Onasemnogene abeparvovec in spinal muscular atrophy: predictors of efficacy and safety in naïve patients with spinal muscular atrophy and following switch from other therapies

Pane, Marika; Berti, Beatrice; Capasso, Antonio; Coratti, Giorgia; Varone, Antonio; D’Amico, Adele; Messina, Sonia; Masson, Riccardo; Sansone, Valeria; Agosto, Caterina; Bruno, Claudio; Ricci, Federica; Pini, Antonella; Gagliardi, Delio; Filosto, Massimiliano; Corti, Stefania; Leone, Daniela; Palermo, Concetta; Onesimo, Roberta; Sanctis, Roberto De; Ricci, Martina; Bitetti, Ilaria; Sframeli, Maria; Dosi, Claudia; Albamonte, Emilio; Ticci, Chiara; Brolatti, Noemi; Bertini, E.; Finkel, Richard S.; Pera, Maria Carmela; Bravetti, Chiara; Piastra, Marco; Genovese, Orazio; Cicala, Gianpaolo; Forcina, Nicola; Carnicella, Sara; Stanca, Giulia; Sacchini, Michele; Catteruccia, Michela; Tosi, Michele; Cutrera, Renato; Chierchi, Claudio; Chiarini, Maria Beatrice; Salmin, Francesca; Pedemonte, Marina; Govoni, Alessandra; Mizzoni, Irene; Morando, Simone; Zanin, Riccardo; Rolle, Enrica; Salomon, Eleonora; Giannotta, Melania; Scarpini, Gaia; Toscano, Antonio; Gitto, Eloisa; Materia, Roberto; D’Alessandro, Rossella

doi:10.1016/j.eclinm.2023.101997

Cited by 20 publications

(10 citation statements)

References 29 publications

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“…Real-world evidence of 21 patients aged ≥2 years at onasemnogene abeparvovec infusion reported an estimated 3.8-point gain in CHOP-INTEND scores after gene therapy (follow-up duration not reported) ( 25 ). A separate study ( 22 ) reported an increase of 5.1 points in mean CHOP-INTEND scores from baseline to 12 months (47.1 vs. 52.2 points, respectively) in 19 SMA type 1 patients with ≥2 SMN2 copies aged >2 years at onasemnogene abeparvovec treatment, which is similar to the 7.7-point increase reported here (46.0 vs. 53.7 points from baseline to 12 months, respectively). Our study also showed new motor milestones, improved language ability, and increased developmental quotient scores in most Griffiths III subscales at 12 months, however, most scores were clinical (< 70) indicating that these patients have an overall developmental delay.…”

Section: Discussionsupporting

confidence: 81%

Motor and neurocognitive profiles of children with symptomatic spinal muscular atrophy type 1 with two copies of SMN2 before and after treatment: a longitudinal observational study

Bitetti,

Manna,

Stella

et al. 2024

Front. Neurol.

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IntroductionSpinal muscular atrophy (SMA) is a neurodegenerative disease caused by mutations in the survival motor neuron 1 (SMN1) gene. In clinical studies, gene replacement therapy with onasemnogene abeparvovec (formerly AVXS-101, Zolgensma®, Novartis) was efficacious in improving motor functioning in children with SMA. However, its effects on cognitive and language skills are largely unknown.MethodsThis longitudinal observational study evaluated changes in motor and neurocognitive functioning over a 1-year period after administration of onasemnogene abeparvovec in 12 symptomatic SMA type 1 patients with two copies of SMN2 aged 1.7–52.6 months at administration. Motor functioning was measured using the Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND) while neurocognitive assessment was measured using Griffiths III. Motor milestones and language ability were also assessed at each timepoint.Results and discussionStatistically significant increases in median CHOP-INTEND scores from baseline were observed at 1, 3, 6, and 12 months after onasemnogene abeparvovec administration (all p ≤ 0.005). Most (91.7%) patients were able to roll over or sit independently for >1 min at 12 months. Significant increases in the Griffiths III Foundations of Learning, Language and Communication, Eye and Hand Coordination, and Personal-Social-Emotional subscale scores were observed at 12-months, but not in the Gross Motor subscale. Speech and language abilities progressed in most patients. Overall, most patients showed some improvement in cognitive and communication performance after treatment with onasemnogene abeparvovec in addition to significant improvement in motor functioning and motor milestones. Evaluation of neurocognitive function should be considered when assessing the global functioning of patients with SMA.

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Section: Discussionsupporting

confidence: 81%

Motor and neurocognitive profiles of children with symptomatic spinal muscular atrophy type 1 with two copies of SMN2 before and after treatment: a longitudinal observational study

Bitetti,

Manna,

Stella

et al. 2024

Front. Neurol.

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“…On the other hand, there is increasing real world evidence of infants with 4 SMN2 treated after their identification on screening, [10][11][12] but a general consensus on the need to treat them has not been yet formulated. In 2018 a US based working group developed a treatment algorithm for infants identified by newborn screening (NBS) suggesting to treat as early as possible all infants with 3 or fewer SMN2 copies.…”

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confidence: 99%

Clinical Phenotype of Pediatric and Adult Patients With Spinal Muscular Atrophy With Four SMN2 Copies: Are They Really All Stable?

Ricci,

Cicala,

Capasso

et al. 2023

Annals of Neurology

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ObjectiveThe aim of this study was to provide an overview of the clinical phenotypes associated with 4 SMN2 copies.MethodsClinical phenotypes were analyzed in all the patients with 4 SMN2 copies as part of a nationwide effort including all the Italian pediatric and adult reference centers for spinal muscular atrophy (SMA).ResultsThe cohort includes 169 patients (102 men and 67 women) with confirmed 4 SMN2 copies (mean age at last follow‐up = 36.9 ± 19 years). Six of the 169 patients were presymptomatic, 8 were classified as type II, 145 as type III (38 type IIIA and 107 type IIIB), and 8 as type IV. The remaining 2 patients were asymptomatic adults identified because of a familial case. The cross‐sectional functional data showed a reduction of scores with increasing age. Over 35% of the type III and 25% of the type IV lost ambulation (mean age = 26.8 years ± 16.3 SD). The risk of loss of ambulation was significantly associated with SMA type (p < 0.0001), with patients with IIIB and IV less likely to lose ambulation compared to type IIIA. There was an overall gender effect with a smaller number of women and a lower risk for women to lose ambulation. This was significant in the adult (p = 0.009) but not in the pediatric cohort (p = 0.43).InterpretationOur results expand the existing literature on natural history of 4 SMN2 copies confirming the variability of phenotypes in untreated patients, ranging from type II to type IV and an overall reduction of functional scores with increasing age. ANN NEUROL 2023

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“…[53][54][55] Additionally, some studies have evaluated the use of onasemnogene abeparvovec in patients who had previously been treated with other specific therapies, such as nusinersen or Risdiplam. 53,54 The SPR1NT phase 3 study has provided crucial evidence on the efficacy of gene replacement therapy in pre-symptomatic children with SMA. 56,57 In children with three SMN2 copies, all 15 participants stood independently before 24 months, within the expected developmental window.…”

Section: Sod1-alsmentioning

confidence: 99%

“…51,52 Real-world studies have confirmed the efficacy of the gene replacement therapy in an expanded age range of patients eligible for treatment, including those up to two years old, and also patients with three copies of SMN2, regardless of the type of SMA. [53][54][55] Additionally, some studies have evaluated the use of onasemnogene abeparvovec in patients who had previously been treated with other specific therapies, such as nusinersen or Risdiplam. 53,54 The SPR1NT phase 3 study has provided crucial evidence on the efficacy of gene replacement therapy in pre-symptomatic children with SMA.…”

Section: Sod1-alsmentioning

confidence: 99%

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Gene-based therapies for neuromuscular disorders

Zanoteli,

França,

Marques

2024

Arq Neuropsiquiatr

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Neuromuscular diseases (NMD) include a broad group of medical conditions with both acquired and genetic causes. In recent years, important advances have been made in the treatment of genetically caused NMD, and most of these advances are due to the implementation of therapies aimed at gene regulation. Among these therapies, gene replacement, small interfering RNA (siRNA), and antisense antinucleotides are the most promising approaches. More importantly, some of these therapies have already gained regulatory approval or are in the final stages of approval. The review focuses on motor neuron diseases, neuropathies, and Duchenne muscular dystrophy, summarizing the most recent developments in gene-based therapies for these conditions.

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Onasemnogene abeparvovec in spinal muscular atrophy: predictors of efficacy and safety in naïve patients with spinal muscular atrophy and following switch from other therapies

Cited by 20 publications

References 29 publications

Motor and neurocognitive profiles of children with symptomatic spinal muscular atrophy type 1 with two copies of SMN2 before and after treatment: a longitudinal observational study

Motor and neurocognitive profiles of children with symptomatic spinal muscular atrophy type 1 with two copies of SMN2 before and after treatment: a longitudinal observational study

Clinical Phenotype of Pediatric and Adult Patients With Spinal Muscular Atrophy With Four SMN2 Copies: Are They Really All Stable?

Gene-based therapies for neuromuscular disorders

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