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
Papzimeos: what flexibility did regulators accept, and why?
zopapogene imadenovec · HPV6/11 antigens (gorilla adenovirus)
Flexibility accepted
GLPCriticised but acceptedBeyond the letter
Definitive repeat-dose toxicology study non-GLP, in wild-type mice only; murine antigen processing likely differs from human
Why: No safety findings at about 5-fold the clinical dose · Other reason
“The dose level assessed in this non-GLP toxicology study provides a 5-fold safety factor for the clinical dose level with the caveat that the processing and binding sequences in wildtype mice is likely different than the peptides recognized by human T cells .”
“The lack of safety findings in this definitive repeat administration safety study conducted in mice provide limited support for the safety of the clinical route of administration and clinical dose level.”
BiodistributionAcceptedBeyond the letter
No biodistribution or shedding studies
Why: Product characteristics and nonclinical safety profile · Low-risk modality
“No biodistribution (BD), genotoxicity, carcinogenicity, reproductive and developmental toxicity, juvenile, nor dedicated local tolerance studies of PRGN-2012 were conducted. These studies are not warranted based on the product characteristics and nonclinical safety profile of PRGN-2012.”
DARTAcceptedBeyond the letter
No developmental and reproductive toxicity studies
Why: Locally administered adenovectors have a well-defined, predictable biodistribution profile · Class precedent
“Locally administered adenovectors (SC or intramuscular) have a well-defined and predictable BD profile that is consistent despite differences in vector serotypes, transduction methods, payload, and manufacturing processes; thus, PRGN-2012 is expected to behave similarly to human .”
“This reviewer agrees with the rationale provided by the applicant for not conducting developmental and reproductive toxicology studies.”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity or tumorigenicity studies
Why: Adenovectors are non-integrating; adenovirus has not shown significant tumorigenicity risk in humans · Low-risk modality · Class precedent
“Per the applicant, studies were not conducted to evaluate carcinogenicity as adenovectors are non-integrating. Therefore, the risk for insertional mutagenesis is not a major concern. In addition, previous data indicates adenovirus has not demonstrated a significant risk for tumorigenicity in humans.”
“This reviewer agrees with the rationale provided by the applicant for not conducting carcinogenicity/tumorigenicity studies.”
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
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