Sarclisa
isatuximab
Species
Monkey
Longest study
3 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Conducted Stated
Speciesopen answer page →
Species
Cynomolgus monkey only (non-binding species, off-target toxicity assessment)
“The antibody does not bind to its target in animal species typically used in toxicology studies; however, a repeat-dose toxicology study in monkeys was conducted to investigate the potential off-target effects of isatuximab.”
Why that species
Binds only human and chimpanzee CD38; no binding to mouse, rat, rabbit, pig, cynomolgus or rhesus CD38; no pharmacologically relevant species
“The antibody bound to human and chimpanzee CD38, but did not bind to CD38 from the mouse, rat, rabbit, pig, or cynomolgus and rhesus monkey.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkey; monkey-reactive surrogates were evaluated but differed in tissue cross-reactivity
“The pattern of tissue cross-reactivity of both ch38SB25 and chOKT10 surrogates in monkey tissues was significantly different from the pattern of tissue-cross-reactivity observed with isatuximab in human tissues”
Study lengthopen answer page →
Longest pivotal study
3 weeks
“Because an appropriate species for preclinical safety testing could not be identified, toxicology studies with isatuximab were limited to a repeat-dose (once weekly for 3 weeks) toxicity study in cynomolgus monkeys (preceded by a small exploratory study)”
Pivotal GLP studies
GLP 3-week cynomolgus monkey IV study, 20, 50 or 100 mg/kg/week, once weekly
“The weekly repeated intravenous administration of isatuximab for 3 weeks to cynomolgus monkeys at doses of 20, 50 or 100 mg/kg/week resulted in no isatuximab-related findings in any parameters and in any groups.”
Route in tox
IV
“Study title/ Study number: SAR650984 - Repeat-dose (once weekly for 3 weeks) intravenous (0.5-hour infusion) toxicity study in cynomolgus monkeys / TSK0154”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“The FDA concurs with the Applicant that genotoxicity studies are not warranted per ICH guidance S6.”
Carcinogenicity
Not conducted; not warranted for the indication
“No fertility and early embryonic development, or carcinogenicity studies have been conducted or are warranted based on the proposed indication.”
Reproductive & developmental
No studies; weight of evidence from CD38 knockout models: fetal CD38+ immune cell depletion and reduced bone density
“Effects observed in target antigen CD38 knockout animal models include the depletion of fetal CD38 positive immune cells and a decrease in bone density.”
Safety pharmacology
Incorporated into repeat-dose monkey study; no effects on ECG, blood pressure, behavior or respiration up to 100 mg/kg/week
“No isatuximab-related effects were noted in this study on ECG parameters, blood pressure, gross behavior profile (including body temperature), and respiratory function up to the highest dose tested of 100 mg/kg/ week.”
First doseopen answer page →
First-in-human starting dose
MABEL and in vitro receptor occupancy: 0.0001 mg/kg, about 10% predicted CD38 occupancy in B and T cells
“Based on the overall data, the recommended starting human dose for the first-in-human study was 0.0001 mg/kg, which is approximately 10% of the predicted CD38 receptor occupancy measured in normal human B and T cells.”
NOAEL / key findings
Monkey NOAEL 100 mg/kg/week, highest dose; no isatuximab-related findings
“Therefore, under these study conditions, the dose of 100 mg/kg/week was considered to be the no-observed adverse effect level (NOAEL)”
Risksopen answer page →
Immune & cytokine safety
No significant cytokine release from human PBMCs or WBCs in vitro
“In contrast, no significant release of cytokines was observed after isatuximab incubation under any of the various assays and conditions used and for any of the donors tested.”
Biodistribution & persistence
Human TCR: lymphoid tissues and bone marrow, plus pituitary endothelium and prostate epithelium
“The TCR test indicated that isatuximab-specific binding was mainly in the lymphoid tissues (spleen, thymus, lymph node and tonsil) and in the bone marrow; binding was also detected in the pituitary gland (endothelial cells) and prostate gland (glandular epithelial cells).”
Modality-specific risk
No relevant tox species; safety assessment relies on mechanism of action and clinical findings
“The safety assessment of isatuximab for general toxicity is mainly based on the mechanism of action (MOA) and findings in patients.”