Positive Safety and Efficacy Data for Intrathecal Administration of Gene Therapy for SMA

Norman Putzki, MD, Global Development Head of Neuroscience and Gene Therapy at Novartis, discusses positive safety and efficacy data for OAV101 IT, an investigational gene therapy for spinal muscular atrophy (SMA). It is similar to Zolensma (onasemnogene abeparvovec) but is administered intrathecally to significantly reduce the dosage needed. SMA is a group of genetic neuromuscular disorders that affect the motor neurons. The loss of motor neurons causes progressive muscle weakness and loss of movement due to atrophy. Many types of SMA mainly affect the muscles involved in walking, sitting, arm movement, and head control. Breathing and swallowing may also become difficult as the disease progresses. SMA type 1, 2, 3, and 4 are caused by genetic changes in the SMN1 gene and extra copies of the nearby related gene, SMN2, modify the severity of SMA. There are other rarer types of SMA caused by changes in different genes. OAV101 IT is an investigational, intrathecal, one-time gene replacement therapy designed to target the genetic cause of SMA through the replacement of the SMN1 gene. Positive safety and efficacy data from the phase 3 clinical trial program testing this treatment was presented at the 2025 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference. Results come from the phase 3 STEER clinical trial and the phase 3b STRENGTH clinical trial Phase 3 STEER Study The STEER study was a registrational study evaluating the safety and efficacy of OAV101 IT in treatment naïve patients ages 2 to less than 18 years with SMA type 2. These patients were able to sit at the time of treatment, but had never walked independently. In total, 126 participants received either OAV101 IT or a sham procedure. Mean age at dosing was 5.89 in the treatment group and 5.87 in the sham group. At the end of a 52-week follow-up period, it was observed that the trial had met its primary endpoint of change from baseline to 52 weeks in Hammersmith Functional Motor Scale Expanded (HFMSE) score, with OAV101 IT at a statistically significant improvement of 2.39 points, compared to 0.51 points in the sham group. Secondary endpoints were also favorable toward OAV101 IT but did not reach statistical significance. Adverse event (AE) incidence was similar in both groups, with the most common AEs being upper respiratory tract infection and pyrexia. The most frequent serious AEs were pneumonia, vomiting, and lower respiratory tract infection. Phase 3b STRENGTH Study The STRENGTH study was an open label study evaluating the safety, efficacy, and tolerability of OAV101 IT in patients ages 2 to less than 18 years with SMA who had discontinued treatment with nusinersen or risdiplam. In total, 27 patients enrolled with a mean age of 7.4 years. The mean duration of prior nusinersen and risdiplam treatment were 4.32 and 2.98 years, respectively. The primary motor endpoint of efficacy as measured by HFMSE, demonstrated stabilization with an increase from baseline to 52 weeks in HFMSE least squares of 1.05. The safety profile remained favorable and consistent with what was observed in the STEER study. All patients in the STRENGTH study experienced at least one AE, with the most frequent being common cold, pyrexia, and vomiting. A total of 13 patients experienced AEs considered related to treatment. Chapters: Introduction 00:00 SMA Pathophysiology 00:24 Benefits of Intrathecal Administration 1:58 Clinical Trials Overview 3:56 Long-Term Follow-Up 5:14 Improvement on Disease Progression 6:48 Forward-Looking Statements 7:56