Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)No carcinogenicity studies with vector or novel excipient; weight-of-evidence assessment for a non-advanced cancer indication
Casgevy: what flexibility did regulators accept, and why?
exagamglogene autotemcel · BCL11A enhancer (CRISPR-Cas9, ex vivo HSC)
Flexibility accepted
Efficacy modelAcceptedBeyond the letter
No in vivo proof-of-concept study; no disease model for TDT or SCD, so engraftment and editing persistence studied in NSG xenotransplant mice
Why: No relevant animal disease model; in vitro data showed beneficial editing and HbF expression levels · No relevant species
“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.”
“Overall, the primary pharmacodynamic studies provided adequate evidence that potential beneficial levels of genome editing and HbF expression can be reached, despite the lack of a relevant disease animal model.”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies; NSG toxicity/tumorigenicity study of limited validity, so tumorigenic risk addressed by in silico and in vitro editing analyses
Why: Off-target editing and chromosomal aberration risk sufficiently addressed using in silico and in vitro approaches · Weight of evidence
“However, the significance of the in vivo model used for addressing the tumorigenic risk associated with potential off-target editing and/or chromosomal translocations induced during the editing process of the CD34+ hHSPCs is limited, as the validity of the model remains questionable.”
“Thus, the tumorigenic risk of exa-cel needs to be addressed primarily by the evaluation of the potential of SPY101-RNP to induce off-target editing and chromosomal aberrations, which has been sufficiently addressed using in silico and in vitro approaches.”
GenotoxicityAcceptedBeyond the letter
No dedicated chromosomal translocation studies (e.g. CAST-Seq); translocation risk estimated indirectly from large-insertion rates
Why: Other methods such as CAST-Seq unlikely to detect translocations · Weight of evidence
“However, as the likelihood of detecting chromosomal translocations using other methods such as CAST-Seq is expected to be low, omission of additional chromosomal translocation studies is acceptable.”
Safety marginCriticised but acceptedBeyond the letter
Single-dose NSG toxicity study dose gave only a 1.6-fold margin over the maximum human cell dose
Why: Main safety concern is off-target editing and genotoxicity, addressed in the genotoxicity evaluation · Weight of evidence
“The dose level of 1 x 106 CD34+ hHSPCs/mouse administered in the single dose toxicity study is acceptable, despite the fact that there is only a 1.6-fold safety margin as compared to the max. human dose level of 20 x 106 cells/kg.”
“However, the main safety concern of exa-cel is associated with editing at critical potential off-target sites and associated genotoxicity that might induce tumorigenic events. This risk is addressed mainly in the non-clinical genotoxicity evaluation, which included evaluation of both on-target and off-target editing.”
DARTAcceptedBeyond the letter
No developmental and reproductive toxicity studies
Why: No reproductive organ findings, very low distribution to reproductive organs; acceptable on product characteristics and safety profile · Weight of evidence · Low-risk modality
“No DART studies were conducted with CTX001. The applicant’s rationale for not conducting DART studies include: i) no CTX001-related pathologic findings were observed in reproductive organs in the completed toxicology study (Study Report No. 1016-2465), ii) very low distribution of CTX001 to reproductive organs was reported in the completed biodistribution study (Study Report No. 1016-2475),”
“Reviewer comment: This is acceptable based on the product characteristics and safety profile.”
Same question, other gene therapies
Beqvez
fidanacogene elaparvovec · Factor IXDefinitive 3-month monkey GLP toxicity study used a closely related predecessor vector, not the clinical product
Elevidys
delandistrogene moxeparvovec · Micro-dystrophinNo developmental and reproductive toxicology studies
Fayuvi
rebisufligene etisparvovec · SGSH (AAV9)No genotoxicity or carcinogenicity/tumorigenicity studies; weight-of-evidence risk assessment instead
Genglycos
pariglasgene brecaparvovec · G6PC (AAV8)No carcinogenicity/tumorigenicity studies; justified by low integration risk of episomal AAV8 vector and literature
Glybera
alipogene tiparvovec · LPL (AAV1)Toxicity evaluated in a single species (wild-type mice) only
Hemgenix
etranacogene dezaparvovec · Factor IXSeveral toxicology studies used predecessor vector AMT-060 (wild-type hFIX) instead of the final product
Imlygic
talimogene laherparepvec · GM-CSF (oncolytic HSV-1)No genotoxicity studies; non-integrating HSV-1 episome
Itvisma
onasemnogene abeparvovec (intrathecal) · SMN1 (AAV9, intrathecal)No NOAEL in the pivotal intrathecal NHP study; DRG, spinal cord, nerve and brain findings at the clinical-equivalent dose
Kebilidi
eladocagene exuparvovec · AADCNo in vivo pharmacology studies with the product; in vitro human cell data plus published literature only
Kresladi
marnetegragene autotemcel · ITGB2 (LVV, ex vivo HSC)Clinical product not tested; surrogate murine Lin- HSPCs transduced with the clinical vector used for definitive toxicology and biodistribution
Lenmeldy
atidarsagene autotemcel · ARSA (LVV, ex vivo HSC)No reproductive and developmental toxicity studies
Luxturna
voretigene neparvovec · RPE65No reproductive toxicity studies; gonadal biodistribution in dogs and primates used instead
Lyfgenia
lovotibeglogene autotemcel · HBB T87Q (LVV, ex vivo HSC)No traditional carcinogenicity studies; insertional mutagenesis assessed by in vitro immortalization assay and integration site analysis
Otarmeni
lunsotogene parvec · OTOF (AAV, intracochlear)No genotoxicity or carcinogenicity/tumorigenicity studies; tumorigenicity risk to be assessed in a postmarketing study
Papzimeos
zopapogene imadenovec · HPV6/11 antigens (gorilla adenovirus)Definitive repeat-dose toxicology study non-GLP, in wild-type mice only; murine antigen processing likely differs from human
Roctavian
valoctocogene roxaparvovec · Factor VIIINo carcinogenicity or tumorigenicity studies (nor safety pharmacology or DART studies)
Skysona
elivaldogene autotemcel · ABCD1 (LVV, ex vivo HSC)Safety tested only in single-dose studies in immunodeficient myeloablated mice given healthy-donor transduced cells
Strimvelis
autologous CD34+ cells transduced with ADA (no INN) · ADA (gamma-retroviral, ex vivo HSC)No tumorigenicity study: long-term engraftment of transduced cells in mice not achievable; risk assessed from clinical data and vector literature
Tudriqev
vusolimogene oderparepvec · GALV-GP + GM-CSF (oncolytic HSV-1)Rat toxicology, biodistribution and DART studies used the murine surrogate mRP1 (murine GM-CSF); clinical product tested only in tumor-bearing mice
Vyjuvek
beremagene geperpavec · COL7A1 (HSV-1, topical)Toxicity tested in a single species (mouse), chosen only on historical use
Waskyra
etuvetidigene autotemcel · WAS (LVV, ex vivo HSC)Pharmacology and toxicology done with murine surrogate HSPCs transduced with the WAS vector in mice, not the human product
Zevaskyn
prademagene zamikeracel · COL7A1 (RV-modified keratinocyte sheets)No carcinogenicity or tumorigenicity studies; insertional oncogenesis risk deferred to a long-term postmarketing safety study
Zolgensma
onasemnogene abeparvovec · SMN1Pivotal toxicity in neonatal mice only; no adequate safety study in a species closer to human (NHP study non-GLP, low-dose pilot)
Zynteglo
betibeglogene autotemcel · HBB T87Q (LVV, ex vivo HSC)No carcinogenicity studies; low risk of oncogenic transformation concluded from the available vector data