Ansuvimab

1 INDICATIONS AND USAGE EBANGA is indicated for the treatment of infection caused by Zaire ebolavirus in adult and pediatric patients, including neonates born to a mother who is RT-PCR positive for Zaire ebolavirus infection [see Dosage and Administration (2.2) and Clinical Studies (14) ] . EBANGA™ (ansuvimab-zykl) is a Zaire ebolavirus glycoprotein (EBOV GP)-directed human monoclonal antibody indicated for the treatment of infection caused by Zaire ebolavirus in adult and pediatric patients, including neonates born to a mother who is RT-PCR positive for Zaire ebolavirus infection. ( 1 ) Limitation of Use The efficacy of EBANGA has not been established for other species of the Ebolavirus and Marburgvirus genera . Zaire ebolavirus can change over time, and factors such as emergence of resistance or changes in viral virulence could diminish the clinical benefit of antiviral drugs. Consider available information on drug susceptibility patterns for circulating Zaire ebolavirus strains when deciding whether to use EBANGA. Limitations of Use: The efficacy of EBANGA has not been established for other species of the Ebolavirus and Marburgvirus genera. Zaire ebolavirus can change over time, and factors such as emergence of resistance, or changes in viral virulence could diminish the clinical benefit of antiviral drugs. Consider available information on drug susceptibility patterns for circulating Zaire ebolavirus strains when deciding whether to use EBANGA.

2 DOSAGE AND ADMINISTRATION The recommended dose of EBANGA for adult and pediatric patients is 50 mg/kg reconstituted, further diluted, and administered as a single intravenous infusion over 60 minutes. ( 2.1 , 2.2 ) See Full Prescribing Information for instructions on preparation, dilution and administration of EBANGA injection. ( 2.2 ) 2.1 Recommended Dosage for Adult and Pediatric Patients The recommended dosage of EBANGA is 50 mg/kg administered as a single intravenous (IV) infusion over 60 minutes. EBANGA must be reconstituted with Sterile Water for Injection, USP then further diluted in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP prior to IV infusion [see Dosage and Administration (2.2) ] . 2.2. Preparation, Administration, and Storage Instructions EBANGA must be prepared and administered under the supervision of a health care professional. 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. Table 1: EBANGA Volume, Diluent Volume and Total Infusion Volume by Body Weight Weight in kg Volume of EBANGA Diluent Volume (mL) The recommended diluent volume ensures the final concentration of the diluted solution is approximately 8-30 mg/mL. , For IV bag administration, the diluent volume column includes the volume of diluent needed to remain in the infusion bag. Final Infusion Volume (mL) Syringe or Infusion Bag Volume for IV Administration 0.5 kg 1 mL/kg 2.5 mL 3 mL 10 mL syringe compatible with IV infusion pump 1 kg 5 mL 6 mL 2 to 10 kg 10 mL 12 to 20 mL 25 mL IV bag 11 to 25 kg 25 mL 36 to 50 mL 50 mL IV bag 26 to 50 kg 50 mL 76 to 100 mL 100 mL IV bag 51 to 100 kg 100 mL 151 to 200 mL 250 mL IV bag 101 kg and above 150 mL 251 mL and above 500 mL IV bag 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.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions Including Infusion-Associated Events [see Warnings and Precautions (5.1) ] The most frequently reported adverse events (≥ 5%) after administration of EBANGA were pyrexia, tachycardia, diarrhea, vomiting, hypotension, tachypnea, and chills. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ridgeback Biotherapeutics, LP at 1-833-846-3789 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 may not reflect the rates observed in practice. Overall, 424 adult and pediatric subjects with Zaire ebolavirus infection received EBANGA in one clinical trial and as part of an expanded access program during the 2018 Zaire ebolavirus outbreak in the Democratic Republic of Congo (DRC). In the PALM trial, the safety of EBANGA was evaluated in a multi-center, open-label, randomized controlled trial, in which 173 subjects (119 adults and 54 pediatric subjects) with confirmed Zaire ebolavirus infection received EBANGA as a single 50 mg/kg IV infusion and 168 subjects received an investigational control [see Clinical Studies (14) ] . All subjects received optimized standard of care treatment (oSOC). The median age of the study population that received EBANGA was 26 years (range: 1 day to 85 years). Fifty-five percent (55%) of enrolled subjects were female and 45% were male. During the same outbreak, 251 subjects (173 adults and 78 pediatric subjects) with laboratory-confirmed Zaire ebolavirus infection received EBANGA under an expanded access program; 57% of whom were female and 43% of whom were male. Ages ranged from 6 days to 80 years, with a median age of 25 years. Common Adverse Events Table 2 summarizes 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 subjects who received EBANGA may have been confounded by the signs and symptoms of the underlying Zaire ebolavirus infection. Twenty nine percent (n=51) of subjects 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 subjects who received EBANGA was fever (Table 2). The adverse event profile in adult and pediatric subjects treated with EBANGA was similar. Table 2: Adverse Events That Occurred During Infusion in >10% of Adult and Pediatric Subjects in the PALM Trial Adverse Event Adverse events in this table were reported on the day of infusion, and included signs and symptoms that occurred during or immediately after infusion EBANGA (N=173) % Control Investigational therapy administered as three separate infusions (N=168) % Pyrexia 17 58 Tachycardia 9 32 Diarrhea Adverse events that occurred during infusion but were not pre-specified. 9 18 Vomiting 8 23 Hypotension 8 31 Tachypnea 6 28 Chills The term chills includes other similar adverse events including rigors and tremors 5 33 Hypoxia , 3 11 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 subjects who received EBANGA: diarrhea, pyrexia, abdominal pain, and vomiting. Evaluation of these symptoms may have been confounded by the underlying Zaire ebolavirus infection. Discontinuation and Infusion Rate Adjustments Approximately 99% of subjects who received EBANGA in the PALM trial were able to complete their dose within one hour. Two subjects who received EBANGA (1%) did not receive their complete infusion. In eight subjects (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 3 presents selected laboratory abnormalities (worsening to Grade 3 or 4 compared to baseline) in the PALM trial. Table 3: Selected Grade 3 and 4 Laboratory Abnormalities a , Worsened Grade from Baseline in the PALM Trial Laboratory Test Graded per Division of AIDS (DAIDS) v2.1 EBANGA N=173 % Control N=168 % ULN= upper limit of normal Sodium, high ≥ 154 mmol/L 5 4 Sodium, low < 125 mmol/L 7 11 Potassium, high ≥ 6.5 mmol/L 15 12 Potassium, low < 2.5 mmol/L 6 8 Creatinine (mg/dL) > 1.8 × ULN or ≥ 1.5 × baseline Based on a ULN of 1.2 mg/dL. 27 23 Alanine aminotransferase (U/L) ≥ 5 × ULN Based on a ULN of 47U/L. 12 14 Aspartate aminotransferase (U/L) ≥ 5 × ULN Based on a ULN of 38 U/L. 13 18 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity from using ansuvimab-zykl. There are no data to assess the effects of potential immunogenicity on efficacy and safety in subjects with Zaire ebolavirus infection.

12.3 Pharmacokinetics Limited data from 18 healthy subjects 22 to 56 years of age suggests that the pharmacokinetic profile of ansuvimab-zykl is consistent with the profile of other IgG1 monoclonal antibodies. Pharmacokinetic data are not available for Zaire ebolavirus infected patients. Specific Populations The effect of age, renal impairment or hepatic impairment on the pharmacokinetics of ansuvimab-zykl is unknown.