Onasemnogene abeparvovec is clinically beneficial across a broad population of patients with SMA.Intrathecal onasemnogene abeparvovec (OAV101 IT), a one-time gene transfer therapy, significantly improves motor function in treatment-naïve patients with spinal muscular atrophy (SMA), as shown by the period 1 results of the phase III STEER study.
At week 52, the OAV101 IT group had a greater change from baseline in Hammersmith Functional Motor Scale-Expanded (HFMSE) score than the sham group (2.39 vs 0.51 points; p=0.0074). The greater improvement with OAV101 IT was observed as early as week 4 and continued through week 52. [Nat Med 2026;32:481-487]
Secondary endpoints
The secondary efficacy endpoints did not achieve statistical significance according to the prespecified multiple-testing strategy, but numerical advantages were observed with OAV101 IT vs sham.
Overall, the change in Revised Upper Limb Module (RULM) score from baseline to week 52 was greater with OAV101 IT than with sham (2.44 vs 0.92; p=0.0122). This was also seen as early as week 4 and continued through week 52.
The advantages of OAV101 IT over sham were evident in children aged 2 to <5 years (HFMSE: 3 vs 1.56; p=0.1097; RULM: 3.27 vs 1.82; p=0.0873) and in those aged 5 to <18 years (1.60 vs −0.86 and 1.42 vs −0.31, respectively).
There were more HFMSE 3-point responders in the OAV101 IT group than the sham group at week 52 in the overall cohort (39.2 percent vs 26 percent; odds ratio [OR], 2.03; p=0.0879) and in both younger (48.8 percent vs 37.9 percent; OR, 1.27; p=0.6448) and older subgroups (27.3 percent vs 9.5 percent).
Safety profile
The OAV101 IT and sham groups had similar rates of adverse events (AEs; 97.3 percent and 90.2 percent), serious AEs (SAEs; 28 percent and 33.3 percent), and AEs of special interest (AESIs; 16 percent and 13.7 percent). With OAV101 IT, the most frequent AEs were upper respiratory tract infection (a known SMA comorbidity) and transient pyrexia, and the most frequent SAEs were pneumonia and vomiting.
The incidence of vomiting (within 72 hrs after administration) was higher with OAV101 IT than sham (14.7 percent vs 2 percent). Of note, vomiting is a known complication of lumbar puncture and a potential AE of OAV101 IT.
Regarding AESIs with OAV101 IT, the most common was hepatotoxicity (9.3 percent), followed by transient thrombocytopenia (5.3 percent) and signs/symptoms suggestive of dorsal root ganglia toxicity (2.7 percent). There were no cardiac AEs, thrombotic microangiopathy, or new malignancies in either group.
“The overall safety findings were acceptable [and indicate] a favourable benefit−risk profile,” the researchers said.
Single therapy with a fixed dose
Nusinersen and risdiplam are two currently available treatments for SMA, but both require lifelong administration, which may be met with noncompliance, the researchers noted.
“OAV101 IT offers a fixed dose that reduces systemic viral vector exposure, making it a potential one-time treatment for a broad range of SMA patients regardless of age and weight,” they said.
The study included 126 SMA patients aged 2 to <18 years (mean age at dosing 5.88 years, 50.8 percent female) who were sitting but had never walked independently. In period 1, the participants were randomized 3:2 to OAV101 IT or sham and followed until week 52. After completing period 1, eligible participants entered period 2, wherein treatment was switched. Approximately 94 percent of participants had three SMN2 gene copies.
“[The findings] demonstrate the clinical benefits of OAV101 IT across a broad SMA population spanning a wide range of ages and baseline motor function levels,” the researchers said.