most common adverse reactions (incidence ≥5%) were elevated ALT, headache, blood creatine kinase elevations, flu-like symptoms, infusion-related reactions, fatigue, malaise and elevated AST. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring at 1-866-915-6958 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 clinical practice. The safety of HEMGENIX was evaluated in two clinical studies (the first study enrolled 3 subjects and the second study 54 subjects). Both studies enrolled adult male subjects with moderately severe or severe Hemophilia B (N = 57), who received a single intravenous dose of 2 × 10 13 gc/kg body weight of HEMGENIX. All subjects entered a follow-up period of 5 years. No serious adverse reactions were reported [see Clinical Studies (14) ] . The most common adverse reactions observed in ≥5% of subjects post-dose are listed in Table 2: Table 2. Adverse Reactions (Incidence ≥5%) Following Treatment with HEMGENIX Adverse Reactions ≥5% Subjects (%) (N = 57) Alanine aminotransferase increased 24 (42%) Headache 10 (18%) Blood creatine kinase increased 24 (42%) Flu-like symptoms 8 (14%) Infusion-related reactions Infusion-related reaction: In 7 subjects symptoms occurred during infusion, in 12 subjects after infusion. Symptoms occurring in ≥ 5% of subjects were: Dizziness, Flu-like symptoms and Headache. Symptoms occurring in < 5% of subjects were: Abdominal pain, Abdominal discomfort, Chest discomfort, Chills, Eye pruritus, Fever (Pyrexia), Flushing, Hives (Urticaria), Infusion site reaction, and Tachycardia. Eleven subjects recovered on the day or day one after infusion. Eight subjects recovered within 8 days after infusion. (see below) 19 (33%) Hypersensitivity 2 1of 2 hypersensitivity reactions – 12 minutes after initiation of administration of HEMGENIX, the patient experienced high blood pressure, red eyes, feeling warm, dizziness, coughing, dyspnea, elevated heart rate, shivering, and leg cramps. Infusion was stopped and not restarted. Only 10% of the HEMGENIX dose was administered. The patient recovered on the same day after treatment with intravenous diphenhydramine and intramuscular epinephrine. 2 of 2 hypersensitivity reactions – 10 minutes after initiation of administration of HEMGENIX, the patient experienced itching, tightness of throat, and swelling of the right side of the neck. The HEMGENIX dose was not interrupted and administered in full. All symptoms resolved on the same day without treatment. (4%) Fatigue 7 (12%) Aspartate aminotransferase increased 24 (42%) Nausea 4 (7%) Malaise 7 (12%) Infusion-related reactions were observed in 19 subjects. Infusions were temporarily interrupted in 3 subjects and resumed at a slower infusion rate after treatment with antihistamines and/or corticosteroids. In one subject, infusion was stopped and not resumed (see footnote of Table 2 ). There were 24 subjects who had elevated ALT values from Day 8 to 731 post-administration. Five subjects had ALT elevations >2-3× ULN (range = 89 IU/L – 130 IU/L), one subject had an ALT elevation > 3-5× ULN (193 IU/L) and one subject had an ALT elevation > 5× ULN (275 IU/L). The subject who had the ALT elevation >5× ULN occurred 3 weeks after HEMGENIX administration. Five subjects had AST elevations > 2-3× ULN (range = 71 IU/L – 118 IU/L), three subjects had AST elevations > 3-5× ULN (range = 127 IU/L – 163 IU/L) and one subject had an AST elevation > 5× ULN (327 IU/L). The subject who had the AST elevation > 5× ULN occurred 11 months post-HEMGENIX administration. Seventeen subjects had elevations in ALT levels within the first 4 months after HEMGENIX infusion (range = 41 IU/L – 275 IU/L), eleven of these subjects' ALT levels resolved within 4 months post-infusion (range = 41 IU/L – 275 IU/L) and five of these subjects' ALT levels never normalized as of last follow-up (range of values at 2-year follow-up = 48 IU/L – 110 IU/L). Seven additional subjects had ALT elevations with onset between Months 6 to 24 (range = 42 IU/L-193 IU/L), five of these subjects had additional risk factors for having elevated transaminase levels including Hepatitis C and Human Immunodeficiency Virus (HIV). ALT levels never normalized as of last follow-up (range of values at 2-year follow-up = (59 IU/L- 193 IU/L) in three of the subjects with ALT elevations with onset between Months 6 to 24. Nineteen subjects had elevations in AST levels within 3 months after HEMGENIX infusion (range = 32 IU/L- 163 IU/L). Nine of these subjects' AST elevations resolved within 4 months post-infusion (range = 35 IU/L – 163 IU/L), three resolved within 7 to 13 months post-infusion (range = 35 IU/L – 62 IU/L), and seven of these subjects' AST levels never normalized as of last follow-up (range of values at 2-year follow-up = 36 IU/L – 327 IU/L). The remaining 5 subjects with AST elevation had onset of between 6 months and 2 years post-infusion (range = 36 IU/L – 127 IU/L), and AST levels had not normalized as of the last follow-up for one subject (AST at 2-year follow-up = 127 IU/L) who had additional risk factors for having elevated transaminase levels. Nine subjects with ALT elevations received a tapered course of corticosteroids. The mean duration of corticosteroid treatment for the elevated ALT was 81.4 days. Nineteen of the 24 subjects with ALT elevations also had a related AST elevation. Twenty-one subjects had elevated transaminase levels and were not treated with corticosteroids. [see Clinical Studies (14) ] .

12.3 Pharmacokinetics Vector Biodistribution (within the body) and Vector Shedding (excretion/secretion) Nonclinical data Biodistribution of HEMGENIX was evaluated after intravenous administration in healthy male mice and non-human primates (NHPs). The highest levels of vector DNA were detected in the liver and adrenal glands in both species. Vector DNA was also detected in all reproductive tissues examined (epididymis, seminal vesicles, and testes). In a mating study evaluating a predecessor of HEMGENIX, transmission of vector DNA to naïve female mice following mating with dosed males was not observed [see Nonclinical Toxicology (13.2) ]. Clinical data Following administration of the predecessor of HEMGENIX at doses of 5 ×10 12 (N = 5) and 2 × 10 13 gc/kg (N = 5) in a clinical study, the pharmacokinetics of vector DNA in blood and viral shedding in saliva, nasal secretions, semen, urine, and feces were characterized. Clearance of vector DNA as confirmed by 3 subsequent measurements below limit of detection (LOD), was achieved in all subjects at both dose levels from all the matrices except for semen, where clearance was achieved in 9/10 subjects. One subject was unable to produce semen due to a historical medical condition and, therefore, shedding from semen could not be assessed. The maximum time to clearance of vector DNA was 22 weeks for urine, 26 weeks for saliva and nasal secretions, 40 weeks for feces, 52 weeks for semen, and 159 weeks for blood. Subsequently, the pharmacokinetics of vector DNA in blood, and viral shedding in semen following HEMGENIX administration was characterized in 2 clinical studies. In an initial clinical study (N = 3), clearance of vector DNA from semen and blood (i.e., confirmed with 3 subsequent measurements below LOD of vector DNA) was achieved in 2/3 subjects, and in all subjects, respectively, after 3 years post-administration. One subject did not return the required number of semen samples to assess the shedding status as per the definition of 3 subsequent measurements below LOD of vector DNA. In the clinical efficacy study (N = 54), a total of 56% (30/54) of subjects achieved absence of vector DNA from blood and 69% (37/54) from semen by Month 24. Several subjects did not return the required number of blood and semen samples to assess the shedding status as per the definition of 3 subsequent measurements below LOD of vector DNA. Considering results obtained from 2 available consecutive samples below LOD, a total of 40/54 (74%) and 47/54 (87%) subjects were identified to have reached absence of vector DNA from blood and semen, respectively, at 24 months post-administration.