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
Zynteglo: what flexibility did regulators accept, and why?
betibeglogene autotemcel · HBB T87Q (LVV, ex vivo HSC)
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies; low risk of oncogenic transformation concluded from the available vector data
Why: Low risk of oncogenic transformation; postmarketing observational study of insertional oncogenesis required · Weight of evidence
“These data support the conclusion that transduction of HSCs with BB305 LVV has a low risk for oncogenic transformation. Carcinogenicity and developmental and reproductive toxicity studies were not conducted with beti-cel.”
“As insertional oncogenesis is a potential risk of treatment with ZYNTEGLO, the Applicant agreed to conduct the following postmarketing study as a safety Postmarketing Requirement.”
DARTAcceptedBeyond the letter
No developmental and reproductive toxicity studies
Why: No adverse findings in reproductive tissues of mice given murine beti-cel; not warranted given product characteristics and safety profile · Weight of evidence · Low-risk modality
“Developmental and Reproductive Toxicology Studies: Per the applicant, developmental and reproductive toxicology studies were not conducted because there were no adverse findings in the male and female reproductive tissues of mice administered murine beti-cel, based on the results of Study #4”
“These studies are not warranted based on the product characteristics and safety profile.”
GLPCriticised but acceptedBeyond the letter
Pivotal in vivo studies were combined pharmacology-toxicity studies in mice, not fully GLP-compliant
Why: Combined studies still allowed assessment of primary pharmacodynamics and toxicity · Other reason
“Even if not fully compliant to GLP principles, these four in vivo combined studies allowed the assessment of both primary pharmacodynamics and toxicity.”
SpeciesVerdict not stated
In vivo pharmacology and toxicology used a murine surrogate (BB305-transduced mouse bone marrow cells) in thalassemic and wild-type mice
“In vivo pharmacology and toxicology studies were conducted to evaluate the activity and safety of BB305 LVV-transduced murine BM cells (BMCs) following primary and secondary transplantation in β-thalassemic and wild-type C57BL/6 mice, respectively.”
Safety pharmacologyAcceptedBeyond the letter
No safety pharmacology studies
Why: No circulatory, respiratory, neurologic or digestive effects in any in vivo study · Weight of evidence
“No safety pharmacology studies were performed which is considered acceptable as there was no evidence of adverse effects on the circulatory, respiratory, neurologic or digestive systems observed in any of the in vivo studies conducted.”
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
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)