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
Tudriqev: what was done before first-in-human, and what came after?
vusolimogene oderparepvec · GALV-GP + GM-CSF (oncolytic HSV-1)
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 Tudriqev 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: NOAEL = highest dose tested of mRP1 in rats, 1x10^7 PFU/animal/injection; no adverse findings (FDA summary basis for approval, p. 13)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Rat repeat-dose mRP1 study (16 doses every 3 days for 7 weeks) with follow-up up to 6 months after final dose
“In a follow-up study, 16 doses (every 3 days for 7 weeks) of mRP1 were administered to healthy rats. mRP1 DNA was not detected in any neurologic tissues and there was no evidence of viral reactivation at any time point up to 6 months post-final dosing, indicating minimal risk of latency and reactivation of mRP1.”
Pivotal GLP studies
Single and repeat-dose mRP1 studies in healthy rats (16 doses, 6-month follow-up); repeat IT TUDRIQEV in tumor-bearing mice (5 doses)
“Toxicology studies evaluating TUDRIQEV and mRP1 were conducted in tumor-bearing immunocompetent mice and healthy rats, respectively.”
DART package
Species: DART
Pregnant rat (repeat IV mRP1, GD 4 to 16, embryofetal)
“Developmental and reproductive toxicology studies were conducted in pregnant rats following repeat IV administrations of between 9x104 - 1x106 PFU mRP1/animal/injection over gestation days (GD) 4 to 16 corresponding to early- and mid-organogenesis.”
Reproductive & developmental
Embryofetal study in pregnant rats (mRP1 IV, GD 4-16): no malformations or growth effects; minimal placental transfer
“no embryofetal structural abnormalities or adverse effects on embryofetal growth were observed following repeat IV mRP1 administration.”
PPND / ePPND: when
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.
Carcinogenicity
Species: carcinogenicity
Not conducted (not warranted based on product characteristics and safety profile)
“Studies to evaluate the safety pharmacology, genotoxicity, and carcinogenicity of TUDRIQEV were not conducted. These studies are not warranted based on the product characteristics and safety profile.”
Carcinogenicity model
Not conducted (not warranted based on product characteristics and safety profile)
“Studies to evaluate the safety pharmacology, genotoxicity, and carcinogenicity of TUDRIQEV were not conducted. These studies are not warranted based on the product characteristics and safety profile.”
Carcinogenicity timing
Not required (not warranted based on product characteristics and safety profile)
“Studies to evaluate the safety pharmacology, genotoxicity, and carcinogenicity of TUDRIQEV were not conducted. These studies are not warranted based on the product characteristics and safety profile.”
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