NDC 61755-018 Inmazeb

Atoltivimab, Maftivimab, And Odesivimab-ebgn

NDC Product Code 61755-018

NDC 61755-018-01

Package Description: 1 VIAL, SINGLE-DOSE in 1 CARTON > 14.5 mL in 1 VIAL, SINGLE-DOSE (61755-018-00)

NDC Product Information

Inmazeb with NDC 61755-018 is a a human prescription drug product labeled by Regeneron Pharmaceuticals, Inc.. The generic name of Inmazeb is atoltivimab, maftivimab, and odesivimab-ebgn. The product's dosage form is injection, solution and is administered via intravenous form.

Labeler Name: Regeneron Pharmaceuticals, Inc.

Dosage Form: Injection, Solution - A liquid preparation containing one or more drug substances dissolved in a suitable solvent or mixture of mutually miscible solvents that is suitable for injection.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Inmazeb Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • ATOLTIVIMAB 241.7 mg/14.5mL
  • MAFTIVIMAB 241.7 mg/14.5mL
  • ODESIVIMAB 241.7 mg/14.5mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • HISTIDINE (UNII: 4QD397987E)
  • HISTIDINE MONOHYDROCHLORIDE MONOHYDRATE (UNII: X573657P6P)
  • POLYSORBATE 80 (UNII: 6OZP39ZG8H)
  • SUCROSE (UNII: C151H8M554)
  • WATER (UNII: 059QF0KO0R)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Regeneron Pharmaceuticals, Inc.
Labeler Code: 61755
FDA Application Number: BLA761169 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: BLA - A product marketed under an approved Biologic License Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 10-14-2020 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Inmazeb Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

INMAZEB 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)].

Other

Limitations of UseThe efficacy of INMAZEB 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 INMAZEB.

  • Preparation for Intravenous InfusionThe 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 2500 mg of atoltivimab, 2500 mg of maftivimab, and 2500 mg of odesivimab.Determine the number of vials needed based on the calculated dose in volume (mL). Refer to Table 1 to determine the calculated dose based on volume (mL) of INMAZEB per patient's weight (kg). Multiple INMAZEB vials may be needed. Each vial contains 14.5 mL of INMAZEB solution. For example, for a 50 kg patient, the volume of INMAZEB needed is 150 mL (11 vials).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 1). The total volume of the infusion solution to be administered is based on the patient's body weight and is specified in Table 1.Select a diluent solution infusion bag 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 equal to the calculated dose in volume (mL) of INMAZEB. Then add the calculated volume of INMAZEB to the bag.For example, 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.Table 1: INMAZEB Infusion Volumes and Times by Body WeightBody Weight (kg)Volume of INMAZEB per kg of Body WeightThe dose is 50 mg of atolivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg of body weight (a volume of 3 mL/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. 5% Dextrose Injection, USP is recommended for neonates.Infusion Time0.5 to less than 13 mL per kg of body weight74 hours1 to 1.9152 to 3.9253 hours4 to 7508 to 1510016 to 382502 hours39 to 7950080 to 1491,000150 and above2,0004 hoursMix 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 2.Do not freeze the diluted solution.Discard any unused medicinal product or waste material.Table 2: Diluted INMAZEB Solution Storage ConditionsDiluent Used to Prepare Solution for InfusionDiluted INMAZEB Solution Storage Conditions0.9% Sodium Chloride Injection, USPStore 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 or Lactated Ringer's Injection, USPStore 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.

  • AdministrationINMAZEB must be administered by a healthcare provider.Allow the diluted infusion solution to come to room temperature prior to administration.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 1). It is important to follow the infusion time outlined in Table 1 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.

Discontinuation and Infusion Rate Adjustments in the PALM TrialApproximately 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 TrialTable 4 presents selected laboratory abnormalities (worsening to Grade 3 or 4 compared to baseline) for adult and pediatric subjects in the PALM trial.Table 4: Selected Grade 3 and 4 Laboratory Abnormalities, Worsened Grade from Baseline for Adult and Pediatric Subjects in the PALM TrialLaboratory TestGraded per Division of AIDS (DAIDS) v2.1INMAZEBN=154%ControlN=168%ULN = upper limit of normalSodium, high ≥ 154 mmol/L94Sodium, low < 125 mmol/L711Potassium, high ≥ 6.5 mmol/L1312Potassium, low < 2.5 mmol/L98Creatinine (mg/dL) ≥ 1.8 × ULNULN for creatinine was 1.2 mg/dL. Criterion for increase to ≥ 1.5 × from baseline was applied if the worsening grade was higher.1523Alanine aminotransferase (U/L) ≥ 5 × ULN1014Aspartate aminotransferase (U/L) ≥ 5 × ULN2118

Risk SummaryZaire ebolavirus infection 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 and an expanded access program in which pregnant women with Zaire ebolavirus infection were treated with INMAZEB demonstrate the high rate of maternal and fetal/neonatal morbidity consistent with published literature regarding the risk associated with underlying maternal Zaire ebolavirus infection. 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 INMAZEB have not been conducted. Human monoclonal antibodies, such as INMAZEB, are transported across the placenta; therefore, INMAZEB has the potential to be transferred from the mother to the developing fetus.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk Maternal, fetal and neonatal outcomes are poor among pregnant women infected with Zaire ebolavirus. The majority of such pregnancies result in maternal death with miscarriage, stillbirth, or neonatal death. Treatment should not be withheld due to pregnancy.

Risk SummaryThe Centers for Disease Control and Prevention recommend that patients with confirmed Zaire ebolavirus not breastfeed their infants to reduce the risk of postnatal transmission of Zaire ebolavirus infection.There are no data on the presence of atoltivimab, maftivimab, and odesivimab-ebgn 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 atoltivimab, maftivimab, or odesivimab-ebgn are unknown.

Specific PopulationsThe effect of age (< 21 or > 60), renal impairment, or hepatic impairment on the pharmacokinetics of atoltivimab, maftivimab, and odesivimab is unknown.

Mechanism of ActionINMAZEB is a combination of three recombinant human IgG1κ monoclonal antibodies each targeting the Zaire ebolavirus glycoprotein (GP). Zaire ebolavirus encodes a sole envelope protein, the glycoprotein, which mediates virus attachment and membrane fusion with the host cell membranes. In addition, GP is expressed on the surface of Zaire ebolavirus infected host cells making it a target for antibodies that can mediate killing of these cells by antibody dependent cellular cytotoxicity and/or other effector functions. The 3 antibodies that make up the combination can bind the GP simultaneously. The mean KD values for atoltivimab, odesivimab, and maftivimab were 7.84 nM, 8.26 nM, and 3.34 nM, respectively, as determined by surface plasmon resonance. Maftivimab is a neutralizing antibody that blocks entry of the virus into susceptible cells. Odesivimab is a non-neutralizing antibody that induces antibody-dependent effector function through FcyRIIIa signaling when bound to its target. Odesivimab also binds to the soluble form of Zaire ebolavirus glycoprotein (sGP). Atoltivimab combines both neutralization and FcyRIIIa signaling activities.

Antiviral ActivityIn a live virus infection assay on Vero cells, maftivimab neutralized Mayinga, Kikwit, and Makona strains of Zaire ebolavirus, with a concentration between 0.2 and 1.2 nM (0.03 and 0.18 μg/mL) providing 80% inhibition of viral infection in a plaque-reduction neutralization test (PRNT-80). Atoltivimab and odesivimab did not demonstrate any neutralizing activity in this assay. Effector function activity of INMAZEB individual antibodies was assessed with an EBOV Makona-GP expressing cell line and Jurkat/NFAT-Luc/FcγRIIIa reporter effector cells. The EC50 values of atoltivimab and odesivimab were 2.9 nM and 1.6 nM, respectively, whereas maftivimab did not exhibit any FcγRIIIa signaling activity at the maximum concentration tested, 40 nM.Treatment of Zaire ebolavirus infected rhesus macaques with a single intravenous dose of INMAZEB (50 mg of atolivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg) generally protected infected animals from Zaire ebolavirus mediated death when drug was administered 5 days post-infection.

ResistanceNo clinical data are available on the development of EBOV resistance to INMAZEB. The cell culture development of EBOV resistance to INMAZEB has not been assessed to date. A GP_E280G amino acid substitution identified by routine surveillance in the Democratic Republic of the Congo resulted in a loss of neutralization activity of at least 134-fold mediated by the single human monoclonal antibody atoltivimab in a lentivirus-based pseudovirus system. A GP_E564K substitution identified in an infected NHP PK study resulted in a loss of neutralization activity of at least 215-fold mediated by the single human monoclonal antibody maftivimab in a lentivirus-based pseudovirus system. The clinical significance of these substitutions is unknown.

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

Hypersensitivity Reactions Including Infusion-Associated EventsInform patients that hypersensitivity reactions including infusion-associated events have been reported during and post-infusion with INMAZEB and to immediately report if they experience any symptoms of systemic hypersensitivity reactions [see Warnings and Precautions (5.1)].

LactationInstruct patients with Zaire ebolavirus infection not to breastfeed because of the risk of passing Zaire ebolavirus to the baby [see Use in Specific Populations (8.2)].

Manufactured by: Regeneron Pharmaceuticals, Inc. 777 Old Saw Mill River Road Tarrytown, NY 10591-6707 U.S. License No. 1760 INMAZEB trademark is owned by Regeneron Pharmaceuticals, Inc. ©2020 Regeneron Pharmaceuticals, Inc. All rights reserved. Revised: October 2020

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. 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 [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.

3 Dosage Forms And Strengths

INMAZEB is a clear to slightly opalescent and colorless to pale yellow solution available as:Injection: 241.7 mg of atoltivimab, 241.7 mg of maftivimab, and 241.7 mg of odesivimab per 14.5 mL (16.67 mg/16.67 mg/16.67 mg per mL) in a single-dose vial.

4 Contraindications

None.

5.1 Hypersensitivity Reactions Including Infusion-Associated Events

Hypersensitivity reactions including infusion-associated events have been reported during and post-infusion with INMAZEB. These may include acute, life-threatening reactions during and after the infusion. Monitor all patients for signs and symptoms including, but not limited to, hypotension, chills and elevation of fever, during and following INMAZEB infusion. In the case of severe or life-threatening hypersensitivity reactions, discontinue the administration of INMAZEB immediately and administer appropriate emergency care [see Adverse Reactions (6.1)].Infusion could not be completed in 1% of subjects who received INMAZEB due to infusion-associated adverse events. 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 Adverse Reactions (6.1)].

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)]

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 Zaire ebolavirus 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 Zaire ebolavirus 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 3 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 Zaire ebolavirus 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 3: Adverse Events That Occurred during INMAZEB Infusion in ≥10% of Adult and Pediatric Subjects in the PALM TrialAdverse EventAdverse 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 infusionINMAZEB(N=154)%ControlInvestigational therapy administered as three separate infusions(N=168)%Pyrexia (Elevation in fever)5458Chills3933Tachycardia2032Tachypnea1928VomitingAdverse events that were not pre-specified1923Hypotension1531Diarrhea1118Hypoxia1011The 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 Zaire ebolavirus infection.

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.

7.1 Vaccine Interactions

No vaccine-therapeutic interaction studies have been performed in human subjects using INMAZEB. However, because of the potential for INMAZEB to inhibit replication of a live vaccine virus indicated for prevention of Zaire ebolavirus infection and possibly reduce the efficacy of the vaccine, avoid the concurrent administration of a live vaccine during treatment with INMAZEB. The interval between live vaccination following initiation of INMAZEB therapy should be in accordance with current vaccination guidelines. The efficacy of INMAZEB among subjects who reported receipt of a recombinant live vaccine prior to their enrollment in the PALM clinical trial was similar to subjects who did not receive a vaccine.

8.4 Pediatric Use

The safety and effectiveness of INMAZEB for the treatment of infection caused by Zaire ebolavirus have been established in pediatric patients from birth to less than 18 years of age. Use of INMAZEB for this indication is supported by evidence from a multi-center, open label, randomized controlled trial of INMAZEB in adults and pediatric subjects that included 39 pediatric subjects birth to less than 18 years of age, including neonates born to a mother who is RT-PCR positive for Zaire ebolavirus infection. The 28-day mortality and safety in adult and pediatric subjects treated with INMAZEB were similar [see Adverse Reactions (6.1) and Clinical Studies (14)]. An additional 38 pediatric subjects from birth to less than 18 years of age received INMAZEB in an expanded access program.

8.5 Geriatric Use

Clinical studies of INMAZEB did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 154 subjects with Zaire ebolavirus infection who received INMAZEB in the randomized controlled trial, 5 (3.2%) were 65 years or older. The limited clinical experience has not identified differences in responses between the elderly and younger subjects.

11 Description

Atoltivimab, maftivimab, and odesivimab-ebgn is a combination of Zaire ebolavirus glycoprotein (GP) directed recombinant human IgG1 human monoclonal antibodies of similar structure. The human monoclonal antibodies, atoltivimab, maftivimab, and odesivimab are produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell suspension culture and have an approximate molecular weight of 145 kDa, 146 kDa and 144 kDa, respectively.INMAZEB (atoltivimab, maftivimab, and odesivimab-ebgn) injection for intravenous use is a sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution, that is free from visible particulates. Each vial contains 241.7 mg of atoltivimab, 241.7 mg of maftivimab, and 241.7 mg of odesivimab in 14.5 mL. Each mL contains 16.67 mg of atoltivimab, 16.67 mg of maftivimab, 16.67 mg of odesivimab, and L-histidine (0.74 mg), L-histidine monohydrochloride monohydrate (1.09 mg), polysorbate 80 (1 mg), sucrose (100 mg), and Water for Injection, USP with a pH of 6.0.

12.1 Mechanism Of Action

INMAZEB is an antiviral drug combination of three recombinant human IgG1κ monoclonal antibodies (atoltivimab, maftivimab, and odesivimab) that inhibit Zaire ebolavirus [see Microbiology (12.4)].

12.2 Pharmacodynamics

Atoltivimab, maftivimab, and odesivimab exposure-response relationships and the time course of pharmacodynamic response are unknown.

12.3 Pharmacokinetics

No pharmacokinetic data are available in patients with Zaire ebolavirus 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 5.Table 5: Pharmacokinetic Parameters of INMAZEB Administered IV in Healthy SubjectsAtoltivimab50 mg/kgINMAZEB 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. Maftivimab50 mg/kgOdesivimab50 mg/kgSystemic Exposure (n=6)Mean (SD) Cmax, mg/L1,220 (101)1,280 (68.0)1,260 (81.2)Mean (SD) AUCinf, mg day/L17,100 (4,480)18,700 (4,100)25,600 (5,040)DistributionMean (SD) Volume of Distribution at Steady State, mL/kg58.2 (2.66)57.6 (3.89)56.0 (3.16)EliminationMean (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)

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity, genotoxicity, and fertility studies have not been conducted with INMAZEB.

14 Clinical Studies

The efficacy of INMAZEB was evaluated in PALM, a multi-center, open-label, randomized controlled trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID; NCT03719586). The trial was conducted in the Democratic Republic of Congo, where an outbreak began in August 2018, and enrolled 681 subjects of all ages, including pregnant women, with documented Zaire ebolavirus infection and symptoms of any duration who were receiving optimized standard of care (oSOC). Subjects were randomized to receive INMAZEB (50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg) intravenously as a single infusion, an investigational control 50 mg/kg intravenously every third day, for a total of 3 doses, or other investigational drugs. Eligible subjects had a positive reverse transcriptase-polymerase chain reaction (RT-PCR) for the nucleoprotein (NP) gene of Zaire ebolavirus and had not received other investigational treatments (with the exception of experimental vaccines) within the previous 30 days. Neonates ≤7 days of age were eligible if the mother had documented infection. Neonates born to a mother who had cleared Zaire ebolavirus following a course of her assigned investigational medication were also eligible to be enrolled at investigator discretion regarding the likelihood that the neonate was infected. Randomization was stratified by reverse transcription-PCR cycle threshold calculated using NP targets (CtNP ≤22.0 vs >22.0; corresponding to high and low viral load, respectively) and Ebola Treatment Unit (ETU) site. All subjects received oSOC consisting of a minimum of intravenous fluids, daily clinical laboratory testing, correction of hypoglycemia and electrolyte imbalances, and broad-spectrum antibiotics and antimalarials, as indicated .The primary efficacy endpoint was 28-day mortality. The primary analysis population includes all subjects who were randomized and concurrently eligible to receive either INMAZEB or the investigational control during the same time period of the trial.The demographics and baseline characteristics are provided in Table 6 below.Table 6: Demographics and Baseline Characteristics in PALM TrialParameterINMAZEB(N=154)Control(N=153)CtNP = cycle threshold calculated using NP targets; IQR = interquartile range; AST=Aspartate aminotransferase; ALT=Alanine aminotransferase; ETU=Ebola treatment unitMean age (years)2831Age <1 month (%)1 (1%)2 (1%)Age 1 month to <1 year (%)4 (3%)1 (1%)Age 1 year to < 6 years (%)18 (12%)13 (8%)Age 6 years to <12 years (%)8 (5%)4 (3%)Age 12 years to <18 years (%)8 (5%)8 (5%)Age 18 years to <50 years (%)93 (60%)105 (69%)Age 50 years to <65 years (%)17 (11%)18 (12%)Age ≥65 years (%)5 (3%)2 (1%)Female (%)90 (58%)80 (52%)  Positive result on pregnancy testPregnancy positive test was calculated based on subjects who had pregnancy test result., n (%)2/67 (3%)4/61 (7%)RT-PCR CtNP cycle threshold ≤22, n6664Median RT-PCR CtNP (IQR)22.7 (20.1, 28.1)22.9 (18.8, 26.4)Median creatinine (IQR)1.0 (0.7, 4.0)1.1 (0.7, 3.2)Median AST (IQR)225.5 (98.0, 941.0)351.0 (109, 1404.0)Median ALT (IQR)165.0 (56.0, 418.0)223.5 (47.0, 564.0)Median days from onset of symptoms to randomization (IQR)5.0 (3.0, 7.0)5.0 (3.0, 7.0)Reported Vaccination with rVSV-ZEBOV vaccine, n (%)34 (22%)41 (27%)  <10 days before ETU admission20/34 (59%)21/41 (51%)  ≥10 days before ETU admission14/34 (41%)18/41 (44%)  Timing unknown0/34 (0%)2/41 (5%)The PALM trial was stopped early on the basis of a pre-specified interim analysis showing a statistically significant reduction in mortality for INMAZEB compared to control.Mortality efficacy results are shown in Table 7.Table 7: Mortality Rates in PALM TrialEfficacy EndpointsINMAZEBBoth INMAZEB and Control were administered with optimized standard of care(N=154)Control(N=153)Overall28-day mortality, n (%)52 (34%)78 (51%)Mortality rate difference relative to control (95% CI)-17.2 (-28.4, -2.6)p-ValueThe result is significant according to the interim stopping boundary, p<0.0280.0024Baseline Viral LoadHigh viral load (CtNP ≤ 22)Cepheid GeneXpert Ebola® Assay used for detection of Zaire ebolavirus RNAn=66n=6428-day mortality, n (%)42 (64%)56 (88%)Mortality rate difference relative to control (95% CI)-23.9 (-43.8, -6.4)Low viral load (CtNP > 22)n=88n=8828-day mortality, n (%)10 (11%)22 (25%)Mortality rate difference relative to control (95% CI)-13.6 (-31.8, -1.4)Age groupAdults (age ≥18 years)39/115 (34%)67/125 (54%)12 to < 18 years of age2/8 (25%)4/8 (50%)6 to < 12 years of age1/8 (13%)1/4 (25%)< 6 years of age10/23 (43%)6/16 (38%)SexMale21/64 (33%)31/73 (42%)Female31/90 (34%)47/80 (59%)Figure 1: Kaplan-Meier Curve for Overall Mortality

16 How Supplied/Storage And Handling

  • INMAZEB (atoltivimab, maftivimab, and odesivimab-ebgn) injection is a clear to slightly opalescent and colorless to pale yellow solution. It is supplied in a carton containing one single dose vial of:241.7 mg of atoltivimab, 241.7 mg of maftivimab, and 241.7 mg of odesivimab per 14.5 mL (16.67 mg/16.67 mg/16.67 mg per mL) (NDC 61755-018-01)

Storage And Handling

Prior to dilutionStore INMAZEB vial refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze or shake.

After dilutionINMAZEB does not contain preservatives. It is always recommended to administer intravenous medication immediately after preparation when possible. Store the diluted INMAZEB solution as specified according to Table 8 below. Do not freeze the diluted solution [see Dosage and Administration (2.2)].Table 8: Diluted INMAZEB Solution Storage ConditionsDiluent Used to Prepare Solution for InfusionDiluted INMAZEB Solution Storage Conditions0.9% Sodium Chloride Injection, USPStore 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 or Lactated Ringer's Injection, USPStore at room temperature up to 25°C (77°F) for no more than 4 hours or refrigerated or at 2°C to 8°C (36°F to 46°F) for no more than 4 hours.

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