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. 2024 Oct 7:47:101092.
doi: 10.1016/j.lanepe.2024.101092. eCollection 2024 Dec.

Efficacy and safety of gene therapy with onasemnogene abeparvovec in children with spinal muscular atrophy in the D-A-CH-region: a population-based observational study

Claudia Weiß  1   2   3 , Lena-Luise Becker  1   2   4   3   5 , Johannes Friese  2   3 , Astrid Blaschek  4   5 , Andreas Hahn  6 , Sabine Illsinger  7 , Oliver Schwartz  8 , Günther Bernert  9 , Maja von der Hagen  10 , Ralf A Husain  11 , Klaus Goldhahn  12 , Janbernd Kirschner  13 , Astrid Pechmann  13 , Marina Flotats-Bastardas  14 , Gudrun Schreiber  15 , Ulrike Schara  16 , Barbara Plecko  17 , Regina Trollmann  18 , Veronka Horber  19 , Ekkehard Wilichowski  20 , Matthias Baumann  21 , Andrea Klein  22 , Astrid Eisenkölbl  23 , Cornelia Köhler  24 , Georg M Stettner  25 , Sebahattin Cirak  26 , Oswald Hasselmann  27 , Angela M Kaindl  1   2   4   3   5 , Sven F Garbade  28 , Jessika Johannsen  29 , Andreas Ziegler  28 ; SMArtCARE and Swiss-Reg-NMD study group
Collaborators, Affiliations

Efficacy and safety of gene therapy with onasemnogene abeparvovec in children with spinal muscular atrophy in the D-A-CH-region: a population-based observational study

Claudia Weiß et al. Lancet Reg Health Eur. .

Abstract

Background: Real-world data on gene addition therapy (GAT) with onasemnogene abeparvovec (OA), including all age groups and with or without symptoms of the disease before treatment are needed to provide families with evidence-based advice and realistic therapeutic goals. Aim of this study is therefore a population-based analysis of all patients with SMA treated with OA across Germany, Austria and Switzerland (D-A-CH).

Methods: This observational study included individuals with Spinal Muscular Atrophy (SMA) treated with OA in 29 specialized neuromuscular centers in the D-A-CH-region. A standardized data set including WHO gross motor milestones, SMA validated motor assessments, need for nutritional and respiratory support, and adverse events was collected using the SMArtCARE registry and the Swiss-Reg-NMD. Outcome data were analyzed using a prespecified statistical analysis plan including potential predictors such as age at GAT, SMN2 copy number, past treatment, and symptom status.

Findings: 343 individuals with SMA (46% male, 54% female) with a mean age at OA of 14.0 months (range 0-90, IQR 20.0 months) were included in the analysis. 79 (23%) patients were clinically presymptomatic at the time of treatment. 172 (50%) patients received SMN2 splice-modifying drugs prior to GAT (risdiplam: n = 16, nusinersen: n = 154, both: n = 2). Functional motor improvement correlated with lower age at GAT, with the best motor outcome in those younger than 6 weeks, carrying 3 SMN2 copies, and being clinically presymptomatic at time of treatment. The likelihood of requiring ventilation or nutritional support showed a significantly increase with older age at the time of GAT and remained stable thereafter. Pre-treatment had no effect on disease trajectories. Liver-related adverse events occurred significantly less frequently up to 8 months of age. All other adverse events showed an even distribution across all age and weight groups.

Interpretation: Overall, motor, respiratory, and nutritional outcome were dependent on timing of GAT and initial symptom status. It was best in presymptomatic children treated within the first six weeks of life, but functional motor scores also increased significantly after treatment in all age groups up to 24 months. Additionally, OA was best tolerated when administered at a young age. Our study therefore highlights the need for SMA newborn screening and immediate treatment to achieve the best possible benefit-risk ratio.

Funding: The SMArtCARE and Swiss-Reg-NMD registries are funded by different sources (see acknowledgements).

Keywords: Gene addition therapy; Gene therapy; Onasemnogene abeparvovec; SMA; Spinal muscular atrophy; Zolgensma.

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Conflict of interest statement

No author received financial support for the present manuscript. CW received honoraria for presentations and/or travel support from Novartis, Roche and Biogen and participated on advisory boards for Novartis, Roche and Biogen. JF received honoraria from Novartis for presentations. AB received honoraria for presentations from Roche and Pfizer and attend advisory boards for Roche and Pfizer. SI received honoraria for presentations and advisory board meetings from Novartis and Roche. OS received honoraria from Biogen, support for attending meetings from Novartis and participated on an advisory board for Novartis. GB received honoraria for advisory boards and/or presentations from Novartis, Roche and Biogen and support for attending meetings from Novartis. MvdH received grants from Deutsche Gesellschaft für Muskelkranke and Innovationsfond (INTEGRATE ATMP and KoCoN), honoraria from Pfizer, Biogen and PTC Therapeutics, and participated on advisory boards for Roche, Sarepta, Novartis, and Pfizer. RAH received consulting fees from Biogen and honoraria for presentations from Novartis, and participated on advisory boards by Novartis and Roche. KG participated on an industry symposium and an advisory board by Novartis. JK received funding for clinical research from Biogen, Novartis, Roche, ScholarRock and Biohaven, consulting fees from Biogen, Novartis and Roche, payment for educational activities from Biogen, Novartis and Roche and attended a data safety monitoring board for Biogen. AP received research funding form Roche, Novartis and Biogen. MFB received consulting fees for advisory boards from Roche, Novartis and Biogen and payment for presentations from Novartis and Biogen. GS received honoraria for a case report and participated on an advisory board for Novartis. US received honoraria for presentations from Biogen, Novartis and Roche and support for attending meetings from Roche and Novartis. BP received honoraria for a presentation from Biogen and participated on advisory boards for Novartis and Biogen. RT received honoraria for presentations from Desitin, PTC and Roche and participated on advisory boards for PTC, Roche and Santhera. VH attended an adivisory board for Biogen. MB received compensation for advisory boards and speakers honoraria from Novartis, Biogen and Roche and compensation for travel costs to meetings from Roche. AK is clinical lead of the Swiss Reg NMD, attended advisory board meetings of Novartis and received honorarium for a presentation by Novartis. AE received honoraria and payment for expert testimony from Biogen, Roche and Novartis, support for attending meetings from Biogen and Roche and participated on an advisory board for Biogen, Roche and Novartis. GMS participated on advisory boards from Biogen, Novartis and Roche and is member of the steering board for Swiss-Reg-NMD. SC received payment for a presentation. JJ received compensation for advisory boards and funding for travel or speaker honoraria from Avexis/Novartis, Biogen, IFT, Roche, PTC, Pfizer and Sarepta Therapeutics. AZ received compensation for advisory boards and funding for travel or speaker honoraria from Avexis/Novartis, Biogen, ITF, Roche, Pfizer and Sarepta Therapeutics. LLB, AH, EW, CK, OH, and SFG indicated no potential conflicts of interest to disclose.

Figures

Fig. 1
Fig. 1
CHOP INTEND, HFMSE and HINE scores before and after GAT. Individual course of (A) CHOP INTEND, (D) HFMSE and (G) HINE over 12 months categorized by age groups (linear mixed model, LMM). CHOP INTEND scores increased significantly in all age categories up to 24 months (p < 0.001) and correlated inversely with age at GAT (p < 0.001). Increases in HFMSE scores correlated inversely with age at GAT. Increase in HINE correlated inversely with age at GAT (p < 0.001). Light gray lines depict individual courses, width of figures the number of patients represented and triangles mean values. (B) CHOP INTEND, (E) HFMSE and (H) HINE courses over the observation period in months categorized by age groups at time of GAT (linear mixed model, LMM). CHOP INTEND scores increased significantly in patients treated up to 24 months (all: p < 0.0001), however in patients treated 24–36 months (p = 1.00) and >36 months (p = 1.00), scores did not increase significantly. Score increase correlated inversely with age at GAT, with the highest increase in children treated ≤6 weeks (p < 0.001). Follow-up HFSME scores increased significantly from 6 to 12 months after GAT in patients treated ≤6 weeks and 6 weeks-8 months. Baseline to follow-up HFMSE-scores significantly increased from 8 to 24 and 24–36 months (p < 0.001). In patients treated >36 months, scores did not increase significantly (p = 0.6968). HFSME score increase correlated inversely with the age at GAT. HINE increase significantly in patients treated ≤6 weeks (p < 0.001), 1–8 months (p < 0.001), 8–24 months (p < 0.001) and 24–36 months (p = 0.03684). In patients treated >36 months, scores did not increase significantly (p = 0.1655). Overall age groups, HINE score increases correlated inversely with the age at GAT, with the highest increase in children treated ≤6 weeks (LMM: p < 0.001). Predicted (C) CHOP INTEND, (F) HFMSE and (I) HINE in a Generalized Additive Model (GAM). Wavy lines indicate a change in CHOP INTEND scores, with blue values being lower than red ones. CHOP INTEND, HFMSE and HINE scores were significantly higher over the follow-up period the younger the patients were at GAT (GAM, p < 0.0001 each), and patients treated younger crossed more motor score lines.
Fig. 2
Fig. 2
Effect graphs for CHOP INTEND and HINE in a linear mixed model (LMM). Effect graph of the interaction between follow-up-time and SMN2 copy number show generally increased (A) CHOP INTEND- and (B) HINE-baseline scores in the group with 3 vs. 2 SMN2-copies (p < 0.001). However, motor outcome trajectories did not change after GAT. (C) Effect graph of the interaction between follow-up-time and pre-medication with either nusinersen or risdiplam show generally increased CHOP INTEND scores in the group with pre-medication (p < 0.001). However, motor outcome trajectories did not change after GAT in comparison to those under pretreatment with either nusinersen or risdiplam (p = 0.254). (D) The same effect is seen in HINE scores, however baseline HINE scores are not significantly different in pretreated children vs. therapy naïve ones. (E) Effect graph of the interaction between follow-up-time and symptomatic vs. presymptomatic at GAT show generally increased CHOP INTEND scores and baseline (p < 0.001) but not trajectories ((p = 0.09) in the group with a presymptomatic at GAT. CHOP INTEND in presymptomatic children rapidly reaches saturation niveau of >60 points. Therefore, significantly higher baseline HINE-scores scores and HINE outcome trajectories in presymptomatic children are reflected in (F).
Fig. 3
Fig. 3
Outcome of the motor milestone independent sitting, standing, and walking. The probability to achieve the motor milestones of free sitting (A), free standing (B), and free walking (C) after GAT in the age categories ≤6 weeks (turquoise), 6 weeks to 8 months (orange), 8–24 months (purple), 24–36 months (pink), and 36–90 months (green). Vertical lines depict censored observations when milestone was not reached at the last recorded visit. Vertical dashed lines mark the 99th percentile for normal development according to the World Health Organization Multicentre Growth Reference Study [WHO-MGRS12]. Note that for >30 months follow-up, only few measurements are available. The graphs D, E and F show a Kaplan Meyer analysis of patients reaching the milestone sitting (D), standing (E) and walking (F) depending on still being presymptomatic at time of GAT. Patients without symptoms at GAT (green) reach the milestones of (D) sitting, (E) standing and (F) walking significantly earlier and more often than patients with symptoms at GAT (p < 0.0001).
Fig. 4
Fig. 4
Liver related adverse events. Liver related adverse events were reported significantly higher in children >8 months of age at treatment whereas all other adverse events occurred age independent (p = 0.005 0–6 weeks at GAT; p < 0.0001 1–8 months).
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