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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

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Candidate therapeutic name/denomination

ZMapp™ Remdesivir (formerly GS-5734) REGN3470-3471-3479 (REGN-EB3)

VRC-EBOMAB092-00-AB (mAb114)

Manufacturer/developer

Mapp Biopharmaceutical Gilead Sciences, Inc. Regeneron Pharmaceuticals Inc.* *This project has been funded in whole or in part 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”

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, US

Short description of candidate therapeutic:

An equimolar mixture of three mouse/human chimeric IgG1, kappa mAbs, c13C6-FR1, c2G4 and c4G7; each of these were derived from three mouse mAbs directed against three epitopes in EBOV glycoprotein.

Remdesivir (formerly GS-5734) is a prodrug of a modified adenine nucleoside analog GS-441524. Remdesivir undergoes efficient metabolic conversion in cells and tissues to active nucleoside triphosphate metabolite that inhibits viral RNA polymerases, but not host RNA or DNA polymerases. Remdesivir exhibits a potential for clinical efficacy against Ebola virus and other filovirus infections based on the following: 1) Potent in vitro activity in multiple relevant cell types against multiple Ebola virus isolates, including the 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.

Co-formulated cocktail of three fully human monoclonal antibodies that target the Zaire ebolavirus glycoprotein (GP)

mAb114 is a recombinant human IgG1 antibody produced in a Chinese Hamster Ovary (CHO) cell line. Proof of concept studies performed with mAb114 demonstrated 100% protection after a single dose administration either one day or five days after lethal Ebola Virus Zaire (EBOV) challenge in non-human primates (NHP). mAb114 was also found to be safe and well tolerated in a Phase I dose-escalation study up to 50mg/kg.

https://www.who.int/ebola/drc-2018/treatments-approved-for-compassionate-use-update/en/



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6) Potent therapeutic efficacy in Ebola virus-infected rhesus monkeys, the most relevant in vivo preclinical model of EVD, at drug exposures that were well tolerated and can be safely achieved in humans. The in vivo therapeutic efficacy has been demonstrated in non-human primates against multiple Ebola virus variants including Kikwit/1995 and Makona/2014 as well as against Marburg virus Angola/2005 infections. 7) Tissue distribution studies in non-human primates indicate effective penetration and distribution of remdesivir into immune privileged sites (genital tract, eye, and to some extent brain) that may represent a persistent reservoir of Ebola virus. Relatively high levels of remdesivir metabolites were also detected in human semen following single and repeated administration of remdesivir, suggesting potential for antiviral effect in human genital tract. 8) Sufficient supply of remdesivir drug product is available in a stable lyophilized formulation that does not require cold chain for transport and storage.

Virus/species/ strain

Zaire ebolavirus Consistent antiviral activity against all tested filoviruses (Ebola Zaire, Sudan, Bundibugyo, and Marburg). Similar antiviral activity was observed also against pathogenic coronaviruses (MERS and SARS CoV) and paramyxoviruses (Nipah and Hendra).

Ebolavirus/Zaire ebolavirus Ebolavirus/Zaire ebolavirus Human Monoclonal Antibody (IgG1)

Proposed indication for use

Zaire ebolavirus disease Primary indication currently in clinical development is for the treatment of laboratory-confirmed Ebola virus infection. In addition, preclinical data support expansion into treatment of Marburg virus and other filovirus infections as well as into filovirus post exposure prophylaxis.

Treatment of Ebola disease and post-exposure prophylaxis after high risk exposure to Zaire ebolavirus

To treat patients with laboratory confirmed Ebola virus infection.

Target population

Patients of any age with Zaire ebolavirus disease, including pregnant women All patients including children of any age and pregnant women with laboratory confirmed Ebola virus infection.

Children and adults, including pregnant women

Ebola virus infected children and adults who have not yet developed irreversible end organ failure such as cardiac or respiratory failure or fulminant hepatic failure where death is imminent. Pregnant women are permitted under the current EAP.

Dose regimen (include information on rationale for dose selection and human PK data if available)

Three doses of 50 mg/kg delivered by intravenous infusion spaced three days apart. No human PK data are yet available. The dose rationale was chosen based on the trends toward greater efficacy with repeated doses in NHP Study 3 (see below), and on the theoretical grounds that high levels of antibody should be maintained until the patient’s own immune response is adequate to prevent relapse from potential viral reservoirs.

The remdesivir dosing regimen for adult and

adolescent (≥ 40 kg) patients with acute EVD is as

follows: single remdesivir 200 mg IV loading dose (infused over 30 min) on Day 1 of treatment followed by 9 to 13 once daily 100 mg IV (infused over 30 min) maintenance doses. The recommended Remdesivir dosing duration is a total of 10 days, but dosing may be continued for an additional 4 days at 100 mg IV once daily if Ebola virus remains detectable in plasma at day 10 of treatment. For pediatric patients with body weight < 40 kg, a body weight-based dosing regimen of one loading dose of remdesivir 5 mg/kg IV (infused over 30 min) on Day 1

• 150 mg/kg single dose, intravenous • Rationale: In rhesus macaque dose ranging study, the 100 mg/kg and 150 mg/kg led to the highest survival with 8 of 9 animals surviving in each group. The 50 mg/kg led to a reduction in survival with 7 of 9 animals surviving. In addition, there was a dose-response in reduction in peak AST and ALT levels, with maximum reduction in AST and ALT peak levels at 150 mg/kg. • Human PK data: The pharmacokinetics of each antibody was linear, with mean

Dose Regimen: VRC-EBOMAB092-00-AB (mAb114) is administered by a single IV infusion of 50mg/kg of body weight (actual or estimated body weight). Rationale: Preclinical data in the NHP animal model informed the doses of mAb114 (5 to 50 mg/kg) that are being evaluated in ongoing and future studies in humans. In the Good Laboratory Practice (GLP) toxicity study, mAb114 doses ranging from 50 to 500 mg/kg per week were well tolerated,




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followed by 9 to 13 once daily remdesivir 2.5 mg/kg IV (infused over 30 min) maintenance doses will be administered. Use of this weight-based regimen is expected to maintain remdesivir exposure that is comparable to that observed in adults. There are no clinical safety or pharmacokinetic (PK) data available for remdesivir in patients with renal and/or hepatic impairment. Given the benefit:risk ratio in patients with acute EVD, no dose modification is recommended at the present time for patients with renal and/or hepatic impairment. Pharmacokinetics: The PK of the exact proposed dosing regimen has not been evaluated, but sufficient clinical data exists to support this regimen. Following single-dose, 2-hour IV infusion of remdesivir solution formulation at doses ranging from 3 to 225 mg, remdesivir exhibited a dose-linear PK. Repeated once-daily 1-hour infusions of 150 mg remdesivir solution formulation demonstrated time-linear PK through 14 days. Following single-dose, 2-hour IV administration of remdesivir solution formulation at doses of 75 and 150 mg, remdesivir exhibited similar PK profiles as the lyophilized formulation (data not shown). Table 1 shows the PK of remdesivir and the active triphosphate metabolite, GS-443902, after IV infusion of the lyophilized formulation (please refer to the Annex 1 on pg.13) Even though remdesivir 75 mg administered IV over 30 minutes provided similar parent exposure as the same dose administered over 2 hours, PBMC exposure of GS-443902 was higher than remdesivir 150 mg administered IV over 2 hours. This data supports the administration over the shorter time interval of 30 minutes as a more effective dosing method for maximizing the intracellular levels of the active metabolite GS-443902. A prolonged intracellular half-life of more than 35 hours was observed for GS-443902 in PBMCs, supporting the once-daily dosing of remdesivir. Furthermore, an accumulation ratio of 2.7 to 3.5-fold for intracellular metabolites suggests that a 200 mg remdesivir loading dose will better facilitate the achievement of subsequent steady-state PBMC levels of GS-443902 following repeat 100 mg daily maintenance dosing of remdesivir, which might be critical in the treatment of acutely infected patients. 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

half-lives of 27.3 for REGN3471, 21.7 days for REGN3470, and 23.3 days for REGN3479. • Immunogenicity data: In the healthy adult study, no participants tested positive for anti-REGN3470, anti-REGN3471, or anti-REGN3479 antibodies.

with mAb114 demonstrating linear kinetics and a 7- to 15-day half-life. Preliminary evidence in a NHP model of Ebola virus disease (EVD) showed both 30 mg/kg and 50 mg/kg doses of mAb114 were protective when administered as a single IV infusion up to five days post-EBOV challenge. Human PK Data: Overall IV Half-life (T ½) of mAb114 (9/18 Phase I study participants analyzed): 24.2 (+/-1.8) Days (Mean (+/-Standard Error)).




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infected rhesus and cynomolgus monkeys successfully treated with remdesivir. Efficacy studies in EBOV infected rhesus and Marburg virus-infected cynomolgus monkeys treated with a single 10 mg/kg loading dose followed by 11 days of a once-daily 5 mg/kg maintenance dose of remdesivir provided 100% and 83% survival, respectively, against the lethal effects of filovirus when initiated on Day 4 and 5 post infection, respectively. The recommended dosing regimen reflects the current estimation of the effective dose. The efficacy of this dosing regimen in Ebola infected patients has not been determined in a controlled randomized clinical study. The final human dosing regimen might be further modified based on the outcome of future clinical trials as well as animal models of EVD. The 200 mg loading dose and 100 mg maintenance dose for up to 13 days is lower than that previously administered to and well-tolerated by one patient with active Ebola virus meningitis who received 2 days of remdesivir 150 mg IV once daily followed by 12 days of remdesivir 225 mg IV once daily. In addition, 150 mg IV once daily dosing for up to 14 days was generally well tolerated in healthy volunteers supporting the use of 100 mg daily doses of remdesivir for up to 14 days in EBOV-infected patients.

Route of administration (Parenteral [IM, ID, SC] as injectable/non-injectable, oral) Please note if special training or equipment or other medications for administration and monitoring are required.

Three intravenous infusions at 3 day intervals, first infusion given over four hours with four rate escalations at 15 minute intervals with vital signs monitoring at each escalation, then hourly vital signs until completion of the infusion. The second and third infusions each have two escalation steps, and require 3.5 hours for completion. A battery-operated infusion pump simplifies administration by eliminating the need for drop counting. When ZMapp is available expressed via the CHO-cell platform (see below under Production, expected availability mid to late 2019), the infusions are expected to each last one hour, and without rate escalation stages.

Intravenous infusion for 30 minutes. No special training or equipment is required for the drug administration. If possible, daily monitoring or renal (creatinine and BUN) and liver (ALT, AST) functions should be performed.

Intravenous (IV) Administration: mAb114 should be administered IV over about 30 minutes or longer based on factors such as subject tolerance. For patients infected with Ebola, it is recommended to administer the product within approximately 60 minutes. The mL/hr infusion rate may vary based on the total volume needed to administer a full dose. Infusion should continue until the bag is empty. Preparation: Preparation of mAb114 for IV administration will require Sterile Water for Injection (to reconstitute the product) and 0.9% sodium chloride, USP (normal saline for infusion). Normal saline (100 mL preferred) and weight-based amount of reconstituted mAb114 will be added to a sterile empty bag (250 mL preferred) for IV infusion. 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 preservative-free, white to off-white or yellow lyophilized solid containing 150 mg remdesivir that is to be reconstituted with 29 mL of sterile water for

The co-formulated REGN-EB3 cocktail is supplied as a sterile aqueous solution containing 50 mg/mL protein with equal

Lyophilized drug product in vials, 400 mg of mAb114 per vial




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Stored and shipped frozen at -20 +/- 5 °C. May be stored at 2-8°C for 6 months at treatment sites if a -20° freezer is not available, but cannot be transported in the thawed state.

injection and diluted into intravenous infusion fluids prior to intravenous administration. It is supplied as a sterile product in a single use, 50 mL Type I clear glass vial. Each vial is sealed with a rubber stopper and an aluminum overseal with a plastic flip-off cap. In addition to the active ingredient, the lyophilized formulation contains the following inactive ingredients: water for injection, betadex sulfobutyl ether sodium (SBECD), and hydrochloric acid and/or sodium hydroxide. Hydrochloric acid and/or sodium hydroxide are used to adjust the formulation to a pH of 3.0 to 4.0.

proportions of all three antibodies in a 20 mL glass vial.

Storage & shelf-life (temperature, stability at given temperature)

Stable for > 48 months at -20 +/- 5 ° C. Stable for 6 months at 2-8° C. Current stability data support the lyophilized product shelf-life of 3 years when stored at < 30 °C. Additional product stability data is being collected. The final stability data is expected to support a shelf-life of 5 years.

Ongoing stability studies support REGN EB3 storage at 4°C for 36 months (recommended storage condition). Studies at this condition are continuing to establish long term shelf life. REGN-EB3 can be shipped and stored at 2-8°C. Stress stability studies were done to identify optimal conditions for shipping in tropical, resource-limited settings. REGN-EB3 drug product was physically and chemically stable at room temperature (25°C) for up to 6 months and at 45°C for up to 3 months, when agitated (vortexed at ambient temperature) for 120 min, or when subjected to 8 freeze-thaw cycles (freezing at -30°C and thawing at 25°C).

Stored lyophilized at 2-8°C (Not frozen) Vials shown to be stable at room temperature (25±3°C) for 1 day

Co-administration with other therapeutics and/or vaccines

No known incompatibilities or contraindications for co-administration. Co-administration of remdesivir with other investigational products has not yet been tested in animals or in clinic. There are no known incompatibilities or contraindications for co-administration of remdesivir with ZMapp or other antibodies. No inhibition of VSV replication (backbone for current Ebola vaccine) by remdesivir was observed in vitro.

Compatibility with other therapeutics and /or vaccine has not been studied.

None tested so far

Production There are 240 treatment courses of ZMapp in stock (calculated according to a patient weight of 47 kg, which was the average weight of the patients (pediatric and adult) treated during the PREVAIL II trial in West Africa). This does not include an additional 35 treatment courses sent to DRC for use during the current outbreak, which are enumerated separately since an unknown fraction of these may be used before start of an RCT.

Large scale GMP manufacture of remdesivir has been established. As of October 2018, a total of 19,000 doses are available for immediate use, equivalent to 1,900 treatment courses based on the currently proposed dosing regimen. Five thousand doses of the lyophilized remdesivir drug product are stored in Basel, Switzerland for immediate distribution to affected regions. Sufficient supply of remdesivir drug substance is available to support manufacture of an additional 20,000 treatment courses.

850 vials (50 treatment courses) were shipped to the DRC for utilization since May 2018. Sufficient doses available for utilization in the randomized controlled trial- based on understanding from WHO meeting on 11-Oct-2018 Scalability: We are currently transferring a large scale production process to support REGN-EB3 manufacturing, in accordance with the current BARDA Ebola US government contract

Number of treatments available: 28 treatment courses available to ship. 883 treatment courses currently being manufactured and available by the end of 2018. Another 1200 treatment courses will be available in 2019 Produced with an industry standard fully scalable process (currently being manufactured in 1000L bioreactors)

Clinical trials completed

ZMapp has been administered to 36 patients in a single Phase I/II clinical trial (PREVAIL II) in Liberia, Guinea, Sierra Leone, and the United States (see Table below). ZMapp has also been administered under expanded access or

Phase 1 (Safety, tolerability and PK) single and multiple dose studies in healthy human adult subjects have been completed.

First in Human Normal Healthy Volunteer Study is completed

VRC 608 “Safety and Pharmacokinetics of a Human Monoclonal Antibody, VRC-EBOMAB092-00-AB (Mab114),




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ongoing or planned

compassionate use provisions to at least 25 patients. Limited safety and no efficacy information is available from this experience.

Phase 2 randomized clinical trial (RCT) study in Ebola male survivors is ongoing in Liberia and Guinea; the study is sponsored by NIAID. Single dose ADME study in human healthy subjects using radiolabeled material is planned for early 2019.

Normal Healthy Volunteer Phase 3 safety study in ~450 subjects is planned to start Q12019 Expanded Access Protocol in DRC outbreak – Ongoing (NCT03576690)

Administered Intravenously to Health Adults” (NCT03478891)

Efficacy

Pre-clinical efficacy in NHP: NHP Study 1 examined the efficacy of ZMappA (c13C6-FR1 and c2G4 produced in Nicotiana and 4G7 produced in mouse hybridoma cells) administered intravenously 3 days post infection was investigated in rhesus macaques. Rhesus macaques were infected with 4,000 tissue culture infectious doses (TCID50) units of EBOV intramuscularly (Kikwit strain; 7U EBOV-K). This viral dose was established as a 100% lethal dose historically at the testing facility and is estimated to be approximately 1000 LD50.

NHP Study 2: Treated with three doses of ZMapp beginning 3, 4, or 5 days after IM challenge with 1,000 TCID50 of EBOV-K.

NHP study 3 examined the efficacy of different ZMapp dose levels (50 mg/kg and 25 mg/kg) and frequency of ZMapp administrations (one, two or three 50 mg/kg dose administrations). Briefly, animals were challenged intramuscularly with a dose of 1066 plaque forming units with USAMRIID’s Passage 3 (P3) 7U EBOV Kikwit challenge material. Animals were then treated with either ZMapp or saline on Days 5, 8 and 11 post-EBOV infection.

Pre-clinical efficacy in NHP: Various treatment regimens of remdesivir have been tested in EBOV-infected rhesus monkeys and in Marburg-infected cynomolgus monkeys. All studies were randomized, blinded, and placebo controlled with at least N=6 animals per treatment arm. In the initial study, infected animals treated with 3 to 10 mg/kg of remdesivir administered once daily by IV injection for 12 days beginning 3 days post Ebola virus inoculation exhibited 100% survival combined with a significant suppression of EVD clinical symptoms including amelioration of behavioral depression, changes in hematology and coagulation parameters, as well as serum chemistry markers of kidney and liver toxicity, and no signs of drug-related toxicities. Fifty percent of animals treated with 10 mg/kg remdesivir remained free of any physical signs of EVD throughout the 28 day duration of the study. In comparison, all vehicle-treated animals succumbed to Ebola virus infection by day 9. The impact on survival and clinical symptoms of EVD in Ebola virus-infected drug-treated animals was due to the potent suppression of virus replication. Animals treated with 10 mg/kg remdesivir beginning Day 3 post infection exhibited pronounced suppression of plasma viral RNA levels with a mean reduction of −3.9 log10 on Day 5 compared to the vehicle-treated control group. Plasma viral RNA in three out of six animals treated with 10 mg/kg remdesivir decreased below the lower limit of quantification (LLOQ; 8 × 104 RNA copies/mL) by Day 5. By Day 12, all animals treated with 10 mg/kg remdesivir had plasma viral RNA below the lower limit of detection by PCR. No genotypic resistance was detected in vivo using deep sequencing of the entire EBOV RNA pol (L) gene from infected rhesus monkeys. Treatment with a 10 mg/kg remdesivir initiated on Day 3 post-infection was associated with 100% survival in rhesus monkeys infected with EBOV Makona/2014. All vehicle-treated control animals died on the study. Treatment of rhesus monkeys infected with EBOV Kikwit/1995 for a total of 12 days with 5 mg/kg remdesivir, with or without a single loading dose of 10 mg/kg, initiated 4 days post infection, resulted in 100%

Pre-clinical efficacy in NHP: Evidence of efficacy and improved survival of Zaire Ebola virus inoculated rhesus macaques (or other NHPs) following treatment with the drug versus controls. Information on surrogate markers, -validated or reasonably expected to predict efficacy, e.g. viral load decreases if available The therapeutic potential of REGN3470-3471-3479 has been demonstrated in EBOV challenge studies in non-human primates (NHPs). These studies showed that the antibody cocktail can treat an established EBOV infection and aid recovery of animals from advanced Ebola disease when administered as 3 doses of 50 mg/kg at days 5, 8, and 11, 2 doses of 50 mg/kg at days 5 and 8, or a single dose of 150 mg/kg at day 5 post-infection with EBOV. Cumulatively, antibody treated animals showed 86% survival in the 150mg/kg single dose groups, compared to 6% survival in the placebo groups. Additionally, the minimum efficacious dose of the REGN3470-3471-3479 cocktail was determined in animals receiving a single dose of 150 mg/kg, 100 mg/kg, 50 mg/kg, or 10 mg/kg of the antibody cocktail on day 5 post infection. A single-dose of the cocktail showed a dose-dependent post-exposure protection against lethal EBOV disease with 100 mg/kg as the lowest dose tested that gave best control of symptoms (incidence of rash, shorter duration of fever, and lower incidence of liver damage). Treatment of NHPs with a single 150mg/kg dose on day 5 post-challenge resulted in a rapid drop in viral load from median of 8.0log10GE/ml (~ GP Ct of 24.5) on day 5 to 6.3log10GE/ml (~ GP Ct of 31) on day 8. 150mg/kg single dose also resulted in control of ALT/AST levels in treated animals with both peaking under 300 in treated animals. In contracts

Pre-clinical efficacy in NHP: Evidence of efficacy and improved survival of Zaire Ebola virus inoculated rhesus macaques (or other NHPs) following treatment with the drug versus controls. mAb114 has been tested in macaques that were exposed to a lethal (1000 PFU) intramuscular (IM) dose of EBOV Kikwit. In three separate experiments, NHP were treated IV with three infusions of 50 mg/kg mAb114 IV (24-hr intervals). In the first two experiments, treatment was initiated 1 day after infectious challenge and in the third experiment treatment initiated 5 days after challenge. All treated animals remained free of clinical and laboratory abnormalities and pretreatment viremia levels of up to 6 log10 GE/mL were rapidly controlled to undetectable levels. Control animals succumbed to EVD on Days 9 and 10 with peak viral loads of approximately 8 log10 GE/mL. To test a simplified single-infusion regimen of mAb114, macaques were exposed to a lethal dose of EBOV (1000 PFU IM) and mAb114 IV was administered just once at a 50 mg/kg dose 1 day post-exposure. All animals in the treatment group survived, while the control animal succumbed to EVD on day 9. The same outcome with 100% protection was achieved with a single dose of 50 mg/kg mAb114 administered 5 days after challenge (the control animal succumbed on day 9). In a dose-sparing study, a single infusion of 30 mg/kg given at day 5 post-EBOV exposure also yielded uniform protection in treated macaques, with the control succumbing on day 10. Information on surrogate markers, -validated or reasonably expected to predict efficacy, e.g.viral load decreases if available Not yet defined




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Information on surrogate markers The following figure plots viral load for NHP Study 1.

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

and 83% survival, respectively. Treatment for 12 days with 5 mg/kg remdesivir without a loading dose initiated on Day 5 post-infection resulted in 50% survival. In comparison, 17% survival was observed in control vehicle treated animals. Treatment of Marburg virus Angola/2005-infected cynomolgus monkeys for a total of 12 days with 5 mg/kg remdesivir administered IV, with a single loading dose of 10 mg/kg initiated 4 or 5 days post infection resulted in 83% survival and reduced Marburg virus disease associated manifestations. Treatment with 5 mg/kg remdesivir (without a loading dose) initiated on Day 5 post-infection resulted in 50% survival compared with no survival in control vehicle treated animals. 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).

placebo treated animals reached AST levels of 1500 and ALT levels of 700. Clinical efficacy data from RCTs – Pre-clinical studies and Clinical trials completed, ongoing or planned (please complete form below). No clinical trials in Ebola infected patients have been conducted.

Clinical efficacy data from RCTs – Pre-clinical studies and Clinical trials completed, ongoing or planned (please complete form below). Safety and Pharmacokinetics of a Human Monoclonal Antibody, VRC-EBOMAB092-00-AB (mAb114), Administered Intravenously to Health Adults (NCT03478891)

Safety data Clinical safety assessment should be provided for the drug at the exposure level proposed for treatment of EVD, considering non-clinical and, if available, clinical data.

Human safety data from PREVAIL II is provided in the separate Table listed on pg.9. Rat toxicology study: A repeat dose 21 day GLP toxicology study in male and female adult Sprague Dawley rats has been conducted by SRI International (Menlo Park, CA). This study evaluated administration of vehicle control or ZMapp at 50 or 100 mg/kg/day once daily for 6 days on Study Days 1, 3, 7, 11, 16, and 21 by an IV bolus injection via the tail vein. Total ZMapp exposure was 300 or 600 mg/kg for the 50 or 100 mg/kg/day dose groups, respectively. The study comprised a main, a recovery, and a satellite group for toxicokinetic (TK) analyses. Endpoints included hematology, serum chemistries, gross pathology, organ weights, and histopathology. Clinical observations were recorded daily throughout treatment and weekly during the recovery phase. In the final

Preclinical safety data: Remdesivir and the parent nucleoside analog GS-441524 were extensively profiled for in vitro cytotoxicity and mitochondrial toxicity in multiple relevant cell types. Both remdesivir and GS-441524 exhibited > 3.5-fold margins in most in vitro toxicity assays. Data from in vitro studies with liver cell culture systems demonstrated that human hepatocytes are susceptible to remdesivir mediated toxicity, likely due to high cellular permeability and effective intracellular metabolism of the drug. Systemic metabolites of remdesivir detected in vivo in plasma do not exhibit any in vitro hepatotoxicity at pharmacologically relevant levels.

First in Human Phase 1 study (Sivapalasingam et al Lancet ID 2018;18:884)

• Randomized, double-blind,

placebo-controlled, dose

escalation study conducted in the

US

• Healthy adults, aged 18-60 years

were assigned to single IV dose of

REGN3470-3471-3479 or placebo

on day 1 in one of the four

sequential ascending IV dose

Pre-clinical safety assessment: Systemic and local toxicities of mAb114 were evaluated in a GLP, 4-week repeated dose IV toxicity study in rhesus monkeys with an 8-week recovery. Male and female rhesus monkeys were assigned to four groups and dosed with mAb114 (Group 1: placebo; Group 2: single 50 mg/kg dose; Group 3: three repeated doses of 50 mg/kg; Group 4: single dose of 500 mg/kg). mAb114 was well-tolerated in rhesus monkeys. There were no mAb114-related mortalities, clinical signs of toxicity, body weight changes, adverse




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If human PK trials or studies in other indications at the exposure level proposed for treatment of EVD have been conducted please include this information In the absence of human data, safety results from animal studies, as well as relevant in vitro data should be provided.

report, a NOAEL could not be established due to adverse hepatotoxicity findings, with the liver identified as the main target organ of ZMapp in the rat. Slight increases in AST (up to 1.4 times), ALT (up to 1.2 times) and AP (up to 1.8 times) were observed in all ZMapp treated groups. Histopathological evaluation identified ZMapp related effects consisting of minimal to moderate hepatocyte hydrophic degeneration, mild to moderate hepatocyte hypertrophy, minimal to marked increased mitotic activity in hepatocytes, disorganization of hepatic architecture and minimal hepatocyte apoptosis in the liver. In addition, minimal to moderate necrosis of veins was observed at the injection sites. Following a 7- week recovery phase, no significant clinical chemistry or histopathologic findings were observed, and only a slight increase in mean liver organ weight was observed in male treatment groups. Serum transaminases returned to normal by the end of the recovery phase suggesting the observed hepatic toxicity was acute and transient. Tissue Cross Reactivity: A preliminary non-GLP tissue cross reactivity (TCR) study evaluating the binding of individual ZMapp mAbs to a limited number of human tissues has been conducted. Unanticipated binding of one or more ZMapp mAbs to evaluated human tissues (heart, brain, liver, kidney, lung, pancreas, spleen and skeletal muscle) was observed. The clinical significance of this “off target” binding is uncertain. A more definitive GLP tissue cross reactivity study evaluating the binding of individual ZMapp mAbs to a full panel of human tissues is described below. A GLP TCR study was performed to further evaluate the potential off target binding observed in the study described above. Panels of rat, non-human primate (NHP), and human tissues were evaluated with biotinylated ZMapp mAbs. Positive controls (HEK 293 cells expressing EBOV glycoprotein) and negative controls (HEK 293 cells) were included to show specificity of staining. Results indicate that sporadic staining in the cytoplasm of macrophages was observed in some tissues. However, as EBOV glycoprotein is a cell-surface antigen and macrophage cytoplasm would not be available for mAb binding in vivo, the observed binding was deemed non-specific and not relevant off-target binding.

The diastereomeric prodrug mixture (remdesivir and its diastereomer at phosphorous in a ~1:1 ratio), and the parent nucleoside, GS-441524, have a low potential for off-target activity. Neither compound significantly inhibited binding to a panel of 87 biological targets (receptors, ion channels, enzymes) at a concentration of 10 μM representing levels significantly above the clinical systemic exposures observed at the recommended doses of remdesivir. Safety pharmacology studies were conducted to examine the potential effects of remdesivir on the respiratory system, central nervous system, and cardiovascular system after IV administration. In a respiratory safety study in rats, remdesivir had no effect on tidal volume or minute volume; however, respiration rates were increased from 0.75 to 6 hours

post-dose in animals administered ≥ 20-mg/kg remdesivir. Respiration rates returned to control levels by 24 hours post-dose, resulting in a no observed effect level (NOEL) for respiratory function in male rats of 5 mg/kg, at exposures 1.1-fold above the estimated GS-441524 Cmax at the 200 mg clinical dose. Remdesivir had no effect on the CNS in rats and no effect on cardiovascular parameters in monkeys at dose levels up to 50 and 10 mg/kg, respectively. The lack of in vivo cardiovascular effect is consistent with the weak in vitro inhibition of the hERG channel by remdesivir. Taken together, the risk for CNS, respiratory, or cardiovascular effects in the clinic is considered low at projected therapeutic exposures. 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.

cohorts (3 mg/kg, 15 mg/kg, 60

mg/kg and 150 mg/kg)

• 24 healthy adults were enrolled,

18 assigned to receive REGN3470-

3471-3479 and 6 to placebo

• 19 treatment emergent adverse

events (TEAES) occurred in the

combined treatment groups and 4

TEAEs in the combined. placebo

groups. All AEs were transient and

mild to moderate in severity.

• The most common TEAE was

headache (6 of 18 participants in

the combined REGN3470-3471-

3479 group vs none of 6

participants in the placebo group).

Headaches were mild to moderate

in severity with onset between 2h

and 27 days after start of study

drug infusion. No deaths, Serious

AEs or infusion reactions were

noted.

• The PK of each antibody was linear

with a mean half-life ranging from

21.7 days and 27.3 days.

• No participant tested positive for

anti-drug antibodies.

effects on clinical pathology or safety pharmacology parameters in any of the groups studied. Evaluations of skin erythema and edema at injection sites and histopathology of injection sites demonstrated local tolerance of repeated IV injections and infusions of mAb114. Based on these data, the No-Observed-Adverse-Effect-Level (NOAEL) was determined to be 500 mg/kg/week of mAb114, the highest dose tested. Safety assessment in humans: mAb114 was found to be safe and well tolerated in a Phase I dose escalation study. For details on local and systemic reactogenicity, please consult Phase I results report from ClinicalTrials.gov




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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




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meningitis and a neonatal patient with acute Ebola infection in the 2014-2016 outbreak, as well as ongoing treatment of confirmed Ebola infection cases in the ongoing outbreak in Eastern DRC treated under MEURI protocol. 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 WHO prequalification: (status and/or expected timeline)

Remdesivir is an investigational product being developed in the US under an investigational new drug (IND) application. It has not received any registration from any regulatory authorities. It has not received WHO prequalification.

N/A Timelines are actively being developed




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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-Controlled, First in Human, Single-Ascending Dose Study Evaluating the Safety, Tolerability, and Pharmacokinetics of Intravenous GS- 5734 in Healthy Adult Subjects

Study of Safety, Tolerability, and Pharmacokinetics of REGN3470-3471-3479 in Healthy Adult Volunteers

Safety and Pharmacokinetics of a Human Monoclonal Antibody, VRC-EBOMAB092-00-AB (MAb114), Administered Intravenously to Health Adults (NCT03478891)

Trial registry number and title

NCT02363322 NCT02777151

NCT03478891)

Phase 1/2 1 1 1

Recruitment Status

72 of a planned 200 participants had been enrolled recruited when the trial ended due to end of the 2014-15 Ebola outbreak

Completed

Completed Completed

Objectives and target population

To establish the safety and efficacy of ZMapp in patients with Ebola virus infection

Safety, tolerability and PK of a single IV infusion dose in healthy human adults. Compare frozen solution and lyophilized formulations.

Safety, tolerability, immunogenicity and pharmacokinetic

To determine MAb114 safety and tolerability and pharmacokinetic (PK) profile in serum Healthy adults ages 18-60 who weigh 220.5 Lb or less

Primary outcome measures

Mortality at Day 28 Safety, tolerability and PK of remdesivir and metabolites in plasma and PBMCs

Incidence and Severity of treatment-emergent adverse events

To evaluate the safety and tolerability of MAb114 administered as a single dose at 5 and 25 and 50 mg/kg IV to healthy adults.

Secondary outcome measures

Comparative frequency of adverse events (AEs) and serious adverse events (SAEs)

Concentration of REGN3470, REGN3471, and REGN3479; Presence or absence of antibodies against REGN 3470,REGN3471, REGN3479

To evaluate the pharmacokinetics of MAb114 at each dose level at representative timepoints throughout the study.

To determine whether anti-drug antibody to MAb114 can be detected in recipients of MAb114

Inclusion and exclusion criteria

Inclusion: Males or females with documented positive PCR for Ebola virus infection within 10 days of enrollment, willingness of study participant to accept randomization to any assigned treatment arm, access to optimized standard-of-care (oSOC) Exclusion: Any serious medical condition that, in the opinion of the site investigator, would place the patient at an unreasonably increased risk through participation in this study, including any past or concurrent 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

Usual Ph1 criteria for healthy adults Healthy Adults Inclusion: Adults 18-60 years of age who weigh less than 100 Kg Exclusion: Women who are breastfeeding or planning to become pregnant (for complete criteria see Phase I results report)

Design and study arms

Randomized controlled trial comparing ZMapp + optimized standard of care to optimized standard of care alone.

Randomized, blinded, placebo controlled. Dose escalation from 3 to 225 mg N=8/arm

Placebo Controlled single ascending dose study of 4 dose levels

This is an open-label, dose-escalation study to examine the safety, tolerability, and PK of MAb114 in healthy adults. The primary hypothesis is that MAb114




12

administration will be safe by the IV route. The secondary hypothesis is that MAb114 will be detectable in human sera with a definable half-life. Group 1: 5 mg/kg IV; Group 2: 25 mg/kg IV; Group 3: 50 mg/kg IV

Summary of Results

The posterior probability that ZMapp plus the current standard of care was superior to the current standard of care alone was 91.2%. The overall 28-day crude mortality was 15 percentage points lower among those assigned to ZMapp plus the current standard of care than among those assigned to the current standard of care alone (22% vs. 37%), which corresponds to a 40% lower relative risk of death with ZMapp. The percentage of patients with serious adverse events was similar in the two groups: 37% in the group that received the current standard of care alone and 31% in the group that also received ZMapp. Only one serious adverse event (hypertension) in ZMapp recipients was judged to be related to the infusion itself.

Safety: No dose limiting tox. No AEs > Gr2 No evidence of renal or liver tox. PK: Dose proportional exposure in plasma (remdesivir) and PBMCs (active metabolite). Frozen solution and lyophilized formulations comparable.

REGN3470-3471-3479 was well tolerated, without infusion reactions up to dose of 150 mg/kg; displayed linear pharmacokinetics, and did not lead to detectable immunogenicity.

Product was safe and well tolerated. Average IV Half-life (T ½) of Mab114 24.2 (+/-1.8) Days (Mean (+/-Standard Error))

Publication(s) PREVAIL II Writing Group; Multi-National PREVAIL II Study Team, Davey RT Jr, Dodd L, Proschan MA, Neaton J, Neuhaus Nordwall J, Koopmeiners JS, Beigel J, Tierney J, Lane HC, Fauci AS, Massaquoi MBF, Sahr F, Malvy D. A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection. N Engl J Med. 2016 Oct 13;375(15):1448-1456. PMID: 27732819

Not published Sivapalasingam S et al Lancet ID, 2018;18:P884

Summary of results published in ClinicalTrials.gov Corti D, et al. PMID 26917593 Misasi J, et al. PMID 26917592




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Planned Phase 1 study of ZMapp in healthy adults under FDA Animal Rule Guidelines

A Phase 1, Blinded, Randomized, Placebo-Controlled, Multiple-Dose Study Evaluating the Safety, Tolerability, and Pharmacokinetics of Intravenous GS-5734

R3470-3471-3479 Expanded Access Protocol (EAP) for Treatment of Ebola


Not yet issued NCT03576690

Phase 1 1 N/A

Recruitment Status

Not yet begun Completed Ongoing


To establish the safety and pharmacokinetics of ZMapp in healthy adults Safety, tolerability and PK of repeated IV infusion doses in healthy human adults.

Safety and efficacy (survival)


Safety Safety, tolerability and PK of remdesivir and metabolites in plasma and PBMCs

N/A


Pharmacokinetics, and anti-drug antibody response N/A


Inclusion: Healthy male and female adults ages 18 to 60 Exclusions: Abnormalities by history, physical exam, or safety bloods outside generally accepted bounds for subjects in Phase 1 studies; 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.

Usual Ph1 criteria for healthy adults Children and adults, including pregnant women with confirmed EBOV infection or individuals after high-risk exposure to EBOV


Randomized, double-blind trial comparing escalating doses of ZMapp to placebo

Randomized, blinded, placebo controlled. 150 mg QD for 7 or 14 days N=8/arm

Compassionate use

Summary of Results

NA Safety: No AEs > Gr2 , 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

As of Oct 30th, 29 patients have been treated with REGN3470-3471-3479

Publication(s) NA Not published N/A




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Planned Phase 3 study of ZMapp in healthy adults under FDA Animal Rule Guidelines

Double-blind, Randomized, Two-phase, Placebo-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


Not yet issued

Phase 3 2

Recruitment Status

Not yet begun Ongoing, 38/60 subjects enrolled in Liberia and Guinea


To establish the safety and pharmacokinetics of ZMapp in healthy adults Efficacy, safety, tolerability and PK of remdesivir in male adult survivors of EVD


Safety Antiviral activity over 28 days following the administration of 5 days of IV remdesivir versus placebo in male EVD survivors with evidence of Ebola virus RNA in their semen


Pharmacokinetics, and anti-drug antibody response Safety, tolerability and PK of the 5-day IV regimen in male EVD survivors


Inclusion: Healthy male and female adults ages 18 to 60 Exclusion: Exclusions: Abnormalities by history, physical exam, or safety bloods outside generally accepted bounds for subjects in Phase 1 studies; 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.

Men ≥18 years of age with one of two semen samples with Ebola virus RNA detection within 42 days prior to randomization.


Randomized, double blind trial comparing the therapeutic dose of ZMapp to placebo

Blinded, randomized, two-phase (treatment and longer-term follow-up), two-arm trial of remdesivir versus placebo. 1:1 randomization, N=30/arm.

Summary of Results

NA Results not yet available. DSMB did not recommend any treatment termination or dose reduction based on safety criteria.

Publication(s) NA Not published




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

REMDESIVIR


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