Clinical lot or not: what material did approved gene therapies test?

“Upon request data on some of the batches have been provided. Nevertheless, taken together, not all batches used in the non-clinical PK and toxicity studies are sufficiently representative for the clinical/commercial manufacturing process, but the provided data are considered supportive of the non-clinical profile of the product.”

“Several toxicology studies were conducted using a closely related predecessor product, AAVRh74var- -Padua, which is similar to BEQVEZ except the”

“The pivotal single dose toxicity and tumorigenicity study has been conducted using lots from three healthy donors. The lots were manufactured under non-GMP conditions in a non-GMP facility using the same process and same manufacturer as for GMP material.”

“ELEVIDYS (also named SRP-9001 in the nonclinical studies) has been produced from different manufacturing processes and manufacturing sites including Process A at Nationwide Children’s Hospital, Process B at ThermoFisher, and Process B at Catalent.”

“Different batches of AMT-010 (plasmid derived) were used and the applicant intended to compare AMT-010 and AMT-011 (baculovirus derived) in non clinical bridging studies.”

“The non-clinical development programme was initiated with AMT-060, which has a similar vector backbone as etranacogene dezaparvovec (AMT-061), but lacks the 2-nucleotide change in the hFIX coding sequence (enhancing the FIX activity of Padua FIX variant).”

“The nonclinical development program for ITVISMA evaluated research grade lots, referred to as scAAV9.CBA.SMN, OAV101, and OAV101B, to inform the safety and activity of ITVISMA.”

“Comparability of the clinical lots 2004-101 and PBR-0045- 001 to lots made using the intended commercial process was provided. It is clear that in the initial submission no nonclinical studies had been carried out using the intended commercial formulation.”

“The applicant also used surrogate Lin- HSPCs transduced with the Chim-CD18-WPRE LV transplanted into recipient mice for their definitive in vivo toxicology and BD studies. All cells were transduced with the clinical vector, Chim-CD18-WPRE LV, which is used to produce RP-L201.”

“Therefore, lineage negative (Lin-) mHSPCs (derived from the BM of As2-/- mice) and healthy hHSPCs (derived from umbilical cord blood or BM) transduced with ARSA LVV were used for the majority of the nonclinical studies.”

“Subretinal injection of 1.5 x 1012 vg/eye of a precursor AAV2-hRPE65v2 vector product in normal-sighted dogs resulted in ocular inflammation and retinal degeneration histologically in regions exposed to the vector.”

“In vivo studies were also conducted to assess the activity and safety of mBMCs transduced with BB305 following primary and secondary transplantation in β-thalassemic and wild-type C57BL/6 mice.”

“The nonclinical studies used non-GMP (Good Manufacturing Practice) material, while the clinical product is manufactured under GMP conditions. However, the nonclinical material was determined to be comparable to the clinical investigational drug product based on the process consistency. The same non-GMP lot (B564TOXP1) was used across all three GLP studies to ensure consistency in the pivotal safety and activity studies.”

“Reviewer Note: PAPZIMEOS is referred to as PRGN-2012 (research grade lot) in this review memo. There are no differences between the adenovirus and fusion protein in PRGN-2012 compared to the clinical product, PAPZIMEOS.”

“However, as this study used a batch of BMN 270 drug product manufactured according to process B, which is an early research/development process, it appears that the test article administered to CD1 mice cannot be considered as representative of the clinical formulation produced according to commercial process CPD’.”

“Therefore, CD34+ HSCs from healthy donors (with normal ALDP expression) were used for the in vivo pharmacology/toxicology studies. All cells were transduced with the same LVV, Lenti-D, that is used to produce eli-cel”

“The test item used in the biodistribution studies (referred to as GSK3235757A) comprised of CD34+ cells derived from healthy human UCB transduced with GSK3336223 vector and is accepted as representative of Strimvelis.”

“Toxicology studies evaluating TUDRIQEV and mRP1 were conducted in tumor-bearing immunocompetent mice and healthy rats, respectively.”

“Note: As described in Module 2.4, the VYJUVEK material for the early-phase nonclinical and clinical programs (Phase 1/2) were produced using a production process, while the material in late-phase nonclinical and clinical programs (Phase 3) were produced using a production process.”

“In both models, the test article was comprised of a mouse surrogate test article: lineage￾deficient (Lin-) HSPCs transduced with either the w1.6W or the w1.6W_mut6 (clinical) vector.”

“In the toxicology and biodistribution (BD) study, nonclinical products representative of ZEVASKYN comprised of human acellular dermal matrix and RVV-transduced human keratinocytes (cells alone) were implanted into excisional wounds generated in mice for 4- or 8-weeks.”

“All studies were performed with pre-process A batch material, except for the two 12-week GLP studies (process B).”

“the test articles used during non-clinical studies were surrogates, and consisted of either thalassaemic mouse bone marrow cells transduced with BB305 LVV, or human healthy donor HSCs transduced with BB305 LVV, administered to β-thalassaemic (Hbbth1/th1) mice and immunodeficient NOD scid gamma (NSG) mice, respectively.”