Casgevy
exagamglogene autotemcel
Species
Mouse
Longest study
20 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse only (irradiated NSG immunodeficient xenotransplant mice)
“The toxicity of exa-cel has been evaluated in an in vivo combined GLP toxicity and tumorigenicity study with a duration of 20 weeks in NSG mice.”
Why that species
No relevant disease model; NSG xenotransplant mice support engraftment of human edited cells (most relevant model)
“No in vivo proof-of-concept studies were conducted as no relevant animal disease model for TDT and SCD exists that could be used for evaluation of exa-cel.”
Surrogate molecule
No surrogate; clinical-representative edited human CD34+ cells from healthy donors (surrogate gRNA/cells deemed not relevant)
“The test material used in these studies are representative of test material used in the clinic and derived from healthy donors.”
Study lengthopen answer page →
Longest pivotal study
20 weeks
“Moreover, combined GLP toxicity and tumorigenicity study has been conducted in NSG mice with a duration of 20 weeks.”
Pivotal GLP studies
GLP 20-week single-dose IV toxicity/tumorigenicity study and GLP biodistribution study (8 and 20 weeks) in irradiated NSG mice
“Both GLP studies were conducted as single-dose studies using the intravenous (IV) route reproducing the clinical use of exa-cel.”
Route in tox
Intravenous (single injection after total body irradiation)
“Route of Administration IV injection (0.25 mL/mouse) at Day 0”
Skipped studiesopen answer page →
Genotoxicity
No conventional studies; specialized on-/off-target editing (GUIDE-seq, in silico, hybrid capture) and chromosomal aberration assessments
“No evidence of off-target editing was observed for in-silico and GUIDE-seq identified candidate off-target sites which were assessed by hybrid capture sequencing analyses.”
Carcinogenicity
Not conducted (tumorigenicity evaluated in 20-week NSG study; no tumors)
“No carcinogenicity studies were conducted with CTX001.”
Reproductive & developmental
Not conducted (no reproductive organ findings, low gonadal distribution, non-integrating editing)
“No DART studies were conducted with CTX001.”
Safety pharmacology
No separate studies; selected parameters assessed in GLP toxicity study with no effects
“However, selected safety pharmacology parameters, were investigated in the GLP toxicity study and no effects on CNS, cardiac, respiratory, renal or gastrointestinal systems were observed.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
1x10^6 cells/mouse well tolerated; minor non-adverse red cell changes and spleen/thymus round-cell infiltration; no tumors
“The single dose GLP toxicology study with an observation period of 20 weeks revealed that the single IV injection of 1 x 106 cells/animal of unedited or SPY101-RNP-edited CD34+ hHSPCs into non-lethally irradiated NSG mice was well-tolerated.”
Risksopen answer page →
Immune & cytokine safety
In vitro innate immune (type I IFN) assay showed no activation, but FDA deemed it uninterpretable (positive control failed)
“The study results were uninterpretable since the positive control group of R848 CD34+ cells did not show high levels of expression of IFIT1, TIG1, OAS1, and IL-6 transcripts, which were observed in R848 PBMC cohort.”
Biodistribution & persistence
Human DNA highest in bone marrow, then spleen, blood, lung, liver, kidney; minimal in gonads; stable ~87% editing at 20 weeks
“Human DNA was detected in most of the examined tissues in mice that received a single IV administration of 1 x 106 cells/mouse, with the highest levels detected in the bone marrow, followed by spleen, blood, lung, liver, and kidney.”
Modality-specific risk
Off-target editing, large on-target indels and chromosomal translocations; NSG tumorigenicity model validity questioned
“Thus, the potential genotoxic/tumorigenic risk of exa-cel is solely judged by the in vitro studies investigating off-target gene editing and chromosomal translocations.”