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
Zynteglo: what was done before first-in-human, and what came after?
betibeglogene autotemcel · HBB T87Q (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 Zynteglo 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: No NOAEL defined; no test-article-related mortality or adverse effects at 42x10^6 cells/kg; lymphomas judged incidental (radiation/strain background) (FDA pharmacology/toxicology review, p. 12)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (single administration)
“No repeated dose toxicity studies were performed as the treatment foresees only one unique injection”
Pivotal GLP studies
Combined pivotal POC/biodistribution/single-dose tox/genotox studies in thalassaemic mice (primary and secondary transplant), NSG mice; single IV dose after busulfan
“These in vivo studies (NC-11-002, NC-12-019, B2-15-161 and B2-16-200) were pivotal and combined pharmacology, biodistribution, single-dose toxicity and genotoxicity studies”
DART package
Species: DART
Not conducted (not warranted based on product characteristics and safety profile)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with beti-cel. These studies are not warranted based on the product characteristics and safety profile.”
Reproductive & developmental
Not conducted; no adverse findings in reproductive tissues of mice given murine product
“No developmental and/or reproductive toxicity (DART) studies were submitted to support the use of Zynteglo for the treatment of TDT.”
PPND / ePPND: when
Not conducted: DART not warranted based on product characteristics and safety profile
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with beti-cel. These studies are not warranted based on the product characteristics and safety profile.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not warranted based on product characteristics and safety profile)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with beti-cel. These studies are not warranted based on the product characteristics and safety profile.”
Carcinogenicity model
Not conducted; no tumorigenicity or insertional oncogenesis in studies with transduced β-thalassaemic mouse BMCs or human HSCs
“No tumorigenicity and no evidence of an oncogenesis event related to insertional mutagenesis were observed in the nonclinical studies using BB305 LVV-transduced β-thalassaemic mouse BMCs or human healthy donor HSCs.”
Carcinogenicity timing
Not required (not warranted based on product characteristics and safety profile)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with beti-cel. These studies are not warranted based on the product characteristics and safety profile.”
Same question, other gene therapies
Kebilidi
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Otarmeni
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Roctavian
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Strimvelis
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Zolgensma
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Beqvez
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Casgevy
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Elevidys
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Fayuvi
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Genglycos
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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
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Kresladi
marnetegragene autotemcel · ITGB2 (LVV, ex vivo HSC)Not stated in public reviews
Lenmeldy
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Luxturna
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Lyfgenia
lovotibeglogene autotemcel · HBB T87Q (LVV, ex vivo HSC)Not stated in public reviews
Papzimeos
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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