Spinal Muscular Atrophy (SMA) is a rare neuromuscular disease that causes progressive muscle weakness and affects the ability to breathe, swallow, and move. It is a severe condition caused by a defect in the SMN1 gene, for which therapeutic options have previously been limited, especially for older children.
A single intrathecal (into the space surrounding the spinal cord) injection of the new gene therapy drug, OAV101 IT, significantly improves motor function in children and adolescents with SMA aged over 2 years. It utilizes the active component of Zolgensma (the gene delivery vector). The intrathecal route of administration reduces the systemic spread of the viral vector and side effects. The safety of this approach was previously confirmed in the STRONG study (in patients aged 6 months to 5 years).
Study Details:
The clinical trial evaluated OAV101 IT—a gene replacement therapy designed for patients with SMA aged 2 to 18 years(mean years) who have the ability to sit but have never walked independently.
To assess efficacy, a Phase 3 controlled STEER study was conducted, where a single dose of the medication was compared to a placebo (sham treatment) in 126 patients. Importantly, the study included patients who had not previously received any approved medication for SMA.
In the study, 75 patients received one dose of OAV101 IT, while 51 received a placebo. Patients were observed for 52 weeks. At the start of the study, the distribution of disability was largely equal between the groups: the baseline score of the Hammersmith Functional Motor Scale Expanded (HFMSE) was 18 in both groups, and the score for the Revised Upper Limb Module (RULM) was 17. These details confirm that the groups were evenly distributed regarding age and genetic characteristics before starting treatment.
Earlier gene therapy medication, such as Zolgensma, was intended for children under 2 years of age and administered intravenously. Other therapeutic agents, such as Nusinersen, require repeated intrathecal injections, and Risdiplam must be taken orally daily.
Against the background of these medications, OAV101 IT represents a single-dose gene therapy. Its main advantage lies in the route of administration: the fixed dose is delivered directly to the spinal cord, making it suitable for older children, regardless of their weight and age. The improvement in motor function after receiving OAV101 IT begins from the 4th week and this positive effect is stably maintained for one year (during the course of the study). Its approval by the U.S. Food and Drug Administration (FDA) under the name Itvisma is indeed a significant achievement for patients with SMA.
Study Results:
Motor function in the therapy group increased by points, compared to in the placebo group.
Hand motor skills also significantly improved: the increase in the therapy group was points, compared to in the placebo group.
A difference also emerged between the age subgroups:
In the younger group ( years), HFMSE increased by points ( compared to placebo).
In the older group ( years), an increase of points was recorded, while the placebo group showed a significant decline in this parameter (). This result effectively signifies the halt of disease progression and an improvement in function.
Safety Profile and Side Effects
The frequency of overall adverse events (AEs) was almost similar in both groups (97% in the therapy group and 90% in the placebo group). Serious adverse events (SAEs) were less frequent in the therapy group (28% versus 33%). The most commonly reported were respiratory tract infections and fever, which are typical for patients with SMA. It was also noted that vomiting developed more frequently after intrathecal injection (15% versus 2%).
Special attention was paid to potential risks:
Hepatotoxicity (Liver Damage): Reported in 9% in both groups, manifested as a mild, temporary elevation of liver transaminases.
Thrombocytopenia: A temporary decrease in platelets was noted in the first week of treatment.
Special caution was exercised regarding potential damage to the Dorsal Root Ganglion (DRG). Signs of DRG damage were rarely observed and manifested as paresthesia (specifically, a tingling sensation) in 2 children in the therapy group and 1 child in the placebo group. These events stabilized with subsequent treatment.
No severe complications, such as severe liver failure (Hy’s law) or oncological events, were recorded in the study.
Experts believe that OAV101 IT is a significant turning point in SMA management. The drug specifically acts on nerve cells and contributes to halting disease progression in older patients.
Source: nature medicine
