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
Strimvelis: what flexibility did regulators accept, and why?
autologous CD34+ cells transduced with ADA (no INN) · ADA (gamma-retroviral, ex vivo HSC)
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No tumorigenicity study: long-term engraftment of transduced cells in mice not achievable; risk assessed from clinical data and vector literature
Why: Agreed in scientific advice that tumorigenicity risk could rely on clinical data and literature on similar vectors · Human data · Class precedent
“Accordingly, the SmPC states that carcinogenicity studies have not been conducted as no adequate animal model was available to evaluate the tumourigenic potential of Strimvelis due to the inability to achieve long-term engraftment of transduced cells in mice.”
“In summary, in previous scientific advice, it was agreed that the tumourgenicity risk assessment for GSK2696273 could be based on clinical data and literature on similar vectors if tumourgenicity/general toxicity studies were unsuccessful in allowing for the determination of optimal conditions for a full tumourgenicity study.”
Safety marginAcceptedBeyond the letter
Mouse biodistribution/toxicology dose only about half the highest human dose (cells/kg)
Why: Proposed indication and risk evaluation; vector copy number kept as low as possible · Serious disease
“The doses administered provide only safety margin of approximately half the highest dose administered in humans (20 x106 CD34+ cells/kg).”
“Although it is not possible to establish a safe VCN, this has been maintained at a lowest possible degree that results in sufficient transduction efficiency. Taking into account the proposed indication and the evaluation of the risk of use of the product, the CAT/CHMP considered this issue resolved.”
OtherAcceptedBeyond the letter
Toxicology test item was healthy cord-blood CD34+ cells transduced with the clinical vector, not patient product; test item preparation non-GLP
Why: Test item accepted as representative of the product · Other reason
“Preparation of the test items (transduced and mock-transduced) was performed by MolMed and was not conducted to GLP.”
“The test item used in the biodistribution studies (referred to as GSK3235757A) comprised of CD34+ cells derived from healthy human UCB transduced with GSK3336223 vector and is accepted as representative of Strimvelis.”
BiodistributionAccepted
No nonclinical germline transmission studies of the genetically modified human cells
Why: Low germline transfer risk; animal testing of human cells not meaningful; patients mostly treated before puberty · Low-risk modality · Within the guideline
“It is noted that the risk of germline transfer associated with the administration of genetically modified human cells is considered to be low and animal testing of human cells may be difficult if not meaningful; hence non-clinical germline transmission studies of human genetically modified cells are generally not recommended.”
“However, most ADA-SCID patients are treated within the first few years of life before puberty begins. No further studies with GSK2696273 were conducted and the absence of any additional studies is adequately justified.”
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
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