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
Elevidys: what was done before first-in-human, and what came after?
delandistrogene moxeparvovec · Micro-dystrophin
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 Elevidys 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 4.01x10^14 vg/kg (WT, mdx, neonatal mice); 1.33x10^14 in mdx 12-wk study (hydrocephalus); non-adverse minimal liver findings (FDA pharmacology/toxicology review, p. 2)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose toxicity study (single administration); longest is single-dose IV mouse study with 24-week observation
“To evaluate the toxicity of SRP-9001 when administered as a single dose via IV injection to male mice; animals were observed for either 12 or 24 weeks”
Pivotal GLP studies
GLP single-dose IV mouse studies: 24-week (WT+mdx), 12-week (WT+mdx, Catalent lot), 13-week neonatal juvenile tox
“A 3-month GLP toxicology study (Report No. SR-20-015) evaluated single IV administration of ELEVIDYS (manufactured by Process B at Catalent) in neonatal C57BL/6J WT mice administered 1.33 × 1014 and 4.01 × 1014 vg/kg at post-natal day 1.”
DART package
Species: DART
Not conducted (patient population; no adverse findings in toxicology studies)
“Animal reproductive and developmental toxicity and carcinogenicity studies were not conducted with ELEVIDYS, which is acceptable based on the patient population and lack of ELEVIDYS-related adverse findings in the toxicology studies.”
Reproductive & developmental
Not conducted (male population, no reproductive lesions); neonatal juvenile tox done; low germline signal in testes
“Animal reproductive and developmental toxicity and carcinogenicity studies were not conducted with ELEVIDYS, which is acceptable based on the patient population and lack of ELEVIDYS-related adverse findings in the toxicology studies.”
PPND / ePPND: when
Not conducted: acceptable given patient population and no ELEVIDYS-related adverse toxicology findings
“Animal reproductive and developmental toxicity and carcinogenicity studies were not conducted with ELEVIDYS, which is acceptable based on the patient population and lack of ELEVIDYS-related adverse findings in the toxicology studies.”
Carcinogenicity
Species: carcinogenicity
Not conducted (patient population; no adverse findings in toxicology studies)
“Animal reproductive and developmental toxicity and carcinogenicity studies were not conducted with ELEVIDYS, which is acceptable based on the patient population and lack of ELEVIDYS-related adverse findings in the toxicology studies.”
Carcinogenicity model
Not conducted; applicant cited no cancer reported across 162 AAV clinical trials
“AAV of various serotypes including AAV2 and AAVrh74, have been studied in 162 clinical trials; thus far, no cancer of any type has been reported.”
Carcinogenicity timing
Not conducted: acceptable given patient population and no ELEVIDYS-related adverse toxicology findings
“Animal reproductive and developmental toxicity and carcinogenicity studies were not conducted with ELEVIDYS, which is acceptable based on the patient population and lack of ELEVIDYS-related adverse findings in the toxicology studies.”
Same question, other gene therapies
Kebilidi
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Otarmeni
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Strimvelis
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Zolgensma
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Beqvez
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Fayuvi
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Genglycos
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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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