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Precedia/Gene therapy/Itvisma/Flexibility

Itvisma: what flexibility did regulators accept, and why?

onasemnogene abeparvovec (intrathecal) · SMN1 (AAV9, intrathecal)
Check my plan vs. these
Flexibility accepted
Safety marginVerdict not stated
No NOAEL in the pivotal intrathecal NHP study; DRG, spinal cord, nerve and brain findings at the clinical-equivalent dose
Why: Findings minor and did not increase in severity or incidence over 12 months
“with minor microscopic findings reported 6 weeks post-administration in the dorsal root ganglia (DRG), spinal cord, peripheral nerves, and brain that did not increase in severity or incidence over the 12 month study. These toxicity findings precluded the determination of a no-observed”
✓ VerifiedFDA summary basis for approval, p. 14Source ↗
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity/tumorigenicity or genotoxicity studies; long-term clinical follow-up for malignancies instead
Why: Single administration, known product characteristics, class safety profile; low integration risk with long-term follow-up for malignancies in the RMP · Class precedent · Low-risk modality
“No carcinogenicity, genotoxicity, or repeat dosing were conducted for OAV101B. These studies are not necessary based on the intended ROA, dosing regimen (i.e., single infusion), known product characteristics, and overall safety profile for this class of product.”
✓ VerifiedFDA summary basis for approval, p. 15Source ↗
“Long-term follow-up studies that specifically include the occurrence of new malignancies and tumours as part of the risk management plan in place for OAV101. Therefore, tumorigenicity studies are not needed.”
✓ VerifiedEMA assessment report, p. 45Source ↗
BiodistributionVerdict not stated
Germline transmission risk not evaluable in mouse fertility studies, as mouse germ cells are not transduced
“Although no vertical transmission of OAV101 vector DNA was observed in foetuses, it is important to note that these mouse studies are not appropriate to further evaluate the risk of inadvertent germline transmission, since mice did not reveal any vector DNA in germ cells.”
✓ VerifiedEMA assessment report, p. 45Source ↗
BiodistributionQuestioned
No intrathecal dose below the clinical-equivalent dose tested in NHP; CNS and DRG biodistribution plateau assumption unverified
“The Applicant assumes that this might be due to a plateau that is achieved with the lowest dose tested (1.2 x 1013 vg). However, as no lower dose levels were tested, it remains unclear whether this assumption is indeed correct.”
✓ VerifiedEMA assessment report, p. 41Source ↗

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

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 →