Kebilidi
eladocagene exuparvovec · AADCCountry not stated; the vector (rAAV2-hAADC) was first tested in humans in Parkinson's disease patients by bilateral intraputaminal dosing
Adstiladrin: what was done before first-in-human, and what came after?
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)
Before first-in-human
First-in-human: where
US: all clinical studies, including first-in-human in patients with BCG-unresponsive NMIBC, conducted in the US
“It is acceptable that all clinical studies with nadofaragene firadenovec were conducted in the US (Table 1)”
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 Adstiladrin 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: Local NOAEL not set (urinary tract changes at all doses, reversible); highest non-severely toxic dose 1.25e13 vp rAd-IFN with 25 mg Syn3; bladder/ureter/urethra inflammation (EMA assessment report, p. 37)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Cynomolgus monkey intravesical GLP study, doses on Days 1 and 91, with 2-month recovery
“control on Days 1 and 91, followed by a two month observation period in a GLP toxicology study.”
Pivotal GLP studies
GLP monkey intravesical study: 2 doses (Days 1 and 91) of rAd-IFN/Syn3 at 2.5e11 or 1.25e13 vp/animal, Syn3 alone, placebo; 2-month observation
“on Days 1 and 91, followed by a two month observation period in a GLP toxicology study.”
DART package
Species: DART
Not conducted (not warranted: product characteristics, toxicology results, patient population)
“Carcinogenicity and reproductive and developmental toxicity studies were not performed for rAd-IFN/Syn3. These studies are not warranted based on the product characteristics, results from the toxicology studies, and target patient population.”
Reproductive & developmental
Not conducted (not warranted by product characteristics, tox results, target population)
“Carcinogenicity and reproductive and developmental toxicity studies were not performed for rAd”
PPND / ePPND: when
Not conducted: DART not warranted (product characteristics, toxicology results, target population)
“Carcinogenicity and reproductive and developmental toxicity studies were not performed for rAd-IFN/Syn3. These studies are not warranted based on the product characteristics, results from the toxicology studies, and target patient population.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not warranted: product characteristics, toxicology results, patient population)
“Carcinogenicity and reproductive and developmental toxicity studies were not performed for rAd-IFN/Syn3. These studies are not warranted based on the product characteristics, results from the toxicology studies, and target patient population.”
Carcinogenicity model
Not conducted
“No carcinogenicity studies were conducted with Adstiladrin.”
Carcinogenicity timing
Not conducted: not warranted (product characteristics, toxicology results, target population)
“Carcinogenicity and reproductive and developmental toxicity studies were not performed for rAd-IFN/Syn3. These studies are not warranted based on the product characteristics, results from the toxicology studies, and target patient population.”
Same question, other gene therapies
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
Skysona
elivaldogene autotemcel · ABCD1 (LVV, ex vivo HSC)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