Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)Orthotopic mouse model of human bladder cancer: anti-tumor activity after intravesical rAd-IFN/Syn3
Strimvelis: animal efficacy model or human cells?
autologous CD34+ cells transduced with ADA (no INN) · ADA (gamma-retroviral, ex vivo HSC)
Efficacy evidence
SCID-hu xenograft mice: transduced CD34+ cells engrafted and produced vector-marked, transgene-expressing T and B cells
“In vivo: Immunodeficient mice were implanted with human hematolymphoid tissues (SCID-hu mice), irradiated and transplanted with a single dose of cultured/transduced CD34+ cells. The transduced CD34+ cells engrafted in mice, produced vector-marked and transgene expressing T and B cells and maintained in vivo lymphoid reconstitution capacity.”
Why that model
Ethical limits on harvesting human bone marrow; human-to-mouse xenotransplantation models used instead
“Because ethical restrictions of harvesting of human bone marrow for experimental purposes limit in vivo studies of the human hematolymphoid system, substitute human to small animal xenotransplantation models has been employed.”
Reviewer's view of the efficacy data
CAT/CHMP: gene expressed at relevant sites at an appropriate level with functional activity realised
“Pharmacology studies indicated that the gene is expressed at the relevant site(s) at an appropriate level and that functional activity is realised.”
Same question, other gene therapies
Beqvez
fidanacogene elaparvovec · Factor IXHemophilia B mice given BEQVEZ: liver hFIX-R338L expression and hemostatic FIX activity
Casgevy
exagamglogene autotemcel · BCL11A enhancer (CRISPR-Cas9, ex vivo HSC)Edited human CD34+ cells engrafted in NSG mice retained >90% on-target editing at 16 weeks
Elevidys
delandistrogene moxeparvovec · Micro-dystrophinRodent DMD models: mdx mice and Dmdmdx rats (force, muscle pathology, micro-dystrophin expression)
Fayuvi
rebisufligene etisparvovec · SGSH (AAV9)MPS IIIA mouse pharmacology study (survival, brain GAG, Morris water maze, GFAP, neuropathology); SGSH knock-out cells in vitro
Genglycos
pariglasgene brecaparvovec · G6PC (AAV8)G6PC-deficient GSDIa mouse model: dose-dependent increases in hepatic G6Pase activity and fasting glucose
Glybera
alipogene tiparvovec · LPL (AAV1)LPL-/- mice and LPL-deficient cats: triglyceride-lowering pharmacodynamic activity
Hemgenix
etranacogene dezaparvovec · Factor IXHemophilia B mouse (B6.129P2-F9tm1Dws) with predecessor vector AMT-060: dose-dependent liver transduction, hFIX protein and activity
Imlygic
talimogene laherparepvec · GM-CSF (oncolytic HSV-1)Syngeneic mouse melanoma (B16F10-muNectin1) with clinical virus: significant anti-tumour effect after one or three intratumoral doses
Itvisma
onasemnogene abeparvovec (intrathecal) · SMN1 (AAV9, intrathecal)SMA piglet model, IT research-grade vector (scAAV9.CBA.SMN): prevented hindlimb weakness and slowed disease progression
Kebilidi
eladocagene exuparvovec · AADCIn vitro studies in human cells (AADC expression and biological activity) only
Kresladi
marnetegragene autotemcel · ITGB2 (LVV, ex vivo HSC)CD18HYP and CD18KO LAD-I mice given vector-transduced murine Lin- cells: engraftment and enhanced neutrophil extravasation to inflamed sites
Lenmeldy
atidarsagene autotemcel · ARSA (LVV, ex vivo HSC)As2-/- MLD mice given ARSA-LV murine HSPCs: improved motor conduction, rotarod coordination and neuropathology vs GFP-LV controls
Luxturna
voretigene neparvovec · RPE65RPE65-mutant dogs: improved pupillary responses, ERGs and visual behavior, reduced nystagmus
Lyfgenia
lovotibeglogene autotemcel · HBB T87Q (LVV, ex vivo HSC)Transgenic SCD mice given marrow cells transduced with a related βA-T87Q vector: βA-T87Q expression and correction of sickling
Otarmeni
lunsotogene parvec · OTOF (AAV, intracochlear)Otof-Q828X homozygous deafness mouse: dose-dependent ABR threshold recovery with otoferlin expression in IHCs
Papzimeos
zopapogene imadenovec · HPV6/11 antigens (gorilla adenovirus)HPV antigen-specific T-cell responses in immunized healthy wild-type C57BL/6 mice; no disease model
Roctavian
valoctocogene roxaparvovec · Factor VIIIRag2-/- x FVIII-/- haemophilia A mice: blood loss and bleeding time almost corrected to wild-type levels
Skysona
elivaldogene autotemcel · ABCD1 (LVV, ex vivo HSC)Healthy-donor Lenti-D HSCs in myeloablated immunodeficient mice: bone marrow and brain engraftment with ABCD1 expression and ALDP production
Tudriqev
vusolimogene oderparepvec · GALV-GP + GM-CSF (oncolytic HSV-1)Human tumor cell lines in vitro; murine surrogate mRP1 in syngeneic lymphoma, colorectal and melanoma tumor-bearing mice
Vyjuvek
beremagene geperpavec · COL7A1 (HSV-1, topical)Hypomorphic DEB mouse model and wild-type BALB/c mice: dermal transduction, COL7 expression, anchoring fibrils
Waskyra
etuvetidigene autotemcel · WAS (LVV, ex vivo HSC)WAS-deficient mice transplanted with WAS LVV-transduced murine Lin- BM cells: increased B cells, platelets, granulocytes; improved T, B and DC function
Zevaskyn
prademagene zamikeracel · COL7A1 (RV-modified keratinocyte sheets)Representative RVV-transduced keratinocyte grafts in mouse excisional wounds: cells stayed localized, Col7 expression up to 12 months
Zolgensma
onasemnogene abeparvovec · SMN1SMNdelta7 SMA mouse model: single IV clinical vector lots gave dose-dependent survival improvement
Zynteglo
betibeglogene autotemcel · HBB T87Q (LVV, ex vivo HSC)β-thalassaemic mouse model given BB305 LVV-transduced mouse BMCs: correction of the β-thalassaemic phenotype