Sarclisa

“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.”

“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.”

“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”

“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.”

“Due to the lack of an appropriate pharmacologically relevant animal species for a study assessing the effects of isatuximab on embryo-fetal development, the evaluation of the reproductive and developmental toxicity of isatuximab is based on a weight of evidence (WOE) approach using literature on the involvement of CD38 in reproduction and development.”

“No carcinogenicity studies were performed with isatuximab.”

“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”

“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)”

“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.”

“Study title/ Study number: SAR650984 - Repeat-dose (once weekly for 3 weeks) intravenous (0.5-hour infusion) toxicity study in cynomolgus monkeys / TSK0154”

“The FDA concurs with the Applicant that genotoxicity studies are not warranted per ICH guidance S6.”

“No fertility and early embryonic development, or carcinogenicity studies have been conducted or are warranted based on the proposed indication.”

“Effects observed in target antigen CD38 knockout animal models include the depletion of fetal CD38 positive immune cells and a decrease in bone density.”

“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.”

“The FDA concurs with the Applicant that genotoxicity studies are not warranted per ICH guidance S6.”

“The FDA concurs with the Applicant that genotoxicity studies are not warranted per ICH guidance S6.”

“The FDA concurs with the Applicant that genotoxicity studies are not warranted per ICH guidance S6.”

“In line with relevant guidelines no genotoxicity, carcinogenicity and reproductive toxicity studies were conducted (ref. ICH S6, ICH S9; SmPC section 5.3).”

“No fertility and early embryonic development, or carcinogenicity studies have been conducted or are warranted based on the proposed indication.”

“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.”

“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.”

“Therefore, under these study conditions, the dose of 100 mg/kg/week was considered to be the no-observed adverse effect level (NOAEL)”

“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.”

“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).”

“The safety assessment of isatuximab for general toxicity is mainly based on the mechanism of action (MOA) and findings in patients.”

“All samples collected from animals treated with batch C1053598 (20, 50 and 100 mg/kg/week) were found to be ADA negative, while the majority of the samples from animals (4 out of 6) that received the batch VAB-LCX1-000004, which was beyond its current shelf-life, were ADA positive, with titers ranging from 160 to 320.”

“In antidrug-antibody (ADA) evaluable patients from all completed studies (N=564), the incidence of treatment emergent ADAs was low (2.3%), with 2 patients having a persistent treatment induced ADA (0.35%). However, since no confirmed positive ADA samples were detected in the pivotal Phase 3 study, the neutralizing ADA status was not determined.”

“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.”

“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)”

“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.”

“Due to the lack of an appropriate pharmacologically relevant animal species for a study assessing the effects of isatuximab on embryo-fetal development, the evaluation of the reproductive and developmental toxicity of isatuximab is based on a weight of evidence (WOE) approach using literature on the involvement of CD38 in reproduction and development.”

“Effects observed in target antigen CD38 knockout animal models include the depletion of fetal CD38 positive immune cells and a decrease in bone density.”

“Prenatal and Postnatal Development The Applicant's Position: No study or assessment conducted. The FDA's Assessment: FDA concurs based on the ICH S9 guidance.”

“No carcinogenicity studies were performed with isatuximab.”

“In line with relevant guidelines no genotoxicity, carcinogenicity and reproductive toxicity studies were conducted (ref. ICH S6, ICH S9; SmPC section 5.3).”

“No fertility and early embryonic development, or carcinogenicity studies have been conducted or are warranted based on the proposed indication.”

“Therefore, under these study conditions, the dose of 100 mg/kg/week was considered to be the no-observed adverse effect level (NOAEL)”

“A xenograft model with a Non-Hodgkin Lymphoma (NHL) cell line in severe combined immunodeficient (SCID) mice (SU DHL-8 tumours; study IMP23­018) was used to provide in vivo POC for isatuximab.”

“From the pharmacokinetic point of view, the SCID mice with a xenograft consisting of cells from a CD38 expressing cancer cell line was the most relevant species for non-clinical efficacy testing.”

“Notwithstanding the limitations of the model: whether the use of an NHL cell line is representative for the proposed indication (MM), the model not fully simulating a systemic tumour, the extent of mediated cytotoxicity as this model lacks T and B cells, this study provides evidence for the anti-tumour effect of isatuximab towards CD38.”