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. 2024 Oct;13(5):1483-1504.
doi: 10.1007/s40120-024-00653-2. Epub 2024 Sep 2.

Effectiveness of Nusinersen in Adolescents and Adults with Spinal Muscular Atrophy: Systematic Review and Meta-analysis

Tim Hagenacker  1 , Lorenzo Maggi  2 , Giorgia Coratti  3 , Bora Youn  4 , Stephanie Raynaud  4 , Angela D Paradis  5   6 , Eugenio Mercuri  3
Affiliations

Effectiveness of Nusinersen in Adolescents and Adults with Spinal Muscular Atrophy: Systematic Review and Meta-analysis

Tim Hagenacker et al. Neurol Ther. 2024 Oct.

Abstract

Introduction: Nusinersen clinical trials have limited data on adolescents and adults with 5q-associated spinal muscular atrophy (SMA). We conducted a systematic literature review (SLR) and meta-analysis to assess effectiveness of nusinersen in adolescents and adults with SMA in clinical practice.

Methods: Our search included papers published 12/23/2016 through 07/01/2022 with ≥ 5 individuals ≥ 13 years of age and with ≥ 6 months' data on ≥ 1 selected motor function outcomes [Hammersmith Functional Motor Scale-Expanded (HFMSE), Revised Upper Limb Module (RULM), and Six-Minute Walk Test (6MWT)]. For meta-analysis, effect sizes were pooled using random-effects models. To understand treatment effects by disease severity, subgroup meta-analysis by SMA type and ambulatory status was conducted.

Results: Fourteen publications including 539 patients followed up to 24 months met inclusion criteria for the SLR. Patients were age 13-72 years and most (99%) had SMA Type II or III. Modest improvement or stability in motor function was consistently observed at the group level. Significant mean increases from baseline were observed in HFMSE [2.3 points (95% CI 1.3-3.3)] with 32.1% (21.7-44.6) of patients demonstrating a clinically meaningful increase (≥ 3 points) at 18 months. Significant increases in RULM were consistently found, with a mean increase of 1.1 points (0.7-1.4) and 38.3% (30.3-47.1) showing a clinically meaningful improvement (≥ 2 points) at 14 months. Among ambulatory patients, there was a significant increase in mean 6MWT distance of 25.0 m (8.9-41.2) with 50.9% (33.4-68.2) demonstrating a clinically meaningful improvement (≥ 30 m) at 14 months. The increases in HFMSE were greater for less severely affected patients, whereas more severely affected patients showed greater improvement in RULM.

Conclusions: Findings provide consolidated evidence that nusinersen is effective in improving or stabilizing motor function in many adolescents and adults with a broad spectrum of SMA.

Keywords: Adolescents; Adults; Hammersmith Functional Motor Scale–Expanded; Motor function; Nusinersen; Revised Upper Limb Module; Six-Minute Walk Test; Spinal muscular atrophy.

Plain language summary

Motor neurons are specialized cells in the brain and spinal cord that control the function of muscles. People with spinal muscular atrophy (SMA) do not make enough survival motor neuron (SMN) protein, which motor neurons need to function. As a result, people with SMA experience decreased muscle function that gets worse over time. Nusinersen is a drug that increases the amount of SMN protein made in the brain and spinal cord. However, most clinical trials of nusinersen have been in infants and children with SMA. Less is known about the effects of nusinersen in teenagers and adults with SMA who may have less severe but still progressive forms of the disease. In this manuscript, we first conducted a thorough review and analysis of research published by investigators who treated teenagers and adults with nusinersen for up to 24 months. We then used an additional analysis, called a meta-analysis, that allowed us to combine the information from several articles, so that we could better understand whether nusinersen helped these patients. We looked at 3 tests that investigators used to see how nusinersen affected patients’ motor function. The Hammersmith Functional Motor Scale–Expanded (HFMSE) assesses upper and lower limb motor function; the Revised Upper Limb Module (RULM) evaluates upper limb function; and the Six-Minute Walk Test (6MWT) measures the maximum distance a person can walk in 6 minutes. Our study showed that nusinersen can improve motor function or prevent motor function from getting worse in many teenagers and adults with SMA.

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Conflict of interest statement

Tim Hagenacker received grants/research support from Biogen, Novartis, and Roche, and honoraria or consulting fees from Biogen, Novartis, and Roche. Lorenzo Maggi received a grant from Biogen and honoraria for speaking, and consulting fees or compensation for congress participations from Amicus Therapeutics, Biogen, Janssen Pharmaceutics, Roche, and Sanofi Genzyme. Giorgia Coratti has received honoraria for speaking and compensation for congress participation from AveXis, Biogen, BioLogix, Novartis, and Roche. Bora Youn and Angela D. Paradis are employees of Biogen and may hold stock in the company. Stephanie Raynaud is a former employee of Biogen and may have held stock in the company at the time of the study. Eugenio Mercuri has served on advisory boards for SMA studies for AveXis, Biogen, Ionis, Novartis, and Roche; as Principal Investigator for ongoing Biogen/Ionis and Roche clinical trials; and has received funding from Famiglie SMA Italy, Italian Telethon, and SMA Europe.

Figures

Fig. 1
Fig. 1
PRISMA diagram
Fig. 2
Fig. 2
Summary of meta-analysis for HFMSE. a Mean HFMSE differences from baseline. b Percentage of patients with clinically meaningful HFMSE response (≥ 3 points). The black dot and error bars represent the pooled estimate and the corresponding 95% CI, respectively, from each model in the meta-analysis. CI confidence interval, HFMSE Hammersmith Functional Motor Scale–Expanded
Fig. 3
Fig. 3
Summary of meta-analysis for RULM. a Mean RULM difference from baseline. b Percentage of patients with clinically meaningful RULM response (≥ 2 points). The black dot and error bars represent the pooled estimate and the corresponding 95% CIs, respectively, from each model in the meta-analysis. Meta-analysis for clinically meaningful RULM response at 14 months in Type II patients was not conducted; only one publication [21] reported such outcome. CI confidence interval, RULM Revised Upper Limb Module
Fig. 4
Fig. 4
Summary of meta-analysis for 6MWT. a Mean 6MWT differences from baseline. b Percentage of patients with clinically meaningful 6MWT response (≥ 30 m). The black dot and error bars represent the pooled estimate and the corresponding 95% CI, respectively, from each model in the meta-analysis. 6MWT Six-Minute Walk Test, CI confidence interval
See this image and copyright information in PMC

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