Zolgensma (onasemnogene abeparovec-xioi) is a systemic AAV9 gene therapy for the treatment of SMA type 1, with significant benefits in preservation and motor neuron function and dramatic departure from the severe weakness and ventilatory failure which characterized the natural history. Considering risk-benefit, there is distinct benefit to the transformative use of systemic gene therapy in SMA type 1. A box warning for the drug advises to carefully track signs of acute liver injury and thrombocytopenia and includes guidance on the use of glucocorticoids during the first month after treatment.
In the current study, we characterized the immunological findings contributing to safety findings following Zolgensma use. Study subjects included all SMA type 1 infants identified between 5/19 to 12/20. In April 2020,
SMA newborn screening was begun in FL, so the study population included patients age 0.5 – 24 mos. All patients qualified for treatment based on Smn2 copy number, CHOP INTEND, and anti-AAV9 antibody <1:50). Importantly, one patient identified as a newborn did not meet initial antibody screening criterial due to passive transfer of maternal antibody vs in utero exposure. Baseline evaluation included clinical assessment, AAV-antibody titer, safety labs, d-dimer and complete complement profile. Post infusion time course was evaluated at 1 hour, 24 hours, 72 hours, 5, 7, 10, 14, 21 and 30 days post infusion.
In 11 patients who underwent standard infusion of Zolgensma, the key laboratory findings of thrombocytopenia and elevated AST/ALT were observed. New findings from assessment of early time points after infusion were consistent across the cohort which ranged in age and body weight between 3.1 kg to 11.7 kg. All subjects showed a rapid onset of IgM antibody response between 3-4 days post infusion followed by rise in IgG titer which increased 10,000 fold from baseline by 30 days. The first observed laboratory abnormality is a decline in platelet count on day 1 followed by positive d-dimer signal at 72 hours post infusion. In all patients, change in d-dimer and onset of increase in IgM results in activation of the classical complement pathway. The single subject who had possible in utero exposure to AAV9 was treated with an immune modulation regimen to block IgM production and attenuate the IgG response. Complement was not activated in this patient. Further investigation of the immune responses following Zolgensma is warranted.