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”
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).”
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 outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
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”
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