Itvisma

“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.”

“IT administration of scAAV9.CBA.SMN demonstrated a 55-79% transduction efficiency of choline acetyltransferase (ChAT) positive motor neurons in NHP spinal cords.”

“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.”

“Additional single-dose studies in the newborn Friend Virus B (FVB) mouse strain and NHPs further demonstrated high tolerability to OAV101 or scAAV9.CBA.SMN following ICV or IT administration, respectively, with no major safety signals.”

“Fertility and early embryonic development (FEED) studies were conducted in healthy male and female FVB mice administered a single intravenous injection of OAV101B.”

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

“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.”

“These studies demonstrated that OAV101 was well tolerated at this dose level up to 12 months post injection, with minor microscopic findings reported 6 weeks post-administration in the dorsal root ganglia (DRG), spinal cord, peripheral nerves, and brain that did not increase in severity or incidence over the 12 month study.”

“A single IT dose of onasemnogene abeparvovec was administered at three dose levels: 1.20 × 10 13 vg/animal (equivalent to the clinical therapeutic dose), 3.0 × 10 13 vg/animal, and 6.0 × 10 13 vg/animal.”

“Additional single-dose studies in the newborn Friend Virus B (FVB) mouse strain and NHPs further demonstrated high tolerability to OAV101 or scAAV9.CBA.SMN following ICV or IT administration, respectively, with no major safety signals.”

“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.”

“Long-term follow-up studies that specifically include the occurrence of new malignancies and tumours as part of the risk management plan in place for OAV101. Therefore, tumorigenicity studies are not needed.”

“These studies demonstrated that OAV101 was well tolerated at this dose level up to 12 months post injection, with minor microscopic findings reported 6 weeks post-administration in the dorsal root ganglia (DRG), spinal cord, peripheral nerves, and brain that did not increase in severity or incidence over the 12 month study.”

“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.”

“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.”

“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.”

“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.”

“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).”

“Anti-AAV9 antibody responses were consistent and robust across all studies, with all participants developing high titers that remained elevated through study completion.”

“Biodistribution (BD) of OAV101 demonstrated the highest titers in the liver, DRG, and spinal cord, with lower levels reported in the periphery, including gonads.”

“Elevated liver enzyme levels (aspartate and alanine amino transferase) and single cell necrosis of hepatocytes were observed in select NHPs at 6 weeks post-administration but resolved by 12 months post-administration.”

“Increases from baseline in anti-AAV9 antibody titers were reported in all patients with a median anti-AAV9 antibody titers of ≥ 1:819,200 at 12 months following ITVISMA injection in both studies. During the 12-month period following ITVISMA injection in Study 1 and Study 2, positive anti-SMN antibodies were observed in 5/75 (6.7%) and 2/27 (7.4%) of ITVISMA-treated patients, respectively.”

“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.”

“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 single IT dose of onasemnogene abeparvovec was administered at three dose levels: 1.20 × 10 13 vg/animal (equivalent to the clinical therapeutic dose), 3.0 × 10 13 vg/animal, and 6.0 × 10 13 vg/animal.”

“Fertility and early embryonic development (FEED) studies were conducted in healthy male and female FVB mice administered a single intravenous injection of OAV101B.”

“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.”

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

“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.”

“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).”

“In a piglet model of SMA, scAAV9.CBA.SMN administered by the IT ROA prevented the development of hindlimb muscle weakness and slowed overall disease progression.”

“All the submitted studies / publications have already been evaluated during marketing authorisation application for Zolgensma and are addressed below.”

“Thus, a rough comparison, not taking into consideration ICV versus IT and differences between mice and men, would conclude that the clinically targeted intrathecal dose is not achievable in patients. Support for the clinical dose should be derived from clinical data.”

“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.”

“ITVISMA is a non-replicating recombinant AAV9 vector that delivers a functional copy of the human survival motor neuron gene (SMN1) to transduced cells.”

“Summary Basis for Regulatory Action Date: November 24, 2025”