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Atlas/Gene therapy/Kebilidi/Safety margin

Kebilidi: what safety margin did regulators accept?

eladocagene exuparvovec · AADC
Check my plan vs. these
Safety margin at NOAEL
Rat highest dose (NOAEL) gives a safety margin of 21 over the clinical dose, scaled by brain weight
“Based on the study results, the highest dose administered (7.5×109 vg) in the study provides a safety margin of 21 over the human dose used in clinical studies, as calculated by the applicant.”
✓ VerifiedEMA assessment report, p. 40Source ↗
NOAEL / key findings
Rat NOAEL 7.5x10^9 vg (highest dose; ~21x margin by brain weight); no significant adverse findings
“Since there were no toxicologically significant findings at the high dose, the no observed adverse effect level (NOAEL) was set at the high dose (7.5x109 vg).”
✓ VerifiedEMA assessment report, p. 36Source ↗

Same question, other gene therapies

Adstiladrin

nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)
Monkey-to-human local exposure multiple (dose-based) 3.11x for nadofaragene firadenovec, 1.87x for Syn3

Beqvez

fidanacogene elaparvovec · Factor IX
NHP: 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 IX
NHP 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

Luxturna

voretigene neparvovec · RPE65
NHP 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)

Zolgensma

onasemnogene abeparvovec · SMN1
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

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

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

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 →