Hemgenix

1 INDICATIONS AND USAGE HEMGENIX is 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. ( 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 Critical Administration-related Information For single-use intravenous infusion only. For patient selection: Perform Factor IX inhibitor titer testing. Do not administer HEMGENIX for patients with positive FIX inhibitors or a prior history for FIX inhibitors. 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. Perform laboratory tests to evaluate active hepatitis B and C. Postpone HEMGENIX treatment until patient does not have active hepatitis B or C infection as active infection may reduce the efficacy of HEMGENIX and/or increase the risk of adverse reactions [see Warnings and Precautions (5.2) ] . 2.2 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: HEMGENIX dose (in ML) = 72 × 2 = 144 mL Number of HEMGENIX vials needed = 144 (mL) / 10(mL per vial) = 14.4 vials = 15 Vials (rounded up) HEMGENIX can be administered only once. 2.3 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 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 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: Table 1. 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 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. Table 2. Volume of saline solution to be withdrawn based on 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. Prior to dilution, inspect each of the HEMGENIX single-dose vials. If particulates, cloudiness, or discoloration is visible, DO NOT use the vial(s). Gently swirl the vials 3 times (about 10 seconds) to homogenize the HEMGENIX suspension. To avoid foaming, DO NOT shake the HEMGENIX vial(s). Remove the plastic flip-off cap from the vials and disinfect the rubber stopper with a sterilizing agent (for example sterile 70% isopropyl alcohol). 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. 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. 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. 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). Label the infusion bag(s). 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. 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. 2.4 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 Table 3. 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. DO NOT infuse HEMGENIX faster than 500 mL/hour 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. For post administration monitoring [see Warnings and Precautions (5.2 , 5.4 , 5.5) , Clinical Trial Experience (6.1) ]

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Infusion reactions: Monitor during administration and for at least 3 hours after end of infusion. If symptoms occur, slow or interrupt administration. Re-start administration at a slower infusion once resolved. ( 2.3 , 5.1 ) Hepatotoxicity: Monitor transaminase levels once per week for 3 months and thereafter monthly up to 1 year after HEMGENIX administration to mitigate the risk of potential hepatotoxicity. Consider corticosteroid treatment should elevations occur and as clinically indicated ( 5.2 ) Hepatocellular carcinogenicity: For patients with preexisting risk factors consider liver ultrasound and alpha-fetoprotein testing following administration. ( 5.4 ) Monitoring Laboratory tests: Monitor for Factor IX activity and Factor IX inhibitors. ( 5.5 ) 5.1 Hypersensitivity and Infusion-Related Reactions Moderate to severe hypersensitivity and infusion-related reactions have occurred with HEMGENIX treatment [see Adverse Reactions (6) ] . Anaphylaxis may occur with HEMGENIX treatment. Symptoms may include chest tightness, headaches, abdominal pain, lightheadedness, flu-like symptoms, shivering, flushing, rash, and hypertension. Monitor patients for signs or symptoms of hypersensitivity and infusion-related reaction throughout the infusion period and for at least 3 hours after end of infusion. Do not infuse the product faster than 500 mL/hour [see Adverse Reactions (6) ] . In the event of hypersensitivity or infusion reaction during administration, the infusion may be slowed or stopped. If the infusion is stopped, restart at a slower rate when the symptoms have resolved. Consider treatment with a corticosteroid or antihistamine for management of the reaction [see Clinical Trial Experience (6.1) ] . 5.2 Hepatotoxicity Hepatotoxicity with elevated liver transaminase has occurred after HEMGENIX treatment due to intravenous administration of a liver-directed AAV vector [see Adverse Reactions (6) ] . Transaminitis may be immune mediated and reduce the therapeutic efficacy of the AAV-vector based gene therapy. Monitor ALT levels by testing weekly for 3 months and thereafter monthly for up to 1 year following administration of HEMGENIX to mitigate risk of immune-mediated hepatotoxicity and potential decrease in Factor IX activity. Investigate alternative causes of ALT and other transaminase elevations. In case of increased ALT levels above the upper limit of normal or double baseline levels consider a course of corticosteroid, with a subsequent taper, along with Factor IX activity monitoring Monitor ALT until it returns to baseline, or until after completion of corticosteroid treatment or as clinically indicated. [see Clinical Trial Experience (6.1) ] 5.3 Immune-mediated neutralization of the AAV5 vector capsid In AAV-vector based gene therapies, preexisting neutralizing anti-AAV antibodies may impede transgene expression at desired therapeutic levels. Immune-mediated neutralizing antibodies to AAV5 vector capsid occurred after treatment with HEMGENIX. Following treatment with HEMGENIX all patients developed neutralizing anti-AAV5 antibodies. 5.4 Hepatocellular carcinogenicity Hepatocellular carcinoma related to HEMGENIX has not been observed. Hepatocellular carcinoma may develop after treatment with HEMGENIX due to the integration of liver-targeting AAV vector DNA into the genome. Monitor for hepatocellular carcinomas for five years following administration of HEMGENIX in patients at high risk for hepatocellular carcinoma through abdominal ultrasound screenings and serum alfa-fetoprotein (AFP) levels. [see Clinical Trials Experience (6.1) ] . 5.5 Monitoring Laboratory Tests Monitor plasma Factor IX activity (e.g., weekly for 3 months) by performing either activated partial thromboplastin time (aPTT)-based one-stage clotting assay (OSA) or chromogenic substrate assay (CSA). Factor IX activity results may be lower with CSA compared to OSA [ see Pharmacodynamics (12.2) ]. Monitor Factor IX activity using same assay. Use same reagents and reference standards for OSA and CSA to minimize inconsistencies in Factor IX activity. 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) ] . Use of exogenous Factor IX concentrates before and after HEMGENIX administration may impede assessment of endogenous, HEMGENIX-derived Factor IX activity. Monitor patients through appropriate clinical observations and laboratory tests for the development of inhibitors to Factor IX after HEMGENIX administration. Perform an assay that detects Factor IX inhibitors if bleeding is not controlled, or plasma Factor IX activity levels decrease.

6 ADVERSE REACTIONS 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 (study 1 enrolled 3 patients and study 2 enrolled 54 patients). Both studies enrolled adult male patients 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. Three patients in study 1 and 50 of 54 patients from study 2 completed the study-specific 5-year follow-up period. No serious adverse reactions were reported [see Clinical Studies (14) ] . The most common adverse reactions observed in ≥5% of patients post-dose are listed in Table 4: Table 4. Adverse Reactions (Incidence ≥5%) Following Treatment with HEMGENIX Months 0-24 Adverse Reactions ≥5% Patients (%) (N = 57) Alanine aminotransferase increased 23 (40%) Headache 10 (18%) Blood creatine kinase increased 24 (42%) Flu-like symptoms 8 (14%) Infusion-related reactions Infusion-related reaction: Symptoms occurred during and after infusion in 7 and 12 patients, respectively. Infusions were temporarily interrupted and resumed at a slower infusion rate after treatment with antihistamines and/or corticosteroids in 3 patients. Eleven patients recovered on the day of or day after infusion, and eight patients recovered within 8 days after infusion. (see below) 19 (33%) Hypersensitivity 2 Hypersensitivity reactions occurred within 10-12 minutes following initiation of HEMGENIX infusion. One patient needed supportive therapy and received only 10% of the intended HEMGENIX dose. The other patient did not receive supportive therapy and received the full HEMGENIX dose. Symptoms resolved in both patients on the same day. (4%) Fatigue 7 (12%) Aspartate aminotransferase increased 24 (42%) Nausea 4 (7%) Malaise 7 (12%) Hepatic transaminases were monitored weekly for 3 months and then monthly thereafter till 1 year following HEMGENIX administration. There were 23 patients who had asymptomatic elevated ALT values > ULN during the first 2-years post-administration (median ALT = 65, range = 41-275). Seventeen of 23 patients had elevated ALT levels in the first 4 months after HEMGENIX administration. The remaining 6 patients had elevated ALT levels between months 4-24. ALT levels were elevated in 9 patients at the end of the 2-year follow-up period. Four patients had ALT elevations >2-3× ULN (range = 89 IU/L – 130 IU/L), one patient had an ALT elevation > 3-5× ULN (range = 157 IU/L – 214 IU/L) and one patient had an ALT elevation > 5× ULN (275 IU/L). The patient who had the ALT elevation >5× ULN occurred 3 weeks after HEMGENIX administration. The remaining seventeen patients had ALT elevation ≤2× ULN. Nine patients with ALT elevations received a tapered course of corticosteroids based on a schedule as outlined in Table 5. The median (range) time to corticosteroid initiation was 41 (22-61) days. The median (range) duration of corticosteroid treatment for the elevated ALT was 73 (51-130) days. Fourteen patients had elevated ALT levels and were not treated with corticosteroids. Table 5. 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. , Corticosteroid taper may be individualized based on trend of ALT decline, Factor IX activity, the patient's medical condition, corticosteroid tolerance, and adverse reactions to corticosteroid therapy. 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 Between 2 and 5 years after treatment, fourteen patients who had asymptomatic elevations in ALT above ULN after treatment (median ALT = 72, range = 42-65) and were not treated with corticosteroids during that period. Of the 14 patients, 6 patients had elevated ALT > ULN prior to year 2. At the end of the 5-year follow-up period, 6 patients had ALT values > ULN (median = 63, range = 49-119). Two of the 6 patients had alternative causes explaining their ALT elevation. Two patients treated with corticosteroids in the first year of follow-up, already had ALT values > ULN prior to treatment and continued to have ALT elevations through the 5-year follow up. Other clinically significant adverse reactions include hepatocellular carcinoma in one patient with preexisting risk factors for developing hepatic cancer (history of hepatitis B and hepatitis C infections, and alcohol use), in whom relatedness was assessed as not likely related to HEMGENIX treatment based on vector integration site analyses and whole genome sequencing.

8.1 Pregnancy Risk Summary HEMGENIX is not intended for administration in women. No adverse effects on mating rate and fertility indices or fetal weights were observed in healthy naïve female mice mated with healthy male mice that were intravenously administered a predecessor of HEMGENIX product 6 days prior to mating. Vector DNA was not detected in the uterus, placenta, or fetus. In the United States 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.