2.1 Dose

The recommended dose of HEMGENIX is 2 × 1013 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:

The multiplication factor 2 represents the per kilogram dose (2 × 1013 gc/kg) divided by the amount of genome copies per mL of the HEMGENIX solution (1 × 1013 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 can be administered only once.

2.2 Preparation

The vials are for single-dose only.

2.3 Administration

5.1 Infusion Reactions

Infusion reactions, including hypersensitivity reactions and anaphylaxis, may occur. Symptoms may include chest tightness, headaches, abdominal pain, lightheadedness, flu-like symptoms, shivering, flushing, rash, and hypertension. Closely monitor patients for signs or symptoms of an infusion 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 an infusion reaction during administration, the infusion may be slowed or stopped. If the infusion is stopped, restart at a slower rate when the infusion reaction has resolved. Consider treatment with a corticosteroid or antihistamine for management of an infusion reaction [see Dosage and Administration (2.1)].

5.2 Hepatotoxicity

Intravenous administration of a liver-directed AAV vector could potentially lead to liver transaminase elevations (transaminitis). Transaminitis, particularly when observed in the first 3 months after HEMGENIX administration, is presumed to occur due to immune-mediated injury of transduced hepatocytes and may reduce the therapeutic efficacy of the AAV-vector based gene therapy.

In clinical studies with HEMGENIX, most subjects had asymptomatic, and predominantly mild elevations in transaminases. Elevated ALT levels occurred most often in the first 4 months after HEMGENIX administration. There were some subjects who had a late onset of elevated ALT levels between Months 6-24 (range = 42 IU/L-193 IU/L); however, all of these ALT values were <2× ULN with the exception of one subject. Three additional subjects had AST elevations with onset and resolution between Months 6 and 12 (range = 41 IU/L – 96 IU/L).

In one subject, an ALT elevation >5× ULN occurred 24 days after HEMGENIX administration and resolved by 51 days post-HEMGENIX administration. There was one subject who had an AST elevation > 5× ULN that occurred 11 months post-HEMGENIX administration and resolved to <2× ULN eight days later.

The majority of the elevated ALT values returned to baseline, however 9 subjects' ALT values never resolved to normal (range at 2-year follow up = 48 IU/L – 193 IU/L) [see Adverse Reactions (6)].

Closely monitor transaminase levels once per week for 3 months after HEMGENIX administration to mitigate the risk of potential hepatotoxicity. Continue to monitor transaminases in all patients who developed liver enzyme elevations until liver enzymes return to baseline [see Dosage and Administration (2.3)].

In case of increased ALT levels above the upper limit of normal or double baseline levels, consider implementing a course of corticosteroid, along with human Factor IX activity monitoring [see Dosage and Administration (2.3)].

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. Following treatment with HEMGENIX all subjects developed neutralizing anti-AAV antibodies. Currently, there is no validated neutralizing anti-AAV5 antibody assay.

In the clinical studies with HEMGENIX, an unvalidated clinical trial assay was utilized to assess preexisting neutralizing anti-AAV5 antibodies. The subject sub-group with detectable preexisting neutralizing anti-AAV5 antibodies up to titers of 1:678 showed mean Factor IX activity that was numerically lower compared to that subject sub-group without detectable preexisting neutralizing anti-AAV5 antibodies. Subjects, with and without preexisting neutralizing anti-AAV5 antibodies, demonstrated hemostatic protection. In one subject with a preexisting neutralizing anti-AAV5 antibody titer of 1:3212, no human Factor IX expression was observed, and restart of the exogenous Factor IX prophylaxis was needed for bleeding events. [see Clinical Studies (14)].

5.4 Hepatocellular carcinogenicity

The integration of liver-targeting AAV vector DNA into the genome may carry the theoretical risk of hepatocellular carcinoma development.

HEMGENIX is composed of a non-replicating AAV5 vector whose DNA persists largely in episomal form. Random integration of HEMGENIX vector DNA to the human DNA at low frequency is possible. No HEMGENIX-associated clonal expansion or carcinogenicity was observed in clinical studies [see Clinical Studies (14)]. One subject with preexisting risk factors for developing hepatic cancer developed a hepatocellular carcinoma, which was assessed as not likely related to HEMGENIX treatment based on vector integration site analyses and whole genome sequencing.

Patients with preexisting risk factors for hepatocellular carcinoma (e.g., patients with cirrhosis, advanced hepatic fibrosis, hepatitis C or B, non-alcoholic fatty liver disease (NAFLD), chronic alcohol consumption, non-alcoholic steatohepatitis (NASH), and advanced age) should receive abdominal ultrasound screenings and be monitored regularly (e.g., annually) for alpha-fetoprotein (AFP) elevations in the 5 years following administration [see Dosage and Administration (2.3)].

5.5 Monitoring Laboratory Tests

After HEMGENIX administration, regularly monitor patient's Factor IX activity levels.

When using an in vitro activated partial thromboplastin time (aPTT)-based one-stage clotting assay (OSA) for determining Factor IX activity, plasma Factor IX activity results can be affected by both the type of aPTT reagent and the reference standard used in the assay. This is important to consider particularly when changing the laboratory and/or reagents used in the assay. Therefore, the same assay and reagents are recommended to be used to monitor Factor IX activity over time.

The results of Factor IX activity tests are lower if measured with chromogenic substrate assay (CSA) compared to OSA.

In the clinical efficacy study with HEMGENIX, the post-dose Factor IX activity measured with CSA returned lower values with the mean CSA to OSA Factor IX activity ratio ranging from 0.41 to 0.55.

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.

6.1 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 × 1013 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:

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)].

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

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 subjects 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 subjects compared to subjects aged 18 to 65 years, and no dose adjustment was made [see Clinical Studies (14)].

8.6 Hepatic Impairment

Limited clinical data in subjects with liver impairment indicate numerically lower FIX activity as compared to subjects without hepatic impairment [see Clinical Pharmacology (12.3)]. In the clinical studies, no dose adjustment was made in subjects with hepatic pathologies. The safety and efficacy in subjects 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 subjects with mild and moderate renal impairment [see Clinical Pharmacology (12.3)]. In the clinical studies, no dose adjustment was made in these subjects. The safety and efficacy in subjects with severe renal impairment and end-stage renal disease have not been studied.

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.6 Immunogenicity

In clinical studies sustained humoral immune response to infused AAV5 capsid was observed in all subjects following treatment with HEMGENIX. The neutralizing anti-AAV5 antibody levels raised above the upper limit of quantification by week 3 post-administration and remained elevated, as measured at month 24 post-dose. Re-administration of HEMGENIX in the presence of high anti-AAV5 antibody titer has not been evaluated. Currently, there is no validated neutralizing anti-AAV5 antibody assay.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No traditional nonclinical carcinogenicity or mutagenicity studies were conducted with HEMGENIX; such studies were not indicated. No adverse effects were observed in mating rates and fertility indices in healthy naïve female mice following mating with males that were administered the predecessor of HEMGENIX [see Use in specific populations (8.3)]. To evaluate vector integration, host genomic DNA was isolated from liver tissue obtained from healthy mice and NHPs following intravenous administration of the predecessor of HEMGENIX. For both species, the identified rAAV5-hFIX vector DNA sequences represented episomal forms that were not integrated into the host DNA. A low level of integrated rAAV5-hFIX DNA was distributed throughout the host genome with no predilection to specific integration sites, including in genes associated with malignant transformation in humans.

13.2 Animal Toxicology and/or Pharmacology

A pharmacology study was conducted in a murine model of Hemophilia B (B6.129P2-F9tm1Dws. Intravenous administration of the predecessor of HEMGENIX at dose levels ranging from 5×1011 to 2.3×1014 gc/kg, resulted in dose-dependent increases in plasma hFIX protein levels, plasma hFIX clotting activity, and vector transduction in the liver at 4 weeks post-dose.

Intravenous administration of HEMGENIX resulted in a no-observed-adverse-effect-level of 5 × 1013 gc/kg (the maximum dose level administered) in healthy mice and 9 × 1013 gc/kg in NHPs. Vector biodistribution to the liver and hFIX protein levels in the plasma occurred in a dose-dependent manner in both species. Anti-hFIX antibodies developed in 5 out of 12 NHPs administered HEMGENIX, which correlated with a decline in circulating hFIX protein levels beginning at 13 weeks post-dose.

One out of 10 healthy mice administered 5 × 1013 gc/kg of HEMGENIX or the predecessor of HEMGENIX developed pulmonary thrombi at 13 weeks post-dose. This dose level is 2.5-fold higher than the recommended dose level for HEMGENIX. Compared to concurrent controls, prolonged prothrombin time, decreased activated partial thromboplastin time and decreased heart rates were observed in NHPs administered 9 × 1013 gc/kg of HEMGENIX during the 26-week study. This dose level is 4.5-fold higher than the recommended dose level for HEMGENIX.

16.1 How Supplied

HEMGENIX is supplied as sterile, preservative-free, clear, and colorless suspension. HEMGENIX has a nominal concentration of 1 × 1013 gc/mL.

HEMGENIX is provided as a customized kit to meet dosing requirements for each patient [see Dosage and Administration (2.1)], with each kit containing 10 (ten) to 48 (forty-eight) single-use vials (NDC 0053-0099-01), each with an extractable volume of no less than 10 mL of HEMGENIX (see5). The total number of vials in each kit corresponds to the dosing requirement for the individual patient depending on the patient`s body weight [see Dosage and Administration (2.1)]. The customized kit is accompanied with patient`s specific identifier number (Lot) on the outer carton. Each HEMGENIX kit may contain different drug product lots.

Kit sizes and National Drug Codes (NDC) are provided in Table 5:

16.2 Storage and Handling

• HEMGENIX is shipped at 2°C to 8°C (36°F to 46°F).
• Upon receipt, store HEMGENIX vials in a refrigerator at 2°C to 8°C (36°F to 46°F).
• Store HEMGENIX in the original carton until use.
• Protect HEMGENIX from light until time of dilution and administration.
• Do NOT FREEZE.