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
Beqvez: what was done before first-in-human, and what came after?
fidanacogene elaparvovec · Factor IX
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 Beqvez 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: NHP 1-5x10^12 vg/kg (2-10x clinical): no adverse findings, no thrombosis; mouse deaths linked to brain/skin findings (FDA pharmacology/toxicology review, p. 2)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (single administration)
“Repeat-dose toxicity studies were not performed because fidanacogene elaparvovec is intended for single administration to patients.”
Pivotal GLP studies
GLP single IV NHP study (30/90-day recovery, to day 542); 12-month mouse study; GLP 2-year NHP integration study
“A GLP Toxicity Study of -hFIX-Padua by Intravenous Infusion in Monkeys with a 30- or 90- day Recovery Period”
DART package
Species: DART
Not conducted (hemophilia B almost exclusively male; not intended for women)
“Per applicant, hemophilia B is almost exclusively limited to male subjects, and BEQVEZ is not intended for administration in women.”
Reproductive & developmental
Not conducted (male-only population); rabbit semen shedding/germline study only
“This reviewer agrees that the omission of dedicated embryo-fetal development studies and pre- and postnatal development studies is acceptable.”
PPND / ePPND: when
Not conducted: hemophilia B population almost exclusively male; not intended for women
“Per applicant, hemophilia B is almost exclusively limited to male subjects, and BEQVEZ is not intended for administration in women. This reviewer agrees that the omission of dedicated embryo-fetal development studies and pre- and postnatal development studies is acceptable.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not warranted given product characteristics, BD/toxicology results, patient population)
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, and carcinogenicity/tumorigenicity of BEQVEZ were not conducted. These studies are not warranted based on the product characteristics, results from the biodistribution and toxicology studies, and patient population.”
Carcinogenicity model
Not conducted; 2-year NHP vector integration study showed no hepatocellular hyperplasia or carcinoma
“In a 2-year vector integration study in NHPs administered 5 × 1012 vg/kg, there was no indication that integration of vector DNA into host cell DNA resulted in altered liver function, hepatocellular hyperplasia or carcinoma.”
Carcinogenicity timing
Not conducted: not warranted (product characteristics, biodistribution and toxicology results)
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, and carcinogenicity/tumorigenicity of BEQVEZ were not conducted. These studies are not warranted based on the product characteristics, results from the biodistribution and toxicology studies”
Same question, other gene therapies
Kebilidi
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Otarmeni
lunsotogene parvec · OTOF (AAV, intracochlear)United States and unnamed ex-US sites: DB-OTO-001 (7 US, 4 ex-US sites), the only clinical study
Roctavian
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Strimvelis
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Zolgensma
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Casgevy
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Elevidys
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Fayuvi
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Genglycos
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Hemgenix
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Imlygic
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Itvisma
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Kresladi
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Lenmeldy
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Luxturna
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Lyfgenia
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Papzimeos
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Skysona
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Tudriqev
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Vyjuvek
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Waskyra
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Zevaskyn
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Zynteglo
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