Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)Neutralizing anti-adenovirus and anti-IFNa2b antibodies in most high-dose monkeys, persisting through observation period
Roctavian: which risks did reviewers probe?
valoctocogene roxaparvovec · Factor VIII
Immune & cytokine safety
Anti-AAV5 antibodies in all species; anti-hFVIII antibodies cross-reacting with murine FVIII caused bleeding phenotype (species-specific)
“These anti-hFVIII antibodies cross-reacted with the murine endogenous FVIII, leading to a loss of endogenous FVIII activity, a bleeding phenotype, and subsequent visceral lesions (in heart, lungs and epididymis) associated with haemorrhages.”
Biodistribution & persistence
Liver highest, then lung, heart, lymph nodes, kidney, spleen, marrow, testis, brain; mRNA mainly liver; NHP brain <1% of liver
“Following IV administration of 2.13 × 1014 vg/kg ROCTAVIAN, the highest vector DNA concentration was detected in the liver, followed by the lung, heart, lymph nodes, kidney, spleen, bone marrow, testis, and brain through 6 months post-administration.”
Modality-specific risk
Vector integration/insertional mutagenesis (CRL request; BMN307 mouse liver tumors), anti-transgene immunity, germline transmission
“The CRL also included a recommendation for the applicant to provide additional data to address the risks of vector integration and insertional mutagenesis.”
Same question, other gene therapies
Beqvez
fidanacogene elaparvovec · Factor IXAnti-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-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
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