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Novartis has presented new clinical data on gene therapy (onasemnogen abeparvovec), a one time treatment for spinal muscular atrophy (SMA). The completed phase III SPR1NT clinical trial showed that children with three copies of the SMN2 backup gene, treated with pre-symptomatology, achieved key motor development stages appropriate for their age, including standing and walking skills2. In addition, post hoc analyzes of data from the START, STR1VE-EU and STR1VE-US studies (n = 65) showed that children with SMA type 1 achieved or maintained significant indicators of bulb function after gene therapy, including the ability to speak, swallow, and meet needs. nutritional and maintaining an open airway 3. This information was presented at the 2022 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, and included partial actual clinical practice data from the RESTORE Registry, and a review of US patient records who switched from SMA treatment to gene therapy.
Untreated children with three backups of the SMN2 gene develop SMA type 2, a form of the disease that manifests itself in the stage of sitting alone without support and the vast majority of them cannot stand and walk on their own. 2 out of 2 children (1%) learned to walk independently, and most of them (14 out of 15, i.e. 93%) achieved this ability in the development window, i.e. at the time when this ability is achieved by healthy peers (according to the adopted classification in child development according to the World Health Organization – WHO). All 11 children (15%) achieved the primary endpoint of standing for ≥ 73 seconds, and 15 of 100 children (3%) achieved this ability in the WHO window of development. In addition, none of the children in this group required feeding and respiratory support throughout the study. There were also no serious adverse events related to the treatment (gene therapy) used.
«The results of the SPR1NT study again confirm the significant effect of onasemnogen abeparvovec when used in children at risk of developing SMA who are treated before symptoms develop. In contrast to the natural course of SMA, children treated with gene therapy for prophylaxis acquire standing and walking skills with little or no symptoms of neuromuscular disease. Many of these children achieve patterns of motor development that are not different from those seen in healthy peers without SMA »says the drug. Kevin Strauss, MD, Medical Director of the Clinic for Special Children in Pennsylvania. “These data clearly demonstrate the value of screening newborns for SMA so that the disease is diagnosed at an early stage, allowing treatment to be started to ensure the best possible outcomes”.
The bulb’s motor neurons control the muscles needed to carry out activities such as swallowing, speaking and chewing, while SMA-related disability can lead to choking, malnutrition, infection and death3. Given that there is no universally accepted definition of bulb function, post hoc analyzes of data on children with SMA type 1 who received gene therapy in the START, STR1VE-EU and STR1VE-US studies (n = 65) adopted a definition of bulb function. based on a composite endpoint with three main components: communication, swallowing and airway maintenance. Of the patients who could retrospectively and descriptively assess all components, 80% (16/20) achieved the composite endpoint.
«The effect of type 1 SMA on bulb function often leads to debilitating complications such as an increased risk of aspiration as well as the social consequences of impaired speech development. These data from a post hoc analysis suggest that gene therapy may have a significant impact on the child’s well-being »says the drug. Shephard Mpofu, MD, senior vice president and medical director of Novartis Gene Therapies. “The additional data presented reinforce the consistent, meaningful and clinically relevant therapeutic benefits of applying gene therapy in real-world clinical practice, including patients not treated in clinical trials.”
Final results for the triple gene copy group of the SPR1NT study
SPR1NT is a Phase III, open-label, multicentre, single-arm study designed to evaluate the safety and efficacy of a single gene therapy infusion in presymptomatic patients ≤ 6 weeks of age with a diagnosis of SMA based on genetic testing and the presence of two or three copies of the SMN22 gene. The mean age at the time of administration of gene therapy in the group of patients with three gene copies was 28,7 days (9–43 days). 14 patients with two copies of the SMN2 gene and 15 patients with three copies of the SMN2 gene were treated. Most patients (> 80%) with three copies of the SMN2 gene develop type 2 SMA, which accounts for 30% of all SMA2 cases. According to the natural course of the disease, type 2 patients with SMA never acquire the ability to walk independently without intervention.
Final results for the group of patients with three gene copies (n = 15):
- 100% of patients (15/15) achieved the primary endpoint of standing for ≥ 3 seconds by age 24 months alone, while 14 of these reached this key developmental stage in the WHO development window.
- Fourteen patients (93%) acquired the ability to walk independently, 11 of whom reached this key developmental stage in the WHO development window.
- All patients (100%) did not require respiratory or nutritional support during the study period4.
All patients experienced at least one adverse event (AE) post-dose – 8 (53%) were considered treatment related4. There were no treatment-related serious adverse events. Three patients experienced serious adverse events (SAEs), all resolved and not related to treatment.
The final results for patients with two copies of the SPR1NT gene were presented at the European Academy for Neurology (EAN) virtual congress in 2021. For more information, see here.
Post hoc analysis of the pad activity
Post hoc analyzes were performed descriptively of pooled data from one Phase I (START) and two Phase III studies (STR1VE-EU and STR1VE-US) to evaluate the components of bulb function in children with symptomatic type 1 SMA following gene therapy 3. Bulb function has been defined as integrity within the cranial nerves that allows the patient to communicate through speech comprehension with a stranger, swallow food and fluids, and meet nutritional needs while maintaining an open airway. The study retrospectively looked at the proportion of patients who achieved each endpoint and all three endpoints at predetermined time or post-study completion (24 months in START and 18 months in STR1VE-EU and STR1VE-US).
- A total of 65 patients aged <6 months at the time of treatment with gene therapy were analyzed.
- Sixty-five patients were analyzed for swallowing (START [n = 11]; STR1VE-EU [n = 32]; STR1VE-US [n = 22]). In the START and STR1VE-US studies, communication skills were assessed only in patients from families whose mother tongue is English; not all patients achieved results for all three assessment measures (START [n = 4]; STR1VE-US [n = 16]).
- Ninety-five percent of patients (19/20) achieved the endpoint of communication skills.
- Ninety-two percent of the patients (60/65) had at least one normal swallowing result.
- Ninety-two percent of patients (60/65) did not report any event indicative of an inability to maintain an open airway.
- Overall, 80% of patients (16/20) achieved the composite endpoint of the ability to speak, the ability to swallow properly and the ability to maintain an open airway.
About gene therapy
Onasemnogen abeparvovec is the only approved gene therapy for the treatment of spinal muscular atrophy (SMA) and the only treatment for SMA that aims to directly eliminate the genetic cause responsible for disease development by restoring the missing or non-functional SMN1 gene activity with a single single intravenous infusion to inhibit disease progression by stably expressing the SMN protein. Gene therapy is now approved in over 40 countries, and more than 2000 patients worldwide have been treated with the drug in clinical trials, controlled access programs and commercial settings1. Novartis Gene Therapies is successively committed to improving the treatment options for children with SMA and continues to evaluate the use of gene therapy in its clinical trial program, as well as investigating the intrathecal route of OAV101 administration in patients with late-onset SMA.
Novartis Gene Therapies holds – with Nationwide Children’s Hospital – an exclusive worldwide license for AAV9 gene therapy intravenous and intrathecal administration for the treatment of all types of SMA, an exclusive worldwide license from REGENXBIO to use any recombinant AAV vector in its proprietary portfolio in as part of in vivo gene therapy for the treatment of SMA in humans, an exclusive worldwide license agreement with Genethon for the in vivo introduction of the AAV9 vector into the central nervous system for the treatment of SMA and a non-exclusive worldwide license agreement with AskBio for the use of its auto-complementary DNA technology in treat SMA.