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
Casgevy: what was done before first-in-human, and what came after?
exagamglogene autotemcel · BCL11A enhancer (CRISPR-Cas9, 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 Casgevy 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: 1x10^6 cells/mouse well tolerated; minor non-adverse red cell changes and spleen/thymus round-cell infiltration; no tumors (EMA assessment report, p. 44)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (single administration)
“A repeat-dose toxicity study was not performed and is not required as exa-cel is intended for single-dose administration only.”
Pivotal GLP studies
GLP 20-week single-dose IV toxicity/tumorigenicity study and GLP biodistribution study (8 and 20 weeks) in irradiated NSG mice
“Both GLP studies were conducted as single-dose studies using the intravenous (IV) route reproducing the clinical use of exa-cel.”
DART package
Species: DART
Not conducted (not warranted given product characteristics and safety profile)
“Developmental and reproductive toxicity studies and carcinogenicity studies were not conducted with CASGEVY. These studies are not warranted based on the characteristics and safety profile of the product.”
Reproductive & developmental
Not conducted (no reproductive organ findings, low gonadal distribution, non-integrating editing)
“No DART studies were conducted with CTX001.”
PPND / ePPND: when
Not conducted: DART not warranted (product characteristics and safety profile)
“Developmental and reproductive toxicity studies and carcinogenicity studies were not conducted with CASGEVY. These studies are not warranted based on the characteristics and safety profile of the product.”
Carcinogenicity
Species: carcinogenicity
Not conducted; tumorigenicity assessed in irradiated NSG mice instead
“Developmental and reproductive toxicity studies and carcinogenicity studies were not conducted with CASGEVY. These studies are not warranted based on the characteristics and safety profile of the product.”
Carcinogenicity model
Tumorigenicity in irradiated NSG mice, single IV dose followed 20 weeks: no tumor formation
“Mice received single IV administration of 1 x 106 cells/mouse and were followed for 20 weeks. There were no significant adverse findings or tumor formation.”
Carcinogenicity timing
Not conducted: not warranted (product characteristics and safety profile)
“Developmental and reproductive toxicity studies and carcinogenicity studies were not conducted with CASGEVY. These studies are not warranted based on the characteristics and safety profile of the product.”
Same question, other gene therapies
Kebilidi
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Otarmeni
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Strimvelis
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Zolgensma
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Beqvez
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Imlygic
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Itvisma
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Kresladi
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Lenmeldy
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Luxturna
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Lyfgenia
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Papzimeos
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Skysona
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Tudriqev
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Vyjuvek
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Waskyra
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Zevaskyn
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Zynteglo
betibeglogene autotemcel · HBB T87Q (LVV, ex vivo HSC)Not stated in public reviews