Gene replacement therapy with onasemnogene abeparvovec in children with spinal muscular atrophy aged 24 months or younger and bodyweight up to 15 kg: an observational cohort study

Weiß, Claudia; Ziegler, Andreas; Becker, Lena‐Luise; Johannsen, Jessika; Brennenstuhl, Heiko; Schreiber, Gudrun; Flotats‐Bastardas, Marina; Stoltenburg, Corinna; Hartmann, H.; Illsinger, Sabine; Denecke, Jonas; Pechmann, Astrid; Müller‐Felber, Wolfgang; Vill, Katharina; Blaschek, Astrid; Smitka, Martin; Stam, Lieske van der; Weiß, Katja; Winter, Benedikt; Goldhahn, Klaus; Plecko, Barbara; Horber, Veronka; Bernert, G.; Husain, Ralf A.; Rauscher, Christian; Trollmann, Regina; Garbade, Sven F.; Hahn, Andreas; Hagen, Maja von der; Kaindl, Angela M.

doi:10.1016/s2352-4642(21)00287-x

Cited by 64 publications

(82 citation statements)

References 26 publications

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“…Thus far, published clinical trials and real-world data for the safe and efficacious administration of onasemnogene abeparvovec has focussed on monotherapy in homogeneous and narrow populations, limiting the generalisability of treatment outcomes. [4][5][6][7][8] Most trials have included treatment-na€ ıve children aged ≤6 months and weighing below 8.4 kg. 4,8 Those trials have shown improvements in survival and respiratory and bulbar function and attainment of motor milestones, especially in children treated presymptomatically.…”

Section: Introductionmentioning

confidence: 99%

Onasemnogene abeparvovec in spinal muscular atrophy: an Australian experience of safety and efficacy

D’Silva

Holland

Kariyawasam

et al. 2022

Ann Clin Transl Neurol

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Objective: To provide a greater understanding of the tolerability, safety and clinical outcomes of onasemnogene abeparvovec in real-world practice, in a broad population of infants with spinal muscular atrophy (SMA). Methods: A prospective cohort study of children with SMA treated with onasemnogene abeparvovec at Sydney Children's Hospital Network, Australia was conducted from August 2019 to November 2021. Safety outcomes included clinical and laboratory evaluations. Efficacy assessments included World Health Organisation (WHO) motor milestones, oral and swallowing abilities, and requirements for respiratory support. The implementation of a model of care for onasemnogene abeparvovec administration in health practice is described. Results: 21 children were treated (age range, 0.65-24 months; body weight range, 2.5-12.5 kg) and 19/21 (90.4%) had previous nusinersen. Transient treatment-related side effects occurred in all children; vomiting (100%), transaminitis (57%) and thrombocytopaenia (33%). Incidence of moderate/severe transaminitis was significantly greater in infants weighing ≥8 kg compared with <8 kg (p < 0.05). Duration of prednisolone following treatment was prolonged (mean 87.5 days, range 57-274 days). 16/21 (76%) children gained at least one WHO motor milestone. Stabilisation or improvement in bulbar or respiratory function was observed in 20/21 (95.2%) patients. Implementation challenges were mitigated by developing standard operating procedures and facilitating exchange of knowledge. Interpretation: This study provides real-world evidence to inform treatment decisions and guide therapeutic expectations for onasemnogene abeparvovec and combination therapy for SMA in health practice, especially for children weighing ≥8 kg receiving higher vector loads. Proactive clinical and laboratory surveillance is essential to facilitate individualised management of risks.

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Section: Introductionmentioning

confidence: 99%

Onasemnogene abeparvovec in spinal muscular atrophy: an Australian experience of safety and efficacy

D’Silva

Holland

Kariyawasam

et al. 2022

Ann Clin Transl Neurol

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“…Recent reports on outcome of three clinical trials of onasemnogene on SMA patients of ages younger than 6 months to 2 years showed mixed results (Day et al, 2021 ; Mercuri et al, 2021 ; Weiß et al, 2022 ). Statistically significant benefits of onasemnogene treatment were noted in most SMA patients (Day et al, 2021 ; Mercuri et al, 2021 ; Weiß et al, 2022 ). Notably, patients previously treated with nusinersen also benefited from gene therapy (Weiß et al, 2022 ).…”

Section: Challenges Associated With Gene Therapy Of Smamentioning

confidence: 99%

“…Statistically significant benefits of onasemnogene treatment were noted in most SMA patients (Day et al, 2021 ; Mercuri et al, 2021 ; Weiß et al, 2022 ). Notably, patients previously treated with nusinersen also benefited from gene therapy (Weiß et al, 2022 ). However, findings revealed several treatment-related adverse events.…”

Section: Challenges Associated With Gene Therapy Of Smamentioning

confidence: 99%

“…However, findings revealed several treatment-related adverse events. For instance, pyrexia was the universal adverse event in all three clinical trials with onasemnogene (Day et al, 2021 ; Weiß et al, 2022 ). Additional adverse events included bronchiolitis, pneumonia, respiratory distress, and respiratory syncytial virus bronchiolitis in younger SMA patients (Day et al, 2021 ).…”

Section: Challenges Associated With Gene Therapy Of Smamentioning

confidence: 99%

“…Consistently, immunological assays confirmed an immune response against AAV9 capsid proteins (Thomsen et al, 2021 ). While inflammatory response of liver could be mitigated to certain extent by prednisolone, continued accumulation of SMN transcripts and protein in liver remain a concern in the long run (Thomsen et al, 2021 ; Weiß et al, 2022 ). Peripheral tissues, including intercostal muscle, diaphragm and pancreas of SMA patients treated with onasemnogene also showed abnormal high expression of SMN transcripts, raising concerns similar to those noted with liver (Thomsen et al, 2021 ).…”

Section: Challenges Associated With Gene Therapy Of Smamentioning

confidence: 99%

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Commentary: Current Status of Gene Therapy for Spinal Muscular Atrophy

Rossoll

Singh

2022

Front. Cell. Neurosci.

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Real-world Associations of US Cystic Fibrosis Newborn Screening Programs With Nutritional and Pulmonary Outcomes

et al. 2022

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ImportanceNewborn screening (NBS) for cystic fibrosis (CF) has been universal in the US since 2010, but its association with clinical outcomes is unclear.ObjectiveTo describe the real-world effectiveness of NBS programs for CF in the US on outcomes up to age 10 years.Design, Setting, and ParticipantsThis was a retrospective cohort study using CF Foundation Patient Registry data from January 1, 2000, to December 31, 2018. The staggered implementation of NBS programs by state was used to compare longitudinal outcomes among children in the same birth cohort born before vs after the implementation of NBS for CF in their state of birth. Participants included children with an established diagnosis of CF born between January 1, 2000, to December 31, 2018, in any of the 44 states that implemented NBS for CF between 2003 and 2010. Data were analyzed from October 5, 2020, to April 22, 2022.ExposuresBirth before vs after the implementation of NBS for CF in the state of birth.Main Outcomes and MeasuresLongitudinal trajectory of height and weight percentiles from diagnosis, lung function (forced expiratory volume in 1 second, [FEV1] percent predicted) from age 6 years, and age at initial and chronic infection with Pseudomonas aeruginosa using linear mixed-effects and time-to-event models adjusting for birth cohort and potential confounders.ResultsA total of 9571 participants (4713 female participants [49.2%]) were eligible for inclusion, with 4510 (47.1%) in the pre-NBS cohort. NBS was associated with higher weight and height percentiles in the first year of life (weight, 6.0; 95% CI, 3.1-8.4; height, 6.6; 95% CI, 3.8-9.3), but these differences decreased with age. There was no association between NBS and FEV1 at age 6 years, but the percent-predicted FEV1 did increase more rapidly with age in the post-NBS cohort. NBS was associated with older age at chronic P aeruginosa infection (hazard ratio, 0.69; 95% CI, 0.54-0.89) but not initial P aeruginosa infection (hazard ratio, 0.88; 95% CI, 0.77-1.01).Conclusions and RelevanceNBS for CF in the US was associated with improved nutritional status up to age 10 years, a more rapid increase in lung function, and delayed chronic P aeruginosa infection. In the future, as highly effective modulator therapies become available for infants with CF, NBS will allow for presymptomatic initiation of these disease-modifying therapies before irreversible organ damage.

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Gene replacement therapy with onasemnogene abeparvovec in children with spinal muscular atrophy aged 24 months or younger and bodyweight up to 15 kg: an observational cohort study

Cited by 64 publications

References 26 publications

Onasemnogene abeparvovec in spinal muscular atrophy: an Australian experience of safety and efficacy

Onasemnogene abeparvovec in spinal muscular atrophy: an Australian experience of safety and efficacy

Commentary: Current Status of Gene Therapy for Spinal Muscular Atrophy

Real-world Associations of US Cystic Fibrosis Newborn Screening Programs With Nutritional and Pulmonary Outcomes

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