Novartis Advances Intrathecal Zolgensma for Older SMA Patients, Showing Promise in Phase 3 Trials

Novartis has unveiled encouraging results from two pivotal clinical trials evaluating an intrathecal formulation of its gene therapy Zolgensma for older patients with spinal muscular atrophy (SMA). The data, set to be presented at the Muscular Dystrophy Association's annual conference, support the potential for this new administration route to expand treatment options for a broader range of SMA patients.

Steer Trial Demonstrates Significant Motor Function Improvement

The phase 3 Steer trial, which enrolled treatment-naïve SMA patients aged 2 to below 18 years, showed that intrathecal Zolgensma (coded OAV101 IT) led to a 2.39-point improvement on the Hammersmith Functional Motor Scale Expanded (HFMSE) one year after treatment. This improvement was statistically significant compared to the 0.51-point improvement observed in the sham control group.

The HFMSE, a clinically validated scale for evaluating motor ability in SMA types 2 and 3, has a maximum score of 66, with higher scores indicating better motor function. A change above two points is generally considered clinically relevant, underscoring the importance of the Steer trial results.

Dr. Crystal Proud, a principal investigator at the Children's Hospital of the King's Daughters, stated, "Findings from the two trials support the potential for OAV101 IT to be a meaningful treatment option for people living with SMA with a goal of maintaining or improving motor function through a one-time therapy."

Strength Trial Shows Promise for Treatment-Experienced Patients

In the phase 3b Strength trial, Novartis tested intrathecal Zolgensma in patients aged 2 to less than 18 years who had previously tried but discontinued treatment with Biogen's Spinraza or Roche's Evrysdi. Results demonstrated consistent safety with the Steer trial and stabilization in motor function over a one-year period.

Treatment-experienced patients in the Strength trial saw incremental gains of an average 0.17 points and overall stable motor function as measured by HFMSE. Dr. Norman Putzki, who heads up neuroscience drug development at Novartis, emphasized the significance of these results, noting that the one-time gene therapy could reduce the burden of chronic treatment while providing favorable safety and motor function stabilization.

Safety Profile and Regulatory Plans

The most frequent side effects of intrathecal Zolgensma were respiratory infections, fever, and vomiting. Liver toxicity, a known concern with intravenous Zolgensma, was observed at similar rates in the Steer trial for both the treatment and control groups (9.3% and 9.8%, respectively). Most liver enzyme increases were mild and transient, with no cases meeting Hy's law criteria for serious drug-induced liver injury.

Novartis plans to file the intrathecal form of Zolgensma with regulatory agencies in the first half of 2025. The company estimates that intrathecal Zolgensma could become a multibillion-dollar product at peak, potentially expanding treatment options for older SMA patients who cannot receive the current intravenous formulation due to weight restrictions.