Positive safety and efficacy results announced from the phase III program for onasemnogene abeparvovec (OAV101 IT) in patients aged two to <18 years with spinal muscular atrophy (SMA).-Novartis

 Novartis announced positive safety and efficacy results from the Phase III program for investigational intrathecal onasemnogene abeparvovec (OAV101 IT) in a broad population of patients aged two to <18 years with spinal muscular atrophy (SMA). In the Phase III STEER study, treatment with OAV101 IT led to a statistically significant 2.39-point improvement on the Hammersmith Functional Motor Scale Expanded (HFMSE), a gold standard for SMA-specific assessment of motor ability and disease progression, vs. 0.51 points in the sham control arm (P=0.0074)..In the Phase IIIb STRENGTH study, treatment with OAV101 IT in patients who have discontinued treatment with nusinersen or risdiplam demonstrated stabilization of motor function over 52 weeks of follow-up. These data will be presented during the Muscular Dystrophy Association (MDA) Clinical and Scientific Conference held in Dallas, Texas, from March 16–19, 2025. The results add to the growing body of evidence within the OAV101 IT development program, which has evaluated a broad population of over 170 patients with SMA, spanning a total of over 6.4 years across the STEER, STRENGTH and Phase I/II STRONG studies.

 “In the STEER study evaluating treatment-naïve patients, OAV101 IT demonstrated a statistically significant improvement in motor function across a broad SMA population,” said Crystal Proud, M.D., Pediatric Neurologist and a Principal Investigator at Children's Hospital of the King's Daughters. “These results – paired with those in the STRENGTH study – 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.”

 OAV101 IT is an investigational gene replacement therapy designed to directly address the genetic root cause of the disease by replacing the nonworking SMN1 gene with a single dose. It is the first investigational gene replacement therapy to provide clinical benefit in both children and young adults with SMA with a favorable safety profile, underscoring the potential of this therapy to provide patients the opportunity to avoid repeated treatment administration.

 “The data presented from our OAV101 IT program reinforce our belief in this therapy, which has the potential to have a meaningful impact on a broad range of people with SMA through its continuous benefit via a one-time dose,” said Shreeram Aradhye, M.D., President, Development and Chief Medical Officer, Novartis. “Together with patients, caregivers and healthcareprofessionals, we are committed to continuing to advance our mission to lead innovation in SMA treatment and broaden therapy options with our gene replacement therapies.”

STEER Study; In the registrational STEER study, efficacy and safety were studied in treatment naïve patients with SMA Type 2, aged two to less than 18 years who were able to sit, but had never walked independently. Results for OAV101 IT were compared against a sham control, a procedure designed to mimic the administration of an investigational drug, without delivering any active treatment. One hundred twenty-six (126) patients received either OAV101 IT (n=75) or a sham procedure (n=51). Mean (range) age at dosing was 5.89 (2.1–16.6) years in the treatment group and 5.87 (2.4–14.2) years in the sham arm. At the end of the 52-week period, all eligible patients had received both OAV101 IT and the sham procedure.

Key findings:

• i.The trial met its primary endpoint of change from baseline to 52 weeks in HFMSE score, with OAV101 IT demonstrating a statistically significant 2.39-point improvement on the HFMSE vs 0.51 points in the sham group (overall difference, 1.88 points; P=0.0074).
• ii. All secondary endpoints consistently favor OAV101 IT, despite not achieving statistical significance due to the pre-planned multiple testing procedure.
• iii. The overall incidence of adverse events (AEs), serious AEs (SAEs), and AEs of special interest was similar between both groups.

The most common AEs for both groups in the STEER study were upper respiratory tract infection and pyrexia. The most frequent SAEs were pneumonia and vomiting for the OAV101 IT group and pneumonia and lower respiratory tract infection for the sham group. Instances of transaminase increases were infrequent; most were low-grade and transient. There were no cases of Hy’s law.

 STRENGTH Study; The open label Phase IIIb STRENGTH study evaluated the safety, tolerability and efficacy of OAV101 IT in patients with SMA aged two to less than 18 years who had discontinued treatment with nusinersen or risdiplam. In the study, 27 patients were enrolled with a mean (range) age of 7.4 years (2.4-17.7). Mean duration of prior risdiplam and nusinersen treatment were 2.98 and 4.32 years, respectively.

Key findings:

• i. OAV101 IT demonstrated a favorable safety profile that was consistent with STEER study.
• ii. The motor endpoint of efficacy, HFMSE, demonstrated stabilization for the overall study population over 52 weeks.
  • iii. The increase from baseline to 52 weeks in HFMSE least squares (LS) total score was 1.05.

All patients in the STRENGTH study experienced at least one AE. The most frequent AEs were common cold, pyrexia and vomiting. A total of 13 patients (48.1%) experienced AEs considered to be related to study treatment. No AEs leading to death or study discontinuation were reported.