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
Skysona: what was done before first-in-human, and what came after?
elivaldogene autotemcel · ABCD1 (LVV, ex vivo HSC)
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 Skysona 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: True NOAEL not determined; ~5x10^7 CD34+ cells/kg (max feasible, 10x minimum clinical dose); early deaths in both test and control groups (FDA pharmacology/toxicology review, p. 2)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (single autologous IV administration)
“As Lenti-D Drug Product is intended for a single autologous IV administration, not performing any repeat-dose toxicity studies is acceptable.”
Pivotal GLP studies
Single 92-day GLP IV toxicity/biodistribution study (NC-12-007) in myeloablated NSG mice, 1x10^6 cells/mouse; no repeat-dose studies
“A 92-day GLP toxicology study in myeloablated mice evaluated a single administration of 1x106 Lenti-D transduced healthy human CD34+ HSCs/mouse.”
DART package
Species: DART
Not conducted (acceptable given product characteristics and safety profile)
“Reproductive and developmental toxicity studies were not performed for eli-cel which is acceptable based on the product characteristics and safety profile.”
Reproductive & developmental
Not conducted; no findings in reproductive tissues in mouse GLP study
“Studies were not conducted to evaluate this safety endpoint based on the product type and due to the lack of findings in reproductive tissues in Study #10.”
PPND / ePPND: when
Not conducted; acceptable given product characteristics and safety profile
“Reproductive and developmental toxicity studies were not performed for eli-cel which is acceptable based on the product characteristics and safety profile.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Traditional carcinogenicity studies were not conducted as they are not suitable for assessing this product type.”
Carcinogenicity model
Not conducted (traditional studies not suitable for this product type)
“Traditional carcinogenicity studies were not conducted as they are not suitable for assessing this product type.”
Carcinogenicity timing
Not required; omission acceptable given nature of product
“No repeat-dose toxicology, dedicated carcinogenicity, juvenile or developmental and reproductive toxicology studies were performed, and their omission is acceptable considering the nature of the product.”
Same question, other gene therapies
Kebilidi
eladocagene exuparvovec · AADCCountry not stated; the vector (rAAV2-hAADC) was first tested in humans in Parkinson's disease patients by bilateral intraputaminal dosing
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
autologous CD34+ cells transduced with ADA (no INN) · ADA (gamma-retroviral, ex vivo HSC)Israel: first administered in 2000 to one ADA-SCID patient at Hadassah University, Jerusalem (pilot study)
Zolgensma
onasemnogene abeparvovec · SMN1United States: single-site trial in 15 infants with SMA
Beqvez
fidanacogene elaparvovec · Factor IXNot stated in public reviews
Casgevy
exagamglogene autotemcel · BCL11A enhancer (CRISPR-Cas9, ex vivo HSC)Not stated in public reviews
Elevidys
delandistrogene moxeparvovec · Micro-dystrophinNot stated in public reviews
Fayuvi
rebisufligene etisparvovec · SGSH (AAV9)Not stated in public reviews
Genglycos
pariglasgene brecaparvovec · G6PC (AAV8)Not stated in public reviews
Glybera
alipogene tiparvovec · LPL (AAV1)Not stated in public reviews
Hemgenix
etranacogene dezaparvovec · Factor IXNot stated in public reviews
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
voretigene neparvovec · RPE65Not stated in public reviews
Lyfgenia
lovotibeglogene autotemcel · HBB T87Q (LVV, ex vivo HSC)Not stated in public reviews
Papzimeos
zopapogene imadenovec · HPV6/11 antigens (gorilla adenovirus)Not stated in public reviews
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