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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. 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. 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. 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. 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.

Abstract licence: CC BY-NC

Given the lifelong progression of spinal muscular atrophy (SMA), understanding the long-term effects of nusinersen treatment is crucial. Prior systematic literature reviews (SLRs) consolidated evidence on the real-world effectiveness of nusinersen in adolescents and adults; however, the publications included in these reviews had a limited follow-up of 10–14 months. As newer publications with longer follow-up and more diverse groups have emerged, we conducted an updated SLR and meta-analysis to evaluate the long-term effectiveness of nusinersen treatment in adolescents and adults across a broad spectrum of SMA. The updated SLR included papers published from July 1, 2022 (previous search date) to August 4, 2024 with ≥ 5 individuals ≥ 13 years of age and with ≥ 6 months’ data on ≥ 1 selected motor function outcome (Hammersmith Functional Motor Scale–Expanded [HFMSE], Revised Upper Limb Module [RULM], and Six-Minute Walk Test [6MWT]). Changes in motor function after initiating nusinersen were summarized across studies included in the previous and updated SLR. Effect sizes were pooled using random-effects models in the meta-analysis. To understand treatment effects by disease severity, a subgroup meta-analysis by ambulatory status was conducted. Seventeen publications including 650 individuals from 16 countries followed up to 57 months met the inclusion criteria for the updated SLR. Individuals ranged in age from 13 to 71 years, and approximately 40% were ambulatory. Mean or median improvements or stability in motor function over the follow-up period were consistently reported across 31 studies (including 14 from a previous SLR) over 4 years. In the meta-analysis, statistically significant increases from baseline were observed in all three motor function outcomes. Mean HFMSE improvements were greater among ambulant individuals, while mean RULM improvements were greater among non-ambulant individuals. Our findings demonstrate the long-term effectiveness of nusinersen in many adolescents and adults from a diverse SMA population, which could support informed decision-making in clinical practice. People living with spinal muscular atrophy (SMA) produce less survival motor neuron (SMN) protein, leading to motor neuron damage and reduced motor function over time. Nusinersen is an approved treatment for SMA that works by increasing the levels of SMN protein made in the body. Since SMA is a lifelong genetic condition, it is important to understand the long-term effects of nusinersen treatment, especially in adolescents and adults who are underrepresented in clinical trials. We reviewed the scientific literature to find information (published between July 1, 2022 and August 4, 2024) on how effective nusinersen is in treating adolescents and adults with SMA. We found 17 studies that included data on 650 people with SMA from 16 countries, aged 13–71 years. Approximately 40% of these people with SMA were able to walk, and many studies had collected data for over 2 years after these people had started nusinersen treatment. A previous search of the literature up to July 1, 2022 had found 14 studies on how effective nusinersen is in adolescents and adults, but data in these studies had only been collected for 10–14 months after starting nusinersen treatment in most people. We considered data from all 31 studies to provide a more thorough assessment of how effective nusinersen is in adolescents and adults. These data suggest that many individuals from a diverse SMA population experience improved or stable motor function over a 4-year period. This information may help patients, caregivers, clinicians, and policymakers to make informed decisions.

Abstract licence: CC BY-NC

Nusinersen is a designer drug for spinal muscular atrophy (SMA) and was the first approved treatment for this once deadly disease. It is an antisense oligonucleotide that pairs with a specific locus of the Survival Motor Neuron 2 (SMN2) gene, to modify splicing and generate an increase in full-length SMN2 transcript. This in turn increases expression of survival motor neuron protein, deficiency of which results in motor neuron dysfunction and reduced cellular survival, the principal cause of SMA. Pre-clinical studies of nusinersen in animal models of SMA demonstrated substantial clinical responses and proof-of-concept, leading to successful clinical trials in symptomatic children and then in infants. Nusinersen's favorable safety profile after repeated lumbar intrathecal delivery as well as improvement in motor function and survival resulted in US regulatory approval for SMA in 2016. Other countries have followed with variable coverage policies depending upon age, weight, genotype and/or clinical severity. In the current treatment era, two populations of individuals with SMA exist: symptomatic patients identified in the clinic and pre-symptomatic patients (having no or few early clinical features of disease) largely identified by newborn screening. Real-world experience with nusinersen, the topic of this focused review, presents post-approval data in a broad range of patients beyond those studied in clinical trials. The favorable clinical response and safety profile are discussed, as well as the emerging new phenotypes of disease. Nusinersen, one of three FDA-approved drugs for SMA (as of 2025) remains an important therapeutic consideration for infants, children and adults with SMA.

Abstract licence: CC BY-NC