Ebanga
ansuvimab
Sources:FDA integrated review ↗
Species
Monkey
Longest study
4 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rhesus monkey only
“The ansuvimab-zykl nonclinical safety studies included a good laboratory practice (GLP) 4 week, intravenous, repeat-dose toxicology study in rhesus monkeys”
Why that species
Rhesus monkey is the lethal EBOV challenge model used for proof of concept
“The activity of ansuvimab-zykl was evaluated in three in vivo proof-of-concept studies in which rhesus monkeys were challenged with uniformly lethal doses of Kikwit 8U EBOV (1000 pfu).”
Surrogate molecule
No surrogate; the clinical antibody was tested in rhesus monkeys
“No adverse ansuvimab-zykl-related findings were observed in the GLP 4-week toxicology study in rhesus monkeys up to the highest dose tested”
Species: general tox
Rhesus monkey only (GLP 4-week IV repeat-dose study)
“The ansuvimab-zykl nonclinical safety studies included a good laboratory practice (GLP) 4 week, intravenous, repeat-dose toxicology study in rhesus monkeys”
Species: DART
Not conducted: not generally required for biologics against exogenous targets (ICH S6(R1))
“Dedicated reproductive toxicology studies have not been conducted with ansuvimab-zykl. In accordance with ICH S6(R1), reproductive toxicology studies are generally not required for biologics to exogenous targets.”
Species: carcinogenicity
Not conducted (single IV dose; ICH S1A, S6(R1))
“In accordance with ICH S1A and ICH S6(R1), carcinogenicity studies are not required as ansuvimab-zykl will be administered as a single intravenous (IV) infusion.”
Surrogate used in
No surrogate used; ansuvimab-zykl itself tested in rhesus monkeys
“The ansuvimab-zykl nonclinical safety studies included a good laboratory practice (GLP) 4 week, intravenous, repeat-dose toxicology study in rhesus monkeys”
Study lengthopen answer page →
Longest pivotal study
4 weeks
“A 4-Week Intravenous Toxicity Study With an 8-Week Recovery Period in Rhesus Monkeys (Study #1016-1363):”
Pivotal GLP studies
GLP 4-week IV repeat-dose study in rhesus monkeys, with recovery groups
“A 4-Week Intravenous Toxicity Study With an 8-Week Recovery Period in Rhesus Monkeys (Study #1016-1363):”
Route in tox
IV (bolus and infusion)
“Drug was administered by IV bolus to low-dose and mid-dose animals, and by IV infusion to control and high-dose animals.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted with ansuvimab-zykl. In accordance with International Council for Harmonisation (ICH) S6(R1), genotoxicity studies are not required for biologics.”
Carcinogenicity
Not conducted; not required for single-dose IV administration (ICH S1A, S6(R1))
“In accordance with ICH S1A and ICH S6(R1), carcinogenicity studies are not required as ansuvimab-zykl will be administered as a single intravenous (IV) infusion.”
Reproductive & developmental
Not conducted; generally not required for biologics to exogenous targets (ICH S6(R1))
“Dedicated reproductive toxicology studies have not been conducted with ansuvimab-zykl. In accordance with ICH S6(R1), reproductive toxicology studies are generally not required for biologics to exogenous targets.”
Safety pharmacology
ECG, blood pressure, respiratory rate and neurological exam within 4-week monkey study; no drug-related changes
“Assessments of safety pharmacology (electrocardiography, blood pressure, respiratory rate, and a neurological evaluation) were performed in the 4-week repeat-dose toxicology study in rhesus monkeys (Study #1016-1363).”
Genotox: Ames
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted with ansuvimab-zykl. In accordance with International Council for Harmonisation (ICH) S6(R1), genotoxicity studies are not required for biologics.”
Genotox: in vitro mammalian
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted with ansuvimab-zykl. In accordance with International Council for Harmonisation (ICH) S6(R1), genotoxicity studies are not required for biologics.”
Genotox: in vivo
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted with ansuvimab-zykl. In accordance with International Council for Harmonisation (ICH) S6(R1), genotoxicity studies are not required for biologics.”
Carcinogenicity model
Not conducted (single IV dose; ICH S1A, S6(R1))
“In accordance with ICH S1A and ICH S6(R1), carcinogenicity studies are not required as ansuvimab-zykl will be administered as a single intravenous (IV) infusion.”
Carcinogenicity timing
Not required: single IV infusion (ICH S1A, S6(R1))
“In accordance with ICH S1A and ICH S6(R1), carcinogenicity studies are not required as ansuvimab-zykl will be administered as a single intravenous (IV) infusion.”
hERG / QT
No drug-related ECG or cardiac changes in 4-week rhesus safety pharmacology assessments
“Assessments of safety pharmacology (electrocardiography, blood pressure, respiratory rate, and a neurological evaluation) were performed in the 4-week repeat-dose toxicology study in rhesus monkeys (Study #1016-1363). No drug-related changes in cardiac or neurological parameters were observed.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Ebanga don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for monoclonal antibodies
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
This product's starting point
NOAEL / key findings: NOAEL 500 mg/kg/dose (highest dose); no adverse drug-related toxicity; 7.6-fold AUC margin (FDA integrated review, p. 85)
NOAEL / key findings
NOAEL 500 mg/kg/dose (highest dose); no adverse drug-related toxicity; 7.6-fold AUC margin
“NOAEL =500 mg/kg/dose (AUClast =222664 µg.day/mL at Day 22, gender-averaged) Exposure multiple =7.6”
Risksopen answer page →
Immune & cytokine safety
No exposure or activity changes suggesting meaningful anti-drug antibody formation in monkeys
“No clear changes in drug exposure or ex vivo EBOV GP binding activity were observed in this study, suggesting that no meaningful anti-drug antibody formation occurred in this study.”
Biodistribution & persistence
No off-target binding in normal human tissue cross-reactivity study
“No off-target binding was observed with ansuvimab-zykl in any tissue under the conditions of this study.”
Modality-specific risk
Potential immunogenicity, as with all therapeutic proteins
“As with all therapeutic proteins, there is potential for immunogenicity.”
Anti-drug antibodies: animals
Monkey ADA samples collected but not analyzed; no exposure or GP-binding changes suggesting meaningful ADA
“In addition, blood samples were collected from the 4-week toxicology study on Days 1, 8, 22, 29, 57, and 78 to measure immunogenicity, but these samples were not analyzed. No clear changes in drug exposure or ex vivo EBOV GP binding activity were observed in this study, suggesting that no meaningful anti-drug antibody formation occurred in this study.”
Anti-drug antibodies: patients
No ADA detected post-dose; two baseline samples screening-positive; assay incompletely validated
“While no ADAs were detected in serum samples obtained following the administration of ansuvimab-zykl, two baseline serum samples tested positive in the screening assay. However, interpretation of these observations is limited by the incomplete validation of the ADA detection assay used in this study”
Label warnings
- Hypersensitivity Reactions Including Infusion-Associated Events
Hypersensitivity & infusion reactions
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
United States (NIH Clinical Center, Bethesda, Maryland): single-dose study in healthy adults
“ansuvimab-zykl in 50 mg/kg, NIH Clinical None healthy adults. n=10 Center Vaccine Randomization: Secondary: Evaluation None - To evaluate PK of Clinic, ansuvimab-zykl at Bethesda, Blinding: each dose level at Maryland.”
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Ebanga don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for monoclonal antibodies
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
This product's starting point
NOAEL / key findings: NOAEL 500 mg/kg/dose (highest dose); no adverse drug-related toxicity; 7.6-fold AUC margin (FDA integrated review, p. 85)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
4-week IV rhesus monkey study with 8-week recovery
“A 4-Week Intravenous Toxicity Study With an 8-Week Recovery Period in Rhesus Monkeys (Study #1016-1363):”
Pivotal GLP studies
GLP 4-week IV repeat-dose study in rhesus monkeys, with recovery groups
“A 4-Week Intravenous Toxicity Study With an 8-Week Recovery Period in Rhesus Monkeys (Study #1016-1363):”
DART package
Species: DART
Not conducted: not generally required for biologics against exogenous targets (ICH S6(R1))
“Dedicated reproductive toxicology studies have not been conducted with ansuvimab-zykl. In accordance with ICH S6(R1), reproductive toxicology studies are generally not required for biologics to exogenous targets.”
Reproductive & developmental
Not conducted; generally not required for biologics to exogenous targets (ICH S6(R1))
“Dedicated reproductive toxicology studies have not been conducted with ansuvimab-zykl. In accordance with ICH S6(R1), reproductive toxicology studies are generally not required for biologics to exogenous targets.”
PPND / ePPND: when
Not conducted: reproductive studies generally not required for biologics to exogenous targets (ICH S6(R1))
“Dedicated reproductive toxicology studies have not been conducted with ansuvimab-zykl. In accordance with ICH S6(R1), reproductive toxicology studies are generally not required for biologics to exogenous targets.”
Carcinogenicity
Species: carcinogenicity
Not conducted (single IV dose; ICH S1A, S6(R1))
“In accordance with ICH S1A and ICH S6(R1), carcinogenicity studies are not required as ansuvimab-zykl will be administered as a single intravenous (IV) infusion.”
Carcinogenicity model
Not conducted (single IV dose; ICH S1A, S6(R1))
“In accordance with ICH S1A and ICH S6(R1), carcinogenicity studies are not required as ansuvimab-zykl will be administered as a single intravenous (IV) infusion.”
Carcinogenicity timing
Not required: single IV infusion (ICH S1A, S6(R1))
“In accordance with ICH S1A and ICH S6(R1), carcinogenicity studies are not required as ansuvimab-zykl will be administered as a single intravenous (IV) infusion.”
Safety marginopen answer page →
Safety margin at NOAEL
Rhesus 4-week NOAEL 500 mg/kg/dose (AUC 222664 µg.day/mL) = 7.6x human exposure
“NOAEL =500 mg/kg/dose (AUClast =222664 µg.day/mL at Day 22, gender-averaged) Exposure multiple =7.6”
NOAEL / key findings
NOAEL 500 mg/kg/dose (highest dose); no adverse drug-related toxicity; 7.6-fold AUC margin
“NOAEL =500 mg/kg/dose (AUClast =222664 µg.day/mL at Day 22, gender-averaged) Exposure multiple =7.6”
Efficacy evidenceopen answer page →
Efficacy evidence
Lethal EBOV Kikwit challenge in rhesus monkeys: single 50 mg/kg up to 5 days postchallenge prevented mortality
“The activity of ansuvimab-zykl was evaluated in three in vivo proof-of-concept studies in which rhesus monkeys were challenged with uniformly lethal doses of Kikwit 8U EBOV (1000 pfu). These studies demonstrated that a single dose of 50 mg/kg ansuvimab-zykl prevented EBOV-induced mortality in these animals as late as 5-days postchallenge relative to controls.”
Why that model
Adequate, well-controlled EBOV trials are challenging, so development initially targeted the Animal Rule pathway
“Given the challenges of conducting adequate and well-controlled trials for treatment of EBOV infection, the development program for ansuvimab-zykl was initially based on fulfilling the necessary criteria for potential approval under the Animal Rule pathway.”
Reviewer's view of the efficacy data
FDA: NHP data sufficient to support proof-of-concept and the single 50 mg/kg IV clinical dose
“However, the NHP data were sufficient to support the proof-of-concept and use of a single 50 mg/kg IV dose of ansuvimab-zykl in the PALM Trial and expanded access program.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted with a condition
No dedicated reproductive toxicology studies; tissue cross-reactivity study in human fetal/neonatal tissues requested postmarketing
Why: ICH S6(R1): generally not required for biologics to exogenous targets; no reproductive findings in monkey study or off-target binding · Within the guideline · Weight of evidence
“Dedicated reproductive toxicology studies have not been conducted with ansuvimab-zykl. In accordance with ICH S6(R1), reproductive toxicology studies are generally not required for biologics to exogenous targets.”
“In addition, no male or female reproductive toxicities were observed in the 4-week repeat-dose toxicology study in rhesus monkeys (Study #1016-1363), and no off-target binding was observed in the tissue cross-reactivity study in human tissues (Study #20101338). A tissue cross-reactivity study in human fetal and/or neonatal tissues will be requested in a postmarketing commitment (PMC).”
Efficacy modelAcceptedBeyond the letter
Nonhuman primate efficacy program, begun for the Animal Rule, was incomplete when the outbreak occurred
Why: Available NHP data sufficient for proof-of-concept and to support the single 50 mg/kg IV clinical dose · Serious disease
“When the 2018 Eastern DRC outbreak occurred, the nonclinical program was progressing but was incomplete. However, the NHP data were sufficient to support the proof-of-concept and use of a single 50 mg/kg IV dose of ansuvimab-zykl in the PALM Trial and expanded access program.”
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