What safety margins were accepted for approved gene therapies?

“There appears to be progressive and dose-related muscle toxicity at the recommended clinical dose. This has been shown to be reversible.”

“At the injection sites, histopathological findings including myodegenerative changes and sub-acute inflammation were consistently found in all three single dose toxicity studies upon IM administration of either 1x 1012 or 1 x1013 gc/kg AMT-010 and AMT-011, respectively.”

“These toxicity findings precluded the determination of a no-observed”

“At 6 weeks post-administration, all dose levels resulted in acute, minimal to moderate mononuclear cell inflammation and neuronal degeneration across multiple anatomical sites, including the cerebrum, cerebellar white matter, brain stem, dorsal root ganglia, and various nerve structures (trigeminal, dorsal spinal, spinal, and peripheral nerves).”

“The doses administered provide only safety margin of approximately half the highest dose administered in humans (20 x106 CD34+ cells/kg).”

“In this study, mice were administered 10 x106 CD34+ cells/kg (approximately the midpoint of the dose range to be infused in human subjects) without test-item-related adverse effects.”

“occurrence of tissue lesions (primarily liver and ventricle) already found in doses 0.7- to 1.4-fold the clinical dose and the striking mortality in mice at doses 2-3 the clinical dose required discussion.”

“Based on the lack of similar cardiovascular toxicities resulting in Zolgensma-related mortality, the low dose of 1.5 x 1014 vg/kg was defined as the maximum tolerated dose (MTD).”

“The dose level of 1 x 106 CD34+ hHSPCs/mouse administered in the single dose toxicity study is acceptable, despite the fact that there is only a 1.6-fold safety margin as compared to the max. human dose level of 20 x 106 cells/kg.”

“The single dose GLP toxicology study with an observation period of 20 weeks revealed that the single IV injection of 1 x 106 cells/animal of unedited or SPY101-RNP-edited CD34+ hHSPCs into non-lethally irradiated NSG mice was well-tolerated.”

“In the toxicology studies, the NOAELs were identified as the highest concentrations evaluated (6.5 x 1013 vg/mL in mice and 7.3 x 1013 vg/mL in monkeys), which provides safety margins of approximately 2.2-fold and 2.4-fold, respectively.”

“The 6-month GLP study in monkeys at dose levels up to 4.4 × 1012 vg/ear demonstrated no DB-OTO-related toxicity, with a NOAEL of 4.4 × 1012 vg/ear.”

“The local exposure multiples between monkeys and humans are low with 3.11 for nadofaragene firadenovec and 1.87 for Syn3NODA based on dose.”

“25 mg Syn3NODA and 1.25x1013 vp rAd-IFN could be considered the highest non-severely toxic dose.”

“Findings in animals dosed at 9x1013 gc/kg included prolonged prothrombin time, decreased activated partial thromboplastin time, and decreased heart rates; however, these changes were not statistically significant, and no adverse effects were observed. This dose level is 4.5-fold higher than the recommended dose level for HEMGENIX.”

“The identified no-observed-adverse-effect-level was 9x1013 gc/kg.”

“The no-observed-adverse-effect-level (NOAEL) in NHPs was 7.5 x 1011vg/eye, which is 5-fold higher than the proposed clinical dose level specified in the applicant’s ‘Dosage and Administration’ section of the label.”

“The no-observed-adverse-effect-level (NOAEL) in NHPs was 7.5 x 1011vg/eye, which is 5-fold higher than the proposed clinical dose level”

“The dose level assessed in this non-GLP toxicology study provides a 5-fold safety factor for the clinical dose level with the caveat that the processing and binding sequences in wildtype mice is likely different than the peptides recognized by human T cells .”

“There were no test article-related findings reported.”

“No test article-related adverse findings were observed in this study, including any findings of thrombosis by microscopic histopathology. The dose levels in this study were between 2 to 10-fold higher than the recommended clinical dose level for BEQVEZ.”

“No test article-related adverse findings were observed in this study, including any findings of thrombosis by microscopic histopathology.”

“Although a no observed effect level (NOAEL) could not be determined, a dose level of 1x106 CD34+ cells/animal or 5x107 CD34+ cells/kg provides an approximately 10-fold safety margin to the recommended minimum dose level to be administered in humans (5x106 CD34+ cells/kg).”

“Although a true no observed adverse effect level (NOAEL) could not be determined, the dose level administered in this study, approximately 5x107 CD34+ cells/kg, represents the maximum feasible dose”

“Based on the study results, the highest dose administered (7.5×109 vg) in the study provides a safety margin of 21 over the human dose used in clinical studies, as calculated by the applicant.”

“Since there were no toxicologically significant findings at the high dose, the no observed adverse effect level (NOAEL) was set at the high dose (7.5x109 vg).”

“A dose level of 1x107 PFU/mouse/injection was 88-fold higher than the maximum human dose level (on a PFU/kg basis) administered in the first-in-human clinical trial (Document No. 4648-00028), and 70-fold higher than the recommended maximum dose level (on a PFU/kg basis) listed in the label for T-VEC.”

“a no-observed-adverse-effect-level (NOAEL) of 107 PFU/kg was achieved, which is approximately 1.7-fold higher than the maximum clinical dose level”

“This study identified NOAELs of 4.1 × 1014 vg/kg in WT mice and 1.33 × 1014 vg/kg in mdx mice.”

“The NOAEL was assigned at 2.0x1014 vg/kg.”

“identified a NOAEL equivalent to 1.3 × 1014 gc/kg of GENGLYCOS”

“No premature mortality or unexpected deaths were observed over the course of the study period in recipient mice.”

“No test article-related mortality, toxicity or hematologic malignancy was observed, with study findings primarily attributed to the As2-/- phenotype, irradiation, and incidental age-related findings.”

“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.”

“ROCTAVIAN-related mortality, adverse clinical observations, and changes in gross pathology were observed at dose levels of 6.53 × 1013 vg/kg and higher, and were associated with fibrosis, hemorrhage, and necrosis in the heart.”

“was 1x107 plaque-forming units (PFU)/animal/injection, which was the determined no-observed-adverse-effect level for all studies.”

“The low dose of 6.9 x 106 pfu was considered as the NOAEL.”

“results do not reveal any increased mortality, tumorigenicity, or other forms of toxicity related to the transduction of mouse SV129 WKO Lin- HSPCs with w1.6W LVV.”

“There were no gross or histopathological findings in any tissue assessed, including the explanted nonclinical products.”

“No test article-related mortality or adverse effects on any parameter was observed.”