Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)Neutralizing anti-adenovirus and anti-IFNa2b antibodies in most high-dose monkeys, persisting through observation period
Beqvez: which risks did reviewers probe?
fidanacogene elaparvovec · Factor IX
Immune & cytokine safety
Anti-hFIX and anti-capsid antibodies in most NHPs, rising over time, correlated with declining hFIX
“The levels of both anti-hFIX and anti-AAV antibodies increased with time, which correlated with a decline in plasma hFIX protein levels.”
Biodistribution & persistence
Vector in all NHP tissues incl. brain/testes; highest liver, spleen, lymph nodes; liver to day 542; rabbit semen to 4 months
“The highest vector DNA concentrations were detected in the liver, spleen, and inguinal lymph nodes.”
Modality-specific risk
AAV vector integration/hepatic oncogenicity; <0.1% integrated, no clonal expansion; thrombosis; germline transmission
“In a 2-year vector integration study in NHPs administered 5 × 1012 vg/kg, there was no indication that integration of vector DNA into host cell DNA resulted in altered liver function, hepatocellular hyperplasia or carcinoma.”
Anti-drug antibodies: animals
NHP: anti-hFIX and anti-AAV capsid antibodies in most animals, rising over time and correlating with declining hFIX levels
“Antibodies that targeted the hFIX protein and the AAV capsid were detected in most dosed animals. The levels of both anti-hFIX and anti-AAV antibodies increased with time, which correlated with a decline in plasma hFIX protein levels.”
Anti-drug antibodies: patients
Sustained neutralizing anti-AAVRh74var antibody increase in all assessed subjects; no FIX inhibitors
“No patients developed FIX inhibitors during the clinical studies using BEQVEZ. A sustained increase in neutralizing anti-AAVRh74var antibodies has been observed after administration of BEQVEZ in all subjects who participated in clinical studies and had neutralizing antibody (nAb) assessment.”
Same question, other gene therapies
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-dystrophinAnti-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 IXAnti-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%
Kebilidi
eladocagene exuparvovec · AADCDose-dependent anti-AAV2 capsid ADA in rats; no effect on biodistribution or expression; anti-AADC not assessed
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 · RPE65Anti-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 VIIIAnti-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 · SMN1Systemic 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