Novartis data again demonstrate age-appropriate development when Zolgensma is used presymptomatically, and post-hoc data reveal SMA Type 1 patients could speak, swallow and maintain airway protection.

 The completed Phase III SPR1NT study demonstrated that children with three copies of the SMN2 back-up gene who were treated presymptomatically achieved age-appropriate motor milestones , including standing and walking.

In addition, a descriptive post-hoc analyses of START, STR1VE-EU and STR1VE-US (n=65) indicated children with SMA Type 1 achieved or maintained important measures of bulbar function following treatment with Zolgensma, including ability to speak; swallow and meet nutritional needs; and maintain airway protection. These data are among a Zolgensma data set being presented during the 2022 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, which also include, in part, real-world data from the RESTORE registry and a chart review of US patients who changed therapy to Zolgensma.

Without treatment, most children with three copies of the SMN2 back-up gene develop SMA Type 2, characterized by the inability to walk independently. In contrast, 14/15 children (93 percent) in the three-copy cohort of SPR1NT went on to walk independently, most (11/15, 73 percent) within the World Health Organization (WHO) window of normal development. All 15 children (100 percent) met the primary endpoint of standing alone greater than 3 seconds, including 14/15 (93 percent) within the WHO window of normal development. All children were free of feeding tube support and ventilatory support of any kind during the study, and no serious, treatment-related adverse events were reported.

Bulbar motor neurons control muscles required for functions like swallowing, speaking and chewing, and impairment from SMA can lead to choking, malnutrition, infection and death. Given there is no widely accepted definition of bulbar function, a post-hoc analyses of children with SMA Type 1 who received Zolgensma in the START, STR1VE-EU and STR1VE-US studies (n=65) defined bulbar function using a composite endpoint including three key components: communication, swallowing and maintenance of airway protection. Of the patients that could be retrospectively and descriptively assessed against all components, 80 percent (16/20) achieved the composite endpoint.

Final SPR1NT Three-Copy Cohort Results : SPR1NT is a Phase III, open-label, single-arm, multi-centre trial designed to evaluate the safety and efficacy of a one-time intravenous infusion of Zolgensma in presymptomatic patients with a genetic diagnosis of SMA and two or three copies of SMN2 who were less than 6 weeks of age. Mean age at dosing in the three-copy cohort was 28.7 days (9–43 days). Fourteen patients with two copies of SMN2 and 15 patients with three copies of SMN2 were treated. Most patients ( greater than 80 percent) with three copies of SMN2 develop SMA Type 2, which accounts for 30 percent of SMA cases. According to natural history, patients with SMA Type 2 never walk independently without intervention.

Three-copy cohort (n=15) final results : • One hundred percent of patients (15/15) met the primary endpoint of standing unassisted for greater than 3 seconds by 24 months of age, including 14 who achieved this milestone within the WHO window of normal development.• Fourteen patients (93 percent) walked independently, 11 of whom achieved this milestone within the WHO window of normal development. • All patients (100 percent) were independent of nutritional and respiratory support for the duration of the study. All patients experienced at least one adverse event (AE) after dosing, eight (53 percent) of which were considered to be treatment-related. There were no serious, treatment-related AEs. Three patients were reported to have had serious adverse events (SAEs), all of which resolved and were not related to treatment.

The final results from the SPR1NT two-copy cohort were presented during the European Academy for Neurology (EAN) Virtual Congress 2021. Bulbar Function Post-Hoc Analysis : The post-hoc analyses descriptively assessed pooled data from one Phase 1 (START) and two Phase III (STR1VE-EU and STR1VE-US) studies to evaluate components of bulbar function in children with symptomatic SMA Type 1 after receiving Zolgensma. Bulbar function was defined as integrity within cranial nerves that enables an individual to speak with comprehension by an unknown listener, swallow food and liquids, and meet nutritional needs while maintaining airway protection. The study retrospectively assessed the percentage of patients who achieved each endpoint and all three endpoints at predetermined times or at the end of the study (24 months of age in START and 18 months of age in STR1VE-EU and STR1VE-US). Summary analysis : • Overall, 65 patients aged <6 months at time of zolgensma treatment were analyzed. • sixty-five patients were analyzed for swallowing (start [n="11];" str1ve-eu [n="32];" str1ve-us [n="22])." communication was only assessed for patients from native english-speaking families in start and str1ve-us; not all patients had outcomes for all three measures (start [n="4];" str1ve-us [n="16])." • ninety-five percent (19 20) met the communication endpoint. • ninety-two percent (60 65) had at least one occurrence of a normal swallow test. • ninety-two percent (60 65) did not report any event indicating the inability to maintain airway protection.• overall, 80 percent (16 20) achieved the composite endpoint of having the ability to speak, being able to swallow normally, and maintaining airway protection.></6>

See-Strauss K. et al." Onasemnogene Abeparvovec in Presymptomatic Spinal Muscular Atrophy: SPR1NT Study Update in Children with Three Copies of SMN2". Abstract presented at the 2022 MDA Clinical & Scientific Conference. 13-16 March 2022.