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.”
Species: general tox
Mouse
“Nonclinical toxicology studies with bezlotoxumab and actoxumab, alone and in combination as bezlotoxumab + actoxumab were performed in mice.”
Species: DART
Not conducted; reproductive toxicity studies not appropriate for antibody to foreign target (ICH S6(R1))
““A short-term safety study in one species can be considered; no additional toxicity studies, including reproductive toxicity studies, are appropriate.” Therefore animal reproduction or developmental toxicity studies have not been conducted with bezlotoxumab.”
Species: carcinogenicity
Not conducted
“No studies have been performed to test the potential of bezlotoxumab for carcinogenicity or genotoxicity.”
Surrogate used in
No surrogate used; clinical antibody tested in mice
“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.
Genotox: Ames
Not conducted
“No studies have been performed to test the potential of bezlotoxumab for carcinogenicity or genotoxicity.”
Genotox: in vitro mammalian
Not conducted
“No studies have been performed to test the potential of bezlotoxumab for carcinogenicity or genotoxicity.”
Genotox: in vivo
Not conducted
“No studies have been performed to test the potential of bezlotoxumab for carcinogenicity or genotoxicity.”
Carcinogenicity model
Not conducted
“No studies have been performed to test the potential of bezlotoxumab for carcinogenicity or genotoxicity.”
Carcinogenicity timing
Not required
“No further toxicology studies would be required to support the MAA, including agreement that the absence of studies on reproduction and development is justified and that neither genotoxicity nor carcinogenicity studies would be required.”
hERG / QT
Not conducted; monoclonal antibodies highly unlikely to inhibit hERG
“Monoclonal antibody therapeutics have very low potential to interact with the extracellular or intracellular (pore) domains on the hERG ion channel and, therefore, are highly unlikely to inhibit hERG channel activity based on their targeted, specific binding properties.”
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
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 >=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.”
Anti-drug antibodies: animals
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.”
Anti-drug antibodies: patients
None of 710 evaluable adults developed ADA through 12 weeks
“Trial 1 and Trial 2 [see Clinical Studies (14) ] , none of the 710 evaluable adult patients with CDI developed anti-bezlotoxumab antibodies (referred to as ADA) through 12 weeks post-treatment.”
Label warnings
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 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
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 >=125 mg/kg/dose alone or with actoxumab (up to 5-fold clinical exposure); no findings of toxicological significance (EMA assessment report, p. 19)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
3-week mouse repeat-dose study (bezlotoxumab and/or actoxumab); recovery phase not stated
“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.”
DART package
Species: DART
Not conducted; reproductive toxicity studies not appropriate for antibody to foreign target (ICH S6(R1))
““A short-term safety study in one species can be considered; no additional toxicity studies, including reproductive toxicity studies, are appropriate.” Therefore animal reproduction or developmental toxicity studies have not been conducted with bezlotoxumab.”
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.”
PPND / ePPND: when
Not conducted: reproductive toxicity studies not considered appropriate (antibody to a foreign target, ICH S6(R1))
“The provided Toxicology investigation is appropriate for an antibody against foreign target according ICH S6(R1) guidance. “A short-term safety study in one species can be considered; no additional toxicity studies, including reproductive toxicity studies, are appropriate.””
Carcinogenicity
Species: carcinogenicity
Not conducted
“No studies have been performed to test the potential of bezlotoxumab for carcinogenicity or genotoxicity.”
Carcinogenicity model
Not conducted
“No studies have been performed to test the potential of bezlotoxumab for carcinogenicity or genotoxicity.”
Carcinogenicity timing
Not required
“No further toxicology studies would be required to support the MAA, including agreement that the absence of studies on reproduction and development is justified and that neither genotoxicity nor carcinogenicity studies would be required.”
Safety marginopen answer page →
Safety margin at NOAEL
Mouse NOAEL >=125 mg/kg/dose up to 5-fold human exposure at 10 mg/kg
“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).”
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).”
Efficacy evidenceopen answer page →
Efficacy evidence
Hamster and mouse C. difficile infection models with actoxumab+bezlotoxumab
“Preclinical in vivo efficacy of actoxumab+bezlotoxumab was evaluated in the Golden Syrian hamster model of infection (at doses of 0.5 to 50 mg/Kg) and in the mouse CDI model (at doses of 2, 5, 10 and 50 mg/Kg).”
Why that model
Infection models available; tested with actoxumab because bezlotoxumab alone has poor efficacy in rodent models
“The protective effects of bezlotoxumab have been shown in vitro in TcdB neutralization assays, and in nonclinical studies in mouse and hamster models of CDI (in combination with actoxumab, since bezlotoxumab alone has poor efficacy in rodent models).”
Reviewer's view of the efficacy data
EMA: limitation that preclinical efficacy rests on the actoxumab combination, not bezlotoxumab alone
“Although clinical study results suggest that neutralization of toxin B is sufficient to reduce the risk of recurrent disease in humans, the preclinical efficacy data rely on the combination of actoxumab and bezlotoxumab instead of bezlotoxumab alone.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAccepted
Foreign bacterial toxin target: no species for target-mediated toxicity; only short-term mouse toxicity studies
Why: Antibody against a foreign target; no species allows target-mediated toxicity assessment · Within the guideline · No relevant species
“This is acceptable as there is no species in which target-mediated toxicity can be investigated.”
“The provided Toxicology investigation is appropriate for an antibody against foreign target according ICH S6(R1) guidance.”
DARTAccepted
No reproductive or developmental toxicity studies
Why: ICH S6(R1) provision for antibodies against foreign targets · Within the guideline
““A short-term safety study in one species can be considered; no additional toxicity studies, including reproductive toxicity studies, are appropriate.” Therefore animal reproduction or developmental toxicity studies have not been conducted with bezlotoxumab.”
“The provided Toxicology investigation is appropriate for an antibody against foreign target according ICH S6(R1) guidance.”
Efficacy modelCriticised but acceptedBeyond the letter
Animal efficacy shown only for the actoxumab plus bezlotoxumab combination, not bezlotoxumab alone
Why: Clinical results suggest toxin B neutralisation alone is sufficient · Human data
“Although clinical study results suggest that neutralization of toxin B is sufficient to reduce the risk of recurrent disease in humans, the preclinical efficacy data rely on the combination of actoxumab and bezlotoxumab instead of bezlotoxumab alone.”
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