Enflonsia
clesrovimab
Species
Rat
Longest study
2 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat only
“The rat was chosen as the relevant animal species for the repeat-dose toxicity study, based on the rationale that systemic exposure of clesrovimab in the rats were sufficient to cover the anticipated clesrovimab exposure in humans.”
Why that species
Viral target not expressed in any species; no off-target effects expected, so rat used to avoid unnecessary NHP use (3R)
“It was therefore agreed that, as no relevant toxicological species exists and no off-target effects were expected in neither NHPs nor in rats, the use of the rat is supported from a 3R perspective in order to avoid unnecessary use of NHPs.”
Surrogate molecule
No surrogate; the clinical antibody was tested in rats
“MK-1654 (clesrovimab) nonclinical safety studies included a good laboratory practice (GLP) 2- week IV/IM repeat-dose toxicology study in Wistar Han rats with a 4-week recovery period”
Species: general tox
Rat only (Wistar Han; 2-week IV/IM study)
“MK-1654 (clesrovimab) nonclinical safety studies included a good laboratory practice (GLP) 2- week IV/IM repeat-dose toxicology study in Wistar Han rats with a 4-week recovery period”
Species: DART
Not conducted (exogenous viral target, ICH S6(R1)); no reproductive toxicity in 2-week rat study
“In accordance with ICH S6(R1), DART studies are generally not needed for biologics to exogenous targets. In addition, no male or female reproductive toxicities were observed in the 2-week repeat-dose toxicology study in rats (Study TT #16-1029)”
Species: carcinogenicity
Not conducted (single-dose administration)
“In accordance with ICH S1A and ICH S6(R1), carcinogenicity studies are not needed because MK-1654 will be administered as a single dose.”
Surrogate used in
No surrogate used; clinical antibody tested in rats
“MK-1654 (clesrovimab) nonclinical safety studies included a good laboratory practice (GLP) 2- week IV/IM repeat-dose toxicology study in Wistar Han rats with a 4-week recovery period”
Study lengthopen answer page →
Longest pivotal study
2 weeks
“MK-1654 (clesrovimab) nonclinical safety studies included a good laboratory practice (GLP) 2- week IV/IM repeat-dose toxicology study in Wistar Han rats with a 4-week recovery period”
Pivotal GLP studies
GLP 2-week Wistar Han rat study: IV 0, 30, 100, 300 mg/kg every 3 days; IM 0 or 25 mg/kg on Days 1 and 13
“IV (Groups 2 to 5): 0, 30, 100, 300 mg/kg once every 3 days (Days 1, 4, 7, 10, 13) IM (Group 1 and 6): 0, 25 mg/kg on Days 1 & 13”
Route in tox
Intravenous and intramuscular
“Route of administration: Intravenous and intramuscular”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted with MK-1654. In accordance with ICH S6(R1), genotoxicity studies are not needed for biologics as they are not anticipated to interact with deoxyribonucleic acid (DNA) or other genetic material.”
Carcinogenicity
Not conducted (ICH S1A, S6(R1)); administered as a single dose
“In accordance with ICH S1A and ICH S6(R1), carcinogenicity studies are not needed because MK-1654 will be administered as a single dose.”
Reproductive & developmental
No dedicated DART studies (exogenous target, ICH S6(R1)); no male or female reproductive toxicity in 2-week rat study
“In accordance with ICH S6(R1), DART studies are generally not needed for biologics to exogenous targets. In addition, no male or female reproductive toxicities were observed in the 2-week repeat-dose toxicology study in rats (Study TT #16-1029)”
Safety pharmacology
Assessed within the GLP 2-week rat toxicology study (FOB)
“Safety pharmacology of MK-1654 was assessed as a component of the GLP 2-week repeat dose toxicology study in Wistar Han rats (Study # TT #16-1029).”
Genotox: Ames
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted with MK-1654. In accordance with ICH S6(R1), genotoxicity studies are not needed for biologics as they are not anticipated to interact with deoxyribonucleic acid (DNA) or other genetic material.”
Genotox: in vitro mammalian
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted with MK-1654. In accordance with ICH S6(R1), genotoxicity studies are not needed for biologics as they are not anticipated to interact with deoxyribonucleic acid (DNA) or other genetic material.”
Genotox: in vivo
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted with MK-1654. In accordance with ICH S6(R1), genotoxicity studies are not needed for biologics as they are not anticipated to interact with deoxyribonucleic acid (DNA) or other genetic material.”
Carcinogenicity model
Not conducted (single-dose administration; ICH S1A, S6(R1))
“In accordance with ICH S1A and ICH S6(R1), carcinogenicity studies are not needed because MK-1654 will be administered as a single dose.”
Carcinogenicity timing
Not required (single dose)
“In accordance with ICH S1A and ICH S6(R1), carcinogenicity studies are not needed because MK-1654 will be administered as a single dose.”
hERG / QT
No hERG study (absence justified by literature review)
“The absence of a hERG study was sufficiently justified based on the scientific review by Vargas et al, 2008, stating that no changes were noted for cardiovascular and respiratory endpoints assessed via routine clinical observations and comprehensive histopathological examination.”
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 Enflonsia 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: No adverse findings; NOAEL 300 mg/kg IV and 25 mg/kg IM (highest doses tested) (FDA integrated review, p. 119)
NOAEL / key findings
No adverse findings; NOAEL 300 mg/kg IV and 25 mg/kg IM (highest doses tested)
“No adverse, product-related findings were observed in the GLP 2-week toxicology study in Wistar Han rats up to the highest doses tested (no-observed-adverse-effect level [NOAEL] =300 mg/kg [IV] and 25 mg/kg [IM]).”
Risksopen answer page →
Immune & cytokine safety
In vitro interleukin release by human white blood cells prompted a clinical hold for potential cytokine release syndrome
“The Agency placed the application on full clinical hold on January 6, 2017, due to the potential risk of cytokine release syndrome (based on demonstration of release of interleukins induced in human white blood cells in an in vitro cytokine release assay).”
Biodistribution & persistence
No off-target binding in tissue cross-reactivity study of adult, juvenile and neonatal human tissues
“No off-target binding was observed with MK-1654 in any tissue observed under the conditions of this study.”
Modality-specific risk
Possible FcRn competition with maternal IgG from YTE modification, potentially reducing passive immunity in infants
“It is unknown if competition could exist between maternal antibodies and clesrovimab for FcRn binding sites/IgG-recycling and if clesrovimab is preferentially recycled over endogenous maternal IgG due to the increased affinity for FcRn through the YTE modification”
Anti-drug antibodies: animals
ADA in 1 female rat (30 mg/kg) from day 28 with markedly reduced individual exposure; no impact on group toxicokinetics
“Anti-drug antibodies (ADA) were detected in one female animal in the 30 mg/kg dose group from day 28 post the first dosing. Even though the individual exposure of the animal was highly diminished, suggesting strong neutralising ADA potential, no substantial impact on overall group mean concentration and toxicokinetic values were noted.”
Anti-drug antibodies: patients
Day 150: 6% (Trial 004) and 5% (Trial 007); through Day 240: 12% and 13%
“In Trial 004 and Trial 007, after receiving the approved recommended dose in RSV season 1, 6% (120/2112) and 5% (13/291) of participants were ADA-positive on Day 150, respectively; and 12% (124/1033) and 13% (34/261) of participants were ADA-positive through Day 240, respectively.”
Label warnings
- Hypersensitivity Including Anaphylaxis
- RSV Diagnostic Test Interference
Hypersensitivity & infusion reactions
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
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.
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 Enflonsia 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: No adverse findings; NOAEL 300 mg/kg IV and 25 mg/kg IM (highest doses tested) (FDA integrated review, p. 119)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
2-week rat (IV/IM) GLP study with 4-week recovery
“MK-1654 (clesrovimab) nonclinical safety studies included a good laboratory practice (GLP) 2- week IV/IM repeat-dose toxicology study in Wistar Han rats with a 4-week recovery period”
Pivotal GLP studies
GLP 2-week Wistar Han rat study: IV 0, 30, 100, 300 mg/kg every 3 days; IM 0 or 25 mg/kg on Days 1 and 13
“IV (Groups 2 to 5): 0, 30, 100, 300 mg/kg once every 3 days (Days 1, 4, 7, 10, 13) IM (Group 1 and 6): 0, 25 mg/kg on Days 1 & 13”
DART package
Species: DART
Not conducted (exogenous viral target, ICH S6(R1)); no reproductive toxicity in 2-week rat study
“In accordance with ICH S6(R1), DART studies are generally not needed for biologics to exogenous targets. In addition, no male or female reproductive toxicities were observed in the 2-week repeat-dose toxicology study in rats (Study TT #16-1029)”
Reproductive & developmental
No dedicated DART studies (exogenous target, ICH S6(R1)); no male or female reproductive toxicity in 2-week rat study
“In accordance with ICH S6(R1), DART studies are generally not needed for biologics to exogenous targets. In addition, no male or female reproductive toxicities were observed in the 2-week repeat-dose toxicology study in rats (Study TT #16-1029)”
PPND / ePPND: when
Not conducted: DART studies not needed for a biologic against an exogenous (viral) target (ICH S6(R1))
“In accordance with ICH S6(R1), DART studies are generally not needed for biologics to exogenous targets.”
Carcinogenicity
Species: carcinogenicity
Not conducted (single-dose administration)
“In accordance with ICH S1A and ICH S6(R1), carcinogenicity studies are not needed because MK-1654 will be administered as a single dose.”
Carcinogenicity model
Not conducted (single-dose administration; ICH S1A, S6(R1))
“In accordance with ICH S1A and ICH S6(R1), carcinogenicity studies are not needed because MK-1654 will be administered as a single dose.”
Carcinogenicity timing
Not required (single dose)
“In accordance with ICH S1A and ICH S6(R1), carcinogenicity studies are not needed because MK-1654 will be administered as a single dose.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat NOAEL 300 mg/kg: >40-fold infant exposure (AUC0-72h and Cmax)
“For the NOAEL of 300 mg/kg, a safety margin of >40-fold based on AUC0-72h and Cmax were obtained for the two age groups in the clinical studies, which is considered sufficient.”
NOAEL / key findings
No adverse findings; NOAEL 300 mg/kg IV and 25 mg/kg IM (highest doses tested)
“No adverse, product-related findings were observed in the GLP 2-week toxicology study in Wistar Han rats up to the highest doses tested (no-observed-adverse-effect level [NOAEL] =300 mg/kg [IV] and 25 mg/kg [IM]).”
Efficacy evidenceopen answer page →
Efficacy evidence
Cotton rat intranasal RSV A2 challenge model dosed with clesrovimab (0.03-2.5 mg/kg)
“Clesrovimab and RB-1 LALA were administered at doses of 0.03, 0.09, 0.28, 0.83, or 2.5 mg/kg to cotton rats. Challenge with 1 x 105 pfu RSV strain A2 followed on the day after immunization.”
Why that model
Parental antibody RB-1 used in main cotton rat studies because YTE increases rodent FcRn binding and reduces exposure
“The use of the parental antibody was justified by the fact that the YTE modification leads to increased binding to the rodent FcRn which, in turn, reduces the overall exposure to the Ab.”
Reviewer's view of the efficacy data
EMA: parental RB-1 efficacy similar to D25 and higher than palivizumab against RSV A and B in cotton rats
“In an in vivo efficacy study in a cotton rat model RB-1, the parental antibody of clesrovimab lacking the Fc modifications, was demonstrated to be of similar efficacy as D25 and of higher efficacy than palivizumab in reducing the pfu of RSV A and RSV B strains in nose and after passive immunization.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAccepted
No relevant toxicology species; short-term toxicity study in rat rather than NHP
Why: Viral target; no relevant toxicological species; no off-target effects expected; avoids unnecessary NHP use · No relevant species · Within the guideline · Other reason
“It was therefore agreed that, as no relevant toxicological species exists and no off-target effects were expected in neither NHPs nor in rats, the use of the rat is supported from a 3R perspective in order to avoid unnecessary use of NHPs.”
DARTAccepted
No dedicated reproductive and developmental toxicity studies
Why: ICH S6(R1): exogenous (viral) target; not indicated for females of reproductive potential · Within the guideline · Other reason
“In accordance with ICH S6(R1), DART studies are generally not needed for biologics to exogenous targets.”
“Lastly, MK-1654 is not indicated for use in females of reproductive potential.”
Juvenile toxAccepted
No juvenile animal studies despite a neonatal and infant indication
Why: Extensive paediatric clinical data; ICH S11 · Human data · Within the guideline
“Additionally, at the current timepoint extensive clinical data exists from the paediatric population and juvenile animal study is therefore not expected to provide any added safety value in accordance with ICH S11.”
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