Kresladi
marnetegragene autotemcel
Species
Mouse
Longest study
4 wk
Genotox
Partial / alternative Partial / alternative
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse only (CD18HYP/CD18KO disease models, recipient mice, NSG mice); no large-animal tox
“The applicant also used surrogate Lin- HSPCs transduced with the Chim-CD18-WPRE LV transplanted into recipient mice for their definitive in vivo toxicology and BD studies.”
Why that species
CD18-deficient mice mimic LAD-I phenotype (impaired neutrophil migration); patient CD34+ cells unavailable
“CD18HYP and CD18KO mice have deficient CD18 expression and impaired neutrophil migration and inflammatory responses similar to LAD-I patients.”
Surrogate molecule
Yes: murine Lin- HSPCs transduced with clinical vector; healthy-donor human CD34+ cells in NSG mice
“The final clinical product and source material was not used in the nonclinical studies summarized in this memo due to feasibility issues obtaining sufficient CD34+ HSCs from LAD-I patients.”
Study lengthopen answer page →
Longest pivotal study
4 weeks
“Mice were sacrificed 1 month after Chim-CD18-WPRE LV transduced Lin- cell transplantation.”
Pivotal GLP studies
Single non-GLP 1-month IV tox/biodistribution/RCL study of transduced murine Lin- HSPCs in irradiated recipient mice (NSR-7)
“A 1-month in vivo toxicology and biodistribution (BD) study was also conducted using recipient mice for safety evaluation of Chim-CD18-WPRE LV transduced Lin- murine HSPCs.”
Route in tox
Intravenous (single administration after irradiation conditioning)
“Route of Administration IV administration”
Skipped studiesopen answer page →
Genotoxicity
Integration site analyses only (mouse and human transduced cells); no standard genotoxicity battery
“8 Analysis of Integration Profile in Mouse Transduced Cells NSR-8 9 Analysis of Integration Profile in Human Transduced Cells NSR-9”
Carcinogenicity
Not conducted (not suitable for product type); no tumorigenicity or preferential oncogene integration observed
“Traditional carcinogenicity studies were not conducted since they are not suitable for assessment of this drug product type.”
Reproductive & developmental
Not conducted (product type; gonadal VCN near background, low germline transmission risk)
“Studies were not conducted to evaluate this developmental and reproductive toxicity based on the product type and due to the lack of concerning findings in reproductive tissues in Study #7 (study report no. NSR-7).”
Safety pharmacology
Not conducted
“Safety pharmacology studies were not conducted for this product.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
No adverse findings; testis degeneration and liver infiltrates attributed to irradiation/background; NOAEL not defined
“No premature mortality or unexpected deaths were observed over the course of the study period in recipient mice.”
Risksopen answer page →
Immune & cytokine safety
Not stated in public reviews
Biodistribution & persistence
VCN in hematopoietic organs; undetectable/low in non-hematopoietic organs and gonads; serum p24 negative (no RCL)
“Hematopoietic reconstitution was observed in the peripheral blood (PB) and BM and measurable VCN was detected in other hematopoietic organs, whereas undetectable or low VCN was observed in non-hematopoietic organs including the gonads.”
Modality-specific risk
Insertional oncogenesis/clonal dominance; polyclonal integration, no preferential integration near MECOM, LMO2, CCND2
“There were no preferred IS in/nearby genes previously associated with insertional mutagenesis in gene therapy trials such as MECOM, LMO2, and CCND2.”