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
Beqvez: what flexibility did regulators accept, and why?
fidanacogene elaparvovec · Factor IX
Flexibility accepted
OtherVerdict not stated
Definitive 3-month monkey GLP toxicity study used a closely related predecessor vector, not the clinical product
“The definitive 3-month GLP toxicity study in cynomolgus monkeys used AAVRh74var-hFIX19-R338L, while a 2-year genetic toxicity vector integration study in monkeys used fidanacogene elaparvovec.”
Efficacy modelAcceptedBeyond the letter
In vivo efficacy in hemophilia B dogs used a canine-FIX surrogate vector, not the clinical product
Why: Surrogate data expected to be representative of the clinical product · Pharmacology or kinetics
“This study did not evaluate the intended clinical product. Animals in this study were administered an AAVRh74var vector encoding the canine factor IX gene. However, safety and activity data resulting from administration of this surrogate would be expected to be representative of BEQVEZ.”
DARTAcceptedBeyond the letter
No embryo-fetal or pre-/postnatal development studies
Why: Hemophilia B almost exclusively affects males; product not intended for women · Other reason
“Per applicant, hemophilia B is almost exclusively limited to male subjects, and BEQVEZ is not intended for administration in women. This reviewer agrees that the omission of dedicated embryo-fetal development studies and pre- and postnatal development studies is acceptable.”
CarcinogenicityAcceptedBeyond the letter
No dedicated carcinogenicity studies; integration-site analyses relied on instead
Why: Integration analyses raise no specific carcinogenicity concern · Weight of evidence
“Dedicated studies on carcinogenicity were not conducted with fidanacogene elaparvovec. Results obtained from integration analyses might not raise any specific carcinogenicity concern so far.”
BiodistributionVerdict not stated
Semen shedding in rabbits only; no assessment of fertility impact or transmission to offspring
“Vector DNA was detectable in semen until 4 months after dosing. No analysis of potential impact on fertility or transmission to offspring was performed.”
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