Which nonclinical studies did approved gene therapies skip?

“Safety pharmacology, pharmacokinetics, toxicology, and genotoxicity studies were also conducted for the exicipient Syn3.”

“Carcinogenicity and reproductive and developmental toxicity studies were not performed for rAd”

“Carcinogenicity and reproductive and developmental toxicity studies were not performed for rAd”

“Based on the IS profile, genotoxicity from vector integration appears to be a low risk.”

“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, and carcinogenicity/tumorigenicity of BEQVEZ were not conducted.”

“This reviewer agrees that the omission of dedicated embryo-fetal development studies and pre- and postnatal development studies is acceptable.”

“No evidence of off-target editing was observed for in-silico and GUIDE-seq identified candidate off-target sites which were assessed by hybrid capture sequencing analyses.”

“No carcinogenicity studies were conducted with CTX001.”

“No DART studies were conducted with CTX001.”

“Per the applicant, genotoxicity studies have not been conducted with SRP-9001 because the literature thus far, supports random integration of AAV vector into the host genome at low frequencies”

“Based on the indication of X-linked DMD which occurs primarily in males and lack of concerning findings in the completed toxicology studies, further assessment of developmental and reproductive toxicology, carcinogenicity/tumorigenicity, and genotoxicity are not warranted at this time.”

“Animal reproductive and developmental toxicity and carcinogenicity studies were not conducted with ELEVIDYS, which is acceptable based on the patient population and lack of ELEVIDYS-related adverse findings in the toxicology studies.”

“Developmental and reproductive toxicity (DART), genotoxicity, and carcinogenicity/tumorigenicity studies were not conducted with FAYUVI.”

“Developmental and reproductive toxicity (DART), genotoxicity, and carcinogenicity/tumorigenicity studies were not conducted with FAYUVI.”

“Developmental and reproductive toxicity (DART), genotoxicity, and carcinogenicity/tumorigenicity studies were not conducted with FAYUVI.”

“studies were not conducted to evaluate genotoxicity as they expect that the risk of DTX401 insertion is low.”

“studies were not conducted to evaluate carcinogenicity/tumorigenicity”

“IV administration of DTX401 at 7 × 1013 gc/kg to pregnant dams at presumed gestational day (GD) 6 resulted in DTX401 DNA detection in placenta but not offspring livers”

“Standard genotoxicity studies, as applied to a conventional chemical drug, are not relevant for this type of product and were not performed.”

“Carcinogenicity studies have not been conducted. The applicant argues that the studies conducted to assess integration are sufficient to address risk of carcinogenicity.”

“Reproductive toxicity was studied in pregnant mice in whom no effects of female reproduction or fetal development were detected.”

“For both species, the majority of the identified vector DNA sequences represented episomal forms that were not integrated into the host DNA.”

“Studies to evaluate the carcinogenicity/tumorigenicity of HEMGENIX were not conducted. These studies are not warranted based on the nonclinical safety profile.”

“However, there were no adverse effects on mating rates or fertility indices.”

“In accordance with ICH S6(R1) guideline, genotoxicity studies were not conducted.”

“No carcinogenicity studies have been conducted (see non-clinical discussion).”

“No effects on embryo-foetal development were observed when talimogene laherparepvec was administered during organogenesis to pregnant mice at doses up to 4 x 108 (400 million) PFU/kg”

“No carcinogenicity, genotoxicity, or repeat dosing were conducted for OAV101B.”

“These studies are not necessary based on the intended ROA, dosing regimen (i.e., single infusion), known product characteristics, and overall safety profile for this class of product.”

“Fertility and early embryonic development (FEED) studies were conducted in healthy male and female FVB mice administered a single intravenous injection of OAV101B. There were no reported adverse effects on fertility, fecundity, or mating behaviors in either sex.”

“It was previously agreed with CHMP that genotoxicity, carcinogenicity and evaluation of insertional mutagenesis studies were not required (EMEA/CHMP/SAWP/236092/2018).”

“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, and carcinogenicity/tumorigenicity of KEBLIDI were not conducted.”

“Given the local administration of eladocagene exuparvovec to the brain and lack of systemic exposure, and the absence of biodistribution to the gonads, the risk for germline transmission is low.”

“8 Analysis of Integration Profile in Mouse Transduced Cells NSR-8 9 Analysis of Integration Profile in Human Transduced Cells NSR-9”

“Traditional carcinogenicity studies were not conducted since they are not suitable for assessment of this drug product type.”

“Studies were not conducted to evaluate this developmental and reproductive toxicity based on the product type and due to the lack of concerning findings in reproductive tissues in Study #7 (study report no. NSR-7).”

“Genotoxicity risk was assessed in vitro using hHSPCs derived from healthy donors and MLD patients and showed no effects of LVV transduction or ARSA overexpression on the proliferation or differentiation of hHSPCs.”

“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with OTL-200.”

“No dedicated reproductive and developmental studies are undertaken.”

“studies to evaluate safety pharmacology, developmental and reproductive toxicity, genotoxicity, and carcinogenicity/tumorigenicity were not conducted for AAV2-hRPE65v2.”

“Thus, the risk for AAV vector-induced insertional mutagenesis/carcinogenesis, particularly in post-mitotic cells such as retinal cells, is considered low.”

“The presence of AAV2-hRPE65v2 was not detected by qPCR in the gonads of healthy NHPs following subretinal administration.”

“Per the applicant, based on these data, the risk of insertional mutagenesis following BB305 transduction is low.”

“No traditional carcinogenicity studies were conducted with lovo-cel which is acceptable based on the product type.”

“Per the applicant, developmental and reproductive toxicology studies were not conducted because there were no adverse findings in the male and female reproductive tissues of mice administered mBMCs transduced with BB305 LVV”

“No genotoxicity studies have been conducted with DB-OTO. The risk of insertional mutagenesis with recombinant AAV vectors is considered to be low.”

“No carcinogenicity studies have been conducted with DB-OTO.”

“Across these nonclinical studies, there was negligible biodistribution of DB-OTO vector to the gonads, no expression of hOTOF mRNA in the gonads, and no gross or microscopic findings in the gonads, suggesting a low reproductive and germline integration risk.”

“PRGN-2012 does not rely on host cell genome integration for expression of the transgene, thus, it has a reduced genotoxic risk and will not result in insertional mutagenesis or position-effect variation.”

“Per the applicant, studies were not conducted to evaluate carcinogenicity as adenovectors are non-integrating. Therefore, the risk for insertional mutagenesis is not a major concern.”

“This reviewer agrees with the rationale provided by the applicant for not conducting developmental and reproductive toxicology studies.”

“In terms of genotoxicity, no studies were performed with BMN 270.”

“As regards carcinogenicity: no carcinogenicity studies were performed with BMN 270.”

“There were no ROCTAVIAN-related adverse changes on mating rates, maternal behavior, and fertility indices.”

“Lenti-D is an autologous human cellular product, therefore, standard genotoxicity studies are not considered relevant.”

“Traditional carcinogenicity studies were not conducted as they are not suitable for assessing this product type.”

“Studies were not conducted to evaluate this safety endpoint based on the product type and due to the lack of findings in reproductive tissues in Study #10.”

“Conventional genotoxicity assays are inappropriate to detect insertional events and would not provide additional information to inform a quantitative risk assessment in humans and hence no studies have been conducted.”

“Accordingly, the SmPC states that carcinogenicity studies have not been conducted as no adequate animal model was available to evaluate the tumourigenic potential of Strimvelis due to the inability to achieve long-term engraftment of transduced cells in mice.”

“No reproductive or developmental toxicity studies were conducted with GSK2696273.”

“Studies to evaluate the safety pharmacology, genotoxicity, and carcinogenicity of TUDRIQEV were not conducted.”

“Studies to evaluate the safety pharmacology, genotoxicity, and carcinogenicity of TUDRIQEV were not conducted.”

“no embryofetal structural abnormalities or adverse effects on embryofetal growth were observed following repeat IV mRP1 administration.”

“No traditional genotoxicity studies were performed.”

“No carcinogenicity studies were performed, and the applicant provided a weight of evidence risk assessment”

“Animal reproductive and developmental toxicity (DART) studies were not conducted with VYJUVEK.”

“No mutagenicity, carcinogenicity and reproductive and developmental toxicity studies have been performed with WASKYRA”

“While, standard carcinogenicity studies are usually not required due to the nature of the advanced medicinal product”

“No carcinogenicity, developmental and reproductive toxicology (DART) studies, and safety pharmacology studies were conducted for WASKYRA.”

“Integration site analysis (ISA) was performed on RDEB keratinocytes (n=6 donors) transduced with RVV. ISA did not indicate clonality at 6-days post-keratinocyte transduction.”

“Carcinogenicity and tumorigenicity studies of ZEVASKYN were not conducted due to absence of neoplastic features on histology, low risk of insertional oncogenesis, and frequent SCC screening recommended for all subjects with RDEB.”

“Developmental and reproductive toxicity (DART) studies of ZEVASKYN were not conducted due to the BD of RVV remaining confined to representative nonclinical products.”

“Recent scientific literature supports low random integration frequencies of recombinant AAV (rAAV) vectors1,2 and lack of hepatic genotoxicity in rAAV2/5 genome integration in NHP and human liver samples.”

“Ongoing clinical trials (under IND #15699) since September 2013 have shown no evidence of tumor formation clinically in any subject administered with AVXS-101.”

“The target patient population for AVXS-101 with infantile-onset SMA are typically less than 1 year of age and sexually immature.”

“Results from an in vitro immortalization (IVIM) assay performed with BB305 LVV-transduced murine BMCs showed low mutagenic potential of BB305 LVV.”

“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with beti-cel.”

“No developmental and/or reproductive toxicity (DART) studies were submitted to support the use of Zynteglo for the treatment of TDT.”