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
Otarmeni: how was the first human dose set?
lunsotogene parvec · OTOF (AAV, intracochlear)
First-in-human starting dose
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
“The selection of the proposed clinical dose concentration of 3 x 1013 vg/mL is supported by the pharmacodynamic modeling (OTOF-10116) of ABR improvements in the Otof-Q828X hom mouse model as well as the safety profile established in the GLP toxicology studies.”
NOAEL / key findings
NOAEL = highest dose (1.3e11 vg/ear mouse; 4.4e12 vg/ear monkey); adverse findings procedure-related (facial paralysis, cochlear damage)
“The 6-month GLP study in monkeys at dose levels up to 4.4 × 1012 vg/ear demonstrated no DB-OTO-related toxicity, with a NOAEL of 4.4 × 1012 vg/ear.”
Same question, other gene therapies
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 · AADCPrior adult PD rAAV2-hAADC clinical doses (up to 3x10^11 vg) scaled by brain mass; 1.8x10^11 vg (~60%)
Luxturna
voretigene neparvovec · RPE65FIH start dose basis not stated; clinical dose chosen over broad efficacious range using safety data (NHP NOAEL 5x clinical dose)
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 · SMN1Mouse 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 IXNot stated in public reviews
Casgevy
exagamglogene autotemcel · BCL11A enhancer (CRISPR-Cas9, ex vivo HSC)Not stated in public reviews
Elevidys
delandistrogene moxeparvovec · Micro-dystrophinNot 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 IXNot 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 VIIINot 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