Appendix 4. Summaries of Evidence from Selected Experimental Therapeutics, As of October 2018

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Candidate ZMapp™ Remdesivir (formerly GS-5734) REGN3470-3471-3479 VRC-EBOMAB092-00-AB therapeutic name/denomina (REGN-EB3) (mAb114) tion Manufacturer/d Mapp Biopharmaceutical Gilead Sciences, Inc. Regeneron Pharmaceuticals Inc.* Vaccine Research Center, National eveloper Institute of Allergy and Infectious *This project has been funded in whole or in part Diseases, National Institutes of Health, US with Federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority, under Contract No. “HHSO100201500013C”

Short description An equimolar mixture of three mouse/human chimeric IgG1, kappa mAbs, Remdesivir (formerly GS-5734) is a prodrug of a Co-formulated cocktail of three fully mAb114 is a recombinant human IgG1 of candidate c13C6-FR1, c2G4 and c4G7; each of these were derived from three mouse modified adenine nucleoside analog GS-441524. human monoclonal antibodies that target antibody produced in a Chinese Hamster therapeutic: mAbs directed against three epitopes in EBOV glycoprotein. Remdesivir undergoes efficient metabolic the Zaire ebolavirus glycoprotein (GP) Ovary (CHO) cell line. Proof of concept conversion in cells and tissues to active nucleoside studies performed with mAb114 triphosphate metabolite that inhibits viral RNA demonstrated 100% protection after a polymerases, but not host RNA or DNA polymerases. single dose administration either one day Remdesivir exhibits a potential for clinical efficacy or five days after lethal Ebola Virus Zaire against Ebola virus and other filovirus infections based (EBOV) challenge in non-human primates on the following: (NHP). mAb114 was also found to be safe 1) Potent in vitro activity in multiple relevant cell types and well tolerated in a Phase I dose- against multiple Ebola virus isolates, including the escalation study up to 50mg/kg. Ebola virus variants isolated during the 2014-16 outbreak in West Africa. 2) Potent and consistent in vitro antiviral activity against diverse species of the ebolavirus family, including Zaire, Sudan, and Bundibugyo viruses, as well as Marburg virus. 3) Preclinical pharmacokinetic profile in non-human primates and other relevant animal species indicating high and persistent levels of pharmacologically active nucleoside triphosphate metabolite in peripheral blood mononuclear cells (PBMCs); this measurement is used as a surrogate for drug levels in cells relevant for Ebola virus infection, supporting once daily administration. 4) Preclinical safety profile supporting safe clinical administration at doses potentially active against Ebola and Marburg virus infections. 5) Clinical safety profile from > 100 human subjects dosed with intravenous remdesivir supports the clinical dosing regimen recommended for the treatment of Ebola. Single and repeated doses of remdesivir were safely administered in Phase 1 studies in healthy human subjects, PREVAIL IV study in male Ebola virus disease (EVD) survivors, as well as during compassionate use for the treatment and post exposure prophylaxis of Ebola infection.

Rationale for Dose Selection: The proposed dosing regimen for patients with Ebola infection was selected to provide similar systemic remdesivir exposure to that observed in filovirus

Training: No special training or equipment required Presentation 100 mg in 10 mL glass vials (5 mL of an aqueous solution of 20 mg/mL) Remdesivir lyophilized formulation for injection is a The co-formulated REGN-EB3 cocktail is Lyophilized drug product in vials, 400 mg preservative-free, white to off-white or yellow supplied as a sterile aqueous solution of mAb114 per vial lyophilized solid containing 150 mg remdesivir that is containing 50 mg/mL protein with equal to be reconstituted with 29 mL of sterile water for

WHO R&D Blueprint – Ad-hoc Expert Consultation on clinical trials for Ebola Therapeutics (https://www.who.int/ebola/drc-2018/treatments-approved-for-compassionate-use-update/en/) Deliberations on design options for randomized controlled clinical trials to assess the safety and efficacy of investigational therapeutics for the treatment of patients with Ebola virus disease Appendix 4. Summaries of evidence from selected experimental therapeutics, as of October 2018 ongoing or compassionate use provisions to at least 25 patients. Limited safety and no Normal Healthy Volunteer Phase 3 safety Administered Intravenously to Health planned efficacy information is available from this experience. Phase 2 randomized clinical trial (RCT) study in Ebola study in ~450 subjects is planned to start Adults” (NCT03478891) male survivors is ongoing in Liberia and Guinea; the Q12019 study is sponsored by NIAID. Single dose ADME study in human healthy subjects Expanded Access Protocol in DRC using radiolabeled material is planned for early 2019. outbreak – Ongoing (NCT03576690) Efficacy Pre-clinical efficacy in NHP: Pre-clinical efficacy in NHP: Pre-clinical efficacy in NHP: Evidence of Pre-clinical efficacy in NHP: Evidence of efficacy and improved survival of Zaire efficacy and improved survival of Zaire NHP Study 1 examined the efficacy of ZMappA (c13C6-FR1 and c2G4 Various treatment regimens of remdesivir have been Ebola virus inoculated rhesus macaques Ebola virus inoculated rhesus macaques produced in Nicotiana and 4G7 produced in mouse hybridoma cells) tested in EBOV-infected rhesus monkeys and in (or other NHPs) following treatment with (or other NHPs) following treatment with administered intravenously 3 days post infection was investigated in rhesus Marburg-infected cynomolgus monkeys. All studies the drug versus controls. Information on the drug versus controls. macaques. Rhesus macaques were infected with 4,000 tissue culture were randomized, blinded, and placebo controlled surrogate markers, -validated or mAb114 has been tested in macaques infectious doses (TCID50) units of EBOV intramuscularly (Kikwit strain; 7U with at least N=6 animals per treatment arm. reasonably expected to predict efficacy, that were exposed to a lethal (1000 PFU) EBOV-K). This viral dose was established as a 100% lethal dose historically at e.g. viral load decreases if available intramuscular (IM) dose of EBOV Kikwit. the testing facility and is estimated to be approximately 1000 LD50. In the initial study, infected animals treated with 3 to In three separate experiments, NHP were 10 mg/kg of remdesivir administered once daily by IV The therapeutic potential of REGN3470- treated IV with three infusions of 50 injection for 12 days beginning 3 days post Ebola virus 3471-3479 has been demonstrated in mg/kg mAb114 IV (24-hr intervals). In inoculation exhibited 100% survival combined with a EBOV challenge studies in non-human the first two experiments, treatment was significant suppression of EVD clinical symptoms primates (NHPs). These studies showed initiated 1 day after infectious challenge including amelioration of behavioral depression, that the antibody cocktail can treat an and in the third experiment treatment changes in hematology and coagulation parameters, as established EBOV infection and aid initiated 5 days after challenge. All well as serum chemistry markers of kidney and liver recovery of animals from advanced Ebola treated animals remained free of clinical toxicity, and no signs of drug-related toxicities. Fifty disease when administered as 3 doses of and laboratory abnormalities and NHP Study 2: Treated with three doses of ZMapp beginning 3, 4, or 5 days percent of animals treated with 10 mg/kg remdesivir 50 mg/kg at days 5, 8, and 11, 2 doses of pretreatment viremia levels of up to 6 after IM challenge with 1,000 TCID50 of EBOV-K. remained free of any physical signs of EVD throughout 50 mg/kg at days 5 and 8, or a single dose log10 GE/mL were rapidly controlled to the 28 day duration of the study. In comparison, all of 150 mg/kg at day 5 post-infection with undetectable levels. Control animals vehicle-treated animals succumbed to Ebola virus EBOV. Cumulatively, antibody treated succumbed to EVD on Days 9 and 10 with infection by day 9. The impact on survival and clinical animals showed 86% survival in the peak viral loads of approximately 8 log10 symptoms of EVD in Ebola virus-infected drug-treated 150mg/kg single dose groups, compared GE/mL. animals was due to the potent suppression of virus to 6% survival in the placebo groups. replication. Animals treated with 10 mg/kg remdesivir Additionally, the minimum efficacious To test a simplified single-infusion beginning Day 3 post infection exhibited pronounced dose of the REGN3470-3471-3479 regimen of mAb114, macaques were suppression of plasma viral RNA levels with a mean cocktail was determined in animals exposed to a lethal dose of EBOV (1000 reduction of −3.9 log10 on Day 5 compared to the receiving a single dose of 150 mg/kg, 100 PFU IM) and mAb114 IV was vehicle-treated control group. Plasma viral RNA in mg/kg, 50 mg/kg, or 10 mg/kg of the administered just once at a 50 mg/kg three out of six animals treated with 10 mg/kg antibody cocktail on day 5 post infection. dose 1 day post-exposure. All animals in NHP study 3 examined the efficacy of different ZMapp dose levels (50 mg/kg remdesivir decreased below the lower limit of A single-dose of the cocktail showed a the treatment group survived, while the and 25 mg/kg) and frequency of ZMapp administrations (one, two or three 50 quantification (LLOQ; 8 × 104 RNA copies/mL) by Day dose-dependent post-exposure control animal succumbed to EVD on day mg/kg dose administrations). Briefly, animals were challenged 5. By Day 12, all animals treated with 10 mg/kg protection against lethal EBOV disease 9. The same outcome with 100% intramuscularly with a dose of 1066 plaque forming units with USAMRIID’s remdesivir had plasma viral RNA below the lower limit with 100 mg/kg as the lowest dose tested protection was achieved with a single Passage 3 (P3) 7U EBOV Kikwit challenge material. Animals were then treated of detection by PCR. No genotypic resistance was that gave best control of symptoms dose of 50 mg/kg mAb114 administered 5 with either ZMapp or saline on Days 5, 8 and 11 post-EBOV infection. detected in vivo using deep sequencing of the entire (incidence of rash, shorter duration of days after challenge (the control animal EBOV RNA pol (L) gene from infected rhesus monkeys. fever, and lower incidence of liver succumbed on day 9). In a dose-sparing damage). study, a single infusion of 30 mg/kg given Treatment with a 10 mg/kg remdesivir initiated on Day Treatment of NHPs with a single at day 5 post-EBOV exposure also yielded 3 post-infection was associated with 100% survival in 150mg/kg dose on day 5 post-challenge uniform protection in treated macaques, rhesus monkeys infected with EBOV Makona/2014. All resulted in a rapid drop in viral load from with the control succumbing on day 10. vehicle-treated control animals died on the study. median of 8.0log10GE/ml (~ GP Ct of 24.5) on day 5 to 6.3log10GE/ml (~ GP Ct Information on surrogate markers, - Treatment of rhesus monkeys infected with EBOV of 31) on day 8. 150mg/kg single dose validated or reasonably expected to Kikwit/1995 for a total of 12 days with 5 mg/kg also resulted in control of ALT/AST levels predict efficacy, e.g.viral load decreases if remdesivir, with or without a single loading dose of 10 in treated animals with both peaking available mg/kg, initiated 4 days post infection, resulted in 100% under 300 in treated animals. In contracts Not yet defined

Clinical efficacy data from RCTs: No data currently available from RCTs; Phase 2 RCT study in EVD male survivors is ongoing in Liberia and Guinea (for details see the table below).

Clinical efficacy data from RCTs

See separate Table describing the PREVAIL II randomized controlled trial listed in Annex 1: Completed ZMapp Phase I/II Safety and Efficacy Study (PREVAIL II). Annex 1 also includes information on Clinical trials completed ongoing or planned: Planned Phase 1 study of ZMapp in healthy adults under FDA Animal Rule Guidelines and Planned Phase 3 study of ZMapp in healthy adults under FDA Animal Rule Guidelines Safety data Human safety data from PREVAIL II is provided in the separate Table listed on Preclinical safety data: First in Human Phase 1 study Pre-clinical safety assessment: Systemic Clinical safety pg.9. Remdesivir and the parent nucleoside analog GS- (Sivapalasingam et al Lancet ID and local toxicities of mAb114 were assessment 441524 were extensively profiled for in vitro 2018;18:884) evaluated in a GLP, 4-week repeated dose should be Rat toxicology study: cytotoxicity and mitochondrial toxicity in multiple • Randomized, double-blind, IV toxicity study in rhesus monkeys with provided for the A repeat dose 21 day GLP toxicology study in male and female adult Sprague relevant cell types. Both remdesivir and GS-441524 placebo-controlled, dose an 8-week recovery. Male and female drug at the Dawley rats has been conducted by SRI International (Menlo Park, CA). This exhibited > 3.5-fold margins in most in vitro toxicity escalation study conducted in the rhesus monkeys were assigned to four exposure level study evaluated administration of vehicle control or ZMapp at 50 or 100 assays. Data from in vitro studies with liver cell culture groups and dosed with mAb114 (Group 1: US proposed for mg/kg/day once daily for 6 days on Study Days 1, 3, 7, 11, 16, and 21 by an IV systems demonstrated that human hepatocytes are placebo; Group 2: single 50 mg/kg dose; • Healthy adults, aged 18-60 years treatment of bolus injection via the tail vein. Total ZMapp exposure was 300 or 600 mg/kg susceptible to remdesivir mediated toxicity, likely due Group 3: three repeated doses of 50 EVD, considering for the 50 or 100 mg/kg/day dose groups, respectively. The study comprised a to high cellular permeability and effective intracellular were assigned to single IV dose of mg/kg; Group 4: single dose of 500 non-clinical and, main, a recovery, and a satellite group for toxicokinetic (TK) analyses. metabolism of the drug. Systemic metabolites of REGN3470-3471-3479 or placebo mg/kg). mAb114 was well-tolerated in if available, Endpoints included hematology, serum chemistries, gross pathology, organ remdesivir detected in vivo in plasma do not exhibit on day 1 in one of the four rhesus monkeys. There were no mAb114- clinical data. weights, and histopathology. Clinical observations were recorded daily any in vitro hepatotoxicity at pharmacologically sequential ascending IV dose related mortalities, clinical signs of throughout treatment and weekly during the recovery phase. In the final relevant levels. toxicity, body weight changes, adverse

WHO R&D Blueprint – Ad-hoc Expert Consultation on clinical trials for Ebola Therapeutics (https://www.who.int/ebola/drc-2018/treatments-approved-for-compassionate-use-update/en/) Deliberations on design options for randomized controlled clinical trials to assess the safety and efficacy of investigational therapeutics for the treatment of patients with Ebola virus disease Appendix 4. Summaries of evidence from selected experimental therapeutics, as of October 2018 If human PK trials report, a NOAEL could not be established due to adverse hepatotoxicity cohorts (3 mg/kg, 15 mg/kg, 60 effects on clinical pathology or safety or studies in findings, with the liver identified as the main target organ of ZMapp in the rat. The diastereomeric prodrug mixture (remdesivir and mg/kg and 150 mg/kg) pharmacology parameters in any of the other indications Slight increases in AST (up to 1.4 times), ALT (up to 1.2 times) and AP (up to its diastereomer at phosphorous in a ~1:1 ratio), and • 24 healthy adults were enrolled, groups studied. Evaluations of skin at the exposure 1.8 times) were observed in all ZMapp treated groups. Histopathological the parent nucleoside, GS-441524, have a low 18 assigned to receive REGN3470- erythema and edema at injection sites level proposed evaluation identified ZMapp related effects consisting of minimal to potential for off-target activity. Neither compound 3471-3479 and 6 to placebo and histopathology of injection sites for treatment of moderate hepatocyte hydrophic degeneration, mild to moderate hepatocyte significantly inhibited binding to a panel of 87 demonstrated local tolerance of repeated • 19 treatment emergent adverse EVD have been hypertrophy, minimal to marked increased mitotic activity in hepatocytes, biological targets (receptors, ion channels, enzymes) at IV injections and infusions of mAb114. conducted please disorganization of hepatic architecture and minimal hepatocyte apoptosis in a concentration of 10 μM representing levels events (TEAES) occurred in the Based on these data, the No-Observed- include this the liver. In addition, minimal to moderate necrosis of veins was observed at significantly above the clinical systemic exposures combined treatment groups and 4 Adverse-Effect-Level (NOAEL) was information the injection sites. Following a 7- week recovery phase, no significant clinical observed at the recommended doses of remdesivir. TEAEs in the combined. placebo determined to be 500 mg/kg/week of In the absence of chemistry or histopathologic findings were observed, and only a slight groups. All AEs were transient and mAb114, the highest dose tested. human data, increase in mean liver organ weight was observed in male treatment groups. Safety pharmacology studies were conducted to mild to moderate in severity. Safety assessment in humans: mAb114 safety results Serum transaminases returned to normal by the end of the recovery phase examine the potential effects of remdesivir on the • The most common TEAE was was found to be safe and well tolerated from animal suggesting the observed hepatic toxicity was acute and transient. respiratory system, central nervous system, and headache (6 of 18 participants in in a Phase I dose escalation study. For studies, as well cardiovascular system after IV administration. In a the combined REGN3470-3471- details on local and systemic as relevant in Tissue Cross Reactivity: respiratory safety study in rats, remdesivir had no reactogenicity, please consult Phase I 3479 group vs none of 6 vitro data should A preliminary non-GLP tissue cross reactivity (TCR) study evaluating the effect on tidal volume or minute volume; however, results report from ClinicalTrials.gov participants in the placebo group). be provided. binding of individual ZMapp mAbs to a limited number of human tissues has respiration rates were increased from 0.75 to 6 hours Headaches were mild to moderate been conducted. Unanticipated binding of one or more ZMapp mAbs to post-dose in animals administered ≥ 20-mg/kg evaluated human tissues (heart, brain, liver, kidney, lung, pancreas, spleen remdesivir. Respiration rates returned to control levels in severity with onset between 2h and skeletal muscle) was observed. The clinical significance of this “off target” by 24 hours post-dose, resulting in a no observed and 27 days after start of study binding is uncertain. A more definitive GLP tissue cross reactivity study effect level (NOEL) for respiratory function in male rats drug infusion. No deaths, Serious evaluating the binding of individual ZMapp mAbs to a full panel of human of 5 mg/kg, at exposures 1.1-fold above the estimated AEs or infusion reactions were tissues is described below. GS-441524 Cmax at the 200 mg clinical dose. noted. A GLP TCR study was performed to further evaluate the potential off target Remdesivir had no effect on the CNS in rats and no • The PK of each antibody was linear binding observed in the study described above. Panels of rat, non-human effect on cardiovascular parameters in monkeys at with a mean half-life ranging from primate (NHP), and human tissues were evaluated with biotinylated ZMapp dose levels up to 50 and 10 mg/kg, respectively. The 21.7 days and 27.3 days. mAbs. Positive controls (HEK 293 cells expressing EBOV glycoprotein) and lack of in vivo cardiovascular effect is consistent with • No participant tested positive for negative controls (HEK 293 cells) were included to show specificity of staining. the weak in vitro inhibition of the hERG channel by Results indicate that sporadic staining in the cytoplasm of macrophages was remdesivir. Taken together, the risk for CNS, anti-drug antibodies. observed in some tissues. However, as EBOV glycoprotein is a cell-surface respiratory, or cardiovascular effects in the clinic is antigen and macrophage cytoplasm would not be available for mAb binding in considered low at projected therapeutic exposures. vivo, the observed binding was deemed non-specific and not relevant off- target binding. The nonclinical toxicology profile of remdesivir has been characterized through the conduct of repeat- dose studies in rats and cynomolgus monkeys with once-daily dosing up to 4 weeks in duration, studies to evaluate the genotoxic potential of the compound, a battery of reproduction and developmental studies (fertility in rats, embryofetal development in rats and rabbits, and a pre- and post-developmental study in rats), and a hemolysis/blood compatibility study. Following repeated dosing in rats and monkeys, the kidney was identified as the target organ. In both species, clinical chemistry, urinalysis, and/or urinary biomarkers were early predictors of the observed kidney changes. There were no changes in the liver function in rats or monkeys based on clinical chemistry parameters, liver weight, or microscopic observations. Remdesivir and GS-441524 exposures (AUC) at the no observed adverse effect levels (NOAELs) are below the predicted steady state exposure in humans at 100 and 200 mg.

Remdesivir is considered non-genotoxic. In the reproductive and development toxicity studies, the only notable finding was a decrease in corpora lutea, a consequent decrease in implantation sites and viable embryos, and lower ovary and uterus/cervix/oviduct weights in the rat fertility study; these changes were observed at a systemically toxic dose. There were no remarkable findings in male rats in the fertility study, no adverse findings in the developmental toxicity studies in rats and rabbits, and no adverse changes in the pre- and postnatal study in rats.

The vehicle used in the IV repeat-dose toxicity studies and the hemolytic potential and plasma compatibility study contained 12% [w/v] betadex sulfobutyl ether sodium (SBECD) in water, pH 3.5 ± 0.1, similar to the vehicle for the Phase 1 clinical studies. The toxicity of SBECD has been well characterized in the remdesivir toxicology studies and in peer-reviewed publications. SBECD-related microscopic findings of diffuse tubule cell vacuolation and focal/multifocal tubule cell hypertrophy in the kidney of rats and monkeys were neither considered adverse nor associated with any clinical pathology effects indicative of changes in kidney function, and have been previously described. There was no notable exacerbation of the SBECD- related effects when administered with remdesivir.

Clinical safety data: Single dose of remdesivir IV infusion from 3 to 225 mg was well tolerated with no dose limiting toxicity observed. No treatment emergent AEs were observed in more than 1 subject per arm. No evidence of renal or liver toxicity was observed. All AEs were Grade 1 or 2.

Multiple-dose IV administration of remdesivir 150 mg once-daily for 7 or 14 days was generally well tolerated. No subjects had a Grade 3 or 4 treatment- emergent laboratory abnormality during the study. Reversible Grade 1 or 2 ALT or AST elevations were observed in several subjects without abnormalities in total bilirubin, alkaline phosphatase (ALP), or albumin. There was no abnormality or clinically significant change in international normalized ratio (INR) in any subjects. Remdesivir did not show any effects on renal function in the multiple-dose study.

To date, remdesivir has been administered on an expanded compassionate access basis to patients with Ebola infection. The treated cases included a 39-year- old female diagnosed with recrudescent Ebola

Remdesivir has been administered to two adult subjects following a high-risk exposure to Ebola or Sudan virus in laboratory settings. A five-day course of remdesivir post-exposure prophylaxis at 100 mg once- daily was well tolerated without any treatment- associated safety observations or laboratory abnormalities. Both subjects remained PCR negative for viral RNA following the remdesivir treatment. Registration and Remdesivir is an investigational product being N/A Timelines are actively being developed WHO developed in the US under an investigational new drug prequalification: (IND) application. It has not received any registration (status and/or from any regulatory authorities. It has not received expected WHO prequalification. timeline)

Annex 1 – Specific tables by candidate therapeutic agents: clinical trials completed ongoing or planned

Completed ZMapp Phase I/II Safety and Efficacy Study (PREVAIL II) A Phase 1, Blinded, Randomized, Placebo- Study of Safety, Tolerability, and Safety and Pharmacokinetics of a Controlled, First in Human, Single-Ascending Dose Pharmacokinetics of REGN3470-3471- Human Monoclonal Antibody, VRC- Study Evaluating the Safety, Tolerability, and 3479 in Healthy Adult Volunteers EBOMAB092-00-AB (MAb114), Pharmacokinetics of Intravenous GS- 5734 in Administered Intravenously to Health Healthy Adult Subjects Adults (NCT03478891)

Trial registry NCT02363322 NCT02777151 NCT03478891) number and title Phase 1/2 1 1 1 Recruitment 72 of a planned 200 participants had been enrolled recruited when the trial Completed Completed Completed Status ended due to end of the 2014-15 Ebola outbreak Objectives and To establish the safety and efficacy of ZMapp in patients with Ebola virus Safety, tolerability and PK of a single IV infusion dose in Safety, tolerability, immunogenicity and To determine MAb114 safety and target infection healthy human adults. pharmacokinetic tolerability and pharmacokinetic (PK) population Compare frozen solution and lyophilized formulations. profile in serum Healthy adults ages 18-60 who weigh 220.5 Lb or less Primary outcome Mortality at Day 28 Safety, tolerability and PK of remdesivir and Incidence and Severity of treatment- To evaluate the safety and tolerability of measures metabolites in plasma and PBMCs emergent adverse events MAb114 administered as a single dose at 5 and 25 and 50 mg/kg IV to healthy adults. Secondary Comparative frequency of adverse events (AEs) and serious adverse events Concentration of REGN3470, REGN3471, To evaluate the pharmacokinetics of outcome (SAEs) and REGN3479; Presence or absence of MAb114 at each dose level at measures antibodies against REGN 3470,REGN3471, representative timepoints throughout the REGN3479 study. To determine whether anti-drug antibody to MAb114 can be detected in recipients of MAb114

Inclusion and Inclusion: Males or females with documented positive PCR for Ebola virus Usual Ph1 criteria for healthy adults Healthy Adults Inclusion: Adults 18-60 years of age who exclusion criteria infection within 10 days of enrollment, willingness of study participant to weigh less than 100 Kg accept randomization to any assigned treatment arm, access to optimized Exclusion: Women who are breastfeeding standard-of-care (oSOC) or planning to become pregnant Exclusion: Any serious medical condition that, in the opinion of the site investigator, would place the patient at an unreasonably increased risk (for complete criteria see Phase I results through participation in this study, including any past or concurrent report) conditions that would preclude randomization to one or more of the assigned treatment arms, prior treatment with any investigational antiviral drug therapy against Ebola infection or investigational anti-Ebola vaccine within 5 half-lives or 30 days, whichever is longer, prior to enrollment, patients who, in the judgment of the investigator, will be unlikely to comply with the requirements of this protocol Design and study Randomized controlled trial comparing ZMapp + optimized standard of care Randomized, blinded, placebo controlled. Placebo Controlled single ascending dose This is an open-label, dose-escalation arms to optimized standard of care alone. Dose escalation from 3 to 225 mg study of 4 dose levels study to examine the safety, tolerability, N=8/arm and PK of MAb114 in healthy adults. The primary hypothesis is that MAb114

Planned Phase 1 study of ZMapp in healthy adults under FDA Animal Rule A Phase 1, Blinded, Randomized, Placebo-Controlled, R3470-3471-3479 Expanded Access Guidelines Multiple-Dose Study Evaluating the Safety, Protocol (EAP) for Treatment of Ebola Tolerability, and Pharmacokinetics of Intravenous GS- 5734 Trial registry Not yet issued NCT03576690 number and title Phase 1 1 N/A Recruitment Not yet begun Completed Ongoing Status Objectives and To establish the safety and pharmacokinetics of ZMapp in healthy adults Safety, tolerability and PK of repeated IV infusion Safety and efficacy (survival) target doses in healthy human adults. population Primary outcome Safety Safety, tolerability and PK of remdesivir and N/A measures metabolites in plasma and PBMCs Secondary Pharmacokinetics, and anti-drug antibody response N/A outcome measures Inclusion and Inclusion: Healthy male and female adults ages 18 to 60 Usual Ph1 criteria for healthy adults Children and adults, including pregnant exclusion criteria Exclusions: Abnormalities by history, physical exam, or safety bloods outside women with confirmed EBOV infection or generally accepted bounds for subjects in Phase 1 studies; pregnancy; any individuals after high-risk exposure to serious medical condition that, in the opinion of the site investigator, would EBOV place the patient at an unreasonably increased risk through participation in the study. Design and study Randomized, double-blind trial comparing escalating doses of ZMapp to Randomized, blinded, placebo controlled. Compassionate use arms placebo 150 mg QD for 7 or 14 days N=8/arm Summary of NA Safety: As of Oct 30th, 29 patients have been Results No AEs > Gr2 , treated with REGN3470-3471-3479 Gr1-2 reversible elevations in ALT/AST observed in several subjects who received remdesivir. No changes in bilirubin, Alk phos or INR. No changes in renal function. PK: At least 2-fold accumulation of metabolites in PBMCs at steady state Publication(s) NA Not published N/A

Planned Phase 3 study of ZMapp in healthy adults under FDA Animal Rule Double-blind, Randomized, Two-phase, Placebo- Guidelines controlled, Phase II Trial of GS 5734 to Assess the Antiviral Activity, Longer-term Clearance of Ebola Virus, and Safety in Male Ebola Survivors with Evidence of Ebola Virus Persistence in Semen

Trial registry Not yet issued number and title Phase 3 2 Recruitment Not yet begun Ongoing, 38/60 subjects enrolled in Liberia and Guinea Status Objectives and To establish the safety and pharmacokinetics of ZMapp in healthy adults Efficacy, safety, tolerability and PK of remdesivir in target male adult survivors of EVD population Primary outcome Safety Antiviral activity over 28 days following the measures administration of 5 days of IV remdesivir versus placebo in male EVD survivors with evidence of Ebola virus RNA in their semen Secondary Pharmacokinetics, and anti-drug antibody response Safety, tolerability and PK of the 5-day IV regimen in outcome male EVD survivors measures Inclusion and Inclusion: Healthy male and female adults ages 18 to 60 Men ≥18 years of age with one of two semen samples exclusion criteria Exclusion: Exclusions: Abnormalities by history, physical exam, or safety with Ebola virus RNA detection within 42 days prior to bloods outside generally accepted bounds for subjects in Phase 1 studies; randomization. pregnancy; any serious medical condition that, in the opinion of the site investigator, would place the patient at an unreasonably increased risk through participation in the study. Design and study Randomized, double blind trial comparing the therapeutic dose of ZMapp to Blinded, randomized, two-phase (treatment and arms placebo longer-term follow-up), two-arm trial of remdesivir versus placebo. 1:1 randomization, N=30/arm. Summary of NA Results not yet available. Results DSMB did not recommend any treatment termination or dose reduction based on safety criteria. Publication(s) NA Not published

Annex 2 – Specific tables by candidate therapeutic agents: additional information referenced in the main text

REMDESIVIR