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 s…

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 …

4 CONTRAINDICATIONS None. None. ( 4 )

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.

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 …