Atoltivimab, Maftivimab, And Odesivimab-Ebgn

1 INDICATIONS AND USAGE INMAZEB is indicated for the treatment of infection caused by Orthoebolavirus zairense in adult and pediatric patients, including neonates born to a mother who is RT-PCR positive for Orthoebolavirus zairense infection [see Dosage and Administration (2.2) , and Clinical Studies (14) ] . INMAZEB is a combination of Orthoebolavirus zairense glycoprotein-directed human monoclonal antibodies (atoltivimab, maftivimab, and odesivimab), indicated for the treatment of infection caused by Orthoebolavirus zairense in adult and pediatric patients, including neonates born to a mother who is RT-PCR positive for Orthoebolavirus zairense infection. ( 1 ) Limitation of Use The efficacy of INMAZEB has not been established for other species of the Orthoebolavirus and Orthomarburgvirus genera . Orthoebolavirus zairense 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 Orthoebolavirus zairense strains when deciding whether to use INMAZEB. Limitations of Use The efficacy of INMAZEB has not been established for other species of the Orthoebolavirus and Orthomarburgvirus genera. Orthoebolavirus zairense 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 Orthoebolavirus zairense strains when deciding whether to use INMAZEB.

2 DOSAGE AND ADMINISTRATION The recommended dosage of INMAZEB is 50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg diluted and administered as a single intravenous infusion. ( 2.1 ) Refer to the Full Prescribing Information for information on preparation and administration. ( 2.2 ) 2.1 Recommended Dosage INMAZEB is a combination of three human monoclonal antibodies co-formulated in a 1:1:1 ratio of atoltivimab, maftivimab, and odesivimab. INMAZEB is available as two different strength presentations, containing either 16.67 mg of each antibody per mL or 33.33 mg of each antibody per mL [see Dosage Forms and Strengths (3) ] . The recommended dosage of INMAZEB is 50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg diluted and administered as a single intravenous infusion as shown in Table 1 [see Dosage and Administration (2.2) ] . 2.2 Preparation and Administration INMAZEB must be prepared and administered under the supervision of a healthcare provider. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. INMAZEB should be clear to slightly opalescent, colorless to pale yellow solution that is free from visible particulates. Discard the vial if the solution is cloudy, discolored or contains particulate matter. Preparation for Intravenous Infusion The recommended dosage is based on 50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg. For example, a patient weighing 50 kg the recommended dosage is 2,500 mg of atoltivimab, 2,500 mg of maftivimab, and 2,500 mg of odesivimab. Determine the number of vials needed based on the calculated dose in volume (mL). – The number of vials needed depends on the INMAZEB strength used. Refer to Table 1 for the corresponding volume per kg needed to withdraw from each available strength presentation to prepare dose. – Multiple INMAZEB vials may be needed. Each vial contains 14.5 mL of INMAZEB solution, regardless of the strength presentation. For example, for a 50 kg patient, the volume of INMAZEB needed is 150 mL (11 vials) if using the 16.67 mg/16.67 mg/16.67 mg per mL solution or 75 mL (6 vials) if using the 33.33 mg/33.33 mg/33.33 mg per mL solution. Table 1: INMAZEB Dosage (Volume per kg) for Intravenous Infusion Preparation When Using the When Using the 241.7 mg of atoltivimab, 241.7 mg of maftivimab, and 241.7 mg of odesivimab per 14.5 mL 483.3 mg of atoltivimab, 483.3 mg of maftivimab, and 483.3 mg of odesivimab per 14.5 mL (16.67 mg /16.67 mg /16.67 mg per mL) Solution (33.33 mg/33.33 mg /33.33 mg per mL) Solution Withdraw 3 mL of solution per kg to prepare the dose Withdraw 1.5 mL of solution per kg to prepare the dose Do not shake the vial. Prior to intravenous infusion, INMAZEB must be further diluted in an intravenous PVC infusion bag containing either 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, or Lactated Ringer's Injection, USP. For neonates, the INMAZEB solution should be diluted in 5% Dextrose Injection, USP (see Table 2 ). The total volume of the infusion solution to be administered is based on the patient's body weight and is specified in Table 2 . Select a diluent solution infusion bag of appropriate fill volume based on the patient's body weight (see Table 2 ). Withdraw and discard from the bag a volume of diluent solution equal to the calculated dose in volume (mL) of INMAZEB. Then add the calculated volume of INMAZEB to the bag. For example: – When using the 16.67 mg/16.67 mg/16.67 mg per mL solution for a 50 kg patient, withdraw and discard 150 mL of diluent from a 500 mL infusion bag. Then add 150 mL of INMAZEB to obtain a total infusion volume of 500 mL. – When using the 33.33 mg/33.33 mg/33.33 mg per mL solution for a 50 kg patient, withdraw and discard 75 mL of diluent from a 500 mL infusion bag. Then add 75 mL of INMAZEB to obtain a total infusion volume of 500 mL. Table 2: INMAZEB Infusion Volumes and Times by Body Weight Body Weight (kg) Total Infusion Volume After Dilution (mL) The recommended infusion volume ensures the final concentration of the diluted solution is 9.5 mg/mL to 23.7 mg/mL for the 16.67 mg/16.67 mg/16.67 mg per mL solution and 9.5 mg/mL to 30 mg/mL for the 33.33 mg/33.33 mg/33.33 mg per mL solution. 5% Dextrose Injection, USP is recommended for neonates. Infusion Time 0.5 to less than 1 7 4 hours 1 to 1.9 15 2 to 3.9 25 3 hours 4 to 7 50 8 to 15 100 16 to 38 250 2 hours 39 to 79 500 80 to 149 1,000 150 and above 2,000 4 hours Mix the diluted solution by gentle inversion. Do not shake. INMAZEB does not contain preservatives. It is always recommended to administer intravenous medication immediately after preparation when possible. Store the diluted INMAZEB solution as specified in Table 3 . Do not freeze the diluted solution. Discard any unused medicinal product or waste material. Table 3: Diluted INMAZEB Solution Storage Conditions Diluent Used to Prepare Solution for Infusion Diluted INMAZEB Solution Storage Conditions 0.9% Sodium Chloride Injection, USP Store at room temperature up to 25°C (77°F) for no more than 8 hours or refrigerated at 2°C to 8°C (36°F to 46°F) for no more than 24 hours. 5% Dextrose Injection, USP Store at room temperature up to 25°C (77°F) for no more than 4 hours or refrigerated at 2°C to 8°C (36°F to 46°F) for no more than 24 hours. Lactated Ringer's Injection, USP Store at room temperature up to 25°C (77°F) for no more than 4 hours or refrigerated at 2°C to 8°C (36°F to 46°F) for no more than 4 hours. Administration INMAZEB must be administered by a healthcare provider. Allow the diluted infusion solution to come to room temperature prior to administration. INMAZEB diluted with 5% Dextrose Injection, USP can be infused at temperatures up to 35°C (95°F). When the temperature is higher than 25°C (77°F), administer the diluted INMAZEB with 5% Dextrose Injection, USP immediately after completion of dose preparation. Administer the diluted infusion solution intravenously through an intravenous line containing a sterile, in-line or add-on 0.2-micron filter. The infusion rate is based on the patient's body weight and prepared infusion volume. Select an appropriate infusion rate for the diluted infusion solution (see Table 2 ). It is important to follow the infusion time outlined in Table 2 based on the patient's weight. The rate of infusion of INMAZEB may be slowed or interrupted if the patient develops any signs of infusion-associated events or other adverse events [see Warnings and Precautions (5.1) ] . Do not mix other medications with INMAZEB. Compatibility studies of INMAZEB have not been performed when co-administering other drugs simultaneously through the same infusion line.

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 common adverse events (incidence ≥20%) were pyrexia, chills, tachycardia, tachypnea, and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Regeneron at 1-844-734-6643 or www.regeneron.com/contact 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 may not reflect the rates observed in practice. Overall, 382 adult and pediatric subjects with Orthoebolavirus zairense infection received INMAZEB in one clinical trial (the PALM trial) and as part of an expanded access program conducted in the Democratic Republic of Congo during a Orthoebolavirus zairense outbreak in 2018-2019. In the PALM trial, the safety of INMAZEB was evaluated in a multi-center, open-label, randomized controlled trial, in which 154 subjects (115 adult subjects and 39 pediatric subjects) received INMAZEB [50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg (3 mL/kg)] intravenously as a single infusion and 168 subjects received an investigational control [see Clinical Studies (14) ] . All subjects received optimized standard of care treatment. During the same outbreak, INMAZEB [50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg (3 mL/kg)] was given to 228 subjects (190 adult subjects and 38 pediatric subjects) in the expanded access program. The safety data described below is derived from the PALM trial. Table 4 summarizes adverse events that were reported during INMAZEB infusion. The evaluation of adverse events in subjects who received INMAZEB may have been confounded by the signs and symptoms of the underlying Orthoebolavirus zairense infection. The most common adverse events reported in at least 20% of subjects who received INMAZEB were pyrexia (or elevation in fever), chills, tachycardia, tachypnea, and vomiting. The adverse event profile in adult and pediatric subjects treated with INMAZEB was similar. Table 4: Adverse Events That Occurred during INMAZEB Infusion in ≥10% of Adult and Pediatric Subjects in the PALM Trial Adverse Event Adverse events in this table were reported as preferred terms from a list of pre-defined or other adverse events that occurred on the day of infusion, and included signs and symptoms that occurred during or immediately after infusion INMAZEB (N=154) % Control Investigational therapy administered as three separate infusions (N=168) % Pyrexia (Elevation in fever) 54 58 Chills 39 33 Tachycardia 20 32 Tachypnea 19 28 Vomiting Adverse events that were not pre-specified 19 23 Hypotension 15 31 Diarrhea 11 18 Hypoxia 10 11 The following pre-specified symptoms, which were assessed on a daily basis while admitted to the treatment unit, were reported in 40% or more of subjects who received INMAZEB: diarrhea, pyrexia, and vomiting. Evaluation of these symptoms may have been confounded by the underlying Orthoebolavirus zairense infection. Discontinuation and Infusion Rate Adjustments in the PALM Trial Approximately 99% of subjects who received INMAZEB in the PALM trial were able to complete their dose within three hours. Two subjects who received INMAZEB (1%) did not receive their complete infusion. One of the two subjects did not complete their INMAZEB infusion because of fever elevation [see Warnings and Precautions (5.1) ] . Selected Laboratory Abnormalities in the PALM Trial Table 5 presents selected laboratory abnormalities (worsening to Grade 3 or 4 compared to baseline) for adult and pediatric subjects in the PALM trial. Table 5: Selected Grade 3 and 4 Laboratory Abnormalities, Worsened Grade from Baseline for Adult and Pediatric Subjects in the PALM Trial Laboratory Test Graded per Division of AIDS (DAIDS) v2.1 INMAZEB N=154 % Control N=168 % ULN = upper limit of normal Sodium, high ≥ 154 mmol/L 9 4 Sodium, low < 125 mmol/L 7 11 Potassium, high ≥ 6.5 mmol/L 13 12 Potassium, low < 2.5 mmol/L 9 8 Creatinine (mg/dL) ≥ 1.8 × ULN ULN for creatinine was 1.2 mg/dL. Criterion for increase to ≥ 1.5 × from baseline was applied if the worsening grade was higher. 15 23 Alanine aminotransferase (U/L) ≥ 5 × ULN 10 14 Aspartate aminotransferase (U/L) ≥ 5 × ULN 21 18 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the study described below with the incidence of antibodies in other studies or to other atoltivimab, maftivimab, and odesivimab products may be misleading. The development of anti-atoltivimab, anti-maftivimab, and anti-odesivimab antibodies was evaluated in 24 healthy adults in a single dose, randomized, double-blind, placebo-controlled, dose escalation study. Immunogenic responses against atoltivimab, maftivimab, and odesivimab were not detected at baseline or through 168 days post-dose in any subjects.

12.3 Pharmacokinetics No pharmacokinetic data are available in patients with Orthoebolavirus zairense infection. The pharmacokinetics of atoltivimab, maftivimab, and odesivimab in 18 healthy subjects 21 to 60 years of age are linear and dose-proportional over the range of 1 mg of atoltivimab, 1 mg of maftivimab, and 1 mg of odesivimab per kg to 50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg (0.02 to 1 times the approved recommended dosage) of INMAZEB following a single intravenous (IV) infusion. Pharmacokinetic parameters for the individual antibodies of INMAZEB are provided in Table 6 . Table 6: Pharmacokinetic Parameters of INMAZEB Administered IV in Healthy Subjects Atoltivimab 50 mg/kg INMAZEB was administered at a total dose of 50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg in a 1:1:1 ratio. Maftivimab 50 mg/kg Odesivimab 50 mg/kg Systemic Exposure (n=6) Mean (SD) C max , mg/L 1,220 (101) 1,280 (68.0) 1,260 (81.2) Mean (SD) AUC inf , mg day/L 17,100 (4,480) 18,700 (4,100) 25,600 (5,040) Distribution Mean (SD) Volume of Distribution at Steady State, mL/kg 58.2 (2.66) 57.6 (3.89) 56.0 (3.16) Elimination Mean (SD) Elimination Half-Life (days) 21.2 (3.36) 22.3 (3.09) 25.3 (3.86) Mean (SD) Clearance (mL/day/kg) 3.08 (0.719) 2.78 (0.558) 2.02 (0.374) Specific Populations The effect of age (< 21 or > 60), renal impairment, or hepatic impairment on the pharmacokinetics of atoltivimab, maftivimab, and odesivimab is unknown.