Besponsa
inotuzumab ozogamicin
Species
MonkeyRat
Longest study
26 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey (neither cross-reactive; target-independent toxicity only)
“The Applicant conducted repeat-dose toxicity studies of up to 6 months duration in rats and cynomolgus monkeys to investigate the chronic toxicity of inotuzumab ozogamicin;”
Why that species
No relevant species: G544 does not bind mouse, rat, rabbit or monkey B cells; tox limited to payload-driven, target-independent effects
“G544 did not bind B cells from mouse, rat, rabbit, or cynomolgus monkey whole blood, or granulocytes, MONO, or T cells from any species evaluated, including humans.”
Surrogate molecule
No surrogate; clinical ADC in non-binding species, plus non-binding calicheamicin ADC (PF-06647259) investigative monkey study
“This study evaluated the target-independent toxicities of antibody-calicheamicin conjugates using a humanized nonbinding IgG1 monoclonal antibody conjugated to calicheamicin via the acid-labile AcBut linker (PF-06647259).”
Species: general tox
Rat and cynomolgus monkey (up to 6 months)
“The Applicant conducted repeat-dose toxicity studies of up to 6 months duration in rats and cynomolgus monkeys to investigate the chronic toxicity of inotuzumab ozogamicin;”
Species: DART
Rat and rabbit (embryo-fetal development)
“Embryo-fetal development studies were conducted in rabbits and rats.”
Species: carcinogenicity
Not conducted
“No carcinogenicity studies were conducted or required to support a marketing application for the current indication.”
Surrogate used in
No surrogate; species lack CD22 cross-reactivity, so toxicology limited to target-independent calicheamicin effects
“The lack of G544 cross-species reactivity indicates the utility of the nonclinical toxicology studies will be limited to the assessment of target-independent toxicities associated with conjugated and unconjugated calicheamicin.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“The Applicant conducted repeat-dose toxicity studies of up to 6 months duration in rats and cynomolgus monkeys to investigate the chronic toxicity of inotuzumab ozogamicin;”
Pivotal GLP studies
GLP 4-week and 26-week once-weekly IV studies in rats and cynomolgus monkeys, with 4-week recovery
“In the 6-month cynomolgus monkey study, inotuzumab ozogamicin was administered IV at doses of 0.5, 1.5, or 5 μg/kg once weekly.”
Route in tox
IV (bolus), consistent with clinical route
“the studies were conducted using the intravenous (IV) route, consistent with the intended clinical route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Conducted: calicheamicin positive in Ames and in vitro micronucleus; ADC clastogenic in mouse micronucleus
“Inotuzumab ozogamicin was clastogenic in mice at doses ≥28 µg/kg (approximately 1.1 mg/m2 of the ADC), consistent with the known DNA-reactive activity of the calicheamicin payload.”
Carcinogenicity
Not conducted (ICH S9); liver adenomas and preneoplastic changes in 6-month rat study
“No carcinogenicity studies were conducted or required to support a marketing application for the current indication.”
Reproductive & developmental
Rat fertility and rat/rabbit EFD conducted: rat embryo-fetal toxicity (resorptions, low fetal weight); no PPND (ICH S9)
“Embryo-fetal development studies were conducted in rabbits and rats.”
Safety pharmacology
Dedicated studies: CV in cynomolgus (transient BP effect), CNS and respiratory in rats
“A cardiovascular (CV) safety pharmacology study with inotuzumab ozogamicin in cynomolgus monkeys identified a small and transient effect on arterial blood pressure; the toxicological significance of this finding is unclear.”
Genotox: Ames
Calicheamicin payload: positive in bacterial reverse mutation test
“The calicheamicin payload was positive in both the bacterial reverse mutation test and the in vitro micronucleus assay.”
Genotox: in vitro mammalian
Calicheamicin payload: positive in in vitro micronucleus assay
“The calicheamicin payload was positive in both the bacterial reverse mutation test and the in vitro micronucleus assay.”
Genotox: in vivo
ADC clastogenic in mouse micronucleus assay at doses ≥28 µg/kg (~1.1 mg/m2)
“Inotuzumab ozogamicin was clastogenic in mice at doses ≥28 µg/kg (approximately 1.1 mg/m2 of the ADC), consistent with the known DNA-reactive activity of the calicheamicin payload.”
Carcinogenicity model
Not conducted (advanced cancer indication)
“No carcinogenicity studies were conducted or required to support a marketing application for the current indication.”
Carcinogenicity timing
Not required for the current indication; none conducted
“No carcinogenicity studies were conducted or required to support a marketing application for the current indication.”
hERG / QT
Calicheamicin payload hERG IC50 >6.77 µM (10,000 ng/mL)
“The IC50 for the inhibitory effect of N-Ac-γ-calicheamicin DMH on hERG potassium channels was >6.77 μM (10,000 ng/mL)”
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 Besponsa 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 ADCs
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
NOAEL / key findings: No NOAEL in rat or monkey chronic studies; liver (sinusoidal injury), hematolymphoid, reproductive organs; monkey glomerulonephritis death at 5 ug/kg (FDA multi-discipline review, p. 34)
NOAEL / key findings
No NOAEL in rat or monkey chronic studies; liver (sinusoidal injury), hematolymphoid, reproductive organs; monkey glomerulonephritis death at 5 ug/kg
“Taken together, the primary inotuzumab ozogamicin target organs identified by the chronic toxicity studies were the liver, hematolymphopoietic tissues, and the male and female reproductive organs.”
Risksopen answer page →
Immune & cytokine safety
Low ADA incidence in rats (10-13%); no ADA detected in monkeys
“In the 4- and 26-week repeat-dose toxicity studies in monkeys, ADA was not detected in any animals after administration of inotuzumab ozogamicin or the G544 antibody.”
Biodistribution & persistence
Limited tissue distribution in rat (tissue:plasma <=0.6; liver highest), minimal brain penetration, longer tissue retention
“Distribution of [3H]inotuzumab ozogamicin radioequivalents into tissues was limited, with tissue-to-plasma AUCinf ratios ≤0.6 for all tissues evaluated.”
Modality-specific risk
Calicheamicin payload: hepatic sinusoidal endothelial injury (VOD precursor), thrombocytopenia, genotoxicity, reproductive toxicity
“consistent with microvascular liver injury and were considered to represent the early stages of veno-occlusive disease that has been reported in clinical trials.”
Anti-drug antibodies: animals
No ADA detected in monkeys in 4- and 26-week studies
“In the 4- and 26-week repeat-dose toxicity studies in monkeys, ADA was not detected in any animals after administration of inotuzumab ozogamicin or the G544 antibody.”
Anti-drug antibodies: patients
3% (7/236) ADA-positive in relapsed or refractory ALL; no neutralizing antibodies
“During a maximum 6 cycles of treatment period in clinical studies of BESPONSA in adult patients with relapsed or refractory ALL, 7/236 (3%) patients tested positive for ADA. No patients tested positive for NAb.”
Label warnings
Boxed warning: HEPATOTOXICITY, INCLUDING HEPATIC VENO-OCCLUSIVE DISEASE (VOD) (ALSO KNOWN AS SINUSOIDAL OBSTRUCTION SYNDROME) and INCREASED RISK OF POST-HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT) NON-RELAPSE MORTALITY
- Hepatotoxicity, Including Hepatic Veno-occlusive Disease (VOD) (also known as Sinusoidal Obstruction Syndrome)
- Increased Risk of Post-Transplant Non-Relapse Mortality
- Myelosuppression
- Infusion Related Reactions
- QT Interval Prolongation
- Embryo-Fetal Toxicity
HepatotoxicityCytopeniasHypersensitivity & infusion reactionsCardiovascularEmbryo-fetal toxicity
US prescribing information, Boxed Warning and 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 Besponsa 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 ADCs
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
NOAEL / key findings: No NOAEL in rat or monkey chronic studies; liver (sinusoidal injury), hematolymphoid, reproductive organs; monkey glomerulonephritis death at 5 ug/kg (FDA multi-discipline review, p. 34)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
6-month (26-week) once-weekly IV studies in rat and cynomolgus monkey
“The Applicant conducted repeat-dose toxicity studies of up to 6 months duration in rats and cynomolgus monkeys to investigate the chronic toxicity of inotuzumab ozogamicin;”
Pivotal GLP studies
GLP 4-week and 26-week once-weekly IV studies in rats and cynomolgus monkeys, with 4-week recovery
“In the 6-month cynomolgus monkey study, inotuzumab ozogamicin was administered IV at doses of 0.5, 1.5, or 5 μg/kg once weekly.”
DART package
Species: DART
Rat and rabbit (embryo-fetal development)
“Embryo-fetal development studies were conducted in rabbits and rats.”
Reproductive & developmental
Rat fertility and rat/rabbit EFD conducted: rat embryo-fetal toxicity (resorptions, low fetal weight); no PPND (ICH S9)
“Embryo-fetal development studies were conducted in rabbits and rats.”
PPND / ePPND: when
PPND not conducted: not required for products to treat advanced cancer
“pre- and postnatal development studies as these studies are not required to support a marketing application for products intended to treat patients with advanced cancer.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No carcinogenicity studies were conducted or required to support a marketing application for the current indication.”
Carcinogenicity model
Not conducted (advanced cancer indication)
“No carcinogenicity studies were conducted or required to support a marketing application for the current indication.”
Carcinogenicity timing
Not required for the current indication; none conducted
“No carcinogenicity studies were conducted or required to support a marketing application for the current indication.”
Safety marginopen answer page →
Safety margin at NOAEL
No NOAEL for rat male reproductive effects, seen at ~0.3x human AUC
“The NOAEL was not identified for the effects on male reproductive organs, which were observed at approximately 0.3 times the human clinical exposure based on AUC (SmPC section 5.3).”
NOAEL / key findings
No NOAEL in rat or monkey chronic studies; liver (sinusoidal injury), hematolymphoid, reproductive organs; monkey glomerulonephritis death at 5 ug/kg
“Taken together, the primary inotuzumab ozogamicin target organs identified by the chronic toxicity studies were the liver, hematolymphopoietic tissues, and the male and female reproductive organs.”
Efficacy evidenceopen answer page →
Efficacy evidence
Subcutaneous xenograft and systemically disseminated ALL mouse models
“The in vivo antitumor activity of inotuzumab ozogamicin was evaluated in xenograft and systemically disseminated ALL mouse models.”
Why that model
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.
Reviewer's view of the efficacy data
FDA: nonclinical pharmacology and toxicology data adequate to support approval
“The nonclinical pharmacology and toxicology data submitted to this BLA are adequate to support the approval of inotuzumab ozogamicin for the proposed indication.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesVerdict not stated
No pharmacologically relevant toxicology species: antibody does not bind rat or monkey CD22, so only target-independent payload toxicity assessed
“The lack of G544 cross-species reactivity indicates the utility of the nonclinical toxicology studies will be limited to the assessment of target-independent toxicities associated with conjugated and unconjugated calicheamicin.”
Safety marginVerdict not stated
No NOAEL for male reproductive organ toxicity in rats; effects at approximately 0.3 times human clinical AUC
“The NOAEL was not identified for the effects on male reproductive organs, which were observed at approximately 0.3 times the human clinical exposure based on AUC (SmPC section 5.3).”
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