Nonclinical precedent Request an invite
Precedia/Gene therapy/Luxturna/Flexibility

Luxturna: what flexibility did regulators accept, and why?

voretigene neparvovec · RPE65
Check my plan vs. these
Flexibility accepted
DARTCriticised but acceptedBeyond the letter
No reproductive toxicity studies; gonadal biodistribution in dogs and primates used instead
Why: No vector in gonads of dogs and primates; limited systemic distribution after subretinal dosing · Weight of evidence
“The CHMP previously gave scientific advice that such studies would not be needed if ‘biodistribution data in two species and two sexes demonstrate lack of vector distribution to the gonads’. The applicant considers its dataset to be in line with this advice from CHMP.”
✓ VerifiedEMA assessment report, p. 21Source ↗
“Ultimately, no explanation for these errors was identified, but gonadal tissues from 18 animals (dogs and primates) were examined with no positive results, which is reassuring.”
✓ VerifiedEMA assessment report, p. 21Source ↗
GenotoxicityAcceptedBeyond the letter
No genotoxicity studies; literature-based discussion of AAV integration instead
Why: Integration expected at random sites; retinal pigment epithelium post-mitotic, so insertional mutagenesis risk limited · Pharmacology or kinetics · Weight of evidence
“The position at the conclusion of these was that the applicant need provide no experimental data with voretigene neparvovec and that a discussion could suffice, if judged adequate.”
✓ VerifiedEMA assessment report, p. 21Source ↗
“AAV integration requires the cells to be dividing and as a consequence, the risk of insertional mutagenesis seems limited: it would not be further understood by requiring experimental work with voretigene neparvovec.”
✓ VerifiedEMA assessment report, p. 21Source ↗
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity or tumorigenicity studies
Why: Two-year rodent studies would not contribute meaningful data; vector administered to post-mitotic retinal tissue · Pharmacology or kinetics
“CHMP also advised that in vivo testing in 2-year carcinogenicity studies in mice or rats would not contribute meaningful data to assessing the risk of carcinogenicity.”
✓ VerifiedEMA assessment report, p. 21Source ↗
Safety pharmacologyAcceptedBeyond the letter
No safety pharmacology studies
“Separate safety pharmacology studies were not conducted and are not deemed to be necessary.”
✓ VerifiedEMA assessment report, p. 19Source ↗

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

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 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

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 →