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Atlas/Gene therapy/Kebilidi/Risks

Kebilidi: which risks did reviewers probe?

eladocagene exuparvovec · AADC
Check my plan vs. these
Immune & cytokine safety
Dose-dependent anti-AAV2 capsid ADA in rats; no effect on biodistribution or expression; anti-AADC not assessed
“The formation of anti-drug antibodies against the AAV2 vector capsid was dose dependent with the highest incidence observed in Group 4 high-dose animals at Days 30 and 180.”
✓ VerifiedEMA assessment report, p. 40Source ↗
Biodistribution & persistence
Mostly CNS, highest in putamen; vector persists to D180 with decline; no blood/CSF shedding in rat
“Persistence of vector DNA was most notable in the putamen, cerebrum, cerebellum, and spinal cord at all time points, with the highest levels in the putamen.”
✓ VerifiedFDA summary basis for approval, p. 11Source ↗
Modality-specific risk
Off-target spread/ectopic dopamine-serotonin expression, poloxamer 188 brain safety, insertional mutagenesis
“That being said, one cannot dismiss the possibility that the transgene will spread to adjacent brain regions (e.g. globus pallidus, caudate, amygdala) at least in some individuals.”
✓ VerifiedEMA assessment report, p. 37Source ↗

Same question, other gene therapies

Adstiladrin

nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)
Neutralizing anti-adenovirus and anti-IFNa2b antibodies in most high-dose monkeys, persisting through observation period

Beqvez

fidanacogene elaparvovec · Factor IX
Anti-hFIX and anti-capsid antibodies in most NHPs, rising over time, correlated with declining hFIX

Casgevy

exagamglogene autotemcel · BCL11A enhancer (CRISPR-Cas9, ex vivo HSC)
In vitro innate immune (type I IFN) assay showed no activation, but FDA deemed it uninterpretable (positive control failed)

Elevidys

delandistrogene moxeparvovec · Micro-dystrophin
Anti-AAV antibodies in mice; NHP: capsid/transgene T-cell responses, liver enzymes, anaphylaxis on redosing with rituximab/sirolimus

Fayuvi

rebisufligene etisparvovec · SGSH (AAV9)
Immunogenicity greater against AAV9 capsid than hSGSH transgene, proportional to dose

Genglycos

pariglasgene brecaparvovec · G6PC (AAV8)
Anti-AAV8 nAbs in all dosed mice and NHPs; AAV8 T-cell responses in mice; sporadic cytokine elevations; juvenile immune stimulation

Glybera

alipogene tiparvovec · LPL (AAV1)
Neutralising anti-AAV1 capsid antibodies blocked readministration; no CD8+ T cells in infiltrates; no anti-LPL antibodies

Hemgenix

etranacogene dezaparvovec · Factor IX
Anti-AAV5 capsid IgG persisting 6 months; anti-hFIX antibodies in 5/12 NHPs reducing FIX levels

Imlygic

talimogene laherparepvec · GM-CSF (oncolytic HSV-1)
Lethal disseminated HSV infection in immunodeficient mice (up to 20% nude, 100% SCID); immunocompetent mice tolerated doses

Itvisma

onasemnogene abeparvovec (intrathecal) · SMN1 (AAV9, intrathecal)
Mononuclear cell inflammation in NHP neural tissue; clinically all patients developed high anti-AAV9 titers, anti-SMN in ~7%

Lenmeldy

atidarsagene autotemcel · ARSA (LVV, ex vivo HSC)
No anti-ARSA antibodies or adverse neurobehavioral effects in mice; anti-ARSA antibodies in 15% of patients clinically

Luxturna

voretigene neparvovec · RPE65
Anti-AAV2 capsid antibodies (dogs, pre-exposed NHPs); minimal T-cell responses; mild ocular inflammation on re-administration

Otarmeni

lunsotogene parvec · OTOF (AAV, intracochlear)
All monkeys anti-AAV1 NAb positive by week 27, no anti-otoferlin antibodies; NAbs not associated with safety signal; minimal cochlear infiltrates

Papzimeos

zopapogene imadenovec · HPV6/11 antigens (gorilla adenovirus)
Intended HPV-specific CD8+ T-cell IFN-gamma/TNF-alpha responses; in silico screen shows low off-target human protein reactivity

Roctavian

valoctocogene roxaparvovec · Factor VIII
Anti-AAV5 antibodies in all species; anti-hFVIII antibodies cross-reacting with murine FVIII caused bleeding phenotype (species-specific)

Tudriqev

vusolimogene oderparepvec · GALV-GP + GM-CSF (oncolytic HSV-1)
No test-article-related adverse findings in tumor-bearing mice; RNAseq showed immune infiltration/inflammation genes in injected tumors

Vyjuvek

beremagene geperpavec · COL7A1 (HSV-1, topical)
Minimal to slight lymphoid hyperplasia in spleen and lymph nodes consistent with inflammatory response to vector

Waskyra

etuvetidigene autotemcel · WAS (LVV, ex vivo HSC)
No dedicated immunotox studies; no anti-WASP antibodies in 27 treated patients

Zevaskyn

prademagene zamikeracel · COL7A1 (RV-modified keratinocyte sheets)
Clinical only: transient anti-Col7 antibodies in 2/7 Phase 1/2a subjects; no systemic immune responses in Phase 3

Zolgensma

onasemnogene abeparvovec · SMN1
Systemic inflammatory response in mice; capsid/transgene immunity proposed for atrial thrombosis; NHP antibodies to vector and transgene

Zynteglo

betibeglogene autotemcel · HBB T87Q (LVV, ex vivo HSC)
No immunotoxicity studies; immunogenicity of beta-A-T87Q-globin not anticipated; patients immunosuppressed by busulfan

Kresladi

marnetegragene autotemcel · ITGB2 (LVV, ex vivo HSC)
Not stated in public reviews

Lyfgenia

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

Skysona

elivaldogene autotemcel · ABCD1 (LVV, ex vivo HSC)
Not stated in public reviews

Strimvelis

autologous CD34+ cells transduced with ADA (no INN) · ADA (gamma-retroviral, ex vivo HSC)
Not stated in public reviews

Summary across all 26 gene therapies →