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
Lenmeldy: what was done before first-in-human, and what came after?
atidarsagene autotemcel · ARSA (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 Lenmeldy 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 formal NOAEL; no test-article toxicity or malignancy at 1x10^6 cells/mouse (40-50x10^6 cells/kg); findings from As2-/- phenotype and irradiation (FDA pharmacology/toxicology review, p. 2)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (single administration); single-dose toxicity assessed within long-term toxicity studies
“No single dose and repeat dose toxicity studies were performed. Single dose toxicity was taken along in the long-term toxicity studies.”
Pivotal GLP studies
GLP toxicology/tumorigenicity study, As2-/- mice, single IV ARSA-LV or mock HSPCs, 52 weeks post-dose
“Toxicology and tumorigenicity study in ARSA KO mice treated with ARSA-/- HSPCs transduced with ARSA.LV Vector”
DART package
Species: DART
Not conducted (ex vivo transduction with replication-incompetent LV; germline risk very limited)
“No dedicated reproductive and developmental studies are undertaken. As the cells are transduced ex vivo with a replication-incompetent lentiviral vector, the risk for transduction of the gametes and consequently the risk from germline transduction can be regarded as very limited and rather theoretical.”
Reproductive & developmental
Not conducted (ex vivo transduction; germline transduction risk very limited)
“No dedicated reproductive and developmental studies are undertaken.”
PPND / ePPND: when
Not conducted; not warranted given product characteristics and safety profile
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with OTL-200. These studies are not warranted based on the product characteristics and safety profile.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not warranted given product characteristics and safety profile)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with OTL-200. These studies are not warranted based on the product characteristics and safety profile.”
Carcinogenicity model
No carcinogenicity study; 12-month GLP tumorigenicity study in As2-/- mice: 2 hepatocellular neoplasms (1 ARSA-LV, 1 mock-LV)
“During the observation period of 12 months after transplantation, only 2 hepatocellular neoplasms were found (1 in ARSA-LV group, 1 in mock-LV group).”
Carcinogenicity timing
Not required (not warranted given product characteristics and safety profile)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with OTL-200. These studies are not warranted based on the product characteristics and safety profile.”
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