Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)Monkey-to-human local exposure multiple (dose-based) 3.11x for nadofaragene firadenovec, 1.87x for Syn3
Zolgensma: what safety margin did regulators accept?
onasemnogene abeparvovec · SMN1
Safety margin at NOAEL
No NOAEL in mice; liver/heart lesions at 0.7- to 1.4-fold the clinical dose, mortality at 2-3 times the clinical dose
“occurrence of tissue lesions (primarily liver and ventricle) already found in doses 0.7- to 1.4-fold the clinical dose and the striking mortality in mice at doses 2-3 the clinical dose required discussion.”
NOAEL / key findings
NOAEL not identified (mouse); MTD 1.5x10^14 vg/kg; heart (atrial thrombosis, myocarditis) and liver toxicity; mortality >=2.4x10^14
“Based on the lack of similar cardiovascular toxicities resulting in Zolgensma-related mortality, the low dose of 1.5 x 1014 vg/kg was defined as the maximum tolerated dose (MTD).”
Same question, other gene therapies
Beqvez
fidanacogene elaparvovec · Factor IXNHP: no adverse findings at doses 2- to 10-fold the recommended clinical dose
Casgevy
exagamglogene autotemcel · BCL11A enhancer (CRISPR-Cas9, ex vivo HSC)NSG mouse toxicity dose gave only a 1.6-fold margin over the maximum human cell dose
Glybera
alipogene tiparvovec · LPL (AAV1)No margin: dose-related muscle toxicity at the recommended clinical dose (mouse)
Hemgenix
etranacogene dezaparvovec · Factor IXNHP no-adverse-effect dose (9x1013 gc/kg) is 4.5-fold the recommended human dose
Imlygic
talimogene laherparepvec · GM-CSF (oncolytic HSV-1)Mouse repeat-dose SC NOAEL ~70x the recommended maximum dose (PFU/kg basis)
Itvisma
onasemnogene abeparvovec (intrathecal) · SMN1 (AAV9, intrathecal)No margin: NHP neural toxicity findings precluded determination of a NOAEL
Kebilidi
eladocagene exuparvovec · AADCRat highest dose (NOAEL) gives a safety margin of 21 over the clinical dose, scaled by brain weight
Luxturna
voretigene neparvovec · RPE65NHP NOAEL (vg/eye) is 5-fold the proposed clinical dose
Otarmeni
lunsotogene parvec · OTOF (AAV, intracochlear)NOAEL concentrations ~2.2x (mouse) and ~2.4x (monkey) the clinical dose concentration (vg/mL)
Papzimeos
zopapogene imadenovec · HPV6/11 antigens (gorilla adenovirus)Mouse repeat-dose level without findings gives ~5-fold safety factor over the clinical dose
Skysona
elivaldogene autotemcel · ABCD1 (LVV, ex vivo HSC)Maximum feasible mouse dose (cells/kg) ~10-fold the minimum recommended human dose; NOAEL not determined
Strimvelis
autologous CD34+ cells transduced with ADA (no INN) · ADA (gamma-retroviral, ex vivo HSC)Mouse dose without test-item-related effects only about half the highest human dose (cells/kg)
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
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
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