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
Lyfgenia: what was done before first-in-human, and what came after?
lovotibeglogene 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 Lyfgenia 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: Applicant designated single tested dose (11x10^6 cells/kg) NOAEL; no test article-related deaths or adverse findings through 6 months; lymphomas background (FDA pharmacology/toxicology review, p. 3)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study; single-transplant mouse studies, longest followed 6 months post-transplant (secondary transplantation)
“In the secondary transplantation study, no deaths or adverse findings attributed to the BB305 LVV-transduced cells occurred through 6 months post-transplantation of 6×106 cells/mouse.”
Pivotal GLP studies
Non-GLP single-dose IV studies: primary transplant in beta-thal mice (4 months) and secondary transplant in C57BL/6 mice (6 months)
“In vivo studies were also conducted to assess the activity and safety of mBMCs transduced with BB305 following primary and secondary transplantation in β-thalassemic and wild-type C57BL/6 mice.”
DART package
Species: DART
Not conducted (no adverse findings in mouse reproductive tissues)
“Per the applicant, developmental and reproductive toxicology studies were not conducted because there were no adverse findings in the male and female reproductive tissues of mice administered mBMCs transduced with BB305 LVV”
Reproductive & developmental
Not conducted (no reproductive tissue findings in mouse studies; busulfan risk addressed in label)
“Per the applicant, developmental and reproductive toxicology studies were not conducted because there were no adverse findings in the male and female reproductive tissues of mice administered mBMCs transduced with BB305 LVV”
PPND / ePPND: when
Not conducted; not warranted given product characteristics and safety profile
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with LYFGENIA™. These studies are not warranted based on the product characteristics and safety profile.”
Carcinogenicity
Species: carcinogenicity
Not conducted (acceptable based on product type)
“No traditional carcinogenicity studies were conducted with lovo-cel which is acceptable based on the product type.”
Carcinogenicity model
No carcinogenicity study; secondary-transplant mouse study: T-cell lymphoma/leukemia within radiation-associated background (15.7-25.3%), considered incidental
“The observed incidence of T-cell lymphoma and/or leukemia was within the reported range (15.7-25.3%) for radiation-associated lymphoma in C57BL/6 mice (E. Will et al. (2007) Mol Ther 15:782-91) and was considered incidental.”
Carcinogenicity timing
Not required (not warranted given product characteristics and safety profile)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with LYFGENIA™. These studies are not warranted based on the product characteristics and safety profile.”
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