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Precedia/Gene therapy/Fayuvi/Tox package

Fayuvi: what was done before first-in-human, and what came after?

rebisufligene etisparvovec · SGSH (AAV9)
Check my plan vs. these

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 Fayuvi 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 5.0x10^13 vg/kg (6-month) and 2.0x10^14 vg/kg (3-month); non-adverse, reversible clinpath/histopath findings (FDA summary basis for approval, p. 11)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery
No repeat-dose study (single administration); longest is 6-month GLP single IV mouse study
“No adverse vector-related findings were observed in the 6-month Good Laboratory Practice (GLP) safety and BD study, which investigated the effect of a single intravenous administration”
✓ VerifiedFDA summary basis for approval, p. 11Source ↗
Pivotal GLP studies
6-month GLP single IV study (5e12-5e13 vg/kg) and 3-month GLP single IV study (5e13-2e14 vg/kg) in WT C57BL/6 mice
“The definitive 3-month GLP safety and BD study investigated the effect of a single IV administration of 5.0x1013 to 2.0x1014 vg/kg FAYUVI in WT C57BL/6 mice.”
✓ VerifiedFDA summary basis for approval, p. 11Source ↗

DART package

Species: DART
Not conducted; addressed by weight-of-evidence risk assessment
“Developmental and reproductive toxicity (DART), genotoxicity, and carcinogenicity/tumorigenicity studies were not conducted with FAYUVI.”
✓ VerifiedFDA summary basis for approval, p. 11Source ↗
Reproductive & developmental
Not conducted; weight-of-evidence risk assessment used
“Developmental and reproductive toxicity (DART), genotoxicity, and carcinogenicity/tumorigenicity studies were not conducted with FAYUVI.”
✓ VerifiedFDA summary basis for approval, p. 11Source ↗
PPND / ePPND: when
Not conducted: DART replaced by weight-of-evidence approach
“Developmental and reproductive toxicity (DART), genotoxicity, and carcinogenicity/tumorigenicity studies were not conducted with FAYUVI. To address these concerns, the Applicant used a weight-of-evidence approach”
✓ VerifiedFDA summary basis for approval, p. 11Source ↗

Carcinogenicity

Species: carcinogenicity
Not conducted; addressed by weight-of-evidence risk assessment
“Developmental and reproductive toxicity (DART), genotoxicity, and carcinogenicity/tumorigenicity studies were not conducted with FAYUVI.”
✓ VerifiedFDA summary basis for approval, p. 11Source ↗
Carcinogenicity model
Not conducted; weight-of-evidence risk assessment instead
“To address these concerns, the Applicant used a weight-of-evidence approach”
✓ VerifiedFDA summary basis for approval, p. 11Source ↗
Carcinogenicity timing
Not conducted: carcinogenicity/tumorigenicity addressed by weight-of-evidence approach
“Developmental and reproductive toxicity (DART), genotoxicity, and carcinogenicity/tumorigenicity studies were not conducted with FAYUVI. To address these concerns, the Applicant used a weight-of-evidence approach”
✓ VerifiedFDA summary basis for approval, p. 11Source ↗

Same question, other gene therapies

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

Kebilidi

eladocagene exuparvovec · AADC
Country not stated; the vector (rAAV2-hAADC) was first tested in humans in Parkinson's disease patients by bilateral intraputaminal dosing

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

valoctocogene roxaparvovec · Factor VIII
Country not stated; first-in-human dose-escalation study 270-201 in patients with severe hemophilia A

Strimvelis

autologous CD34+ cells transduced with ADA (no INN) · ADA (gamma-retroviral, ex vivo HSC)
Israel: first administered in 2000 to one ADA-SCID patient at Hadassah University, Jerusalem (pilot study)

Zolgensma

onasemnogene abeparvovec · SMN1
United States: single-site trial in 15 infants with SMA

Beqvez

fidanacogene elaparvovec · Factor IX
Not stated in public reviews

Casgevy

exagamglogene autotemcel · BCL11A enhancer (CRISPR-Cas9, ex vivo HSC)
Not stated in public reviews

Elevidys

delandistrogene moxeparvovec · Micro-dystrophin
Not stated in public reviews

Genglycos

pariglasgene brecaparvovec · G6PC (AAV8)
Not stated in public reviews

Glybera

alipogene tiparvovec · LPL (AAV1)
Not stated in public reviews

Hemgenix

etranacogene dezaparvovec · Factor IX
Not stated in public reviews

Imlygic

talimogene laherparepvec · GM-CSF (oncolytic HSV-1)
Not stated in public reviews

Itvisma

onasemnogene abeparvovec (intrathecal) · SMN1 (AAV9, intrathecal)
Not stated in public reviews

Kresladi

marnetegragene autotemcel · ITGB2 (LVV, ex vivo HSC)
Not stated in public reviews

Lenmeldy

atidarsagene autotemcel · ARSA (LVV, ex vivo HSC)
Not stated in public reviews

Luxturna

voretigene neparvovec · RPE65
Not stated in public reviews

Lyfgenia

lovotibeglogene autotemcel · HBB T87Q (LVV, ex vivo HSC)
Not stated in public reviews

Papzimeos

zopapogene imadenovec · HPV6/11 antigens (gorilla adenovirus)
Not stated in public reviews

Skysona

elivaldogene autotemcel · ABCD1 (LVV, ex vivo HSC)
Not stated in public reviews

Tudriqev

vusolimogene oderparepvec · GALV-GP + GM-CSF (oncolytic HSV-1)
Not stated in public reviews

Vyjuvek

beremagene geperpavec · COL7A1 (HSV-1, topical)
Not stated in public reviews

Waskyra

etuvetidigene autotemcel · WAS (LVV, ex vivo HSC)
Not stated in public reviews

Zevaskyn

prademagene zamikeracel · COL7A1 (RV-modified keratinocyte sheets)
Not stated in public reviews

Zynteglo

betibeglogene autotemcel · HBB T87Q (LVV, ex vivo HSC)
Not stated in public reviews

Summary across all 26 gene therapies →