What tox package did approved gene therapies have, from first-in-human to approval?

“It is acceptable that all clinical studies with nadofaragene firadenovec were conducted in the US (Table 1)”

“control on Days 1 and 91, followed by a two month observation period in a GLP toxicology study.”

“Carcinogenicity and reproductive and developmental toxicity studies were not performed for rAd-IFN/Syn3. These studies are not warranted based on the product characteristics, results from the toxicology studies, and target patient population.”

“Carcinogenicity and reproductive and developmental toxicity studies were not performed for rAd-IFN/Syn3. These studies are not warranted based on the product characteristics, results from the toxicology studies, and target patient population.”

“rAAV2-hAADC was subsequently tested in the first-in-human clinical trials of patients with Parkinson’s disease at dose levels of 9×1010 and 3×1011 vg via bilateral intra-putaminal dosing (Christine 2009, Muramatsu 2010).”

“Eladocagene exuparvovec is a single dose gene therapy with persistent gene expression through 6 months in rodents (Leidos 8366537, AADC-003) which provides chronic exposure and, therefore, no repeat-dose studies were conducted.”

“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, and carcinogenicity/tumorigenicity of KEBLIDI were not conducted. These studies were not warranted based on the product characteristics and target patient population.”

“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, and carcinogenicity/tumorigenicity of KEBLIDI were not conducted. These studies were not warranted based on the product characteristics and target patient population.”

“Study DB-OTO-001 was conducted in 7 US and 4 ex-US sites.”

“Single-dose toxicology studies were conducted in Otof-Q828X hom mice and cynomolgus monkeys.”

“Developmental and reproductive toxicity, genotoxicity, and carcinogenicity studies were not conducted with DB-OTO. These studies were not warranted based on the IC route of administration, limited systemic exposure, target patient population, and absence of safety concerns in the toxicology studies.”

“Developmental and reproductive toxicity, genotoxicity, and carcinogenicity studies were not conducted with DB-OTO. These studies were not warranted based on the IC route of administration, limited systemic exposure, target patient population, and absence of safety concerns in the toxicology studies.”

“Study 270-201 was a first-in-human, Phase 1/2 open-label, dose-escalation study of ROCTAVIAN”

“No repeat-dose toxicity studies were performed because BMN 270 is a single-dose administration gene”

“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, carcinogenicity/tumorigenicity of ROCTAVIAN were not conducted. These studies were not warranted based on the product characteristics, results from the toxicology studies, and target patient population.”

“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, carcinogenicity/tumorigenicity of ROCTAVIAN were not conducted. These studies were not warranted based on the product characteristics, results from the toxicology studies, and target patient population.”

“GSK2696273 was first administered to humans in 2000 in a pilot clinical study with one subject with confirmed ADA-SCID who had no HLA-identical sibling or prior ERT therapy received treatment and follow-up at Hadassah University (Jerusalem, Israel), with the cooperation of HSRTIGET.”

“Due to the nature of Strimvelis, repeat dose toxicity studies were not conducted since GSK2696273 consists of patient-derived cells that are intended to consist of the ADA gene, to allow for expression of the related ubiquitous protein at or below physiological levels.”

“No reproductive or developmental toxicity studies were conducted with GSK2696273. Patients will receive a low dose of busulfan as pre-conditioning treatment.”

“In summary, in previous scientific advice, it was agreed that the tumourgenicity risk assessment for GSK2696273 could be based on clinical data and literature on similar vectors if tumourgenicity/general toxicity studies were unsuccessful in allowing for the determination of optimal conditions for a full tumourgenicity study.”

“The completed clinical trial enrolled 15 infants with SMA from one site in the United States.”

“No repeat-dose toxicology studies were performed with AVXS-101 since this will be intended for single IV administration only.”

“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, carcinogenicity/tumorigenicity of AVXS-101 were not conducted for AVXS-101. These studies were not warranted based on the product characteristics, results from the toxicology studies, and target patient population.”

“These studies were not warranted based on the product characteristics, results from the toxicology studies, and target patient population.”

“Repeat-dose toxicity studies were not performed because fidanacogene elaparvovec is intended for single administration to patients.”

“Per applicant, hemophilia B is almost exclusively limited to male subjects, and BEQVEZ is not intended for administration in women. This reviewer agrees that the omission of dedicated embryo-fetal development studies and pre- and postnatal development studies is acceptable.”

“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, and carcinogenicity/tumorigenicity of BEQVEZ were not conducted. These studies are not warranted based on the product characteristics, results from the biodistribution and toxicology studies”

“A repeat-dose toxicity study was not performed and is not required as exa-cel is intended for single-dose administration only.”

“Developmental and reproductive toxicity studies and carcinogenicity studies were not conducted with CASGEVY. These studies are not warranted based on the characteristics and safety profile of the product.”

“Developmental and reproductive toxicity studies and carcinogenicity studies were not conducted with CASGEVY. These studies are not warranted based on the characteristics and safety profile of the product.”

“To evaluate the toxicity of SRP-9001 when administered as a single dose via IV injection to male mice; animals were observed for either 12 or 24 weeks”

“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.”

“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.”

“Repeated dose toxicity studies were not conducted as Glybera will be administered once at multiple sites intramuscularly.”

“In vivo carcinogenicity studies have not been conducted. The applicant argued that there is no existing study design that would be accepted as relevant to assess insertional mutagenesis and the risk of oncogenicity”

“No repeated dose toxicity studies were conducted. This is acceptable, as only a single etranacogene dezaparvovec administration is intended in patients”

“As haemophilia B is almost exclusively limited to male patients, and as the current MAA only comprises adult patients, dedicated EFD and PPND studies are not required.”

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

“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.”

“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.”

“A 1-month in vivo toxicology and biodistribution (BD) study was also conducted using recipient mice for safety evaluation of Chim-CD18-WPRE LV transduced Lin- murine HSPCs.”

“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with KRESLADITM. These studies are not warranted based on the drug product characteristics and safety profile.”

“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with KRESLADITM. These studies are not warranted based on the drug product characteristics and safety profile.”

“No single dose and repeat dose toxicity studies were performed. Single dose toxicity was taken along in the long-term toxicity studies.”

“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with OTL-200. These studies are not warranted based on the product characteristics and safety profile.”

“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with OTL-200. These studies are not warranted based on the product characteristics and safety profile.”

“Scheduled Sacrifice Time Points Days 190 (two animals) and 217 (two animals)”

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

“CHMP also advised that in vivo testing in 2-year carcinogenicity studies in mice or rats would not contribute meaningful data to assessing the risk of carcinogenicity.”

“In the secondary transplantation study, no deaths or adverse findings attributed to the BB305 LVV-transduced cells occurred through 6 months post-transplantation of 6×106 cells/mouse.”

“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with LYFGENIA™. These studies are not warranted based on the product characteristics and safety profile.”

“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with LYFGENIA™. These studies are not warranted based on the product characteristics and safety profile.”

“Local tolerance and systemic toxicity were assessed as part of the repeat dose toxicity study of PRGN-2012 in wild type (WT) C57BL/6 mice. PRGN-2012 or GC46.empty vector was administered once weekly for three weeks at 1×1010 VP/administration.”

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

“This reviewer agrees with the rationale provided by the applicant for not conducting carcinogenicity/tumorigenicity studies.”

“As Lenti-D Drug Product is intended for a single autologous IV administration, not performing any repeat-dose toxicity studies is acceptable.”

“Reproductive and developmental toxicity studies were not performed for eli-cel which is acceptable based on the product characteristics and safety profile.”

“No repeat-dose toxicology, dedicated carcinogenicity, juvenile or developmental and reproductive toxicology studies were performed, and their omission is acceptable considering the nature of the product.”

“In a follow-up study, 16 doses (every 3 days for 7 weeks) of mRP1 were administered to healthy rats. mRP1 DNA was not detected in any neurologic tissues and there was no evidence of viral reactivation at any time point up to 6 months post-final dosing, indicating minimal risk of latency and reactivation of mRP1.”

“Studies to evaluate the safety pharmacology, genotoxicity, and carcinogenicity of TUDRIQEV were not conducted. These studies are not warranted based on the product characteristics and safety profile.”

“Analysis of in vivo biodistribution after five weekly repeat ID doses of VYJUVEK in mice at 6.9 x 106 or 3.45 x 107 pfu/dose/mouse resulted in vector detection primarily at the injection site, which declined to baseline by 30 days after the last dose.”

“Animal reproductive and developmental toxicity (DART) studies were not conducted with VYJUVEK. This is acceptable based on the product characteristics and safety profile.”

“No carcinogenicity/tumorigenicity studies with VYJUVEK were performed because available data for both KB103 and wild-type HSV-1 do not indicate a carcinogenic risk in humans.”

“No repeat-dose toxicity studies have been presented by the applicant, which is acceptable considering that the product is intended to be administered to patients as a single administration, with subsequent engraftment into the patient.”

“No carcinogenicity, developmental and reproductive toxicology (DART) studies, and safety pharmacology studies were conducted for WASKYRA. These studies are not warranted based on the drug product characteristics and safety profile.”

“No carcinogenicity, developmental and reproductive toxicology (DART) studies, and safety pharmacology studies were conducted for WASKYRA. These studies are not warranted based on the drug product characteristics and safety profile.”

“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.”

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

“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.”

“No repeated dose toxicity studies were performed as the treatment foresees only one unique injection”

“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with beti-cel. These studies are not warranted based on the product characteristics and safety profile.”

“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with beti-cel. These studies are not warranted based on the product characteristics and safety profile.”