. 2020 Feb 13;46(2):285–297. doi: 10.1007/s00134-020-05949-z

Table 4.

Current anti-Ebola therapies being implemented under compassionate use in the DRC

Drug	Source	Description, mode of action, and strain targeted	Study site, dates, clinical trial registration and status	Study design and primary outcome	Results	Adverse events	General concerns, and comments
MAb114 [51]	Developed by VRC, and manufactured at Cook pharmica (Bloomington, IN, USA)	Human IgG1 monoclonal antibody that targets the Ebola Virus GP Strain targeted: Zaire ebolavirus	Conducted at the US National Institutes of Health (NI) Bethesda, USA. Enrolled healthy subjects outside an outbreak setting NCT03478891 Dose Group 1: Infusion of 5 mg/kg, one dose Group 2: Infusion of 25 mg/kg, one dose Group 3: Infusion of 50 mg/kg, one dose Long term follow-up	Open label phase 1, dose escalation trial Primary outcome was safety and tolerability Group 1: n = 3 Group 2: n = 5 Group 3: n = 10	All mAb114 infusions were safe and well tolerated. A dose-dependent linear pharmacokinetic relationship between dosing groups was noted Half-life was 24.2 days (Standard Error of Mean 0.2) Mean max serum concentration in the 50 mg/kg group: 1961 μg/ml (SD 340) achieved within 2.75 h (SD 1.63) of drug infusion No anti-drug antibody responses were detected	Only 4 subjects had mild systemic symptoms (malaise, myalgia, joint pains and nausea)	Tested in a small human population Ease and speed of administration in an outbreak setting; its formulation is a freeze powder that does not require freezer storage Storage in its lyophilized form remains stable at 40 C for up to 6 months Targets highly conserved epitope on the viral glycoprotein with reduced likelihood for mutation
Remdesivir GS-5734 [53]	Developed by Gilead Sciences (Foster City, CA, USA)	Small molecule nucleotide prodrug with broad spectrum anti-filovirus activity Strains targeted: Zaire ebolavirus, Sudan ebolavirus, Bundibugyo ebolavirus	Dosage: in the 1st case report (Adult patient) 150 mg/kg on day 0 and then dose was increased to 225 mg/kg after availability of additional pre-clinical safety data Efficacy was tested in a placebo-controlled randomized trial in Ebola virus infected NHP	2 Case reports (a 39 year old adult in the UK with a late relapse case of Meningoencephalitis, and in a neonate born to an Ebola positive mother in Guinea) Infected NHP were given IM or IV 3 or 10 mg/kg of the GS-5734 once daily for 12 days or the placebo Primary outcome: Day 28 survival	In both patients, viremia was suppressed after institution of Remdesivir despite earlier failure with MAbs Treatment initiated on day 3 after detection of systemic viremia, survival rates were 50% for the IM 3 mg/kg group, 100% for the 10 mg/kg group and 0% for the placebo group	Slightly elevated serum amylase levels No adverse side effects reported	Promise of efficacy is premised on strong pre-clinical data, anecdotal (2 case reports [54–55]) evidence and robust data from NHP Need for monitoring AST/ALT levels Single high doses offer rapid bioavailability and prolonged higher concentrations that neutralize high Ebola viraemia Effective against persistent virions in immune-protected sites
REGN-3470-3471-3479 [50]	Regeneron pharmaceuticals, Illinois, USA	Cocktail of 3 human monoclonal antibodies targeting non-overlapping epitopes on the Ebola virus Strain targeted Zaire ebolavirus	Conducted in Evansville IL, USA, Drug given to healthy adult subjects outside an outbreak setting. Study dates May 27, 2016 to April 26, 2017 NCT002777151 Dose; (each of the MAbs given in 1:1:1) Cohort 1: IV 3 mg/kg OR placebo Cohort 2: IV 15 mg/kg OR placebo Cohort 3: IV 60 mg/kg OR placebo Cohort 4: IV 150 mg/kg OR placebo	Randomized phase 1, placebo-controlled, dose-escalation trial Primary outcome; Incidence and severity of TEAEs up to 169 days Participants were sequentially enrolled to one of the cohorts and randomized to either the placebo or the investigational drug N = 18 participants were assigned to the intervention group and n = 6 were in the placebo	The antibody pharmacokinetics were linear, corresponding to the different dosage groups Mean half-life was 27.3 days for REGN 3471, 21.7 days, 23. 3 days for REGN 3479 and 21.7 days for REGN-3470 REGN 3470-3471-34479 was well tolerated and did not lead to any immunogenicity Anti-drug antibodies for all the monoclonal antibodies were negative in all patients	19 emergent treatment adverse effects (all mild to moderate in severity) occurred in the treatment group vs 4 in the placebo group. The most common was headache 33% (in 6 out of the 18 participants, who were all in the treatment group) with a probable linear dose response effect	Limited human safety data available from the phase 1 study (only 18 participants) Results from animal models were promising Stable for up to 6 months at a temperatures of 25 °C and up to 3 months at temperatures of 45 °C, similar storage conditions of routine vaccines Single daily dosing thus reduced HW time by patient bedside 3 antibodies bind simultaneously to 3 non-overlapping epitopes on the viral GP potentially reducing risk for mutations
ZMapp [45, 48]	Collaboration between MappBio, Leafbio (San Diego CA, USA) and Defyrus Inc (Toronto, Canada)	A cocktail of 3 chimerized monoclonal antibodies (c13C6, 2G4 and 4G7) chosen from ZMab and MB-003 antibody cocktails They target specific surface epitopes on the Ebola virus glycoprotein Strain targeted Ebolavirus/Zaire ebolavirus	PREVAIL II trial-was based in 4 countries, i.e., Liberia, Sierra Leone, Guinea and USA (11 centers) March-November 2015; study closed before target recruitment due to low patient numbers as countries were nearly declared Ebola free [NCT 02363322] Dosage: IV 50 mg/kg by slow infusion, administered every third day, a total of 3 doses	An open label, multicenter randomized safety and efficacy controlled trial with an adaptive design to update standard of care with the investigation drug. The standard of care included Favipiravir for the group in Guinea Randomized and analyzed patient data along different strata, i.e., PCR Ct value (≤ 22 vs > 22) and location (Liberia/USA/Sierra Leone vs Guinea) Primary outcome: 28 day mortality	Fell short of the targeted population size (72 participants vs 200 required) Mortality was lower in patients with a high viral load (i.e., Ct ≤ 22) in the intervention group vs the control group [47% (7/15) vs 60% (9/15)], failing to meet pre-specified posterior probability 28 day mortality [intervention group 22% (8/36) vs control group 37% (13/35)]; although it achieved a 91,2% posterior probability of superiority over standard care, it failed to reach the set threshold of 97.5% probability to establish efficacy	1 patient developed a serious side effect (hypertension) possibly attributed to ZMapp infusion 8 out of the 93 infusions were stopped due to adverse events (SAEs) 31% (11/36) in the intervention group vs 37% (13/35) in the control group	The PREVAIL study offered the most robust evidence for efficacy of an Ebola therapy. Although study findings were promising, they were not statistically conclusive on the efficacy of ZMapp Concerns include the complexity of administering the drug; side effects; the need for committed staff to monitor patients; and the cold chain requirement 2 of the antibodies of ZMapp have overlapping epitopes thus competing for same binding site, a possible source of vulnerability in case of mutations
Current trial in the DRC Title: investigational therapies for the treatment of people with Ebola Drugs MAb114, Remdesivir, REGN-EB3 and ZMapp [15, 52]			Democratic Republic of Congo, patient enrollment started in November 2018 and stopped in August 2019. The first phase was an interventional trial [NCT03719586]	A multi-centre, open label randomized controlled trial Primary outcome- 28 day mortality Patients randomized to any one of the 3 drugs (MAb114 + oSOC or Remdesivir + oSOC or REGN-EB3 + oSOC) vs control (ZMapp + oSOC) Number of patients enrolled at 681 expected number is 725	Overall 28 day mortality was lower in MAb 114 and REGN-EB3 groups than Remdesivir or ZMapp groups Mortality was lower in patients with low (i.e., PCR Ct-value > 22)-as compared to those with high viral loads (Ct-value ≤ 22)	Although 29 SAEs were noted by the trial investigators, an independent pharmacovigilance committee attributed only 4 SAEs to the 2 drugs (ZMapp and Remdesivir) The 4 SAEs occurred in 3 patients (2 of whom were from the ZMapp group [1 with worsening gastrointestinal symptoms and the other with pre-infusional hypotension], and 1 patient from the Remdesivir group developed hypotension and subsequent cardiac arrest); all 3 patients died	After an interim analysis of 499 patients, the independent DSMB on August 9, 2019 recommended that the trial be modified so that all subsequent patients be given either mAb114 or REGN-EB3. This was on the basis that REGN-EB3 had met criterion for early protocol stopping (reached the efficacy boundary for the surrogate end point of the primary outcome including 10-day follow-up outcomes in all patients). Patients receiving either MAb114 or REGN-EB3 had improved survival outcomes than those receiving ZMapp or remedesivir
MAb114: (NIAID)	See description above	Dosage: 1 dose of 50 mg/kg administered on day 1 as a single infusion	Overall mortality in the MAb114 group was 35.1% (61/174) vs 49.7% (84/169) in the ZMapp subgroup, p = 0.007 In the MAb114 group, mortality in patients with a Ct-value > 22 was 9.9% (10/101) vs 69.9% (51/73) in patients with a Ct-value ≤ 22
Remdesivir: GS-5734 (Gilead Sciences)	See description above	Dosage: IV Loading dose 200 mg for patients > 40 kg and for children < 40 kg 5 mg/kg, then 100 mg in those > 40 kg and 2.5 mg/kg daily for 9–13 days (depending on viral load)	Overall mortality in the Remdesivir group was 53.1% (93/175) vs 49.7% (84/169) in the ZMapp group In the Remdesivir group, mortality in patients with a Ct-value > 22 was 29.0% (29/100) vs 85.3% (64/75) in patients with a Ct-value ≤ 22
REGN-EB3 (REGN-3470-3471-3479) (Regeneron Pharmaceuticals)	See description above	Dosage: 1 dose of 150 mg/kg administered on day 1 as a single infusion	REGN-EB3 group overall mortality, 33.5% (52/155) vs 51.3% (79/154) in the ZMapp group, p = 0.002 In the REGN-EB3, mortality in patients with a Ct-value > 22 was 11.2% (10/89) vs 63.6% (42/66) in patients with a Ct-value ≤ 22
ZMapp (Mapp Biopharma-ceutical)	See description above	Dosage: 3 doses of 50 mg/kg/body weight administered intravenously every third day	See comparison to other 3 drugs above In the ZMapp group, mortality in patients with a Ct-value > 22 was 24.5% (24/98) vs 84.5% (60/70) in patients with a Ct-value ≤ 22

Drug

Source

Description, mode of action, and strain targeted

Study site, dates, clinical trial registration and status

Study design and primary outcome

Results

Adverse events

General concerns, and comments

MAb114 [51]

Developed by VRC, and manufactured at Cook pharmica (Bloomington, IN, USA)

Human IgG1 monoclonal antibody that targets the Ebola Virus GP

Strain targeted: Zaire ebolavirus

Conducted at the US National Institutes of Health (NI) Bethesda, USA. Enrolled healthy subjects outside an outbreak setting

NCT03478891

Dose

Group 1: Infusion of 5 mg/kg, one dose

Group 2: Infusion of 25 mg/kg, one dose

Group 3: Infusion of 50 mg/kg, one dose

Long term follow-up

Open label phase 1, dose escalation trial

Primary outcome was safety and tolerability

Group 1: n = 3

Group 2: n = 5

Group 3: n = 10

All mAb114 infusions were safe and well tolerated. A dose-dependent linear pharmacokinetic relationship between dosing groups was noted

Half-life was 24.2 days (Standard Error of Mean 0.2)

Mean max serum concentration in the 50 mg/kg group: 1961 μg/ml (SD 340) achieved within 2.75 h (SD 1.63) of drug infusion

No anti-drug antibody responses were detected

Only 4 subjects had mild systemic symptoms (malaise, myalgia, joint pains and nausea)

Tested in a small human population

Ease and speed of administration in an outbreak setting; its formulation is a freeze powder that does not require freezer storage

Storage in its lyophilized form remains stable at 40 C for up to 6 months

Targets highly conserved epitope on the viral glycoprotein with reduced likelihood for mutation

Remdesivir

GS-5734 [53]

Developed by Gilead Sciences (Foster City, CA, USA)

Small molecule nucleotide prodrug with broad spectrum anti-filovirus activity

Strains targeted: Zaire ebolavirus, Sudan ebolavirus, Bundibugyo ebolavirus

Dosage: in the 1st case report (Adult patient) 150 mg/kg on day 0 and then dose was increased to 225 mg/kg after availability of additional pre-clinical safety data

Efficacy was tested in a placebo-controlled randomized trial in Ebola virus infected NHP

2 Case reports (a 39 year old adult in the UK with a late relapse case of Meningoencephalitis, and in a neonate born to an Ebola positive mother in Guinea)

Infected NHP were given IM or IV 3 or 10 mg/kg of the GS-5734 once daily for 12 days or the placebo

Primary outcome: Day 28 survival

In both patients, viremia was suppressed after institution of Remdesivir despite earlier failure with MAbs

Treatment initiated on day 3 after detection of systemic viremia, survival rates were 50% for the IM 3 mg/kg group, 100% for the 10 mg/kg group and 0% for the placebo group

Slightly elevated serum amylase levels

No adverse side effects reported

Promise of efficacy is premised on strong pre-clinical data, anecdotal (2 case reports [54–55]) evidence and robust data from NHP

Need for monitoring AST/ALT levels

Single high doses offer rapid bioavailability and prolonged higher concentrations that neutralize high Ebola viraemia

Effective against persistent virions in immune-protected sites

REGN-3470-3471-3479 [50]

Regeneron pharmaceuticals, Illinois, USA

Cocktail of 3 human monoclonal antibodies targeting non-overlapping epitopes on the Ebola virus

Strain targeted Zaire ebolavirus

Conducted in Evansville IL, USA, Drug given to healthy adult subjects outside an outbreak setting. Study dates May 27, 2016 to April 26, 2017

NCT002777151

Dose; (each of the MAbs given in 1:1:1)

Cohort 1: IV 3 mg/kg OR placebo

Cohort 2: IV 15 mg/kg OR placebo

Cohort 3: IV 60 mg/kg OR placebo

Cohort 4: IV 150 mg/kg OR placebo

Randomized phase 1, placebo-controlled, dose-escalation trial

Primary outcome; Incidence and severity of TEAEs up to 169 days

Participants were sequentially enrolled to one of the cohorts and randomized to either the placebo or the investigational drug

N = 18 participants were assigned to the intervention group and n = 6 were in the placebo

The antibody pharmacokinetics were linear, corresponding to the different dosage groups

Mean half-life was 27.3 days for REGN 3471, 21.7 days, 23. 3 days for REGN 3479 and 21.7 days for REGN-3470

REGN 3470-3471-34479 was well tolerated and did not lead to any immunogenicity

Anti-drug antibodies for all the monoclonal antibodies were negative in all patients

19 emergent treatment adverse effects (all mild to moderate in severity) occurred in the treatment group vs 4 in the placebo group. The most common was headache 33% (in 6 out of the 18 participants, who were all in the treatment group) with a probable linear dose response effect

Limited human safety data available from the phase 1 study (only 18 participants)

Results from animal models were promising

Stable for up to 6 months at a temperatures of 25 °C and up to 3 months at temperatures of 45 °C, similar storage conditions of routine vaccines

Single daily dosing thus reduced HW time by patient bedside

3 antibodies bind simultaneously to 3 non-overlapping epitopes on the viral GP potentially reducing risk for mutations

ZMapp [45, 48]

Collaboration between MappBio, Leafbio (San Diego CA, USA) and Defyrus Inc (Toronto, Canada)

A cocktail of 3 chimerized monoclonal antibodies (c13C6, 2G4 and 4G7) chosen from ZMab and MB-003 antibody cocktails

They target specific surface epitopes on the Ebola virus glycoprotein

Strain targeted Ebolavirus/Zaire ebolavirus

PREVAIL II trial-was based in 4 countries, i.e., Liberia, Sierra Leone, Guinea and USA (11 centers)

March-November 2015; study closed before target recruitment due to low patient numbers as countries were nearly declared Ebola free

[NCT 02363322]

Dosage:

IV 50 mg/kg by slow infusion, administered every third day, a total of 3 doses

An open label, multicenter randomized safety and efficacy controlled trial with an adaptive design to update standard of care with the investigation drug. The standard of care included Favipiravir for the group in Guinea

Randomized and analyzed patient data along different strata, i.e., PCR Ct value (≤ 22 vs > 22) and location (Liberia/USA/Sierra Leone vs Guinea)

Primary outcome: 28 day mortality

Fell short of the targeted population size (72 participants vs 200 required)

Mortality was lower in patients with a high viral load (i.e., Ct ≤ 22) in the intervention group vs the control group [47% (7/15) vs 60% (9/15)], failing to meet pre-specified posterior probability

28 day mortality [intervention group 22% (8/36) vs control group 37% (13/35)]; although it achieved a 91,2% posterior probability of superiority over standard care, it failed to reach the set threshold of 97.5% probability to establish efficacy

1 patient developed a serious side effect (hypertension) possibly attributed to ZMapp infusion

8 out of the 93 infusions were stopped due to adverse events (SAEs)

31% (11/36) in the intervention group vs 37% (13/35) in the control group

The PREVAIL study offered the most robust evidence for efficacy of an Ebola therapy. Although study findings were promising, they were not statistically conclusive on the efficacy of ZMapp

Concerns include the complexity of administering the drug; side effects; the need for committed staff to monitor patients; and the cold chain requirement

2 of the antibodies of ZMapp have overlapping epitopes thus competing for same binding site, a possible source of vulnerability in case of mutations

Current trial in the DRC

Title: investigational therapies for the treatment of people with Ebola

Drugs MAb114, Remdesivir, REGN-EB3 and ZMapp [15, 52]

Democratic Republic of Congo, patient enrollment started in November 2018 and stopped in August 2019. The first phase was an interventional trial

[NCT03719586]

A multi-centre, open label randomized controlled trial

Primary outcome- 28 day mortality

Patients randomized to any one of the 3 drugs (MAb114 + oSOC or Remdesivir + oSOC or REGN-EB3 + oSOC) vs control (ZMapp + oSOC)

Number of patients enrolled at 681 expected number is 725

Overall 28 day mortality was lower in MAb 114 and REGN-EB3 groups than Remdesivir or ZMapp groups

Mortality was lower in patients with low (i.e., PCR Ct-value > 22)-as compared to those with high viral loads (Ct-value ≤ 22)

Although 29 SAEs were noted by the trial investigators, an independent pharmacovigilance committee attributed only 4 SAEs to the 2 drugs (ZMapp and Remdesivir)

The 4 SAEs occurred in 3 patients (2 of whom were from the ZMapp group [1 with worsening gastrointestinal symptoms and the other with pre-infusional hypotension], and 1 patient from the Remdesivir group developed hypotension and subsequent cardiac arrest); all 3 patients died

After an interim analysis of 499 patients, the independent DSMB on August 9, 2019 recommended that the trial be modified so that all subsequent patients be given either mAb114 or REGN-EB3. This was on the basis that REGN-EB3 had met criterion for early protocol stopping (reached the efficacy boundary for the surrogate end point of the primary outcome including 10-day follow-up outcomes in all patients). Patients receiving either MAb114 or REGN-EB3 had improved survival outcomes than those receiving ZMapp or remedesivir

MAb114: (NIAID)

See description above

Dosage: 1 dose of 50 mg/kg administered on day 1 as a single infusion

Overall mortality in the MAb114 group was 35.1% (61/174) vs 49.7% (84/169) in the ZMapp subgroup, p = 0.007

In the MAb114 group, mortality in patients with a Ct-value > 22 was 9.9% (10/101) vs 69.9% (51/73) in patients with a Ct-value ≤ 22

Remdesivir:

GS-5734

(Gilead Sciences)

See description above

Dosage: IV Loading dose 200 mg for patients > 40 kg and for children < 40 kg 5 mg/kg, then 100 mg in those > 40 kg and 2.5 mg/kg daily for 9–13 days (depending on viral load)

Overall mortality in the Remdesivir group was 53.1% (93/175) vs 49.7% (84/169) in the ZMapp group

In the Remdesivir group, mortality in patients with a Ct-value > 22 was 29.0% (29/100) vs 85.3% (64/75) in patients with a Ct-value ≤ 22

REGN-EB3

(REGN-3470-3471-3479)

(Regeneron Pharmaceuticals)

See description above

Dosage: 1 dose of 150 mg/kg administered on day 1 as a single infusion

REGN-EB3 group

overall mortality, 33.5% (52/155) vs 51.3% (79/154) in the ZMapp group, p = 0.002

In the REGN-EB3, mortality in patients with a Ct-value > 22 was 11.2% (10/89) vs 63.6% (42/66) in patients with a Ct-value ≤ 22

ZMapp (Mapp Biopharma-ceutical)

See description above

Dosage: 3 doses of 50 mg/kg/body weight administered intravenously every third day

See comparison to other 3 drugs above

In the ZMapp group, mortality in patients with a Ct-value > 22 was 24.5% (24/98) vs 84.5% (60/70) in patients with a Ct-value ≤ 22

AST, Aspartate aminotransferase; ALT, alanine aminotransferase; DSMB, data and safety monitoring board; GP, glycoprotein; IM, intramuscular; HW, healthcare worker; Ig G, immunoglobulin G; IV, intravenous; MAbs, monoclonal antibodies; NIAID, National Institute of Allergy and Infectious Diseases; NHP, non-human primates; PCR Ct-value, polymerase chain reaction-Cycle threshold value; oSOC, optimized standard of care; SAEs, Serious Adverse Events; SD, standard deviation; TEAEs, treatment-emergent adverse effects