Zinplava
bezlotoxumab
Species
Mouse
Longest study
3 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
Mouse only
“Nonclinical toxicology studies with bezlotoxumab and actoxumab, alone and in combination as bezlotoxumab + actoxumab were performed in mice.”
Why that species
Foreign (bacterial toxin) target; no species allows assessment of target-mediated toxicity
“This is acceptable as there is no species in which target-mediated toxicity can be investigated.”
Surrogate molecule
No surrogate; the clinical antibody was tested in mice, alone and combined with actoxumab
“Nonclinical toxicology studies with bezlotoxumab and actoxumab, alone and in combination as bezlotoxumab + actoxumab were performed in mice.”
Study lengthopen answer page →
Longest pivotal study
3 weeks
“No findings of toxicological significance were observed in the single (4 weeks) or repeat-dose toxicity studies (2 or 3 weeks studies) performed with bezlotoxumab and/or actoxumab.”
Pivotal GLP studies
Mouse single-dose (4-week observation) and 2- and 3-week repeat-dose studies, bezlotoxumab alone or with actoxumab
“No findings of toxicological significance were observed in the single (4 weeks) or repeat-dose toxicity studies (2 or 3 weeks studies) performed with bezlotoxumab and/or actoxumab.”
Route in tox
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.
Skipped studiesopen answer page →
Genotoxicity
Not conducted
“No studies have been performed to test the potential of bezlotoxumab for carcinogenicity or genotoxicity.”
Carcinogenicity
Not conducted
“No studies have been performed to test the potential of bezlotoxumab for carcinogenicity or genotoxicity.”
Reproductive & developmental
No dedicated reproductive or developmental studies; no reproductive organ effects or binding in mouse repeat-dose and TCR studies
“There were no notable effects in the male and female reproductive organs in mice based on repeat dose toxicity studies and no binding to reproductive tissues was observed in tissue cross-reactivity studies.”
Safety pharmacology
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 doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Zinplava 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: NOAEL >=125 mg/kg/dose alone or with actoxumab (up to 5-fold clinical exposure); no findings of toxicological significance (EMA assessment report, p. 19)
NOAEL / key findings
NOAEL >=125 mg/kg/dose alone or with actoxumab (up to 5-fold clinical exposure); no findings of toxicological significance
“The no-observed-adverse-effect-level (NOAEL) for bezlotoxumab alone or in combination with actoxumab was ≥125 mg/kg/dose. This is up to 5 fold over the exposure in humans at the clinically recommended dose (10mg/Kg).”
Risksopen answer page →
Immune & cytokine safety
No anti-drug antibodies detected in treated mice
“No anti-bezlotoxumab or anti-actoxumab antibodies were detected in any animals in the test article-treated groups.”
Biodistribution & persistence
Reaches gut lumen at infection site in hamsters, higher in CDI; no toxicologically significant tissue cross-reactivity (human, mouse)
“In vivo tissue distribution studies in hamsters demonstrated that actoxumab and bezlotoxumab reached the site of infection in the lumen of the gut, and were detected at significantly higher levels in hamsters with CDI compared with healthy hamsters.”
Modality-specific risk
Foreign (bacterial toxin) target: no target-mediated toxicity expected; minimal package per ICH S6(R1)
“The provided Toxicology investigation is appropriate for an antibody against foreign target according ICH S6(R1) guidance.”
Similar precedents
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