Beqvez
fidanacogene elaparvovec · Factor IXDefinitive 3-month monkey GLP toxicity study used a closely related predecessor vector, not the clinical product
Adstiladrin: what flexibility did regulators accept, and why?
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies with vector or novel excipient; weight-of-evidence assessment for a non-advanced cancer indication
Why: Limited exposure due to dosing once per three months and low systemic levels of excipient and vector reduce carcinogenicity risk · Weight of evidence · Pharmacology or kinetics
“As the proposed indication (high grade Bacillus Calmette-Guerin unresponsive non-muscle invasive bladder cancer) is not an advanced cancer indication, the omission of carcinogenicity evaluation needed to be supported with a weight-of-evidence (WoE) approach for both the vector and the novel excipient.”
“In summary, the limited exposure due to dosing frequency (not chronic, but once per three months) together with the low systemic levels of Syn3NODA and rAd-IFN/IFNα2b reduce the risk for potential carcinogenicity/tumorigenicity.”
DARTAcceptedBeyond the letter
No reproductive and developmental toxicity studies with vector or excipient Syn3
Why: Transient vector DNA in gonads; intravesical route precludes standard studies; infrequent dosing and limited systemic exposure · Pharmacology or kinetics · Weight of evidence
“Developmental and Reproductive Toxicity studies were not conducted using rAd-IFN/Syn3 or Syn3 alone based on the transient rAd-IFN DNA levels detected in the gonads in the biodistribution analysis of rAd-IFN/Syn3”
“The omission of these studies was not considered significant, given the clinical route of administration and inability to conduct standard studies by this route, and the infrequent dosing and anticipated limited systemic exposure.”
GenotoxicityAcceptedBeyond the letter
No genotoxicity assessment of the adenoviral vector; justified with literature on adenoviral integration
Why: Literature on adenoviral integration in treated patients; new bladder tumours more likely reflect natural course of disease · Human data · Weight of evidence
“Absence of genotoxicity assessment of rAd-IFN was justified with literature information on the potential for adenoviral integration in the host genome from (bladder) cells of NMIBC patients treated with Adstiladrin (after treatment with BCG).”
“However, any new bladder tumour in clinical practice will more likely reflect the natural course of NMIBC rather than insertional mutagenesis.”
BiodistributionCriticised but acceptedBeyond the letter
Vector biodistribution in monkey limited to bladder, liver, kidney and gonads; no full tissue analysis
Why: Impact of limited systemic vector exposure on patient safety anticipated to be low · Pharmacology or kinetics
“In a GLP cynomolgus monkey study, tissue distribution of rAd-IFN was studied following intravesical administration, but only for bladder, liver, kidney and gonad tissue. A full tissue analysis of the presence and persistence of rAd-IFN has not been performed.”
“However, the impact of limited systemic exposure to this vector on patient safety is anticipated to be low.”
Safety marginVerdict not stated
Low local exposure multiples in monkey: 3.11 for vector and 1.87 for Syn3 (dose-based)
“The local exposure multiples between monkeys and humans are low with 3.11 for nadofaragene firadenovec and 1.87 for Syn3NODA based on dose. Effects seen in non-clinical monkey studies at a local level can therefore be of clinical relevance.”
Same question, other gene therapies
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
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