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
Waskyra: what was done before first-in-human, and what came after?
etuvetidigene autotemcel · WAS (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 Waskyra 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; no increased mortality, tumorigenicity or toxicity related to transduced HSPCs; lymphomas were of host origin (EMA assessment report, p. 35)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (single administration with engraftment)
“No repeat-dose toxicity studies have been presented by the applicant, which is acceptable considering that the product is intended to be administered to patients as a single administration, with subsequent engraftment into the patient.”
Pivotal GLP studies
No standalone GLP pivotal tox study; two non-pivotal WKO mouse studies (sublethal/lethal irradiation) plus serial transplant, 12-16 months
“No standalone, GLP in vivo pivotal toxicology study has been performed.”
DART package
Species: DART
Not conducted (patient population, nature of gene therapy, conditioning with developmental toxicants)
“The absence of standard developmental and reproductive toxicity studies with Telethon003 is acceptable in view of the patient population, nature of the gene therapy, and preconditioning regimen with developmental toxicants.”
Reproductive & developmental
Not conducted; no vector in testes, no treatment-related effect on reproductive organs in mouse surrogate study
“No carcinogenicity, developmental and reproductive toxicology (DART) studies, and safety pharmacology studies were conducted for WASKYRA.”
PPND / ePPND: when
Not conducted: DART not warranted based on product characteristics and safety profile
“No carcinogenicity, developmental and reproductive toxicology (DART) studies, and safety pharmacology studies were conducted for WASKYRA. These studies are not warranted based on the drug product characteristics and safety profile.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not suitable for this product type)
“Traditional carcinogenicity studies were not conducted since they are not suitable for assessment of this drug product type.”
Carcinogenicity model
Not conducted; tumorigenicity assessed by IVIM assay and in vivo integration site analysis, no evidence of tumorigenicity
“Traditional carcinogenicity studies were not conducted since they are not suitable for assessment of this drug product type. The nonclinical data provided by the applicant showed no evidence of tumorigenicity using the in vitro immortalization (IVIM) assay (U Modlich, 2009)”
Carcinogenicity timing
Not required (not warranted for this product)
“No carcinogenicity, developmental and reproductive toxicology (DART) studies, and safety pharmacology studies were conducted for WASKYRA. These studies are not warranted based on the drug product characteristics and safety profile.”
Same question, other gene therapies
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Lenmeldy
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Zynteglo
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