Sitra Tauscher-Wisniewski, MD, Vice President of Clinical Development & Analytics at Novartis Gene Therapies, discusses long-term data for onasemnogene abeparvovec (Zolgensma), an FDA-approved gene therapy for spinal muscular atrophy (SMA).
SMA is a genetic disease that affects motor neurons in the spinal cord and control of muscle movement. It is caused by a mutation in the survival motor neuron gene 1 (SMN1) which affects nerve cells and leads to loss of muscle function. The codes for the SMN protein appear to play a role in regulating small nuclear ribonucleoproteins complexes. Lack of that protein leads to cellular imbalances causing the motor neuron endplates to not properly connect to muscle and the motor neurons die.
As Dr. Tauscher-Wisniewski explains, at the 2023 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, the latest data from two long-term follow-up studies of onasemnogene abeparvovec, LT-001, and LT-002, were presented. These data show the continued efficacy and durability of the gene therapy across a range of SMA populations.
Study:
LT-001 is an ongoing long-term follow-up study of patients with SMA who completed the phase 1 START study. Data from this study showed that up to 7.5 years post-dosing, all children who were treated after presenting symptoms of SMA (10/10; 100%) maintained all previously achieved motor milestones. Additionally, all patients (100%) were alive and free of permanent ventilation; Seven patients (70%) of patients did not require regular, daily ventilatory support with BiPAP. All patients were fed orally, with four (40%) not requiring any feeding support. Finally, three patients achieved the milestone of “standing with assistance.” Two of these three patients achieved this milestone without add-on therapy, and the remaining patient achieved it after the addition of nusinersen.
LT-002 is an ongoing follow-up safety and efficacy study of patients with SMA given either onasemnogene abeparvovec given intravenously (IV) or investigational OAV101 intrathecal injection (IT) while enrolled previously in clinical trials.
In the IV cohort (n=63), 39.7% were treated prior to SMA symptom onset (“presymptomatic”) while 60.3% were treated after SMA symptom onset. The mean age of patients was 3.7 years with a mean follow-up of 3.4 years. In the presymptomatic IV cohort, four patients who did not achieve the motor milestone of “walks alone” in the parent study achieved this milestone during the follow-up period. Additionally, motor milestones such as “crawls” and “pulls to stand” were also achieved in the presymptomatic IV cohort during the follow-up period. Out of 36 symptomatic patients in LT-002, 32 (88.9%) achieved or maintained the milestone of “sitting without support.”
For patients in this cohort with at least two assessments available, clinically significant improvement of three or more points on the Hammersmith Functional Motor Scale Expanded (HFMSE) was demonstrated in 13 (81.3%) patients treated prior to SMA symptom onset and 18 (66.7%) patients treated after SMA symptom onset.
In the IT cohort (n=18), the data showed that the mean patient age was 5.3 years with a mean follow-up of 3.6 years. In the follow-up period, all patients (100%) in this cohort continued to show incremental gains and stability in motor function with the achievement of new motor milestones and maintenance of previously achieved milestones. For patients with at least two assessments available, six of 12 (50%) demonstrated a clinically significant improvement of three or more points in HFMSE. Three patients (25%) had more than a 10-point improvement.
Five of 16 patients (31.3%) with at least one milestone assessment achieved a new motor milestone in LT-002.
For more information about SMA and other rare neuromuscular disorders, visit checkrare.com/diseases/musculoskeletal-diseases.
