DRUG INTERACTIONS -summary

1. Vaccine Interactions-                                                                                                                 No vaccine-therapeutic interaction studies have been performed in human subjects using EBANGA. However, because of the potential for EBANGA to inhibit replication of a live vaccine virus indicated for prevention of Zaire ebolavirus infection and possibly reduce the efficacy of the vaccine

The interval between administration of EBANGA therapy and live vaccination should be in accordance with current vaccination guidelines. The efficacy of EBANGA among subjects who reported receipt of a recombinant live vaccine prior to their enrollment in the PALM trial was similar to subjects who did not report receiving a vaccine prior to enrollment

U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  52

-------------------------------CONTRAINDICATIONS------------------------------- None. ------------------------WARNINGS AND PRECAUTIONS----------------------- Hypersensitivity Reactions Including Infusion-Associated Events: Hypersensitivity reactions including infusion-associated events have been reported with EBANGA. These may include acute, lifethreatening reactions during and after the infusion. Monitor patients and in the case of severe or life-threatening hypersensitivity reactions, discontinue the administration of EBANGA immediately and administer appropriate emergency care. (5.1) -------------------------------ADVERSE REACTIONS------------------------------ 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. ------------------------------DRUG INTERACTIONS-------------------------------- Interaction with live vaccine indicated for prevention of Zaire ebolavirus infection: No vaccine interaction studies have been performed. EBANGA may reduce the efficacy of the live vaccine. The interval between administration of EBANGA therapy and live vaccination should be in accordance with current vaccination guidelines. (7.1) --------------------------USE IN SPECIFIC POPULATIONS--------------------- Lactation: Patients infected with Zaire ebolavirus should be instructed not to breastfed due to the potential for Zaire ebolavirus transmission. (8.2) See 17 for PATIENT COUNSELING IN

DOSAGE AND ADMINISTRATION

17 PATIENT COUNSELING INFORMATION Hypersensitivity Reactions Including Infusion-Associated Events Inform patients that hypersensitivity reactions including infusion-associated events have been reported during and post-infusion with EBANGA and to immediately report if they experience any symptoms of systemic hypersensitivity reactions [see Warnings and Precautions (5.1)]. Lactation Instruct patients with Zaire ebolavirus not to breastfeed because of the risk of passing Zaire ebolavirus to the baby [see Use in Specific Populations (8.2)].

Manufactured by: Ridgeback Biotherapeutics, LP 3480 Main Highway, Unit 402 Miami, FL 33133 U.S. License number 2162 [EBANGA™ is a trademark of Ridgeback Biotherapeutics, LP] © 2020 Ridgeback Biotherapeutics, LP. All rights reserved.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action Ansuvimab-zykl is a recombinant human monoclonal antibody with antiviral activity against Zaire ebolavirus [see Microbiology (12.4)].

12.2 Pharmacodynamics Ansuvimab-zykl exposure-response relationship and the time course of pharmacodynamic response is unknown. 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.

12.4 Microbiology Mechanism of Action EBANGA (ansuvimab-zykl) is a recombinant, human IgG1? 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). 9 Reference ID: 4720395 Ansuvimab-zykl binds EBOV GP without the mucin domain with a KD of 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 (IC50 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 Zaire ebolavirus Mayinga with an EC50 value of 0.06 µg/mL. In an EBOV GP lentivirus infectivity assay using HEK293 cells, ansuvimab-zykl inhibited Zaire ebolavirus Mayinga with an EC50 value of 0.09 µg/mL and Zaire ebolavirus Makona with an EC50 value 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 a mAb concentration of 0.03 µg/mL. Treatment of Zaire ebolavirus infected rhesus macaques with a single IV dose of ansuvimab-zykl (50 mg per kg) generally protected infected animals from Zaire ebolavirus mediated death when drug was administered 5 days post-infection. Resistance No nonclinical or clinical studies 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. Immune Response Interaction studies with recombinant live EBOV vaccines and EBANGA have not been conducted [see Drug Interactions (7.1)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy Risk Summary Zaire 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 in which pregnant women with Zaire ebolavirus infection 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 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 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 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.

8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommend that mothers 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 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.

8.4 Pediatric Use The safety and effectiveness of EBANGA 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 EBANGA for this indication is supported by evidence from a multi-center, open label, randomized controlled trial of EBANGA in adults and pediatric subjects that included 54 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. Of the total number of subjects administered EBANGA in the PALM trial, pediatric subjects (1 day to 17 years) accounted for 31% (n=54) of the study population in the PALM trial. The 28-day mortality and safety in adult and pediatric subjects treated with EBANGA were similar [see Adverse Reactions (6.1), and Clinical Studies (14)]. An additional 78 (31%) pediatric subjects from birth to less than 18 years of age received EBANGA in an expanded access program. 8 Reference ID: 4720395

8.5 Geriatric Use Clinical trials of EBANGA did not include sufficient numbers of subjects aged 65 and over to determine whether the safety profile of EBANGA is different in this population compared to younger subjects. Of the total number of subjects administered EBANGA in the PALM trial, 6 subjects (3%) were 65 years or older. The limited clinical experience has not identified differences in responses between the elderly and younger subjects.

11 DESCRIPTION Ansuvimab-zykl is a Zaire ebolavirus (EBOV) glycoprotein 1 (GP1)-directed recombinant, human IgG1 monoclonal antibody. Ansuvimab-zykl is produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology and has an approximate molecular weight of 147 kDa.