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
Glybera: what flexibility did regulators accept, and why?
alipogene tiparvovec · LPL (AAV1)
Flexibility accepted
SpeciesAccepted
Toxicity evaluated in a single species (wild-type mice) only
Why: In accordance with EU gene therapy guidelines · Within the guideline
“The use of a single species for toxicity evaluation is in accordance with the guideline for gene therapy medicinal products EMEA/CHMP/GTWP/587488/2007 and the guideline on the non-clinical studies required before first clinical use of gene therapy”
“The use of a single species for toxicity evaluation can be accepted for Glybera.”
CarcinogenicityAcceptedBeyond the letter
No in vivo carcinogenicity studies; vector integration analyses and literature review instead
Why: No relevant study design exists for insertional mutagenesis and oncogenicity; integration and literature data do not substantiate a tumourigenicity concern · Weight of evidence
“The applicant argued that there is no existing study design that would be accepted as relevant to assess insertional mutagenesis and the risk of oncogenicity: the validity of any study design is questionable.”
“Overall, the CAT and CHMP finally agreed with the applicant that the data do not substantiate a concern for tumourigenicity.”
OtherQuestioned
Nonclinical bridging between plasmid-derived and baculovirus-derived vector used too few mice to be conclusive
“Different batches of AMT-010 were compared and the applicant intended to compare AMT-010 and AMT-011 in bridging studies, but as so few mice were used in each test, the conclusions from these tests very limited.”
Safety marginVerdict not stated
No margin: progressive dose-related muscle toxicity in mice at the recommended clinical dose
Why: Muscle toxicity shown to be reversible
“There appears to be progressive and dose-related muscle toxicity at the recommended clinical dose. This has been shown to be reversible.”
OtherCriticised but acceptedBeyond the letter
No study with a control AAV to separate LPL overexpression from vector effects in muscle toxicity
Why: Such a study would not remove the evidence of concern · Other reason
“The CAT did not fully agree with the applicant’s justification for lack of further experimental evidence to compare the effect of a control adeno-associated virus and AMT-011 to study the significance of LPL overexpression.”
“Such a study would however not remove the evidence of concern and therefore was finally not further requested and the issue considered solved.”
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
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