On 30 December 2024, Novartis reported that its intrathecal (IT) formulation of onasemnogene abeparvovec (OAV101 IT) reached its primary endpoint in a Phase III study in paediatric patients aged two to 17 with type II spinal muscular atrophy (SMA). The positive data could expand the eligible patient population for gene transfer therapy (STEER).
Novartis’ Zolgensma, an intravenous (IV) formulation of onasemnogene abeparvovec, received US Food and Drug Administration (FDA) approval in 2019 and represents the first and only gene transfer therapy for the treatment of SMA. However, the eligible patient population indicated for Zolgensma is restricted to paediatric patients less than two years of age with SMA with biallelic mutations in the survival motor neuron 1 gene. In the STEER study, OAV101 IT demonstrated clinical benefit in treatment-naive type II SMA patients aged 2-17 who were able to sit but had never walked independently. Patients who received OAV101 IT treatment showed an increase from baseline across the study population in total Hammersmith Functional Motor Scale-Expanded scores compared to the control arm who received a sham procedure.
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The safety profile of OAV101 IT was favourable in the STEER trial, with overall adverse events and serious adverse events comparable in the investigational and control arms. The most common adverse events were upper respiratory tract infection, pyrexia, and vomiting. However, safety concerns have previously been raised with OAV101 IT. In 2019, the FDA implemented a partial clinical hold on OAV101 IT due to a preclinical study in which animal findings showed dorsal root ganglia (DRG) mononuclear cell inflammation, which was sometimes accompanied by neuronal cell body degeneration or loss. However, the clinical hold was lifted on the IT formulation in August 2021 based on nonclinical data from a toxicology study in nonhuman primates that addressed safety concerns relating to the risk of DRG injury following IT administration. Novartis plans to share STEER results with regulatory agencies, including the FDA, in 2025. If approved, OAV101 IT could broaden the patient population eligible for gene transfer therapy to include type II SMA patients under 18 years of age. However, key opinion leaders (KOLs) previously interviewed by leading data and analytics company GlobalData noted that the implementation of newborn screening (NBS) initiatives in their countries has greatly facilitated disease detection during the presymptomatic stage and has enabled many eligible patients to receive Zolgensma. As such, the availability of OAV101 IT would be most beneficial to patients where NBS for SMA is not yet adopted in their country or for patients who received a delayed diagnosis. KOLs added that OAV101 IT would be welcomed by patients due to its treatment convenience of a one-time infusion, compared to Biogen’s once-quarterly IT administration of Spinraza and Roche’s once-daily Evrysdi. According to GlobalData’s report Spinal Muscular Atrophy: Opportunity Assessment and Forecast, the combined sales of IT and IV formulations of onasemnogene abeparvovec are projected to increase from $660.6m in 2023 to $763.8m by 2033 in the seven major markets (7MM: US, France, Germany, Italy, Spain, UK, and Japan) due to the growing awareness of SMA and the implementation of NBS across the markets, coupled with an increase in the eligible population for gene transfer therapy.
