How was the first-in-human dose set for approved gene therapies?

“In vivo toxicology/safety studies conducted in NHPs utilized a single IT administration of OAV101 at 1.2 x 1013 vg/animal, considered equivalent to the proposed starting clinical dose level for ITVISMA of 1.2x1014 vg/patient based on a 10-fold difference in CSF volume between NHP and human.”

“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 applicant justified this dose on the basis that clinical studies in adult PD using rAAV2-hAADC reported that doses up to 3x 1011 vg of rAAV2-hAADC in a volume of 4×50 μl were well tolerated following bilateral, intraputaminal infusions during a single operative session.”

“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).”

“The selection of the proposed clinical dose concentration of 3 x 1013 vg/mL is supported by the pharmacodynamic modeling (OTOF-10116) of ABR improvements in the Otof-Q828X hom mouse model as well as the safety profile established in the GLP toxicology studies.”

“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 applicant noted that for phase 1 clinical trials, clinical dose identification was based on 2 criteria identified in animal studies: doubling Delta 7 SMA mouse life span (7.4e+13 vg/kg ) and restoring full life (1.2e+14 vg/kg ) in delta 7 SMA mice.”

“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).”

“Activity was demonstrated in the dose range 1011-1013 gc/kg compared to the proposed human dose of 1x1012 gc/kg.”

“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.”

“The supporting clinical data from the predecessor product that used a similar vector (AAV5) as HEMGENIX was used to inform dosing for later clinical studies, and assessments of vector viral kinetics.”

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

“Because the pharmacology data indicated that efficacy could be achieved over a broad dose range, the determination of the optimal therapeutic dose also relied on safety data.”

“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”

“Repeat administration of a dose level approximately 5-fold higher than the intended clinical dose, assuming a 60-kilogram adult of 5x1011 PU (1x1010 VP/mouse/dose) of PRGN-2012 once weekly on Days 0, 7, and 14 was well tolerated in WT C57BL/6 mice with no safety findings reported at termination after 21 Days.”

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

“The first ADA/SCID clinical protocol for Study Number AD1117054 was based on the optimised transduction conditions from the nonclinical studies described above.”

“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.”

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

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

“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.”

“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”

“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”

“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.”

“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”

“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.”