Etranacogene Dezaparvovec

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.

HEMGENIX is a clear and colorless suspension for intravenous infusion. HEMGENIX is provided in a kit containing 10 to 48 vials. Each kit constitutes a dosage unit based on the patient's body weight. HEMGENIX has a nominal concentration of 1 × 10 13 gc/mL, and each vial contains an extractable volume of not less than 10 mL. HEMGENIX is a suspension for intravenous infusion. ( 3 ) HEMGENIX is provided in kits containing 10 to 48 single-use vials, each kit constituting a dosage unit based on the patient's body weight. ( 3 ) HEMGENIX has a nominal concentration of 1 × 10 13 gc/mL, and each vial contains an extractable volume of not less than 10 mL. ( 3 )

None. None. ( 4 )

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.

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.

No dose adjustment is required in geriatric, hepatic, or renal impaired patients. ( 8.5 , 8.6 , 8.7 )

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.

8.2 Lactation Risk Summary HEMGENIX is not intended for administration in women.

8.3 Females and Males of Reproductive Potential Risk Summary No clinical studies have been performed to evaluate the effects of HEMGENIX on fertility in humans. Twenty days after intravenous administration of a predecessor of HEMGENIX product in healthy male mice, vector DNA was detected in all reproductive tissues examined (epididymis, seminal vesicles, testes, and sperm). However, no differences were observed in mating rates and fertility indices in healthy naïve female mice following mating with the dosed males.

8.4 Pediatric Use The safety and efficacy of HEMGENIX in pediatric patients have not been established.

8.5 Geriatric Use The clinical studies included a total of 6 geriatric patients with Hemophilia B, aged 68 to 75 years at time of enrollment. No meaningful differences in the safety and efficacy profile were observed in these patients compared to patients aged 18 to 65 years, and no dose adjustment was made [see Clinical Studies (14) ] .

8.6 Hepatic Impairment Limited clinical data in patients with liver impairment indicate numerically lower FIX activity as compared to patients without hepatic impairment [see Clinical Pharmacology (12.3) ] . In the clinical studies, no dose adjustment was made in patients with hepatic pathologies. The safety and efficacy in patients with advanced hepatic impairment, including cirrhosis, advanced liver fibrosis, or uncontrolled hepatitis B and C, have not been studied.

8.7 Renal Impairment Limited clinical data are available in patients with mild and moderate renal impairment [see Clinical Pharmacology (12.3) ] . In the clinical studies, no dose adjustment was made in these patients. The safety and efficacy in patients with severe renal impairment and end-stage renal disease have not been studied.

HEMGENIX is an adeno-associated virus serotype 5 (AAV5) based gene therapy designed to deliver a copy of a gene encoding the Padua variant of human coagulation Factor IX (hFIX-Padua). Single intravenous infusion of HEMGENIX results in cell transduction and increase in circulating Factor IX activity in patients with Hemophilia B.