Itvisma: was the clinical lot tested, or a surrogate or earlier version?

Several older rAd-IFN and Syn3NODA DS batches; not all representative of the clinical/commercial manufacturing process. Bridging: Quality data for some batches provided on request; considered supportive of the nonclinical profile

Several toxicology studies used a closely related predecessor product, AAVRh74var-Padua, similar to BEQVEZ. Bridging: Batches used in the pivotal nonclinical biodistribution and toxicity/genotoxicity testing considered representative of clinical batches

Non-GMP lots from three healthy donors made with the same process and manufacturer as the GMP clinical material. Bridging: Toxicology lots were manufactured in a non-GMP facility using the same process and same manufacturer as for GMP material

Nonclinical material from Process A (Nationwide Children’s), Process B at ThermoFisher and Process B at Catalent. Bridging: Process A and Process B products not analytically comparable; commercial product is Process B (Catalent)

Definitive GLP safety and biodistribution studies and all clinical trials used FAYUVI manufactured under GMP conditions via Process A. Bridging: In vivo pharmacology studies bridged in vivo potency between the clinical Process A material and the later manufacturing process

Clinical vector DTX401 in toxicology studies; earlier vector versions encoding the same protein only in pharmacology Studies 1–4. Bridging: Titers from the initial assay converted to the final titer method by a conversion factor; doses reported as equivalents

Plasmid-derived AMT-010 batches and the baculovirus-derived commercial product AMT-011 both used in non-clinical studies. Bridging: AMT-011 qualified independently of AMT-010 on non-clinical data; toxicology and pharmacology studies were repeated with AMT-011

Programme initiated with predecessor AMT-060, same vector backbone but lacking the 2-nucleotide change giving the Padua FIX variant. Bridging: Predecessor and clinical vector showed a comparable safety profile when tested side-by-side in mice and NHPs

Process B (earlier process) material in toxicology studies; Phase III and commercial product made by Process C. Bridging: Comparability between batches from the different manufacturing processes demonstrated

Nonclinical studies used clinical lots 2004-101 and PBR-0045-001, not the intended commercial formulation. Bridging: Comparability of the clinical lots to lots made using the intended commercial process was provided

Surrogate murine Lin- HSPCs transduced with the clinical vector used for the definitive in vivo toxicology and biodistribution studies. Bridging: All cells were transduced with the clinical vector, Chim-CD18-WPRE LV, which is used to produce RP-L201

Murine Lin- HSPCs from As2-/- mice and healthy human HSPCs transduced with ARSA LVV used for most nonclinical studies. Bridging: Remaining nonclinical studies used the clinical LVV, while some studies used vector versions with WPRE or an HA epitope tag

A precursor AAV2-hRPE65v2 vector product was used in normal-sighted dog studies at 1.5 x 1012 vg/eye. Bridging: Commercial lot shown comparable to the clinical material by lot release data and side-by-side comparability testing

Murine bone marrow cells transduced with BB305 used in the primary and secondary transplantation studies, not patient CD34+ cells

Non-GMP DB-OTO lot B564TOXP1 used in all three GLP studies; clinical product manufactured under GMP. Bridging: Nonclinical material judged comparable to the clinical investigational product based on process consistency

Research-grade lot PRGN-2012 of the clinical vector. Bridging: Adenovirus and fusion protein stated to be identical to the clinical product

One mouse study used a batch from early research process B, not representative of the commercial formulation; later studies used clinical-like lots. Bridging: Lots manufactured by the commercial process reported comparable to lots produced with earlier processes

Healthy-donor CD34+ HSCs transduced with the same Lenti-D LVV used to produce the clinical product, not patient cells. Bridging: All cells were transduced with the same LVV, Lenti-D, that is used to produce eli-cel

CD34+ cells from healthy human umbilical cord blood transduced with the GSK3336223 vector, used instead of patient cells. Bridging: The test item was accepted as representative of Strimvelis

Clinical product TUDRIQEV in tumor-bearing mice; murine surrogate mRP1 in healthy rats. Bridging: Clinical-site and commercial-site (Framingham) batches compared in tumor-bearing mice; no differences in toxicology or biodistribution

Early-phase nonclinical studies used the early (Phase 1/2) production process; late-phase nonclinical studies used the Phase 3 process. Bridging: In vivo comparability study (KB103-IVV-010) in immunocompetent mice comparing batches from the two processes

Mouse surrogate: lineage-deficient HSPCs transduced with either the w1.6W or the clinical w1.6W_mut6 vector. Bridging: The clinical w1.6W_mut6 vector was used alongside the earlier w1.6W vector in both mouse models

Representative nonclinical product: RVV-transduced human keratinocytes (cells alone) on human acellular dermal matrix, implanted into mouse wounds

The two 12-week GLP studies used process B material; all other safety studies used pre-process A batch material. Bridging: Current-process lots comparable to the initial clinical lot, including potency-to-vector-genome ratio and survival in a mouse SMA model

Surrogates: BB305 LVV-transduced thalassaemic mouse bone marrow cells or healthy human donor HSCs, not patient cells. Bridging: Surrogate test articles were transduced with BB305 LVV and administered to beta-thalassaemic and NSG mice