Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comparative Study
. 2024 Jun;41(6):2414-2434.
doi: 10.1007/s12325-024-02845-6. Epub 2024 May 5.

Long-Term Comparative Efficacy and Safety of Risdiplam and Nusinersen in Children with Type 1 Spinal Muscular Atrophy

Christos Kokaliaris  1 , Rachel Evans  2 , Neil Hawkins  2   3 , Anadi Mahajan  4 , David Alexander Scott  2 , C Simone Sutherland  5 , Julian Nam  5 , Gautam Sajeev  6
Affiliations
Comparative Study

Long-Term Comparative Efficacy and Safety of Risdiplam and Nusinersen in Children with Type 1 Spinal Muscular Atrophy

Christos Kokaliaris et al. Adv Ther. 2024 Jun.

Abstract

Introduction: Spinal muscular atrophy (SMA) is a severe genetic neuromuscular disease characterized by a loss of motor neurons and progressive muscle weakness. Children with untreated type 1 SMA never sit independently and require increasing levels of ventilatory support as the disease progresses. Without intervention, and lacking ventilatory support, death typically occurs before the age of 2 years. There are currently no head-to-head trials comparing available treatments in SMA. Indirect treatment comparisons are therefore needed to provide information on the relative efficacy and safety of SMA treatments for healthcare decision-making.

Methods: The long-term efficacy and safety of risdiplam versus nusinersen in children with type 1 SMA was evaluated using indirect treatment comparison methodology to adjust for differences between population baseline characteristics, to reduce any potential bias in the comparative analysis. An unanchored matching-adjusted indirect comparison was conducted using risdiplam data from 58 children in FIREFISH (NCT02913482) and published aggregate nusinersen data from 81 children obtained from the ENDEAR (NCT02193074) and SHINE (NCT02594124) clinical trials with at least 36 months of follow-up.

Results: Children with type 1 SMA treated with risdiplam had a 78% reduction in the rate of death, an 81% reduction in the rate of death or permanent ventilation, and a 57% reduction in the rate of serious adverse events compared with children treated with nusinersen. Children treated with risdiplam also had a 45% higher rate of achieving a Hammersmith Infant Neurological Examination, Module 2 motor milestone response and a 186% higher rate of achieving a ≥ 4-point improvement in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders compared with children treated with nusinersen.

Conclusion: Long-term data supported risdiplam as a superior alternative to nusinersen in children with type 1 SMA. Video abstract available for this article. Video abstract (MP4 184542 KB).

Keywords: Clinical trial; Indirect treatment comparison; MAIC; Matching-adjusted indirect comparison; Neuromuscular disease; Nusinersen; Propensity score matching; Risdiplam; SMA; Spinal muscular atrophy.

Plain language summary

Risdiplam and nusinersen are two approved treatments for patients with type 1 spinal muscular atrophy (SMA). There are currently no head-to-head trials that compare the outcomes of these treatments in patients. This study conducted a statistical comparison of the efficacy and safety of risdiplam and nusinersen in children with type 1 SMA who received treatment for at least 36 months. Risdiplam data were collected from 58 children who participated in the FIREFISH trial (NCT02913482). Published combined data were collected from 81 children treated with nusinersen who participated in the ENDEAR (NCT02193074) and SHINE (NCT02594124) trials. Outcomes from the two studies were compared using matching-adjusted indirect comparison (MAIC) methodology. MAIC adjusts for differences in baseline characteristics between patients in two trials to make the populations more similar and reduce bias in the comparison. Results suggested that children with type 1 SMA treated with risdiplam had a 78% reduction in the rate of death and an 81% reduction in the rate of death or permanent ventilation compared with children treated with nusinersen. With risdiplam, children also had a higher rate of achieving motor function responses, and a longer time to the first serious adverse event compared with children treated with nusinersen. These results support risdiplam as a superior alternative to nusinersen in children with type 1 SMA over 36 months of follow-up. Access to long-term data beyond 36 months would allow for additional indirect comparisons between SMA treatments. These comparisons are key to guiding treatment decision-making in the absence of head-to-head trials.

PubMed Disclaimer

Conflict of interest statement

The SLR and data extraction were conducted by Bridge Medical Consulting Ltd., London, UK and funded by F. Hoffmann-La Roche Ltd., Basel, Switzerland. ITC analyses were designed by Visible Analytics, UK, funded by F. Hoffmann-La Roche Ltd. Christos Kokaliaris and Julian Nam are employees of F. Hoffmann-La Roche Ltd. Julian Nam owns stocks in Roche. Rachel Evans is a former employee of Visible Analytics Ltd., which designed the analysis and received consultancy fees and expenses from F. Hoffmann-La Roche Ltd. Neil Hawkins and David Alexander Scott are partners/employees of Visible Analytics Ltd., which designed the analysis and received consultancy fees and expenses from F. Hoffmann-La Roche Ltd. Anadi Mahajan is an employee of Bridge Medical Consulting Ltd., which conducted this SLR and received consultancy fees and expenses from F. Hoffmann-La Roche Ltd. C Simone Sutherland was employed by F. Hoffmann-La Roche Ltd and owns stocks in Roche. Gautam Sajeev is an employee of Analysis Group, Inc. which received consulting fees from Genentech Inc. (a member of the Roche group) for this research. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Figures

Fig. 1
Fig. 1
Overall survival in patients with type 1 SMA treated with risdiplam and nusinersen (primary analysis). Unadjusted survival data from the pooled FIREFISH cohort (orange line) were plotted alongside the data from SHINE-ENDEAR (blue line). Patient baseline characteristics in FIREFISH were matched to the mean values of the baseline characteristics of the nusinersen arm in SHINE-ENDEAR using MAIC methodology, thus generating risdiplam-adjusted data (purple line). Characteristics that were used as adjustment factors in the primary analysis were age at first dose, disease duration, and baseline CHOP-INTEND score. PH test: p = 0.893, not rejecting the null hypothesis. CHOP-INTEND Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders, MAIC matching-adjusted indirect comparison, PH proportional hazard, SMA spinal muscular atrophy
Fig. 2
Fig. 2
Event-free survival in patients with type 1 SMA treated with nusinersen and risdiplam (primary analysis). Event-free survival is defined as alive without the need for permanent ventilation. In FIREFISH, permanent ventilation was defined as ≥ 16 h of NIV/day or intubation for > 21 consecutive days in the absence of, or following the resolution of, an acute reversible event or tracheostomy. In SHINE-ENDEAR, permanent ventilation was defined as either tracheostomy or ≥ 16 h of ventilation/day continuously for > 21 days in the absence of an acute reversible event. Unadjusted survival data from the pooled FIREFISH cohort (orange line) were plotted alongside the data from SHINE-ENDEAR (blue line). Patient baseline characteristics in FIREFISH were matched to the mean values of the baseline characteristics of the nusinersen arm in SHINE-ENDEAR using MAIC methodology, thus generating risdiplam-adjusted data (purple line). Characteristics that were used as adjustment factors in the primary analysis were age at first dose, disease duration, and baseline CHOP-INTEND score. PH test: p = 0.415, not rejecting the null hypothesis. CHOP-INTEND Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders, MAIC matching-adjusted indirect comparison, NIV non-invasive ventilation, PH proportional hazard, SMA spinal muscular atrophy
Fig. 3
Fig. 3
Time to HINE-2 motor milestone response in patients with type 1 SMA treated with risdiplam and nusinersen (primary analysis). Children were classed as a HINE-2 responder if more motor milestones showed improvement than worsening. Improvement was defined as a ≥ 2-point increase in the ability to kick (or maximal score) or a ≥ 1-point increase in head control, rolling, sitting, crawling, standing, or walking. Worsening was defined as a ≥ 2-point decrease in the ability to kick (or lowest score) or a ≥ 1-point decrease in head control, rolling, sitting, crawling, standing, or walking. Unadjusted survival data from the pooled FIREFISH cohort (orange line) were plotted alongside the data from SHINE-ENDEAR (blue line). Patient baseline characteristics in FIREFISH were matched to the mean values of the baseline characteristics of the nusinersen arm in SHINE-ENDEAR using MAIC methodology, thus generating risdiplam-adjusted data (purple line). Characteristics that were used as adjustment factors in the primary analysis were age at first dose, disease duration, and baseline CHOP-INTEND score. PH test: p = 0.003, rejecting the null hypothesis. CHOP-INTEND Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders, HINE-2 Hammersmith Infant Neurological Examination, Module 2, MAIC matching-adjusted indirect comparison PH proportional hazard, SMA spinal muscular atrophy
Fig. 4
Fig. 4
Time to CHOP-INTEND response in patients with type 1 SMA treated with risdiplam and nusinersen (primary analysis). A CHOP-INTEND response was defined as a ≥ 4-point improvement in CHOP-INTEND score from baseline. Unadjusted survival data from the pooled FIREFISH cohort (orange line) were plotted alongside the data from SHINE-ENDEAR (blue line). Patient baseline characteristics in FIREFISH were matched to the mean values of the baseline characteristics of the nusinersen arm in SHINE-ENDEAR using MAIC methodology, thus generating risdiplam-adjusted data (purple line). Characteristics that were used as adjustment factors in the primary analysis were age at first dose, disease duration, and baseline CHOP-INTEND score. PH test: p = 0.020, rejecting the null hypothesis. CHOP-INTEND Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders, MAIC matching-adjusted indirect comparison, PH proportional hazard; SMA spinal muscular atrophy
Fig. 5
Fig. 5
Time to first SAE in patients with type 1 SMA treated with nusinersen and risdiplam (primary analysis). Unadjusted survival data from the pooled FIREFISH cohort (orange line) were plotted alongside the data from SHINE-ENDEAR (blue line). Patient baseline characteristics in FIREFISH were matched to the mean values of the baseline characteristics of the nusinersen arm in SHINE-ENDEAR using MAIC methodology, thus generating risdiplam-adjusted data (purple line). Characteristics that were used as adjustment factors in the primary analysis were age at first dose, disease duration, and baseline CHOP-INTEND score. PH test: p = 0.263, not rejecting the null hypothesis. CHOP-INTEND Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders, MAIC matching-adjusted indirect comparison, PH proportional hazard, SAE serious adverse event, SMA spinal muscular atrophy
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Mercuri E, Sumner CJ, Muntoni F, Darras BT, Finkel RS. Spinal muscular atrophy. Nat Rev Dis Primers. 2022;8(1):52. - PubMed
    1. Lefebvre S, Burglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155–165. - PubMed
    1. Lorson CL, Hahnen E, Androphy EJ, Wirth B. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci USA. 1999;96(11):6307–6311. - PMC - PubMed
    1. Munsat TL, Davies KE. International SMA consortium meeting. (26–28 June 1992, Bonn, Germany) Neuromuscul Disord. 1992;2(56):423–428. - PubMed
    1. Kaneko K, Arakawa R, Urano M, Aoki R, Saiito K. Relationships between long-term observations of motor milestones and genotype analysis results in childhood-onset Japanese spinal muscular atrophy patients. Brain Dev. 2017;39(9):763–773. - PubMed

Publication types

LinkOut - more resources