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Precedia/Gene therapy/Fayuvi/Flexibility

Fayuvi: what flexibility did regulators accept, and why?

rebisufligene etisparvovec · SGSH (AAV9)
Check my plan vs. these
Flexibility accepted
CarcinogenicityVerdict not stated
No genotoxicity or carcinogenicity/tumorigenicity studies; weight-of-evidence risk assessment instead
Why: Concerns addressed by a weight-of-evidence approach instead of dedicated studies · Weight of evidence
“Developmental and reproductive toxicity (DART), genotoxicity, and carcinogenicity/tumorigenicity studies were not conducted with FAYUVI. To address these concerns, the Applicant used a weight-of-evidence approach”
✓ VerifiedFDA summary basis for approval, p. 11Source ↗
DARTVerdict not stated
No developmental and reproductive toxicity studies; weight-of-evidence risk assessment instead
Why: Concerns addressed by a weight-of-evidence approach instead of dedicated studies · Weight of evidence
“Developmental and reproductive toxicity (DART), genotoxicity, and carcinogenicity/tumorigenicity studies were not conducted with FAYUVI. To address these concerns, the Applicant used a weight-of-evidence approach”
✓ VerifiedFDA summary basis for approval, p. 11Source ↗

Same question, other gene therapies

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

fidanacogene elaparvovec · Factor IX
Definitive 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-dystrophin
No developmental and reproductive toxicology studies

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 IX
Several 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 · AADC
No 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 · RPE65
No 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 VIII
No 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 · SMN1
Pivotal 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

Summary across all 26 gene therapies →