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).”
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.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
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.”