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Atlas/Gene therapy/Luxturna/First dose

Luxturna: how was the first human dose set?

voretigene neparvovec · RPE65
Check my plan vs. these
First-in-human starting dose
FIH start dose basis not stated; clinical dose chosen over broad efficacious range using safety data (NHP NOAEL 5x clinical dose)
“Because the pharmacology data indicated that efficacy could be achieved over a broad dose range, the determination of the optimal therapeutic dose also relied on safety data.”
✓ VerifiedEMA assessment report, p. 21Source ↗
NOAEL / key findings
NHP NOAEL 7.5e11 vg/eye (5x clinical); ocular inflammation/retinal degeneration in dogs at 1.5e12 vg/eye; no systemic toxicity
“The no-observed-adverse-effect-level (NOAEL) in NHPs was 7.5 x 1011vg/eye, which is 5-fold higher than the proposed clinical dose level”
✓ VerifiedFDA pharmacology/toxicology review, p. 2Source ↗

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%)

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

Adstiladrin

nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)
Not stated in public reviews

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 →