Onasemnogene abeparvovec gene replacement therapy for spinal muscular atrophy in children: a Moscow experience

OBJECTIVE: To assess the efficacy and safety of onasemnogene abeparvovec (OA) in children with spinal muscular atrophy (SMA) treated between 2021 and 2025 at a Moscow regional rare disease referral center (Morozov Children's City Clinical Hospital). MATERIAL AND METHODS: This study included 20 children with a confirmed diagnosis of 5q spinal muscular atrophy (SMA). Safety was evaluated in all 20 patients for up to 3.5 years following treatment, with adverse events graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v.5.0. Efficacy was analyzed in 16 patients at 8 to 37 months post-injection. Motor function was assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), while general motor development was evaluated using the Hammersmith Infant Neurological Examination, Section 2 (HINE-2). Key motor milestones were compared to established World Health Organization (WHO) norms. Data was analyzed by stratifying patients into two groups: those identified through expanded newborn screening (Group 1) and those diagnosed via high-risk screening (Group 2). RESULTS: In Group 1, the mean age at treatment initiation was 1.9 (1.4-2.8) months, with a mean weight of 4.8 (3.7-6.25) kg. In Group 2, the mean age at treatment was 14.8 (5.5-47) months, with a mean weight of 9 (6-13.7 )kg. Within one week post-OA administration, most patients (19/20) experienced clinical symptoms, including hyperthermia (Group 1: 8/9; Group 2: 10/11), increased regurgitation/vomiting (Group 1: 5/9; Group 2: 6/11), and decreased appetite/refusal to feed (Group 1: 3/9; Group 2: 9/11). These symptoms were more severe in Group 2, requiring intravenous and symptomatic therapy, nasogastric tube placement, and parenteral nutrition in some cases. Grade 1-2 thrombocytopenia (CTCAE v.5) was observed one week post-OA in three patients from Group 2. Elevated hepatic transaminases were observed in 16/20 children: Group 1 - 6/9 (66%), Group 2 - 10/11 (90%). In Group 1, all children experienced Grade 1 elevations (CTCAE v.5), while in Group 2, 6 children had Grade 1 elevations (54%), 2 had Grade 2 (18%), 1 had Grade 3 (9%), and 1 had Grade 4 (>20x ULN) (9%). Asymptomatic troponin I elevations were recorded in 6 children from Group 1 and 4 from Group 2. The median duration of prednisolone administration was 13 weeks (8-24) in Group 1 and 21 weeks (12-42) in Group 2. In Group 1, the mean CHOP INTEND score increased by 11.5 at 4 months, the HINE-2 score increased by 10.5 points at 4 months and 15.5 points at 6 months from baseline; all children achieved main motor milestones according to WHO norms. In Group 2, the mean CHOP INTEND score increased by 4 at 6 months and 7.2 points at 12 months from baseline; the HINE-2 score increased by 2.3 points at 6 months and 4.7 points at 12 months from baseline; five children improved their functional status, and 6/9 children acquired new motor skills. CONCLUSION: This study presents the findings of a long-term assessment of the efficacy and safety profile of drug OA in pediatric patients across various age groups and functional ability levels, including individuals identified through expanded newborn screening. Younger patients exhibited a significantly lower incidence of adverse events and demonstrated superior therapeutic efficacy. The majority of older children experienced either positive progression or stabilization of their condition, outcomes that were largely contingent upon their initial functional status and the duration of the pre-treatment waiting period.