Atoltivimab, Maftivimab, and Odesivimab

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.

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. Injection: 483.3 mg of atoltivimab, 483.3 mg of maftivimab, and 483.3 mg of odesivimab per 14.5 mL (33.33 mg/33.33 mg/33.33 mg per mL) in a single-dose vial. 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. ( 3 ) 483.3 mg of atoltivimab, 483.3 mg of maftivimab, and 483.3 mg of odesivimab per 14.5 mL (33.33 mg/33.33 mg/33.33 mg per mL) in a single-dose vial. ( 3 )

None. None. ( 4 )

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 patients and in the case of severe or life-threatening hypersensitivity reactions, discontinue the administration of INMAZEB immediately and administer appropriate emergency care. ( 5.1 )

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) ] .

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.

Interaction with live vaccine indicated for prevention of Orthoebolavirus zairense infection: No vaccine interaction studies have been performed. INMAZEB may reduce the efficacy of the live vaccine. The interval between live vaccination following initiation of INMAZEB therapy should be in accordance with current vaccination guidelines. ( 7.1 )

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 Orthoebolavirus zairense 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.

Lactation: Patients infected with Orthoebolavirus zairense should be instructed not to breastfeed due to the potential for Orthoebolavirus zairense transmission. ( 8.2 )

8.1 Pregnancy Risk Summary Orthoebolavirus zairense 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 Orthoebolavirus zairense 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 Orthoebolavirus zairense 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 Orthoebolavirus zairense . The majority of such pregnancies result in maternal death with miscarriage, stillbirth, or neonatal death. Treatment should not be withheld due to pregnancy.

8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommend that patients with confirmed Orthoebolavirus zairense not breastfeed their infants to reduce the risk of postnatal transmission of Orthoebolavirus zairense 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.

8.4 Pediatric Use The safety and effectiveness of INMAZEB for the treatment of infection caused by Orthoebolavirus zairense 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 Orthoebolavirus zairense 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 Orthoebolavirus zairense 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.

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