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
Zolgensma: what flexibility did regulators accept, and why?
onasemnogene abeparvovec · SMN1
Flexibility accepted
SpeciesCriticised but acceptedBeyond the letter
Pivotal toxicity in neonatal mice only; no adequate safety study in a species closer to human (NHP study non-GLP, low-dose pilot)
Why: Human clinical data available and preferred for defining the safety profile · Human data
“As in mice a dose of ~≥ 2.2 fold the clinical dose results in mortality, a safety study in an animal species more close to human would have been helpful to determine the safety profile of the product in relation to the dose.”
“As currently human data from clinical studies are available, these data are preferred for determining the safety and efficacy profile of the product.”
Safety marginAccepted with a conditionBeyond the letter
No margin: liver and ventricle lesions in mice at 0.7- to 1.4-fold the clinical dose; mortality at 2-3-fold
Why: Clinical monitoring of vital organ function and an intervention protocol required · Other reason
“The clinical relevance of the observed Zolgensma related effects in animals, with special attention to occurrence of tissue lesions (primarily liver and ventricle) already found in doses 0.7- to 1.4-fold the clinical dose and the striking mortality in mice at doses 2-3 the clinical dose required discussion.”
“An appropriate monitoring system for the functionality of vital organs and a functional intervention protocol when (life-threatening) toxic events would occur should be in place.”
CarcinogenicityCriticised but acceptedBeyond the letter
No genotoxicity, tumorigenicity or vector integration studies
Why: Non-integrative AAV vector; integration expected only to a very low extent · Low-risk modality
“Neither studies on vector integration nor a justification for omission of such studies has been provided in the dossier.”
“As Zolgensma is a non-integrative vector, it can theoretically integrate into DNA to a very low extent. Consequently, the risk for mutagenic and the tumorigenic potential is regarded to be very limited.”
BiodistributionCriticised but acceptedBeyond the letter
No germline transmission studies despite low but persistent vector DNA in gonads
Why: SMA1 patients treated at a very young age; further germline studies judged possibly unnecessary · Weight of evidence · Other reason
“The low but persistent levels of vector DNA observed in gonads should have triggered further non-clinical analyses in accordance with the Guideline on non-clinical testing for inadvertent germline transmission of gene transfer vectors (EMEA/273974/2005).”
“Based on these considerations and the fact that SMA1 patients are treated at a very young age, it may be acceptable that no further non-clinical studies were conducted on inadvertent germline transmission.”
DARTAcceptedBeyond the letter
No developmental and reproductive toxicity, safety pharmacology, genotoxicity or tumorigenicity studies
Why: Not warranted given product characteristics, toxicology results and the target patient population · Low-risk modality · Other reason
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, carcinogenicity/tumorigenicity of AVXS-101 were not conducted for AVXS-101. These studies were not warranted based on the product characteristics, results from the toxicology studies, and target patient population.”
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
Casgevy
exagamglogene autotemcel · BCL11A enhancer (CRISPR-Cas9, ex vivo HSC)No in vivo proof-of-concept study; no disease model for TDT or SCD, so engraftment and editing persistence studied in NSG xenotransplant mice
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
Zynteglo
betibeglogene autotemcel · HBB T87Q (LVV, ex vivo HSC)No carcinogenicity studies; low risk of oncogenic transformation concluded from the available vector data