Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)US: all clinical studies, including first-in-human in patients with BCG-unresponsive NMIBC, conducted in the US
Genglycos: what was done before first-in-human, and what came after?
pariglasgene brecaparvovec · G6PC (AAV8)
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Genglycos don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for gene therapies
FDA expects preclinical proof-of-concept and toxicology studies to identify active dose levels and support the choice of starting dose and escalation. The 2013 guidance gives no numeric formula or scaling rule for the starting dose.
“Selection of potential starting dose level, dose-escalation schedule, and dosing regimen for clinical trials.”
✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 7Source ↗
This product's starting point
NOAEL / key findings: NOAEL 1.0x10^13 gc/kg adult mouse (hepatic necrosis, Kupffer cell changes above); 7.0x10^13 juvenile mouse; ~1.3x10^14 gc/kg NHP (FDA pharmacology/toxicology review, p. 2)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (single administration); longest is 6-month single-dose juvenile NHP study
“One 6-month, single-dose toxicology study was conducted in healthy juvenile non-human primates (NHPs)”
Pivotal GLP studies
Three 92-day single-dose IV studies in adult/juvenile mice; one 6-month single-dose IV GLP study in juvenile cynomolgus monkeys
“One 6-month, single-dose toxicology study was conducted in healthy juvenile non-human primates (NHPs)”
DART package
Species: DART
Mouse only (embryo-fetal development study; separate pre-mating germline transmission study)
“Similarly, IV administration of DTX401 at 7 × 1013 gc/kg to pregnant dams at presumed gestational day (GD) 6 resulted in DTX401 DNA detection in placenta but not offspring livers, and there was no impact on embryofetal development on GD 18.”
Reproductive & developmental
Embryo-fetal development and germline transmission studies in mice; NOAEL 7.0x10^13 gc/kg; no germline integration
“IV administration of DTX401 at 7 × 1013 gc/kg to pregnant dams at presumed gestational day (GD) 6 resulted in DTX401 DNA detection in placenta but not offspring livers”
PPND / ePPND: when
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Carcinogenicity
Species: carcinogenicity
Not conducted
“Per the Applicant, studies were not conducted to evaluate carcinogenicity/tumorigenicity for the following reasons:”
Carcinogenicity model
Not conducted; AAV8 vectors predominantly non-integrating and episomal
“AAV8 vectors are predominantly non-integrating and persist as episomes with low likelihoods of genomic integration.”
Carcinogenicity timing
Not conducted: AAV8 vectors predominantly non-integrating and episomal
“Per the Applicant, studies were not conducted to evaluate carcinogenicity/tumorigenicity for the following reasons: • AAV8 vectors are predominantly non-integrating and persist as episomes with low likelihoods of genomic integration.”
Same question, other gene therapies
Kebilidi
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Otarmeni
lunsotogene parvec · OTOF (AAV, intracochlear)United States and unnamed ex-US sites: DB-OTO-001 (7 US, 4 ex-US sites), the only clinical study
Roctavian
valoctocogene roxaparvovec · Factor VIIICountry not stated; first-in-human dose-escalation study 270-201 in patients with severe hemophilia A
Strimvelis
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Zolgensma
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Beqvez
fidanacogene elaparvovec · Factor IXNot stated in public reviews
Casgevy
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Elevidys
delandistrogene moxeparvovec · Micro-dystrophinNot stated in public reviews
Fayuvi
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Glybera
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Hemgenix
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Imlygic
talimogene laherparepvec · GM-CSF (oncolytic HSV-1)Not stated in public reviews
Itvisma
onasemnogene abeparvovec (intrathecal) · SMN1 (AAV9, intrathecal)Not stated in public reviews
Kresladi
marnetegragene autotemcel · ITGB2 (LVV, ex vivo HSC)Not stated in public reviews
Lenmeldy
atidarsagene autotemcel · ARSA (LVV, ex vivo HSC)Not stated in public reviews
Luxturna
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Lyfgenia
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Papzimeos
zopapogene imadenovec · HPV6/11 antigens (gorilla adenovirus)Not stated in public reviews
Skysona
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Tudriqev
vusolimogene oderparepvec · GALV-GP + GM-CSF (oncolytic HSV-1)Not stated in public reviews
Vyjuvek
beremagene geperpavec · COL7A1 (HSV-1, topical)Not stated in public reviews
Waskyra
etuvetidigene autotemcel · WAS (LVV, ex vivo HSC)Not stated in public reviews
Zevaskyn
prademagene zamikeracel · COL7A1 (RV-modified keratinocyte sheets)Not stated in public reviews
Zynteglo
betibeglogene autotemcel · HBB T87Q (LVV, ex vivo HSC)Not stated in public reviews