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Precedia/Gene therapy/Hemgenix/Flexibility

Hemgenix: what flexibility did regulators accept, and why?

etranacogene dezaparvovec · Factor IX
Check my plan vs. these
Flexibility accepted
OtherAcceptedBeyond the letter
Several toxicology studies used predecessor vector AMT-060 (wild-type hFIX) instead of the final product
Why: AMT-060 differs from the final product in only two base pairs/one amino acid · Other reason
“AMT-060 instead of etranacogene dezaparvovec was used in several toxicological studies provided. This is regarded acceptable as AMT-060 differs only in two base pairs/one amino-acid to the final GTMP AMT-061”
✓ VerifiedEMA assessment report, p. 34Source ↗
DARTAcceptedBeyond the letter
No embryo-fetal, pre/postnatal or juvenile toxicity studies; male mouse germline transmission study only
Why: Haemophilia B almost exclusively affects males and the application covers adults only · Other reason
“As haemophilia B is almost exclusively limited to male patients, and as the current MAA only comprises adult patients, dedicated EFD and PPND studies are not required. Assessment of juvenile toxicity is not warranted in the presented setting.”
✓ VerifiedEMA assessment report, p. 32Source ↗
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity or tumorigenicity studies; liver integration-site analysis in mice and monkeys instead
Why: Nonclinical safety profile; low-level random integration with no predilection for cancer-associated genes · Weight of evidence
“Studies to evaluate the carcinogenicity/tumorigenicity of HEMGENIX were not conducted. These studies are not warranted based on the nonclinical safety profile.”
✓ VerifiedFDA summary basis for approval, p. 11Source ↗
“A low level of integrated vector DNA was distributed throughout the host genome with no predilection to specific integration sites, including in genes associated with malignant transformation in humans.”
✓ VerifiedFDA summary basis for approval, p. 11Source ↗
OtherAccepted with a conditionBeyond the letter
Dorsal root ganglia not examined histologically in monkey toxicity study; deferred to juvenile NHP studies
Why: No adverse spinal cord findings up to the highest dose; DRG to be investigated in juvenile NHP studies under the PIP
“The dorsal root ganglia analysis was not included in the histopathology, but is to be investigated in juvenile NHP studies as part of the future PIP.”
✓ VerifiedEMA assessment report, p. 31Source ↗
“No adverse findings in spinal cord (cervical, lumbar, and thoracic) histopathology, including absence of spinal cord axonopathy, were reported in the NHP study with etranacogene dezaparvovec dose up to 9 × 1013 gc/kg, with a 26-week follow-up.”
✓ VerifiedEMA assessment report, p. 31Source ↗

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

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 →