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Precedia/Gene therapy/Adstiladrin/First dose

Adstiladrin: how was the first human dose set?

nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)
Check my plan vs. these
First-in-human starting dose
Not stated in public reviews
Why it's blank

The public FDA and EMA reviews of Adstiladrin 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: Local NOAEL not set (urinary tract changes at all doses, reversible); highest non-severely toxic dose 1.25e13 vp rAd-IFN with 25 mg Syn3; bladder/ureter/urethra inflammation (EMA assessment report, p. 37)

Full method, every step sourced →

NOAEL / key findings
Local NOAEL not set (urinary tract changes at all doses, reversible); highest non-severely toxic dose 1.25e13 vp rAd-IFN with 25 mg Syn3; bladder/ureter/urethra inflammation
“25 mg Syn3NODA and 1.25x1013 vp rAd-IFN could be considered the highest non-severely toxic dose.”
✓ VerifiedEMA assessment report, p. 37Source ↗

Same question, other gene therapies

Glybera

alipogene tiparvovec · LPL (AAV1)
Not explicitly justified; clinical 1x10^12 gc/kg lies within active range in LPL-/- mice (10^11-10^13); tox covered 10x

Itvisma

onasemnogene abeparvovec (intrathecal) · SMN1 (AAV9, intrathecal)
NHP-tolerated 1.2x10^13 vg/animal scaled 10-fold by CSF volume to human starting dose 1.2x10^14 vg/patient

Kebilidi

eladocagene exuparvovec · AADC
Prior adult PD rAAV2-hAADC clinical doses (up to 3x10^11 vg) scaled by brain mass; 1.8x10^11 vg (~60%)

Luxturna

voretigene neparvovec · RPE65
FIH start dose basis not stated; clinical dose chosen over broad efficacious range using safety data (NHP NOAEL 5x clinical dose)

Otarmeni

lunsotogene parvec · OTOF (AAV, intracochlear)
PD Emax modeling of mouse ABR data: plateau >2e13 vg/mL; clinical 3e13 vg/mL (1.5x), concentration-scaled NOAEL margins 2.2-2.4x

Papzimeos

zopapogene imadenovec · HPV6/11 antigens (gorilla adenovirus)
Not explicitly stated; mouse repeat-dose 1x10^10 VP gives ~5-fold safety factor over clinical 5x10^11 PU dose

Strimvelis

autologous CD34+ cells transduced with ADA (no INN) · ADA (gamma-retroviral, ex vivo HSC)
No nonclinical dose justification stated; first (investigator-initiated) protocol based on nonclinically optimised transduction conditions

Zolgensma

onasemnogene abeparvovec · SMN1
Mouse efficacy: doses doubling (7.4e13) and fully restoring (1.2e14 vg/kg) SMNdelta7 lifespan; MTD 1.5e14 set retrospectively

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

Fayuvi

rebisufligene etisparvovec · SGSH (AAV9)
Not stated in public reviews

Genglycos

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

Hemgenix

etranacogene dezaparvovec · Factor IX
Not stated for FIH; later clinical dosing informed by predecessor AMT-060 clinical data

Imlygic

talimogene laherparepvec · GM-CSF (oncolytic HSV-1)
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

Lyfgenia

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

Roctavian

valoctocogene roxaparvovec · Factor VIII
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 →