These highlights do not include all the information needed to use EBANGA

Reconstitution Instructions

• Aseptically reconstitute and further dilute EBANGA prior to IV infusion. Do not administer as an IV push or bolus.
• More than one vial may be needed for a full dose. Calculate the dose (mg) based on the patient’s actual weight in kg and the number of EBANGA vials required [see Dosage and Administration (2.1)] .
• Prior to reconstitution, allow EBANGA vial(s) to reach ambient temperature (15°C to 27°C [59°F to 81°F]) for approximately 20 minutes. If for any reason reconstitution cannot proceed immediately upon reaching ambient temperature, vials that have NOT been reconstituted may be kept at ambient temperature, protected from light, for no more than 24 hours.
• Immediately upon reaching ambient temperature, use a sterile 10 mL syringe and an 18-gauge needle to withdraw 7.7 mL of Sterile Water for Injection, USP. Insert the needle tip into the EBANGA vial. Holding horizontally, angle the needle down at an approximate 45° angle, above the lyophilized powder, which has a cake-like appearance. Slowly inject the diluent along the wall of the vial and without any air to avoid foaming and bubbles.
• Gently swirl (do NOT shake) for approximately 10 seconds; then set the vial down to rest for at least 10 seconds. Repeat until the cake is dissolved. This may take up to 20 minutes.
• Upon reconstitution, one vial delivers 8 mL of solution that is clear to slightly opalescent and colorless to slightly yellow containing 50 mg/mL of ansuvimab-zykl. Do NOT administer and discard the vial if the reconstituted solution is discolored or contains visible particles.
• Dilute the EBANGA solution immediately upon reconstitution. If needed, the reconstituted solution may be stored refrigerated at 2°C to 8°C (36°F to 46°F), protected from light, for up to 4 hours. This 4-hour window includes time required for further dilution and EBANGA solution should be infused immediately upon further dilution.

Dilution Instructions

• Following reconstitution, EBANGA must be further diluted prior to IV infusion.
  • Use an 18-20 gauge, 1-1.5” needle with an appropriately sized syringe up to 60 mL to perform the dilution steps.
  • Prepare the EBANGA IV dosing solution using an appropriately sized syringe up to 60 mL.
• For patients weighing ≥ 2 kg, prepare the diluent using either a latex-free, di-ethylhexylphthalate (DEHP)-free 0.9% Sodium Chloride Injection USP infusion bag, or latex-free, DEHP-free 5% Dextrose Injection USP infusion bag. For patients weighing 0.5 to < 2 kg use a pump-compatible syringe ( Table 1).
  • For adult and pediatric patients, either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP can be used as the diluent.
  • The total volume of the infusion solution to be administered is based on the patient’s body weight and is specified in Table 1.

For patients weighing 0.5 to < 2 kg:

• • Use a 10 mL syringe compatible with the IV infusion pump.
  • Fill the 10 mL syringe with the appropriate amount of diluent ( Table 1).
  • Add the calculated volume of EBANGA to the 10 mL syringe ( Table 1).
  • Mix the diluted solution by gentle inversion (3 to 5 times) until admixed. Do not shake.

For patients weighing ≥ 2 kg:

• • Select a diluent solution infusion bag size of appropriate fill volume based on the patient’s body weight (see Table 1).
  • Withdraw and discard from the bag a volume of diluent solution that will leave remaining in the bag the appropriate volume based on the patient’s weight (see Table 1). Then add the calculated volume of EBANGA to the bag based on the patient's weight (see Table 1).
    For example, for a 55 kg patient, withdraw and discard 150 mL of diluent from a 250 mL infusion bag. Then add 55 mL of EBANGA to obtain a total infusion volume of 155 mL.
  • Gently invert the IV bag 5 to 10 times until the diluted solution is admixed. Do NOT shake.
• Infuse the EBANGA solution immediately upon dilution. If needed, the diluted infusion solution may be stored refrigerated at 2°C to 8°C (36°F to 46°F), for up to 4 hours. Do not freeze the diluted solution. If refrigerated, allow approximately 20 minutes for the diluted solution to come to ambient temperature prior to use. These time limits include reconstitution time.
  Prepare a medical label including patient weight in kg, date, and time of reconstitution.
• Discard vial(s) and all unused contents.

Administration

• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not administer if discolored or if the vial contains visible particles.
• Do not mix with or administer as an infusion with other medicinal products.
• Prepare the IV infusion line with 1.2 micron in-line filter extension set.
• Administer the IV infusion solution over 60 minutes.
  • The diluted EBANGA IV solution can be infused via a central line or peripheral catheter. Do not administer EBANGA as an IV push or bolus.
  • Do not co-administer other drugs simultaneously through the same infusion line.
  • Infusions may be slowed or stopped if necessary, to alleviate any side effects.
• At the end of the infusion, if a syringe pump was used, then remove the syringe and flush the line with 2 to 5 mL of diluent, but not to exceed the total infusion volume. If an infusion bag was used, replace the empty bag and flush the line by infusing at least 25 mL of the diluent, to ensure complete product administration.

Common Adverse Events

Table 2summarizes the adverse events that were reported in the PALM trial from a pre-defined list of signs and symptoms that occurred during EBANGA infusion. The evaluation of adverse events in participants who received EBANGA may have been confounded by the signs and symptoms of the underlying Orthoebolavirus zairense infection. Twenty nine percent (n=51) of participants who received EBANGA in the PALM Trial experienced a pre-specified infusion-related adverse event. The most common pre-specified infusion-related adverse event reported in at least 10% of participants who received EBANGA was fever ( Table 2). The adverse event profile in adult and pediatric participants treated with EBANGA was similar.

The following pre-specified symptoms, which were assessed on a daily basis during admission while admitted to the treatment unit, were reported in ≥40% of participants who received EBANGA: diarrhea, pyrexia, abdominal pain, and vomiting. Evaluation of these symptoms may have been confounded by the underlying Orthoebolavirus zairenseinfection.

Discontinuation and Infusion Rate Adjustments

Approximately 99% of participants who received EBANGA in the PALM trial were able to complete their dose within one hour. Two participants who received EBANGA (1%) did not receive their complete infusion. In eight participants (5%) the EBANGA infusion rate was decreased due to an AE [see Warnings and Precautions (5.1)] .

Selected Laboratory Abnormalities in the PALM Trial

Table 3presents selected laboratory abnormalities (worsening to Grade 3 or 4 compared to baseline) in the PALM trial.

Risk Summary

Orthoebolavirus zairenseinfection is life-threatening for both the mother and fetus and treatment should not be withheld due to pregnancy (see Clinical Considerations) . Available data from the PALM trial in which pregnant women with Orthoebolavirus zairenseinfection were treated with EBANGA demonstrate the high rate of maternal and fetal/neonatal morbidity consistent with published literature regarding the risk associated with underlying maternal Orthoebolavirus zairenseinfection. These data are insufficient to evaluate for a drug associated risk of major birth defects, miscarriage, or adverse maternal/fetal outcome.

Animal reproduction studies with ansuvimab-zykl have not been conducted. Monoclonal antibodies, such as EBANGA, are transported across the placenta; therefore, EBANGA has the potential to be transferred from the mother to the developing fetus.

Clinical Considerations

Risk Summary

The Centers for Disease Control and Prevention recommend that mothers with confirmed Orthoebolavirus zairensenot breastfeed their infants to reduce the risk of postnatal transmission of Orthoebolavirus zairenseinfection.

There are no data on the presence of ansuvimab-zykl in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to ansuvimab-zykl are unknown.

Specific Populations

The effect of age, renal impairment or hepatic impairment on the pharmacokinetics of ansuvimab-zykl is unknown.

Mechanism of Action

EBANGA (ansuvimab-zykl) is a recombinant, human IgG1κ monoclonal antibody that binds to the glycan cap and inner chalice of the EBOV GP1 subunit. The epitope to which it binds is located within the receptor binding domain of EBOV consisting of amino acids LEIKKPDGS (GP residues 111–119).

Ansuvimab-zykl binds EBOV GP without the mucin-like domain with a K _Dof 0.2 nM at pH 7.4 and 0.6 nM at pH 5.3 as measured by biolayer interferometry. Ansuvimab-zykl blocks binding of EBOV GP1 to the Neiman Pick cell receptor 1 in host cells (half-maximal effective concentration (EC ₅₀) value of 0.09 μg/mL), inhibiting virus entry into the host cell. Ansuvimab-zykl exhibited Fc-mediated Antibody Dependent Cellular Cytotoxicity (ADCC) activity against cells expressing EBOV GP when effector cells were added.

Antiviral Activity

In a live virus plaque-reduction neutralization assay performed in Vero E6 cells, ansuvimab-zykl neutralized Orthoebolavirus zairenseMayinga with an EC ₅₀value of 0.06 µg/mL. In a pseudotyped EBOV GP lentivirus infectivity assay using HEK293 cells, ansuvimab-zykl inhibited Orthoebolavirus zairenseMayinga with an EC ₅₀value of 0.09 μg/mL and Orthoebolavirus zairenseMakona with an EC ₅₀value of 0.15 μg/mL. The ADCC activity of ansuvimab-zykl was assessed in EBOV GP-transduced and non-transduced HEK293T target cells in the presence of antibody with effector cells added at an effector-to-target cell ratio 1:50 and analyzed via flow cytometry. Ansuvimab-zykl mediated ADCC, with maximal activity observed at mAb concentration of 0.03 μg/mL. Treatment of Orthoebolavirus zairenseinfected rhesus macaques with a single IV dose of ansuvimab-zykl (50 mg per kg) generally protected infected animals from Orthoebolavirus zairensemediated death when drug was administered 5 days post-infection.

Antiviral Resistance

No in-vivononclinical or clinical studies specifically evaluating resistance to ansuvimab-zykl have been conducted. The possibility of resistance to ansuvimab-zykl should be considered in patients who either fail to respond to therapy or who develop relapse of disease after an initial period of responsiveness.

Ansuvimab-zykl cell culture resistance studies have been performed using replication competent recombinant vesicular stomatitis virus expressing the EBOV surface glycoprotein (rVSV-EBOV GP). The rVSV-EBOV GP virus was sequentially sub-cultured in six experiments for up to 5 passages in the presence of a concentration range of ansuvimab-zykl (0.08 to 50 µg/mL) to determine if escape mutants developed via selective pressure. A total of seven different amino acid substitutions in the EBOV GP were found ( Table 4). Three of the seven were detected at less than 1% sequence frequency and were not within the ansuvimab-zykl GP epitope or within 5Å of the epitope, and therefore were excluded from further analysis.

The four remaining GP amino acid substitutions (P116H, T144M, R299K and N434K) were further evaluated in a single-cycle neutralization assay using a replication-defective lentiviral vector not expressing envelope pseudotyped with EBOV GP containing each of the substitutions. The P116H and T144M substitutions exhibited resistance to ansuvimab-zykl based on no neutralization detected at the highest concentrations assessed (10 µg/mL) resulting in a >56-fold reduction in susceptibility for each substitution compared to the wild type EBOV GP.

Two additional substitutions within the EBOV GP conserved region (G118E and G118R), which were not found in the studies described above, have been reported in the literature from similar cell culture resistance studies and these substitutions were able to confer >29- and >34-fold reductions in susceptibility to ansuvimab-zykl, respectively. ¹

Of the four resistant substitutions identified under selective pressure in cell culture (P116H, G118E, G118R, and T144M), only G118R has been identified in naturally infected Ebola virus disease patients in low frequency through NGS sequencing.

In Clinical Studies

A post-hoc detailed analysis of currently available EBOV GP sequences in the public database (as of November 2022) was performed to identify all amino acid polymorphisms in the ansuvimab-zykl epitope (GP positions 111-119) and amino acids within 5Å of the epitope. A total of nine sequences out of 3324 available EBOV genomes had amino acid changes, of which two were within the ansuvimab-zykl linear epitope (L111I and L111F) and two within 5Å of the epitope compared to the Kikwit variant (I170L and I170F). Of the nine EBOV GP sequences, six were at the same amino acid location with the same amino acid substitution (I170L), one was at the same location as the previous six, but with a different amino acid substitution (I170F). The remaining two were at the same location but with different amino acid substitutions (L111I and L111F). Overall, four of the nine EBOV GP sequences expressed distinct amino acid substitutions at only two different positions. Phenotypic assessments of these amino acid changes inside of, or within 5Å of the ansuvimab-zykl linear epitope (111-119) were performed with a single-cycle neutralization assay using a replication-defective lentiviral vector not expressing envelope pseudotyped with EBOV GP containing each of the substitutions. The EBOV-GP pseudotyped lentiviral vectors with the I170F and I170L substitutions were found to be inactive and unable to infect target cells. EBOV-GP pseudotyped lentiviral vectors with the L111I and L111F were fully neutralized by ansuvimab-zykl with a potency similar to the Ituri wild type variant and historic Mayinga variant EC ₅₀values and therefore none of the four identified amino acid substitutions are expected to be resistant to ansuvimab-zykl.

PALM Clinical study and MEURI EAP

Samples from a total of 95 participants (79 participants enrolled in the PALM randomized controlled clinical study and 16 participants from the MEURI EAP) including samples from 40 deceased participants and from 36 surviving participants with paired samples taken at baseline (pre-treatment) and after treatment with ansuvimab-zykl where available for EBOV glycoprotein (GP) sequencing. A total of 147 EBOV (GP) genome sequences were produced. When compared to the Kikwit and the Ituri variants, 26 and 14 amino acid substitutions, respectively, were found outside of the region of the ansuvimab-zykl epitope in EBOV GP from PALM trial participants. These amino acid changes were located predominantly in the less conserved mucin-like domain of the EBOV GP. None of these amino acid changes were associated with mortality nor appeared to be driven by ansuvimab-zykl treatment.

The amino acid substitution G118R, which was identified in cell culture selection experiments and had a >34-fold reduction in susceptibility to ansuvimab-zykl, was detected at 9% to 13% frequency by Next Generation Sequencing (NGS) in 10 participant samples (9 of which were survivors) collected prior to treatment with ansuvimab-zykl in the PALM and MEURI EAP ¹; the clinical significance of this substitution is unknown.

Additional post-hoc analysis of NGS data from the viral sequences detected several amino acid substitutions located in the ansuvimab-zykl epitope (K115, P116L, D117G) and within 5Å of the ansuvimab-zykl epitope (Y109C/H, L122P/S, V141A, P146L, C147K, Y171C, F176L). These substitutions, along with two controls that have known resistance (L111F, P116H), were evaluated for reductions in susceptibility to ansuvimab-zykl in comparison to the wild-type EBOV (Mayinga strain) using EBOV GP pseudotyped virus-like particle (PsVLP) infection of HEK293T cells. Out of the 18 PsVLPs produced (including the two controls), P116L showed significant reductions in susceptibility to ansuvimab-zykl, resulting in a mean 29.2-fold change compared to the wild-type EBOV GP. Three substitutions (K115N, D117G, and P146L) exhibited a range of 3.2- to 4.3-fold reduction in susceptibility based on mean reductions relative to wild-type control. Infectivity of the variants in this analysis ranged from 0.21 to 0.86 (where wild-type EBOV infectivity = 1). Table 5provides an overview of the infectivity and fold change of the four variants and two controls from this analysis. The clinical significance of these substitutions is unknown.

Immune Response

Interaction studies with recombinant live EBOV vaccines and EBANGA have not been conducted [see Drug Interactions (7.1)] .