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Mid- and long-term (at least 12 months) follow-up of patients with spinal muscular atrophy (SMA) treated with nusinersen, onasemnogene abeparvovec, risdiplam or combination therapies: A systematic review of real-world study data

Open AccessPublished:April 29, 2022DOI:https://doi.org/10.1016/j.ejpn.2022.04.006

      Highlights

      • Mid- and long-term real-world study data on all types of SMA patients.
      • Studies on nusinersen, onasemnogene abeparvovec and combination therapies included.
      • Mortality, discontinuation of therapy, motor endpoints, and safety endpoints analysed.

      Abstract

      Objectives

      This systematic review aimed to assess mid- and long-term (at least 12 months) real-world study data from all types of spinal muscular atrophy (SMA) patients treated with any of the approved drugs or combination therapies.

      Methods

      A systematic literature search was carried out in five databases. Two authors selected the studies based on pre-defined selection criteria and independently graded the risk of bias at study level.

      Results

      Five hundred forty-six records were identified in the literature search and 22 studies (in 26 publications) were included in the analysis. Nusinersen, onasemnogene abeparvovec and combination therapies improved motor endpoints in SMA type 1 patients. SMA type 2 to type 4 patients treated with nusinersen showed stabilisation or small improvements in motor endpoints with some deterioration observed. Quality of life endpoints, such as respiratory and nutritional support were poorly reported on. Drug-related adverse events occurred rarely in all types of SMA patients with all assessed drugs. Mid- and long-term studies on risdiplam could not be identified.

      Conclusions

      The large quantity of missing data and heterogeneity of studies hinder comparability. Although stability and further improvement on the long-term is still uncertain, the results from the included evidence, as well as from pivotal trials show a striking contrast to the natural progression of the disease.

      Keywords

      1. Introduction

      Spinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease characterized by the lack of muscle control and progressive muscle atrophy. SMA presents as a spectrum of motor and functional disabilities such as difficulties with walking, swallowing, breathing and speaking. Four types (SMA type 1 to type 4) affect infants, children, and adults with reduced levels of the survival of motor neuron (SMN) protein due to deletions and/or mutations of the SMN1 gene. A second SMN gene, SMN2, produces low levels of functional SMN protein that are not sufficient to fully compensate for the lack of the SMN1 gene, but can modulate disease severity to produce a milder phenotype when the number of SMN2 gene copies is increased [
      • Calucho M.
      • Bernal S.
      • Alías L.
      • March F.
      • Venceslá A.
      • Rodríguez-Álvarez Fea
      Correlation between SMA type and SMN2 copy number revisited: an analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases.
      ,
      • Gemeinsamer Bundesausschuss (G-BA)
      Nusinersen (Spinraza®) modul 3 A 5q-assoziierte spinale muskelatrophie (SMA).
      ].
      Within the last years, three disease-modifying treatments have been approved for use in SMA patients. Nusinersen (Spinraza®), an SMN2 splicing modifier, became the first therapy approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of SMA of all types in 2017 [
      European Medicines Agency (EMA)
      Spinraza (Nusinersen).
      ]. The gene therapy onasemnogene abeparvovec (Zolgensma®) was also approved by both agencies in 2020, however, the approved indications differ: the EMA approved it for patients with inherited mutations affecting the SMN1 gene, who have either been diagnosed with SMA type 1 or have up to three copies of the SMN2 gene [
      • European Medicines Agency (EMA)
      Zolgensma (onasemnogene abeparvovec).
      ], while the FDA approved it for the treatment of paediatric patients less than two years of age with SMA with bi-allelic mutations in the SMN1 gene [
      • Food and Drug Administration (FDA)
      ]. Risdiplam (Evrysdi®), the latest approved therapy by the EMA is indicated for the treatment of 5q SMA in patients two months of age and older, with a clinical diagnosis of SMA type 1, type 2 or type 3 or with one to four SMN2 copies [
      European Medicines Agency (EMA)
      Evrysdi (Risdiplam).
      ]. The approvals were based on two pivotal trials each for nusinersen [
      • Finkel R.S.
      • Mercuri E.
      • Darras B.T.
      • et al.
      Nusinersen versus sham control in infantile-onset spinal muscular atrophy.
      ,
      • Mercuri E.
      • Darras B.T.
      • Chiriboga C.A.
      • et al.
      Nusinersen versus sham control in later-onset spinal muscular atrophy.
      ] and risdiplam [
      • Darras B.T.
      • Masson R.
      • Mazurkiewicz-Bełdzińska M.
      • et al.
      Risdiplam-treated infants with type 1 spinal muscular atrophy versus historical controls.
      ,
      • Servais L.
      • Baranello G.
      • Masson R.
      • Mazurkiewicz-Bełdzińska M.
      • Rose K.
      • Vlodavets D.
      Firefish part 2: efficacy and safety of risdiplam (rg7916) in infants with type 1 spinal muscular atrophy (SMA).
      ] and it was based on three pivotal trials for onasemnogene abeparvovec [
      • Day J.W.
      • Finkel R.S.
      • Chiriboga C.A.
      • et al.
      Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial.
      ,
      • Mendell J.
      • Shell R.
      • Lehman K.
      • et al.
      Gene-replacement therapy (GRT) in spinal muscular atrophy type 1 (SMA1): long-term follow-up from the onasemnogene abeparvovec phase 1/2a clinical trial.
      ,
      • Mendell J.R.
      • Al-Zaidy S.A.
      • Lehman K.J.
      • et al.
      Five-Year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy.
      ].
      To our knowledge, this is the first systematic review of SMA-therapies focusing on mid- and long-term follow-up study data and on all approved drugs or their combinations in all types of SMA patients. We aim to present the efficacy and safety results of published real-world study data with at least 12 months of follow-up.

      2. Methods

      In this systematic review we adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and a pre-set review protocol.

      2.1 Search

      A systematic literature search was carried out in five databases (Medline via Ovid, Embase, the Cochrane Library, the Centre for Reviews and Dissemination Database and the International Network of Agencies for Health Technology Assessment Database) in June 2021 complemented with a manual search. Furthermore, to identify ongoing studies, a search in two clinical trials registries (ClinicalTrials.gov and EU Clinical Trials) was conducted in August 2021. The specific search strategy employed in each database can be found in Supplementary Table A.

      2.2 Inclusion criteria

      Study inclusion was based on the pre-defined PICO(S) criteria (population, intervention, comparator, outcomes and study design). All types of SMA patients and any of the three approved drug treatment, alone or in combination, were considered for inclusion. Any effectiveness or safety outcomes with at least 12-months follow-up needed to be reported on. Regarding study types, case reports were excluded and in comparative studies, the comparator should have been best supportive care or standard of care. It was out of the scope of the present review to compare the available drug therapies for the treatment of SMA patients between each other. The systematic search was restricted to articles published in English or German and for the time period January 2017 to May 2021.

      2.3 Selection

      Two review authors independently checked titles and abstracts obtained from literature searches to identify potentially relevant studies for full review. From the full texts, the review authors independently selected the publications that met the selection criteria for inclusion. The review authors resolved disagreements by reaching consensus. A PRISMA flowchart (Fig. 1) displays the process of study selection.
      Fig. 1
      Fig. 1PRISMA flowchart. The PRISMA flow diagram for the systematic review detailing the database searches, the number of abstracts screened, and the full texts retrieved.
      Abbreviations: m = month, n = number, PRISMA = preferred reporting items for systematic reviews and meta-analyses, SMA = spinal muscular atrophy.

      2.4 Extraction

      One review author extracted data using a specially designed data extraction form and the other review author controlled the data extraction forms. Study results are represented in separate tables per approved drug and per study population (SMA type 1, SMA type 1 and 2, SMA type 1 to type 3, SMA type 2 and 3, SMA type 3; and SMA type 2 to type 4). Outcomes were grouped into four main categories: mortality and treatment discontinuation, motor endpoints, quality of life endpoints (respiratory and nutritional support, caregiver or self-evaluation) and any safety endpoints. Motor endpoints could be measured by any of the following instruments: Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), Hammersmith Infant Neurological Examination (HINE-2), (revised) upper limb module for SMA (RULM), Hammersmith Functional Motor Scale Expanded for SMA (HFSME), motor function measure (MFM), Medical Research Council score (MRC) and the 6-min-walk-test (6MWT).

      2.5 Risk of bias assessment

      Two review authors independently graded the risk of bias at study level of included studies using the Institute of Health Economics (IHE) Risk of Bias checklist for case series [
      Institute of Health Economics (IHE)
      Quality Appraisal of Case Series Studies Checklist.
      ]. In case of disagreement, the review authors re-assessed studies and reached agreement by consensus. Overall risk of bias was assessed using a predefined point score (range 0-20): a high score indicates a low risk of bias and a low score indicates a higher risk of bias. The checklist comprises questions about the study objective, study design, study population, intervention and co-interventions, outcome measures, statistical analysis, results and conclusions, and the competing interests and funding of the studies.

      2.6 Data synthesis

      Study results were summarised narratively (qualitative data synthesis) per approved drug and per study population due to the substantial clinical, methodological or statistical heterogeneity. Minimal clinically important differences (MCID) were considered for the outcomes: CHOP INTEND (4 points), HINE-2 (2 points), HFSME (3 points), RULM (2 points) and 6MWT (30 m) [
      CHOP INTEND Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders.
      ,
      HINE - Hammersmith Infant Neurological Examination
      ,
      HMFSE - Hammersmith Functional Motor Sclae Expanded
      , ,
      European Medicines Agency (EMA)
      Briefing Document to the Clinical Trial Readiness in Spinal Muscular Atrophy (SMA) SMA Europe.
      ,
      • Finkel R.
      • Bertini E.
      • Muntoni F.
      • Mercuri E.
      ,
      • Krosschell K.
      • Young S.
      • Cruz R.
      • Mazzella A.
      • Curry M.
      • Peterson I.
      Best Practices for Physical Therapists & Clinical Evaluators in Spinal Muscular Atrophy (SMA). Recommendations to Support the Effective Conduct of Clinical Trials in SMA.
      ,
      • Pierzchlewicz K.
      • Kepa I.
      • Podogrodzki J.
      • Kotulska K.
      Spinal muscular atrophy: the use of functional motor scales in the era of disease-modifying treatment.
      ].

      3. Results

      Five hundred eighty-three articles were identified in the database and hand searches. Five hundred forty-six articles remained after deduplication (Fig. 1).
      Twenty-two studies (in 26 publications) met the inclusion criteria and were included in the present analysis. Nineteen studies (21 publications) assessed nusinersen, one study (three publications) assessed onasemnogene abeparvovec and two studies assessed combination therapy of nusinersen and onasemnogene abeparvovec. No studies were identified for risdiplam that met the inclusion criteria. The onasemnogene abeparvovec and combination therapies studies enrolled exclusively patients with SMA type 1. The nusinersen studies included patients of various SMA types: six studies were on SMA type 1, one study on SMA type 1 and 2, four studies on SMA type 1 to 3, five studies on SMA type 2 and 3, one study on SMA type 3 alone, and two studies on SMA type 2 to 4.
      The number of patients enrolled in the included studies ranged from five to 123. Regarding patient age, six studies enrolled only adult patients, three studies enrolled only children, and thirteen studies enrolled mixed population in terms of age. The follow-up period of the included studies ranged from 12 months to 5.2 years.
      In 21 publications, authors reported they had conflict of interest (honoraria from Ionis Pharmaceuticals and Biogen; Avexis and Roche, Novartis, etc.). Seven studies were manufacturer-funded.
      Double publication on the same study cohort or part of the cohort occurred in three instances: one study [
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ] reported on a smaller cohort of French patients, while another one reported on all French patients [
      • Gómez-García de la Banda M.
      • Amaddeo A.
      • Khirani S.
      • et al.
      Assessment of respiratory muscles and motor function in children with SMA treated by nusinersen.
      ], hence the two publications were considered together in the analysis. The NCT02122952 study population was reported on in three publications [
      • Al-Zaidy S.
      • Pickard A.S.
      • Kotha K.
      • et al.
      Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy.
      ,
      • Al-Zaidy S.A.
      • Kolb S.J.
      • Lowes L.
      • et al.
      AVXS-101 (onasemnogene abeparvovec) for SMA1: comparative study with a prospective natural history cohort.
      ,
      • Lowes L.P.
      • Alfano L.N.
      • Arnold W.D.
      • et al.
      Impact of age and motor function in a phase 1/2A study of infants with SMA type 1 receiving single-dose gene replacement therapy.
      ]. A part of the CS2 study cohort (NCT01703988, NCT02052791) was also reported on in two publications [
      • Darras B.T.
      • Chiriboga C.A.
      • Iannaccone S.T.
      • et al.
      Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies.
      ,
      • Montes J.
      • Dunaway Young S.
      • Mazzone E.S.
      • et al.
      Nusinersen improves walking distance and reduces fatigue in later-onset spinal muscular atrophy.
      ].
      An overview of the included studies is shown in Table 1. Detailed data extraction tables are Supplementary Table B1 – B7.
      Table 1Included studies.
      Author, year (country)Number of patientsAge

      Length of follow-up (m)
      Funding + CoIEndpoints measured
      nusinersen (Spinraza®)
      SMA 1
      Acsadi et al. 2021 [
      • Acsadi G.
      • Crawford T.
      • Muller-Felber W.
      • et al.
      Safety and efficacy of nusinersen in spinal muscular atrophy: the EMBRACE study.
      ] (USA, Germany)
      20Cross-over group: 28.7 m (24.5–65.3)

      Nusinersen group continuing from Part 1: 16.7 m (7.3–48.6)
      28Funding: Biogen, Ionis Pharmaceuticals

      11/11 authors with CoI
      Respiratory support

      HINE-2

      CGI-C

      AEs and SAEs
      Aragon-Gawinska et al. 2020 [
      • Aragon-Gawinska K.
      • Daron A.
      • Ulinici A.
      • et al.
      Sitting in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ] (France, Poland, Belgium, UK)
      5321.9 m–23.3 m14Funding: Association Institute of Myology

      3/9 authors with CoI
      HINE-2

      CHOP INTEND
      Lavie et al. 2021 [
      • Lavie M.
      • Diamant N.
      • Cahal M.
      • et al.
      Nusinersen for spinal muscular atrophy type 1: real-world respiratory experience.
      ] (Israel)
      2013.5 m (1 m–184 m)24Funding: Biogen

      CoI: none declared.
      Respiratory support

      Respiratory hospitalisation

      AEs and SAEs
      Mendonca et al. 2021b [
      • de Holanda Mendonça R.
      • Jorge Polido G.
      • Ciro M.
      • Jorge Fontoura Solla D.
      • Conti Reed U.
      • Zanoteli E.
      Clinical outcomes in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ] (Brazil)
      215 m–120 m6–24Funding: none declared.

      2/5 authors with CoI
      CHOP-INTEND

      HINE-2

      Respiratory support

      Nutritional support

      AEs
      Modrzejewska et al. 2021 [
      • Modrzejewska1 S.
      • Kotulska K.
      • Kopyta I.
      • et al.
      Nusinersen treatment of spinal muscular atrophy type 1— results of expanded access programme in Poland.
      ] (Poland)
      264.79 y (2 y–15 y)18–26Funding: n.r.

      1/13 authors with CoI
      CHOP INTEND

      Respiratory support

      Nutritional support

      AEs
      Pane et al. 2019 [
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • et al.
      Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data.
      ] (Italy)
      852 m–15 y 11 m12Funding: Famiglia SMA

      13/23 authors with CoI
      HINE-2

      CHOP INTEND

      Caregiver evaluation/parent reported questionnaires
      SMA 1 + 2
      Audic et al. 2020 [
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ] (France)
      34 SMA 1

      89 SMA 2 = 

      123
      3 m–16 y12Funding: French Network of Neuromuscular Disorders (FILNEMUS)

      CoI: none declared.
      HINE-2

      CHOP INTEND (<2 y)

      MFM20 (2–5 y), MFM32 INTEND (>6 y)

      Nutritional support

      Respiratory support

      CGI-I

      AEs and SAEs
      Gómez-García de la Banda et al. 2021 [
      • Gómez-García de la Banda M.
      • Amaddeo A.
      • Khirani S.
      • et al.
      Assessment of respiratory muscles and motor function in children with SMA treated by nusinersen.
      ] (France)
      2 SMA 1

      14 SMA 2 = 

      16
      3.5 y–11.5 y14Funding: n.r.

      4/12 authors with CoI
      MFM

      HINE-2

      Respiratory muscle tests and lung function data
      Author, year (country)Number of patientsAge

      Length of follow-up (m)
      Funding + CoIEndpoints measured
      SMA 1 + 2 + 3
      Chachko et al. 2021 [
      • Chacko A.
      • Sly P.D.
      • Ware R.S.
      • et al.
      Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3.
      ] (Australia)
      7 SMA 1

      12 SMA 2

      9 SMA 3 = 

      28
      1.17 y (0.1 y–12.7 y)12Funding: Biogen

      CoI: none declared.
      Pulmonary function

      CHOP INTEND

      RULM

      HFSME

      AHI
      Kariyawasam et al. 2020 [
      • Kariyawasam D.
      • D'Silva A.
      • Howells J.
      • et al.
      Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen.
      ] (Australia)
      6 SMA 1

      10 SMA 2

      4 SMA 3 = 

      20
      4 m–20 y13.8 (4–33.5)Funding: Scholarships, Hospital Foundation

      1/7 authors with CoI
      CMAP

      MUNE

      LSMUP

      HFSME or CHOP INTEND
      Osredkar et al. 2020 [
      • Osredkar D.
      • Jilkova M.
      • Butenko T.
      • et al.
      Children and young adults with spinal muscular atrophy treated with nusinersen.
      ] (Slovenia, Czech Republic)
      16 SMA 1

      32 SMA 2

      13 SMA 3 = 

      61
      2 m–19 y14Funding: Slovenia -University Medical Centre Ljubljana research grant 20180153

      CoI: none declared.
      CHOP INTEND

      HFMS

      HFMSE

      MFM
      Veerapandiyan et al. 2020 [
      • Veerapandiyan A.
      • Eichinger K.
      • Guntrum D.
      • et al.
      Nusinersen for older patients with spinal muscular atrophy: a real-world clinical setting experience.
      ] (USA)
      1 SMA 1

      4 SMA 2

      7 SMA 3 = 

      12
      22 y (12 y–52 y)17.4 (4–26)Funding: n.r.

      2/7 authors with CoI
      RULM

      6MWT

      AEs
      SMA 2 + 3
      Darras et al. 2019 [
      • Darras B.T.
      • Chiriboga C.A.
      • Iannaccone S.T.
      • et al.
      Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies.
      ] (USA)
      11 SMA 2

      17 SMA 3 = 

      28
      2 y–15 y∼32Funding: Biogen, Ionis Pharmaceuticals

      17/17 authors with CoI
      HFMSE

      ULM

      6MWT

      CMAP

      MUNE

      AEs, SAEs
      Montes et al. 2019 [
      • Montes J.
      • Dunaway Young S.
      • Mazzone E.S.
      • et al.
      Nusinersen improves walking distance and reduces fatigue in later-onset spinal muscular atrophy.
      ] (USA)
      1 SMA 2

      13 SMA 3 = 

      14
      35Funding: Biogen

      14/15 authors with CoI
      6MWT
      Hagenacker et al. 2020 [
      • Hagenacker T.
      • Wurster C.D.
      • Gunther R.
      • et al.
      Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study.
      ] (Germany)
      20 SMA 2

      37 SMA 3 = 

      57
      16 y - 65 y14Funding: none declared.

      22/31 authors with CoI
      HFMSE

      RULM

      6MWT

      AEs, SAEs
      Maggi et al. 2020 [
      • Maggi L.
      • Bello L.
      • Bonanno S.
      • et al.
      Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3.
      ] (Italy)
      13 SMA 2

      103 SMA 3 = 

      116
      34 y (18 y–72 y)14Funding: none declared.

      19/41 authors with CoI
      HFMSE

      RULM

      6MWT

      FVC

      AEs
      Mendonça et al. 2021a [
      • Mendonca R.H.
      • Polido G.J.
      • Matsui C.
      • et al.
      Real-world data from nusinersen treatment for patients with later-onset spinal muscular atrophy: a single center experience.
      ] (Brazil)
      14 SMA 2

      27 SMA 3 = 

      41
      10.6 y (10.3)24Funding: none declared.

      2/7 authors with CoI
      HFMSE or CHOP-INTEND
      Moshe-Lilie et al. 2020 [
      • Moshe-Lilie O.
      • Visser A.
      • Chahin N.
      • Ragole T.
      • Dimitrova D.
      • Karam C.
      Nusinersen in adult patients with spinal muscular atrophy: observations from a single center.
      ] (USA)
      9 SMA 2

      13 SMA 3 = 

      22
      36 y (20 y–71 y)24Funding: none declared.

      2/6 authors with CoI
      MRC

      HFMS

      AEs
      SMA 3
      Yeo et al. 2020 [
      • Yeo C.J.J.
      • Simeone S.D.
      • Townsend E.L.
      • Zhang R.Z.
      • Swoboda K.J.
      Prospective cohort study of nusinersen treatment in adults with spinal muscular atrophy.
      ] (USA, Singapur)
      6 SMA329.9 y (24.9 y–56.5 y)17 (14–21)Funding: n.r.

      1/5 authors with CoI
      HFMSE

      RULM

      PedsQL Fatigue scale

      SMAFRS

      6MWT and 10MWT

      AEs
      Author, year (country)Number of patientsAgeLength of follow-up (m)Funding + CoIEndpoints measured
      SMA 2 + 3 + 4
      Binz et al. 2020 [
      • Binz C.
      • Schreiber-Katz O.
      • Kumpe M.
      • et al.
      An observational cohort study on impact, dimensions and outcome of perceived fatigue in adult 5q-spinal muscular atrophy patients receiving nusinersen treatment.
      ] (Germany)
      6 SMA 2

      11 SMA 3

      1 SMA 4 = 

      18
      ≥18y14Funding: Open access funding by Projekt DEAL. No targeted study funding.

      5/8 authors with CoI
      FSS

      MFI

      HRQoL

      6MWT

      HFMSE

      RULM
      De Wel et al. 2020 [
      • De Wel B.
      • Goosens V.
      • Sobota A.
      • et al.
      Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4.
      ] (Belgium)
      14 SMA 3

      2 SMA 4 = 

      16
      37.1 (20 y–66 y)14Funding: partially Biogen

      1/9 authors with CoI
      Hand grip strength

      RULM

      MRC

      6MWT

      HFMSE

      SF-36

      AEs, SAE
      onasemnogene abeparvovec (Zolgensma®)
      SMA 1
      Al-Zaidy et al. 2019a [
      • Al-Zaidy S.
      • Pickard A.S.
      • Kotha K.
      • et al.
      Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy.
      ] (USA)
      123.4 m (0.9 m–7.9 m)24Funding: AveXis, Inc.

      CoI: n.r.
      Respiratory support

      Nutritional support

      Motor milestones
      Al-Zaidy et al. 2019b [
      • Al-Zaidy S.A.
      • Kolb S.J.
      • Lowes L.
      • et al.
      AVXS-101 (onasemnogene abeparvovec) for SMA1: comparative study with a prospective natural history cohort.
      ] (USA)
      123.4 m (0.9 m–7.9 m)24Funding: AveXis, Inc., NN101- NINDS (U01NS079163), Cure SMA, Muscular Dystrophy Association, and SMA Foundation

      15/17 authors with CoI
      CHOP INTEND

      AEs, SAEs
      Lowes et al. 2019 [
      • Lowes L.P.
      • Alfano L.N.
      • Arnold W.D.
      • et al.
      Impact of age and motor function in a phase 1/2A study of infants with SMA type 1 receiving single-dose gene replacement therapy.
      ] (USA)
      121.8 m–5.1 m24Funding: AveXis, Inc.

      12/16 authors with CoI
      Respiratory support

      Nutritional support

      CHOP INTEND
      combination therapy nusinersen (Spinraza®) + onasemnogene abeparvovec (Zolgensma®)
      SMA 1
      Harada et al. 2020 [
      • Harada Y.
      • Rao V.K.
      • Arya K.
      • et al.
      Combination molecular therapies for type 1 spinal muscular atrophy.
      ] (USA)
      517 m–29 m19.2 (8–27.2)Funding: n.r.

      4/10 authors with CoI
      CHOP INTEND

      HINE

      AEs
      Mendell et al. 2021 [
      • Mendell J.R.
      • Al-Zaidy S.A.
      • Lehman K.J.
      • et al.
      Five-Year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy.
      ] (USA)
      1338.9 m (25.4 m–48 m)5.2 y (4.6–6.2) yFunding: Novartis Gene Therapies

      7/12 authors with CoI
      AEs, SAEs
      Abbreviations: 6MWT = 6 min walk test, 10MWT = 10 min walk test, AE = adverse event, AHI = Apnoea-Hypopnoea Index, CGI-C = Clinical Global Impressions scale - Global Improvement, CHOP INTEND = Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders, CMAP = compound muscle action potential, CoI = conflict of interest, ECG = electrocardiogram, FSS = fatigue severity scale, FVC = forced vital capacity, HFMSE =Hammersmith Functional Motor Scale Expanded for SMA, HINE = Hammersmith Infant Neurological Examination, HRQoL = health-related quality of life, LSMUP = largest single motor unit potential, MFI = multidimensional fatigue inventory, MFM = motor function measure, MRC = Medical Research Council, MUNE = motor unit number estimation, n.r. = not reported, PedsQL = pediatric quality of life, OS = overall survival, RULM = revised upper limb module for SMA, SAE = serious adverse event, SF-36 = 36-Item Short Form Survey, SMAFRS = spinal muscular atrophy functional rating scale, WHO-MGRS = WHO Multicentre Growth Reference Study.
      Most studies had a moderate risk of bias because they were single-arm, and open-label (unblinded), often manufacturer-funded and written by authors with conflicts of interests (consultants of the manufacturers). High risk of bias was awarded for the studies, which were conducted retrospectively and did not report on the funding, or the conflict of interest of study authors. Detailed risk of bias assessment (on study level) is included in Supplementary Table C.

      4. Nusinersen

      4.1 SMA type 1

      Six prospective observational studies [
      • Acsadi G.
      • Crawford T.
      • Muller-Felber W.
      • et al.
      Safety and efficacy of nusinersen in spinal muscular atrophy: the EMBRACE study.
      ,
      • Aragon-Gawinska K.
      • Daron A.
      • Ulinici A.
      • et al.
      Sitting in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ,
      • Lavie M.
      • Diamant N.
      • Cahal M.
      • et al.
      Nusinersen for spinal muscular atrophy type 1: real-world respiratory experience.
      ,
      • de Holanda Mendonça R.
      • Jorge Polido G.
      • Ciro M.
      • Jorge Fontoura Solla D.
      • Conti Reed U.
      • Zanoteli E.
      Clinical outcomes in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ,
      • Modrzejewska1 S.
      • Kotulska K.
      • Kopyta I.
      • et al.
      Nusinersen treatment of spinal muscular atrophy type 1— results of expanded access programme in Poland.
      ,
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • et al.
      Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data.
      ] with 225 patients were included for the assessment of efficacy and safety of nusinersen in SMA type 1 patients. One study had a cross-over design [
      • Acsadi G.
      • Crawford T.
      • Muller-Felber W.
      • et al.
      Safety and efficacy of nusinersen in spinal muscular atrophy: the EMBRACE study.
      ], while five studies were single-arm.

      4.1.1 Mortality, discontinuation

      All included patients could be followed-up until the pre-defined last visit in only one of the selected studies [
      • Modrzejewska1 S.
      • Kotulska K.
      • Kopyta I.
      • et al.
      Nusinersen treatment of spinal muscular atrophy type 1— results of expanded access programme in Poland.
      ]. Five studies reported loss to follow-up due to death or other reasons: nine patients under treatment died due to massive aspiration, respiratory failure or pulmonary infection [
      • Aragon-Gawinska K.
      • Daron A.
      • Ulinici A.
      • et al.
      Sitting in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ,
      • Lavie M.
      • Diamant N.
      • Cahal M.
      • et al.
      Nusinersen for spinal muscular atrophy type 1: real-world respiratory experience.
      ,
      • de Holanda Mendonça R.
      • Jorge Polido G.
      • Ciro M.
      • Jorge Fontoura Solla D.
      • Conti Reed U.
      • Zanoteli E.
      Clinical outcomes in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ,
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • et al.
      Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data.
      ], and six patients stopped treatment due to respiratory exacerbations related to infections, lack of motor gain, respiratory degradation, not having met improvement expectations, burden of procedure or concomitant disease [
      • Aragon-Gawinska K.
      • Daron A.
      • Ulinici A.
      • et al.
      Sitting in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ,
      • Lavie M.
      • Diamant N.
      • Cahal M.
      • et al.
      Nusinersen for spinal muscular atrophy type 1: real-world respiratory experience.
      ,
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • et al.
      Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data.
      ]. Twenty-one patients were lost to follow-up without any particular reason [
      • Aragon-Gawinska K.
      • Daron A.
      • Ulinici A.
      • et al.
      Sitting in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ,
      • de Holanda Mendonça R.
      • Jorge Polido G.
      • Ciro M.
      • Jorge Fontoura Solla D.
      • Conti Reed U.
      • Zanoteli E.
      Clinical outcomes in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ,
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • et al.
      Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data.
      ].

      4.1.2 Motor endpoints

      CHOP INTEND scores were measured at baseline in four studies [
      • Aragon-Gawinska K.
      • Daron A.
      • Ulinici A.
      • et al.
      Sitting in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ,
      • de Holanda Mendonça R.
      • Jorge Polido G.
      • Ciro M.
      • Jorge Fontoura Solla D.
      • Conti Reed U.
      • Zanoteli E.
      Clinical outcomes in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ,
      • Modrzejewska1 S.
      • Kotulska K.
      • Kopyta I.
      • et al.
      Nusinersen treatment of spinal muscular atrophy type 1— results of expanded access programme in Poland.
      ,
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • et al.
      Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data.
      ]; data at follow-up were reported in three of them [
      • de Holanda Mendonça R.
      • Jorge Polido G.
      • Ciro M.
      • Jorge Fontoura Solla D.
      • Conti Reed U.
      • Zanoteli E.
      Clinical outcomes in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ,
      • Modrzejewska1 S.
      • Kotulska K.
      • Kopyta I.
      • et al.
      Nusinersen treatment of spinal muscular atrophy type 1— results of expanded access programme in Poland.
      ,
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • et al.
      Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data.
      ], while one study indicated only motor milestone achievements, without any exact scores on the CHOP INTEND scale [
      • Acsadi G.
      • Crawford T.
      • Muller-Felber W.
      • et al.
      Safety and efficacy of nusinersen in spinal muscular atrophy: the EMBRACE study.
      ]. Patients achieved the MCID on the CHOP INTEND scale in all three studies. Motor skills measured by CHOP INTEND improved from baseline 13.4 ± 9.8 [
      • de Holanda Mendonça R.
      • Jorge Polido G.
      • Ciro M.
      • Jorge Fontoura Solla D.
      • Conti Reed U.
      • Zanoteli E.
      Clinical outcomes in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ], 15.66 ± 13.48 [
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • et al.
      Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data.
      ] and 19.11 ± 14.28 [
      • Modrzejewska1 S.
      • Kotulska K.
      • Kopyta I.
      • et al.
      Nusinersen treatment of spinal muscular atrophy type 1— results of expanded access programme in Poland.
      ] by 6.6 at 18 months and by 14 at 24 months [
      • de Holanda Mendonça R.
      • Jorge Polido G.
      • Ciro M.
      • Jorge Fontoura Solla D.
      • Conti Reed U.
      • Zanoteli E.
      Clinical outcomes in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ], by 5.48 at 12 months [
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • et al.
      Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data.
      ] and by 7.39 within 18–26 months [
      • Modrzejewska1 S.
      • Kotulska K.
      • Kopyta I.
      • et al.
      Nusinersen treatment of spinal muscular atrophy type 1— results of expanded access programme in Poland.
      ]. In one study [
      • de Holanda Mendonça R.
      • Jorge Polido G.
      • Ciro M.
      • Jorge Fontoura Solla D.
      • Conti Reed U.
      • Zanoteli E.
      Clinical outcomes in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ], at the 12-month follow-up, in patients with disease duration 12–24 month and on invasive respiratory support, there was a decrease of 0.6 points. At 18 and 24-month follow-up, scores increased again, but data was available for fewer patients. In this study, motor milestone achievements showed no improvement for over 70% of patients, less than 10% achieved sitting and 14% achieved head control.
      HINE-2 was reported in four studies [
      • Acsadi G.
      • Crawford T.
      • Muller-Felber W.
      • et al.
      Safety and efficacy of nusinersen in spinal muscular atrophy: the EMBRACE study.
      ,
      • Aragon-Gawinska K.
      • Daron A.
      • Ulinici A.
      • et al.
      Sitting in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ,
      • de Holanda Mendonça R.
      • Jorge Polido G.
      • Ciro M.
      • Jorge Fontoura Solla D.
      • Conti Reed U.
      • Zanoteli E.
      Clinical outcomes in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ,
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • et al.
      Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data.
      ], however, in one study [
      • Aragon-Gawinska K.
      • Daron A.
      • Ulinici A.
      • et al.
      Sitting in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ] follow-up data was not reported and another study [
      • de Holanda Mendonça R.
      • Jorge Polido G.
      • Ciro M.
      • Jorge Fontoura Solla D.
      • Conti Reed U.
      • Zanoteli E.
      Clinical outcomes in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ] reported no follow-up values, only the proportion of patients reaching the MCID. Motor skills improved from baseline 7.6 ± 5.4 [
      • Acsadi G.
      • Crawford T.
      • Muller-Felber W.
      • et al.
      Safety and efficacy of nusinersen in spinal muscular atrophy: the EMBRACE study.
      ], 0.69 ± 1.23 [
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • et al.
      Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data.
      ], 0–4 [
      • de Holanda Mendonça R.
      • Jorge Polido G.
      • Ciro M.
      • Jorge Fontoura Solla D.
      • Conti Reed U.
      • Zanoteli E.
      Clinical outcomes in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ] by 5.4 at 22 months and by 7.4 at 34 months, and by 1.47 at 12 months [
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • et al.
      Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data.
      ]. Patients reached the MCID threshold in two studies [
      • Acsadi G.
      • Crawford T.
      • Muller-Felber W.
      • et al.
      Safety and efficacy of nusinersen in spinal muscular atrophy: the EMBRACE study.
      ,
      • de Holanda Mendonça R.
      • Jorge Polido G.
      • Ciro M.
      • Jorge Fontoura Solla D.
      • Conti Reed U.
      • Zanoteli E.
      Clinical outcomes in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ]. In the study without exact follow-up values, one of five (at 12 months), one of seven (at 18 months) and two of three (at 24 months) patients reached the MCID [
      • de Holanda Mendonça R.
      • Jorge Polido G.
      • Ciro M.
      • Jorge Fontoura Solla D.
      • Conti Reed U.
      • Zanoteli E.
      Clinical outcomes in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ]. In the other study [
      • Acsadi G.
      • Crawford T.
      • Muller-Felber W.
      • et al.
      Safety and efficacy of nusinersen in spinal muscular atrophy: the EMBRACE study.
      ], 93% of patients were classified as HINE-2 responders; however, 100% of the patients achieved the MCID threshold (the criteria to be classified as a HINE-2 responder was stricter).

      4.1.3 Quality of life endpoints (respiratory support, nutritional support, caregiver evaluation)

      Respiratory support, both invasive (IV) and non-invasive (NIV), was reported in five studies [
      • Acsadi G.
      • Crawford T.
      • Muller-Felber W.
      • et al.
      Safety and efficacy of nusinersen in spinal muscular atrophy: the EMBRACE study.
      ,
      • Lavie M.
      • Diamant N.
      • Cahal M.
      • et al.
      Nusinersen for spinal muscular atrophy type 1: real-world respiratory experience.
      ,
      • de Holanda Mendonça R.
      • Jorge Polido G.
      • Ciro M.
      • Jorge Fontoura Solla D.
      • Conti Reed U.
      • Zanoteli E.
      Clinical outcomes in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ,
      • Modrzejewska1 S.
      • Kotulska K.
      • Kopyta I.
      • et al.
      Nusinersen treatment of spinal muscular atrophy type 1— results of expanded access programme in Poland.
      ,
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • et al.
      Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data.
      ], but follow-up data was available only in four of them [
      • Lavie M.
      • Diamant N.
      • Cahal M.
      • et al.
      Nusinersen for spinal muscular atrophy type 1: real-world respiratory experience.
      ,
      • de Holanda Mendonça R.
      • Jorge Polido G.
      • Ciro M.
      • Jorge Fontoura Solla D.
      • Conti Reed U.
      • Zanoteli E.
      Clinical outcomes in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ,
      • Modrzejewska1 S.
      • Kotulska K.
      • Kopyta I.
      • et al.
      Nusinersen treatment of spinal muscular atrophy type 1— results of expanded access programme in Poland.
      ,
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • et al.
      Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data.
      ]. There was no significant change in the number of patients needing NIV, in one study however, the patients not requiring NIV at baseline (20%) all progressed to needing NIV for less than 16 h a day two to 22 months after treatment initiation [
      • Lavie M.
      • Diamant N.
      • Cahal M.
      • et al.
      Nusinersen for spinal muscular atrophy type 1: real-world respiratory experience.
      ]. In two studies [
      • Modrzejewska1 S.
      • Kotulska K.
      • Kopyta I.
      • et al.
      Nusinersen treatment of spinal muscular atrophy type 1— results of expanded access programme in Poland.
      ,
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • et al.
      Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data.
      ], IV via tracheostomy was initiated during the follow-up period in 2% and 11% of study patients, respectively.
      Nutritional support was reported in five studies [
      • Aragon-Gawinska K.
      • Daron A.
      • Ulinici A.
      • et al.
      Sitting in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ,
      • Lavie M.
      • Diamant N.
      • Cahal M.
      • et al.
      Nusinersen for spinal muscular atrophy type 1: real-world respiratory experience.
      ,
      • de Holanda Mendonça R.
      • Jorge Polido G.
      • Ciro M.
      • Jorge Fontoura Solla D.
      • Conti Reed U.
      • Zanoteli E.
      Clinical outcomes in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ,
      • Modrzejewska1 S.
      • Kotulska K.
      • Kopyta I.
      • et al.
      Nusinersen treatment of spinal muscular atrophy type 1— results of expanded access programme in Poland.
      ,
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • et al.
      Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data.
      ] but only four of them reported follow-up data, which showed no significant change between baseline and follow-up values [
      • Lavie M.
      • Diamant N.
      • Cahal M.
      • et al.
      Nusinersen for spinal muscular atrophy type 1: real-world respiratory experience.
      ,
      • de Holanda Mendonça R.
      • Jorge Polido G.
      • Ciro M.
      • Jorge Fontoura Solla D.
      • Conti Reed U.
      • Zanoteli E.
      Clinical outcomes in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ,
      • Modrzejewska1 S.
      • Kotulska K.
      • Kopyta I.
      • et al.
      Nusinersen treatment of spinal muscular atrophy type 1— results of expanded access programme in Poland.
      ,
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • et al.
      Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data.
      ].
      Caregiver evaluations were collected in three studies [
      • Acsadi G.
      • Crawford T.
      • Muller-Felber W.
      • et al.
      Safety and efficacy of nusinersen in spinal muscular atrophy: the EMBRACE study.
      ,
      • de Holanda Mendonça R.
      • Jorge Polido G.
      • Ciro M.
      • Jorge Fontoura Solla D.
      • Conti Reed U.
      • Zanoteli E.
      Clinical outcomes in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ,
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • et al.
      Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data.
      ]. Any improvement was reported by caregivers’ and investigators’ evaluation equally (100%), while much improvement was reported more often by caregivers (64%) than by investigators (43%) [
      • Acsadi G.
      • Crawford T.
      • Muller-Felber W.
      • et al.
      Safety and efficacy of nusinersen in spinal muscular atrophy: the EMBRACE study.
      ]. In another study overall stability was reported in 15% of patients, general increase in function in 85%, improvement in motor function in 87%, and combination of motor, respiratory and swallowing functions in 13% of patients [
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • et al.
      Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data.
      ]. In the third evaluation of improvements provided by caregivers, a reduction in recurrent infections and a decreased need for secretion aspiration was reported for 60% of patients in need for IV support [
      • de Holanda Mendonça R.
      • Jorge Polido G.
      • Ciro M.
      • Jorge Fontoura Solla D.
      • Conti Reed U.
      • Zanoteli E.
      Clinical outcomes in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ].

      4.1.4 Safety endpoints

      Drug-related adverse events were reported in two studies: in one study none occurred [
      • Modrzejewska1 S.
      • Kotulska K.
      • Kopyta I.
      • et al.
      Nusinersen treatment of spinal muscular atrophy type 1— results of expanded access programme in Poland.
      ], in the other study 14% of patients experienced them [
      • Acsadi G.
      • Crawford T.
      • Muller-Felber W.
      • et al.
      Safety and efficacy of nusinersen in spinal muscular atrophy: the EMBRACE study.
      ]. Procedure-related adverse events were reported in two studies: most frequently post-lumbar puncture syndrome, unsealed puncture site with temporary CFS leakage and post-puncture headache occurred (in 15%, in 7% and in 2% of patients, respectively) [
      • de Holanda Mendonça R.
      • Jorge Polido G.
      • Ciro M.
      • Jorge Fontoura Solla D.
      • Conti Reed U.
      • Zanoteli E.
      Clinical outcomes in patients with spinal muscular atrophy type 1 treated with nusinersen.
      ,
      • Modrzejewska1 S.
      • Kotulska K.
      • Kopyta I.
      • et al.
      Nusinersen treatment of spinal muscular atrophy type 1— results of expanded access programme in Poland.
      ]. One study reported serious adverse events (64%), however not indicating if they were drug-or procedure related [
      • Acsadi G.
      • Crawford T.
      • Muller-Felber W.
      • et al.
      Safety and efficacy of nusinersen in spinal muscular atrophy: the EMBRACE study.
      ].

      4.2 SMA type 1 and type 2, SMA type 1 to type 3

      Five studies (in six publications) [
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ,
      • Gómez-García de la Banda M.
      • Amaddeo A.
      • Khirani S.
      • et al.
      Assessment of respiratory muscles and motor function in children with SMA treated by nusinersen.
      ,
      • Chacko A.
      • Sly P.D.
      • Ware R.S.
      • et al.
      Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3.
      ,
      • Kariyawasam D.
      • D'Silva A.
      • Howells J.
      • et al.
      Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen.
      ,
      • Osredkar D.
      • Jilkova M.
      • Butenko T.
      • et al.
      Children and young adults with spinal muscular atrophy treated with nusinersen.
      ,
      • Veerapandiyan A.
      • Eichinger K.
      • Guntrum D.
      • et al.
      Nusinersen for older patients with spinal muscular atrophy: a real-world clinical setting experience.
      ] were identified, of which one study (two publications) enrolled SMA type 1 and type 2 [
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ,
      • Gómez-García de la Banda M.
      • Amaddeo A.
      • Khirani S.
      • et al.
      Assessment of respiratory muscles and motor function in children with SMA treated by nusinersen.
      ], and four enrolled SMA type 1 to type 3 patients [
      • Chacko A.
      • Sly P.D.
      • Ware R.S.
      • et al.
      Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3.
      ,
      • Kariyawasam D.
      • D'Silva A.
      • Howells J.
      • et al.
      Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen.
      ,
      • Osredkar D.
      • Jilkova M.
      • Butenko T.
      • et al.
      Children and young adults with spinal muscular atrophy treated with nusinersen.
      ,
      • Veerapandiyan A.
      • Eichinger K.
      • Guntrum D.
      • et al.
      Nusinersen for older patients with spinal muscular atrophy: a real-world clinical setting experience.
      ]. One study was of a retrospective design [
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ], another one [
      • Gómez-García de la Banda M.
      • Amaddeo A.
      • Khirani S.
      • et al.
      Assessment of respiratory muscles and motor function in children with SMA treated by nusinersen.
      ] was a prospective observational cohort study with a historical control group, in which the treated SMA cohort was presumably part of the retrospective study’s cohort. Four studies were prospective observational single arm studies [
      • Chacko A.
      • Sly P.D.
      • Ware R.S.
      • et al.
      Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3.
      ,
      • Kariyawasam D.
      • D'Silva A.
      • Howells J.
      • et al.
      Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen.
      ,
      • Osredkar D.
      • Jilkova M.
      • Butenko T.
      • et al.
      Children and young adults with spinal muscular atrophy treated with nusinersen.
      ,
      • Veerapandiyan A.
      • Eichinger K.
      • Guntrum D.
      • et al.
      Nusinersen for older patients with spinal muscular atrophy: a real-world clinical setting experience.
      ]. The five studies included 66 patients with SMA type 1, 161 with SMA type 2 and 33 with SMA type 3.

      4.2.1 Mortality, discontinuation

      Four studies reported loss to follow-up due to death or other reasons [
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ,
      • Chacko A.
      • Sly P.D.
      • Ware R.S.
      • et al.
      Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3.
      ,
      • Kariyawasam D.
      • D'Silva A.
      • Howells J.
      • et al.
      Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen.
      ,
      • Osredkar D.
      • Jilkova M.
      • Butenko T.
      • et al.
      Children and young adults with spinal muscular atrophy treated with nusinersen.
      ]. Eight patients under treatment died [
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ,
      • Chacko A.
      • Sly P.D.
      • Ware R.S.
      • et al.
      Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3.
      ,
      • Osredkar D.
      • Jilkova M.
      • Butenko T.
      • et al.
      Children and young adults with spinal muscular atrophy treated with nusinersen.
      ] (in Ref. [
      • Chacko A.
      • Sly P.D.
      • Ware R.S.
      • et al.
      Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3.
      ] all SMA type 1), three patients discontinued therapy due to tolerability issues with nusinersen or with the functional assessment at follow-up [
      • Kariyawasam D.
      • D'Silva A.
      • Howells J.
      • et al.
      Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen.
      ,
      • Osredkar D.
      • Jilkova M.
      • Butenko T.
      • et al.
      Children and young adults with spinal muscular atrophy treated with nusinersen.
      ], and one patient was excluded from the analysis due to potential negative effects of a spinal surgery [
      • Chacko A.
      • Sly P.D.
      • Ware R.S.
      • et al.
      Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3.
      ]. Patients were lost to follow-up without any particular reason in one study [
      • Veerapandiyan A.
      • Eichinger K.
      • Guntrum D.
      • et al.
      Nusinersen for older patients with spinal muscular atrophy: a real-world clinical setting experience.
      ] (data was not available for the two outcomes in 33%, and in 75% of patients, respectively).

      4.2.2 Motor endpoints

      CHOP INTEND was measured in four studies [
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ,
      • Chacko A.
      • Sly P.D.
      • Ware R.S.
      • et al.
      Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3.
      ,
      • Kariyawasam D.
      • D'Silva A.
      • Howells J.
      • et al.
      Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen.
      ,
      • Osredkar D.
      • Jilkova M.
      • Butenko T.
      • et al.
      Children and young adults with spinal muscular atrophy treated with nusinersen.
      ], in one of them only in patients under two years of age [
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ], in another one [
      • Chacko A.
      • Sly P.D.
      • Ware R.S.
      • et al.
      Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3.
      ] mainly in SMA type 1 patients, and two studies [
      • Kariyawasam D.
      • D'Silva A.
      • Howells J.
      • et al.
      Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen.
      ,
      • Osredkar D.
      • Jilkova M.
      • Butenko T.
      • et al.
      Children and young adults with spinal muscular atrophy treated with nusinersen.
      ] reported only the change from baseline without baseline data. Motor skills improved in SMA type 1 patients at 12-month follow-up from 35.1 to 50.3 [
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ] and from 27.5 to 44.0 [
      • Chacko A.
      • Sly P.D.
      • Ware R.S.
      • et al.
      Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3.
      ]. In one SMA type 2 patient, motor skills improved from baseline 32.0 to 41.0 at 12 month-follow-up [
      • Chacko A.
      • Sly P.D.
      • Ware R.S.
      • et al.
      Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3.
      ]. The improvement from baseline to last follow-up in both studies [
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ,
      • Chacko A.
      • Sly P.D.
      • Ware R.S.
      • et al.
      Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3.
      ] exceeded the MCID.
      Two studies [
      • Kariyawasam D.
      • D'Silva A.
      • Howells J.
      • et al.
      Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen.
      ,
      • Osredkar D.
      • Jilkova M.
      • Butenko T.
      • et al.
      Children and young adults with spinal muscular atrophy treated with nusinersen.
      ] combined CHOP INTEND and HFSME scales to measure the changes in motor scores from baseline. In one of them [
      • Kariyawasam D.
      • D'Silva A.
      • Howells J.
      • et al.
      Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen.
      ] one third of the patients reached the MCID, and two thirds remained stable. The study did not report the type of SMA, or the number of SMN2 copies of the patients who reached improvement, nor those of remaining stable. The other study [
      • Osredkar D.
      • Jilkova M.
      • Butenko T.
      • et al.
      Children and young adults with spinal muscular atrophy treated with nusinersen.
      ] reported a significant improvement in motor scales after 14 months of treatment in SMA type 1 and type 2 patients, while type 3 patients showed a trend towards improvement, but it was not statistically significant. Seventy-three percent of patients showed improvement, 12% showed no improvement and 14% presented decline [
      • Osredkar D.
      • Jilkova M.
      • Butenko T.
      • et al.
      Children and young adults with spinal muscular atrophy treated with nusinersen.
      ].
      HINE-2 scores were available in one study (two publications) [
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ,
      • Gómez-García de la Banda M.
      • Amaddeo A.
      • Khirani S.
      • et al.
      Assessment of respiratory muscles and motor function in children with SMA treated by nusinersen.
      ], however, one of the publications [
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ] reported it only for patients under two years of age. For patients older than two years, MFM scores were available. Motor skills improved in SMA type 1 patients from 7 (range 0–23) to 14.5 (range 7–25) at 12 months [
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ] and in SMA type 1 and type 2 patients from 8 ± 5 to 9 ± 5 at 14 months [
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ,
      • Gómez-García de la Banda M.
      • Amaddeo A.
      • Khirani S.
      • et al.
      Assessment of respiratory muscles and motor function in children with SMA treated by nusinersen.
      ]. The improvement in SMA type 1 patients reached the MCID threshold [
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ], while SMA type 1 and type 2 patients’ HINE-2 scores improved by one point and only seven of 16 patients (44%) reached the MCID [
      • Gómez-García de la Banda M.
      • Amaddeo A.
      • Khirani S.
      • et al.
      Assessment of respiratory muscles and motor function in children with SMA treated by nusinersen.
      ].
      MFM scores were reported in two studies [
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ,
      • Gómez-García de la Banda M.
      • Amaddeo A.
      • Khirani S.
      • et al.
      Assessment of respiratory muscles and motor function in children with SMA treated by nusinersen.
      ], of which one [
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ] reported the MFM scores only for patients older than two years. Motor skills improved from 42 (range 4–87) to 47 (range 6–78) at 12-month follow-up and from 34 ± 17 to 43 ± 17 at 14-month follow-up.
      HFSME scores were reported in one study [
      • Chacko A.
      • Sly P.D.
      • Ware R.S.
      • et al.
      Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3.
      ], in which patients with SMA type 2 and type 3 were evaluated with this scale, while SMA type 1 patients were measured by CHOP INTEND. At 12-month follow-up, motor skills improved in SMA type 2 patients from 32.0 to 34.0 and in SMA type 3 patients from 45.0 to 49.0 [
      • Chacko A.
      • Sly P.D.
      • Ware R.S.
      • et al.
      Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3.
      ].
      RULM scores were reported in two studies [
      • Chacko A.
      • Sly P.D.
      • Ware R.S.
      • et al.
      Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3.
      ,
      • Veerapandiyan A.
      • Eichinger K.
      • Guntrum D.
      • et al.
      Nusinersen for older patients with spinal muscular atrophy: a real-world clinical setting experience.
      ]. Upper limb functional skills improved in one SMA type 1 patient by 1 point at 12 months [
      • Chacko A.
      • Sly P.D.
      • Ware R.S.
      • et al.
      Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3.
      ], in SMA type 2 patients by 0.5 point at 12 months, by 5.3 points at 17.4 months [
      • Chacko A.
      • Sly P.D.
      • Ware R.S.
      • et al.
      Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3.
      ,
      • Veerapandiyan A.
      • Eichinger K.
      • Guntrum D.
      • et al.
      Nusinersen for older patients with spinal muscular atrophy: a real-world clinical setting experience.
      ] and in SMA type 3 patients by 0.9 point at 17.4 months [
      • Veerapandiyan A.
      • Eichinger K.
      • Guntrum D.
      • et al.
      Nusinersen for older patients with spinal muscular atrophy: a real-world clinical setting experience.
      ]. Thus, clinically meaningful improvement was found in only one of the studies and only in the SMA type 2 patients.
      The 6MWT was used only in one study [
      • Veerapandiyan A.
      • Eichinger K.
      • Guntrum D.
      • et al.
      Nusinersen for older patients with spinal muscular atrophy: a real-world clinical setting experience.
      ], in only one patient, with reported improvement but no exact baseline and follow-up data. The 30-foot walk test, applied in the same study in two patients, did not show any improvements from baseline.

      4.2.3 Quality of life endpoints (respiratory support, nutritional support, caregiver evaluation)

      Respiratory support was reported in three studies (four publications) [
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ,
      • Gómez-García de la Banda M.
      • Amaddeo A.
      • Khirani S.
      • et al.
      Assessment of respiratory muscles and motor function in children with SMA treated by nusinersen.
      ,
      • Chacko A.
      • Sly P.D.
      • Ware R.S.
      • et al.
      Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3.
      ,
      • Osredkar D.
      • Jilkova M.
      • Butenko T.
      • et al.
      Children and young adults with spinal muscular atrophy treated with nusinersen.
      ], however, follow-up data on NIV was not available in one of them [
      • Gómez-García de la Banda M.
      • Amaddeo A.
      • Khirani S.
      • et al.
      Assessment of respiratory muscles and motor function in children with SMA treated by nusinersen.
      ]. In all studies, non-significant deterioration could be observed in NIV and stagnation in IV. The patients who started needing NIV during study period had type 1 and type 2 SMA.
      Nutritional support baseline and follow-up data were available in two studies [
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ,
      • Osredkar D.
      • Jilkova M.
      • Butenko T.
      • et al.
      Children and young adults with spinal muscular atrophy treated with nusinersen.
      ] and showed non-significant increase in the number of patients requiring support during the follow-up period (two and one more patients requiring feeding support, respectively).
      Caregiver evaluations were collected in two studies [
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ,
      • Veerapandiyan A.
      • Eichinger K.
      • Guntrum D.
      • et al.
      Nusinersen for older patients with spinal muscular atrophy: a real-world clinical setting experience.
      ]. Caregivers reported much (46%) or very much (6%) improved condition, no change (13%) or minimal improvement (35%), whilst deterioration was not reported by any of the caregivers [
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ]. In the other study [
      • Veerapandiyan A.
      • Eichinger K.
      • Guntrum D.
      • et al.
      Nusinersen for older patients with spinal muscular atrophy: a real-world clinical setting experience.
      ] caregivers reported that 67% of patients achieved improvements in endurance, fine hand movements and hand strengths, additionally, 42% of patients achieved louder and clearer speech.

      4.2.4 Safety endpoints

      Adverse events were related mainly to the lumbar puncture (headache, post lumbar puncture syndrome, nausea and vomiting), and occurred in 20%–40% of patients [
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ,
      • Osredkar D.
      • Jilkova M.
      • Butenko T.
      • et al.
      Children and young adults with spinal muscular atrophy treated with nusinersen.
      ,
      • Veerapandiyan A.
      • Eichinger K.
      • Guntrum D.
      • et al.
      Nusinersen for older patients with spinal muscular atrophy: a real-world clinical setting experience.
      ]. Three studies highlighted that no serious adverse events occurred [
      • Audic F.
      • de la Banda M.G.G.
      • Bernoux D.
      • et al.
      Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
      ,
      • Gómez-García de la Banda M.
      • Amaddeo A.
      • Khirani S.
      • et al.
      Assessment of respiratory muscles and motor function in children with SMA treated by nusinersen.
      ,
      • Osredkar D.
      • Jilkova M.
      • Butenko T.
      • et al.
      Children and young adults with spinal muscular atrophy treated with nusinersen.
      ].

      4.3 SMA type 2 and type 3, SMA type 3, SMA type 2 to type 4

      Five studies (six publications) [
      • Darras B.T.
      • Chiriboga C.A.
      • Iannaccone S.T.
      • et al.
      Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies.
      ,
      • Montes J.
      • Dunaway Young S.
      • Mazzone E.S.
      • et al.
      Nusinersen improves walking distance and reduces fatigue in later-onset spinal muscular atrophy.
      ,
      • Hagenacker T.
      • Wurster C.D.
      • Gunther R.
      • et al.
      Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study.
      ,
      • Maggi L.
      • Bello L.
      • Bonanno S.
      • et al.
      Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3.
      ,
      • Mendonca R.H.
      • Polido G.J.
      • Matsui C.
      • et al.
      Real-world data from nusinersen treatment for patients with later-onset spinal muscular atrophy: a single center experience.
      ,
      • Moshe-Lilie O.
      • Visser A.
      • Chahin N.
      • Ragole T.
      • Dimitrova D.
      • Karam C.
      Nusinersen in adult patients with spinal muscular atrophy: observations from a single center.
      ] were identified for inclusion with SMA type 2 and type 3 patients, one study [
      • Yeo C.J.J.
      • Simeone S.D.
      • Townsend E.L.
      • Zhang R.Z.
      • Swoboda K.J.
      Prospective cohort study of nusinersen treatment in adults with spinal muscular atrophy.
      ] with only SMA type 3 patients, one study [
      • De Wel B.
      • Goosens V.
      • Sobota A.
      • et al.
      Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4.
      ] with SMA type 3 and type 4 and one study [
      • Binz C.
      • Schreiber-Katz O.
      • Kumpe M.
      • et al.
      An observational cohort study on impact, dimensions and outcome of perceived fatigue in adult 5q-spinal muscular atrophy patients receiving nusinersen treatment.
      ] with SMA type 2 to type 4 patients. Five publications were prospective observational single arm studies. Four publications had a retrospective study design (two of these retrospective studies included a historical control group). The included studies assessed in total 93 patients with SMA type 2, 245 with SMA type 3 and three patients with SMA type 4.

      4.3.1 Mortality, discontinuation

      Four studies [
      • Darras B.T.
      • Chiriboga C.A.
      • Iannaccone S.T.
      • et al.
      Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies.
      ,
      • Hagenacker T.
      • Wurster C.D.
      • Gunther R.
      • et al.
      Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study.
      ,
      • Maggi L.
      • Bello L.
      • Bonanno S.
      • et al.
      Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3.
      ,
      • Moshe-Lilie O.
      • Visser A.
      • Chahin N.
      • Ragole T.
      • Dimitrova D.
      • Karam C.
      Nusinersen in adult patients with spinal muscular atrophy: observations from a single center.
      ] reported loss to follow-up with reasons: one patient died of respiratory failure; five patients discontinued treatment due to lack of perceived benefit and poor tolerability of lumbar puncture and two patients withdrew because of adverse drug reactions (two further patients stopped treatment on patients’ wishes without any particular reason). In another study [
      • Mendonca R.H.
      • Polido G.J.
      • Matsui C.
      • et al.
      Real-world data from nusinersen treatment for patients with later-onset spinal muscular atrophy: a single center experience.
      ] four patients were lost to follow-up without any reason.

      4.3.2 Motor endpoints

      CHOP INTEND was measured in one study [
      • Mendonca R.H.
      • Polido G.J.
      • Matsui C.
      • et al.
      Real-world data from nusinersen treatment for patients with later-onset spinal muscular atrophy: a single center experience.
      ] and only in those patients who were unable to sit at the time of baseline measurement. The scores in SMA type 2 and type 3 patients improved from baseline 32.27 by 2.37 at 12-month and by 3.41 at 24-month follow-up, both changes are below the MCID threshold.
      HFMSE scores were measured in eight studies [
      • Darras B.T.
      • Chiriboga C.A.
      • Iannaccone S.T.
      • et al.
      Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies.
      ,
      • Hagenacker T.
      • Wurster C.D.
      • Gunther R.
      • et al.
      Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study.
      ,
      • Maggi L.
      • Bello L.
      • Bonanno S.
      • et al.
      Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3.
      ,
      • Mendonca R.H.
      • Polido G.J.
      • Matsui C.
      • et al.
      Real-world data from nusinersen treatment for patients with later-onset spinal muscular atrophy: a single center experience.
      ,
      • Moshe-Lilie O.
      • Visser A.
      • Chahin N.
      • Ragole T.
      • Dimitrova D.
      • Karam C.
      Nusinersen in adult patients with spinal muscular atrophy: observations from a single center.
      ,
      • Yeo C.J.J.
      • Simeone S.D.
      • Townsend E.L.
      • Zhang R.Z.
      • Swoboda K.J.
      Prospective cohort study of nusinersen treatment in adults with spinal muscular atrophy.
      ,
      • De Wel B.
      • Goosens V.
      • Sobota A.
      • et al.
      Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4.
      ,
      • Binz C.
      • Schreiber-Katz O.
      • Kumpe M.
      • et al.
      An observational cohort study on impact, dimensions and outcome of perceived fatigue in adult 5q-spinal muscular atrophy patients receiving nusinersen treatment.
      ], one of which [
      • Moshe-Lilie O.
      • Visser A.
      • Chahin N.
      • Ragole T.
      • Dimitrova D.
      • Karam C.
      Nusinersen in adult patients with spinal muscular atrophy: observations from a single center.
      ] reported only the change from baseline. Clinically meaningful improvements were recorded in three studies: 12 points at 24-month follow-up [
      • Moshe-Lilie O.
      • Visser A.
      • Chahin N.
      • Ragole T.
      • Dimitrova D.
      • Karam C.
      Nusinersen in adult patients with spinal muscular atrophy: observations from a single center.
      ], 8.5 points at 28-month, 10.8 points at 38-month (in SMA type 2 patients) [
      • Darras B.T.
      • Chiriboga C.A.
      • Iannaccone S.T.
      • et al.
      Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies.
      ], and 3.12 (2.06–4.19) points at 14-month follow-up [
      • Hagenacker T.
      • Wurster C.D.
      • Gunther R.
      • et al.
      Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study.
      ]. Marginal improvements below the MCID threshold, or stabilisation in motor skills were found in five studies: stabilisation at 24-month follow-up [
      • Moshe-Lilie O.
      • Visser A.
      • Chahin N.
      • Ragole T.
      • Dimitrova D.
      • Karam C.
      Nusinersen in adult patients with spinal muscular atrophy: observations from a single center.
      ], +1.8 points at 28-month follow-up in SMA type 3 patients, which stabilised at month 38 [
      • Darras B.T.
      • Chiriboga C.A.
      • Iannaccone S.T.
      • et al.
      Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies.
      ], +2 (1–5) points at 14-month follow-up [
      • Yeo C.J.J.
      • Simeone S.D.
      • Townsend E.L.
      • Zhang R.Z.
      • Swoboda K.J.
      Prospective cohort study of nusinersen treatment in adults with spinal muscular atrophy.
      ], +1.2 points at 14-month follow-up in SMA type 2 patients and +2.85 in SMA type 3 patients [
      • Maggi L.
      • Bello L.
      • Bonanno S.
      • et al.
      Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3.
      ], and +2.1 points at 14-month follow-up [
      • De Wel B.
      • Goosens V.
      • Sobota A.
      • et al.
      Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4.
      ].
      In one study, while only a marginal improvement of 1.6 points was found in the whole study population at 24 months, in the subgroups per SMA type a clinically meaningful improvement was reported (4.5 points) in SMA type 2 patients and a marginal decrease (1 point) in SMA type 3 patients [
      • Mendonca R.H.
      • Polido G.J.
      • Matsui C.
      • et al.
      Real-world data from nusinersen treatment for patients with later-onset spinal muscular atrophy: a single center experience.
      ]. In another study, half of the patients achieved an improvement over the MCID at 14 months (3.13 points), while the other half of the patients’ scores remained stable or deteriorated by 1.43 points. The study failed to report which SMA types the patients belonged to Ref. [
      • Binz C.
      • Schreiber-Katz O.
      • Kumpe M.
      • et al.
      An observational cohort study on impact, dimensions and outcome of perceived fatigue in adult 5q-spinal muscular atrophy patients receiving nusinersen treatment.
      ].
      Two studies reported MRC scores [
      • Moshe-Lilie O.
      • Visser A.
      • Chahin N.
      • Ragole T.
      • Dimitrova D.
      • Karam C.
      Nusinersen in adult patients with spinal muscular atrophy: observations from a single center.
      ,
      • De Wel B.
      • Goosens V.
      • Sobota A.
      • et al.
      Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4.
      ], of which one study [
      • Moshe-Lilie O.
      • Visser A.
      • Chahin N.
      • Ragole T.
      • Dimitrova D.
      • Karam C.
      Nusinersen in adult patients with spinal muscular atrophy: observations from a single center.
      ] reported only the change in the proportion of the maximum possible total score from baseline to last follow-up. This increased by 2.5% and 3.9% at 12 and 24-month follow-up, respectively. The other study [
      • De Wel B.
      • Goosens V.
      • Sobota A.
      • et al.
      Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4.
      ] reported an increase of 2.5 points at 14-month follow-up.
      RULM was measured in six studies [
      • Montes J.
      • Dunaway Young S.
      • Mazzone E.S.
      • et al.
      Nusinersen improves walking distance and reduces fatigue in later-onset spinal muscular atrophy.
      ,
      • Hagenacker T.
      • Wurster C.D.
      • Gunther R.
      • et al.
      Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study.
      ,
      • Maggi L.
      • Bello L.
      • Bonanno S.
      • et al.
      Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3.
      ,
      • Yeo C.J.J.
      • Simeone S.D.
      • Townsend E.L.
      • Zhang R.Z.
      • Swoboda K.J.
      Prospective cohort study of nusinersen treatment in adults with spinal muscular atrophy.
      ,
      • De Wel B.
      • Goosens V.
      • Sobota A.
      • et al.
      Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4.
      ,
      • Binz C.
      • Schreiber-Katz O.
      • Kumpe M.
      • et al.
      An observational cohort study on impact, dimensions and outcome of perceived fatigue in adult 5q-spinal muscular atrophy patients receiving nusinersen treatment.
      ], of which only two studies reported results per SMA type [
      • Montes J.
      • Dunaway Young S.
      • Mazzone E.S.
      • et al.
      Nusinersen improves walking distance and reduces fatigue in later-onset spinal muscular atrophy.
      ,
      • Maggi L.
      • Bello L.
      • Bonanno S.
      • et al.
      Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3.
      ]. Minimal changes below the MCID were found in three studies: +1.6 in SMA type 2, +1.47 and + 0.4 at 14 months in SMA type 3 sitters and walkers respectively [
      • Maggi L.
      • Bello L.
      • Bonanno S.
      • et al.
      Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3.
      ], +1.1 at 14 months in SMA type 3 and type 4 patients [
      • De Wel B.
      • Goosens V.
      • Sobota A.
      • et al.
      Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4.
      ], and +1.09 at 14 months in SMA type 2 and type 3 patients [
      • Hagenacker T.
      • Wurster C.D.
      • Gunther R.
      • et al.
      Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study.
      ]. Clinically meaningful improvements were found in one study: +3 points at 28-month follow-up, and +4 points at 38 months [
      • Montes J.
      • Dunaway Young S.
      • Mazzone E.S.
      • et al.
      Nusinersen improves walking distance and reduces fatigue in later-onset spinal muscular atrophy.
      ].
      Motor milestone achievements in general were reported in one study [
      • Maggi L.
      • Bello L.
      • Bonanno S.
      • et al.
      Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3.
      ], which defined HFMSE and RULM responders as having achieved at least a 3-point change and at least a 2-point change on the respective scale. One of five SMA type 2 patients, and 24 of 46 SMA type 3 patients were considered HFMSE responders. Within the subgroups of sitters and walkers in SMA type 3 patients, this meant that 58% of the sitters and 48% of the walkers responded to the therapy. Considering RULM responders in the same subgroups, in the sitter group 52% of patients, in the walker subgroup, however only 16% responded to the therapy.
      6MWT was reported in five studies (6 publications) [
      • Darras B.T.
      • Chiriboga C.A.
      • Iannaccone S.T.
      • et al.
      Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies.
      ,
      • Montes J.
      • Dunaway Young S.
      • Mazzone E.S.
      • et al.
      Nusinersen improves walking distance and reduces fatigue in later-onset spinal muscular atrophy.
      ,
      • Hagenacker T.
      • Wurster C.D.
      • Gunther R.
      • et al.
      Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study.
      ,
      • Yeo C.J.J.
      • Simeone S.D.
      • Townsend E.L.
      • Zhang R.Z.
      • Swoboda K.J.
      Prospective cohort study of nusinersen treatment in adults with spinal muscular atrophy.
      ,
      • De Wel B.
      • Goosens V.
      • Sobota A.
      • et al.
      Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4.
      ,
      • Binz C.
      • Schreiber-Katz O.
      • Kumpe M.
      • et al.
      An observational cohort study on impact, dimensions and outcome of perceived fatigue in adult 5q-spinal muscular atrophy patients receiving nusinersen treatment.
      ]. Baseline values ranged from 249 to 371 m. Two studies (3 publications) showed an increase exceeding the MCID of 30 m (98 and 92 m change at 35 and 38-month follow-up, mainly in SMA type 3 patients [
      • Darras B.T.
      • Chiriboga C.A.
      • Iannaccone S.T.
      • et al.
      Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies.
      ,
      • Montes J.
      • Dunaway Young S.
      • Mazzone E.S.
      • et al.
      Nusinersen improves walking distance and reduces fatigue in later-onset spinal muscular atrophy.
      ], and 46 m improvement at 14-month follow-up [
      • Hagenacker T.
      • Wurster C.D.
      • Gunther R.
      • et al.
      Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study.
      ]). One study did not report follow-up results [
      • Binz C.
      • Schreiber-Katz O.
      • Kumpe M.
      • et al.
      An observational cohort study on impact, dimensions and outcome of perceived fatigue in adult 5q-spinal muscular atrophy patients receiving nusinersen treatment.
      ], and two studies indicated non-significant change [
      • Yeo C.J.J.
      • Simeone S.D.
      • Townsend E.L.
      • Zhang R.Z.
      • Swoboda K.J.
      Prospective cohort study of nusinersen treatment in adults with spinal muscular atrophy.
      ,
      • De Wel B.
      • Goosens V.
      • Sobota A.
      • et al.
      Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4.
      ].

      4.3.3 Quality of life endpoints (respiratory support, nutritional support, caregiver evaluation)

      NIV was reported in five studies [
      • Maggi L.
      • Bello L.
      • Bonanno S.
      • et al.
      Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3.
      ,
      • Mendonca R.H.
      • Polido G.J.
      • Matsui C.
      • et al.
      Real-world data from nusinersen treatment for patients with later-onset spinal muscular atrophy: a single center experience.
      ,
      • Moshe-Lilie O.
      • Visser A.
      • Chahin N.
      • Ragole T.
      • Dimitrova D.
      • Karam C.
      Nusinersen in adult patients with spinal muscular atrophy: observations from a single center.
      ,
      • Binz C.
      • Schreiber-Katz O.
      • Kumpe M.
      • et al.
      An observational cohort study on impact, dimensions and outcome of perceived fatigue in adult 5q-spinal muscular atrophy patients receiving nusinersen treatment.
      ,
      • De Wel B.
      • Goosens V.
      • Sobota A.
      • et al.
      Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4.
      ]; however, follow-up data was not available in any of the studies. IV baseline data was reported in one study [
      • Moshe-Lilie O.
      • Visser A.
      • Chahin N.
      • Ragole T.
      • Dimitrova D.
      • Karam C.
      Nusinersen in adult patients with spinal muscular atrophy: observations from a single center.
      ] but no follow-up data was available. Nutritional support baseline data was available in one study [
      • Binz C.
      • Schreiber-Katz O.
      • Kumpe M.
      • et al.
      An observational cohort study on impact, dimensions and outcome of perceived fatigue in adult 5q-spinal muscular atrophy patients receiving nusinersen treatment.
      ] without any follow-up data. The respiratory support baseline data showed that 18%–54% of patients required some form of ventilation support.
      Caregiver or self-evaluation was recorded in four studies [
      • Montes J.
      • Dunaway Young S.
      • Mazzone E.S.
      • et al.
      Nusinersen improves walking distance and reduces fatigue in later-onset spinal muscular atrophy.
      ,
      • Yeo C.J.J.
      • Simeone S.D.
      • Townsend E.L.
      • Zhang R.Z.
      • Swoboda K.J.
      Prospective cohort study of nusinersen treatment in adults with spinal muscular atrophy.
      ,
      • De Wel B.
      • Goosens V.
      • Sobota A.
      • et al.
      Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4.
      ,
      • Binz C.
      • Schreiber-Katz O.
      • Kumpe M.
      • et al.
      An observational cohort study on impact, dimensions and outcome of perceived fatigue in adult 5q-spinal muscular atrophy patients receiving nusinersen treatment.
      ], of which three measured fatigue with different tools, and two evaluated activities of daily life with the spinal muscular atrophy functional rating scale (SMAFRS) and with the 36-Item Short Form Survey (SF-36). On the SF-36, no significant improvement but some stabilisation (no change in 6 of 8 subscores) could be shown [
      • De Wel B.
      • Goosens V.
      • Sobota A.
      • et al.
      Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4.
      ]. SMAFRS showed a decline in four of six patients (66%) and stability or improvement in two of six (33%) [
      • Yeo C.J.J.
      • Simeone S.D.
      • Townsend E.L.
      • Zhang R.Z.
      • Swoboda K.J.
      Prospective cohort study of nusinersen treatment in adults with spinal muscular atrophy.
      ]. One of the three studies measuring fatigue showed heterogeneous results [
      • Yeo C.J.J.
      • Simeone S.D.
      • Townsend E.L.
      • Zhang R.Z.
      • Swoboda K.J.
      Prospective cohort study of nusinersen treatment in adults with spinal muscular atrophy.
      ], and the two other studies reported improvements [
      • Montes J.
      • Dunaway Young S.
      • Mazzone E.S.
      • et al.
      Nusinersen improves walking distance and reduces fatigue in later-onset spinal muscular atrophy.
      ,
      • Binz C.
      • Schreiber-Katz O.
      • Kumpe M.
      • et al.
      An observational cohort study on impact, dimensions and outcome of perceived fatigue in adult 5q-spinal muscular atrophy patients receiving nusinersen treatment.
      ].

      4.3.4 Safety endpoints

      All but two studies reported on safety endpoints [
      • Darras B.T.
      • Chiriboga C.A.
      • Iannaccone S.T.
      • et al.
      Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies.
      ,
      • Hagenacker T.
      • Wurster C.D.
      • Gunther R.
      • et al.
      Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study.
      ,
      • Maggi L.
      • Bello L.
      • Bonanno S.
      • et al.
      Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3.
      ,
      • Mendonca R.H.
      • Polido G.J.
      • Matsui C.
      • et al.
      Real-world data from nusinersen treatment for patients with later-onset spinal muscular atrophy: a single center experience.
      ,
      • Moshe-Lilie O.
      • Visser A.
      • Chahin N.
      • Ragole T.
      • Dimitrova D.
      • Karam C.
      Nusinersen in adult patients with spinal muscular atrophy: observations from a single center.
      ,
      • Yeo C.J.J.
      • Simeone S.D.
      • Townsend E.L.
      • Zhang R.Z.
      • Swoboda K.J.
      Prospective cohort study of nusinersen treatment in adults with spinal muscular atrophy.
      ,
      • De Wel B.
      • Goosens V.
      • Sobota A.
      • et al.
      Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4.
      ]. The categorization of adverse events was either not reported in the studies or used in a non-uniform manner. One study reported that non-serious adverse events were mostly unrelated to the drug [
      • Darras B.T.
      • Chiriboga C.A.
      • Iannaccone S.T.
      • et al.
      Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies.
      ]. In two studies only the number of patients who experienced drug- or procedure-related events was reported without the number of events (47% and 23% of patients, respectively) [
      • Hagenacker T.
      • Wurster C.D.
      • Gunther R.
      • et al.
      Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study.
      ,
      • Moshe-Lilie O.
      • Visser A.
      • Chahin N.
      • Ragole T.
      • Dimitrova D.
      • Karam C.
      Nusinersen in adult patients with spinal muscular atrophy: observations from a single center.
      ]. Two other studies reported only the number of drug- or procedure-related events without the number of patients (13 events and 255 events, respectively) [
      • Mendonca R.H.
      • Polido G.J.
      • Matsui C.
      • et al.
      Real-world data from nusinersen treatment for patients with later-onset spinal muscular atrophy: a single center experience.
      ,
      • De Wel B.
      • Goosens V.
      • Sobota A.
      • et al.
      Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4.
      ]. Another study did not report drug-related, only procedure-related events, which occurred in 41% of patients [
      • Maggi L.
      • Bello L.
      • Bonanno S.
      • et al.
      Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3.
      ]. Yet another study did not report if the events were drug-or procedure related [
      • Yeo C.J.J.
      • Simeone S.D.
      • Townsend E.L.
      • Zhang R.Z.
      • Swoboda K.J.
      Prospective cohort study of nusinersen treatment in adults with spinal muscular atrophy.
      ]. Of the studies which reported on serious adverse events, one reported two events [
      • Yeo C.J.J.
      • Simeone S.D.
      • Townsend E.L.
      • Zhang R.Z.
      • Swoboda K.J.
      Prospective cohort study of nusinersen treatment in adults with spinal muscular atrophy.
      ], and three highlighted that no serious adverse events occurred [
      • Darras B.T.
      • Chiriboga C.A.
      • Iannaccone S.T.
      • et al.
      Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies.
      ,
      • Hagenacker T.
      • Wurster C.D.
      • Gunther R.
      • et al.
      Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study.
      ,
      • De Wel B.
      • Goosens V.
      • Sobota A.
      • et al.
      Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4.
      ].

      4.4 Onasemnogene abeparvovec

      Three publications [
      • Al-Zaidy S.
      • Pickard A.S.
      • Kotha K.
      • et al.
      Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy.
      ,
      • Al-Zaidy S.A.
      • Kolb S.J.
      • Lowes L.
      • et al.
      AVXS-101 (onasemnogene abeparvovec) for SMA1: comparative study with a prospective natural history cohort.
      ,
      • Lowes L.P.
      • Alfano L.N.
      • Arnold W.D.
      • et al.
      Impact of age and motor function in a phase 1/2A study of infants with SMA type 1 receiving single-dose gene replacement therapy.
      ], reporting on the same study (NCT02122952) on 12 SMA type 1 patients with a follow-up of 24 months, were included. One of the three studies [
      • Al-Zaidy S.A.
      • Kolb S.J.
      • Lowes L.
      • et al.
      AVXS-101 (onasemnogene abeparvovec) for SMA1: comparative study with a prospective natural history cohort.
      ] compared results of the intervention group with a cohort of untreated SMA type 1 patients and a group of healthy individuals.

      4.4.1 Mortality

      No patients were lost to follow-up and all treated patients survived the 24-month follow-up period.

      4.4.2 Motor endpoints

      Regarding change in the CHOP INTEND scores from baseline, all subgroups (early dosing/low motor group, early dosing/high motor group, late dosing group) reached the MCID threshold with the biggest change of +35 points in the early dosing/low motor group and the lowest change of +16.3 points in the early dosing/high motor group. The mean change of the whole treatment group was +28.3 points. All but one patient learned to sit without support for at least 5 s, and nine patients achieved sitting for at least 30 s. Two patients who achieved standing without support were the ones who could also walk alone. One publication [
      • Al-Zaidy S.
      • Pickard A.S.
      • Kotha K.
      • et al.
      Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy.
      ] stated that 11 patients achieved sitting without support for at least 30 s and two more patients achieved the milestone standing with support after the 24-month follow-up.

      4.4.3 Quality of life endpoints (respiratory support, nutritional support, caregiver evaluation)

      Two patients needed NIV at baseline (both from the late dosing group), which increased to five over the follow-up period during hospitalizations. Upon discharge, the patients did not require any further support. IV support was not needed at both baseline and end of study. Nutritional support was needed in five patients at baseline, which increased to six by the end of the follow-up period.

      4.4.4 Safety endpoints

      Only one of the publications reported adverse events. Of 275 adverse events 53 (19%) were serious, however, only two of these were associated with the treatment itself [
      • Al-Zaidy S.A.
      • Kolb S.J.
      • Lowes L.
      • et al.
      AVXS-101 (onasemnogene abeparvovec) for SMA1: comparative study with a prospective natural history cohort.
      ].

      4.5 Combination therapies of nusinersen and onasemnogene abeparvovec

      Two single-arm observational studies [
      • Mendell J.R.
      • Al-Zaidy S.A.
      • Lehman K.J.
      • et al.
      Five-Year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy.
      ,
      • Harada Y.
      • Rao V.K.
      • Arya K.
      • et al.
      Combination molecular therapies for type 1 spinal muscular atrophy.
      ] with 18 SMA type 1 patients in total, with a follow-up of 19.2 months [
      • Harada Y.
      • Rao V.K.
      • Arya K.
      • et al.
      Combination molecular therapies for type 1 spinal muscular atrophy.
      ] to 5.2 years [
      • Mendell J.R.
      • Al-Zaidy S.A.
      • Lehman K.J.
      • et al.
      Five-Year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy.
      ] were identified.

      4.5.1 Mortality, discontinuation

      No deaths were reported. With combination therapies, the reasons for the concurrent administration of nusinersen and onasemnogene abeparvovec are relevant too. Patients were administered the combination of the two therapies due to the continued need for respiratory and nutritional support, as well as lack of substantial improvements in speech and bulbar function after therapy initiation. Four patients started on nusinersen therapy and completed six to seven doses before onasemnogene abeparvovec administration. In three of four patients nusinersen was continued after some weeks, and only one patient achieved desired motor milestones and CHOP INTEND scores, hence nusinersen was not continued. One patient started on onasemnogene abeparvovec and received additionally five doses of nusinersen [
      • Harada Y.
      • Rao V.K.
      • Arya K.
      • et al.
      Combination molecular therapies for type 1 spinal muscular atrophy.
      ]. The other study’s primary objective was to report on the long-term safety of onasemnogene abeparvovec, however, six of 13 patients received nusinersen after the initial onasemnogene abeparvovec therapy [
      • Mendell J.R.
      • Al-Zaidy S.A.
      • Lehman K.J.
      • et al.
      Five-Year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy.
      ]. The results were not reported separately for the group who received nusinersen as concomitant therapy and for the group who received only onasemnogene abeparvovec.

      4.5.2 Motor endpoints and quality of life endpoints (respiratory support, nutritional support, caregiver evaluation)

      One study [
      • Harada Y.
      • Rao V.K.
      • Arya K.
      • et al.
      Combination molecular therapies for type 1 spinal muscular atrophy.
      ] reported CHOP INTEND and HINE-2 improvements, which crossed the MCID threshold for all participants for whom data was available (five of five patients on the CHOP INTEND scale and two of five patients on HINE-2). Regarding motor milestone achievements, at last follow-up visit, 40% of patients were able to sit independently and stand with support, another 40% were able to sit independently, 20% could only control head and kick legs. The study, however, did not report baseline motor functions. The other study [
      • Mendell J.R.
      • Al-Zaidy S.A.
      • Lehman K.J.
      • et al.
      Five-Year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy.
      ] reported respiratory support and motor milestone achievements only on a subset of participants, the therapeutic dose group. Eight of ten patients in this group remained stable in motor milestones and the remaining 20% achieved the ability to stand with support. Regarding respiratory support, no change could be shown by the end of the follow-up period.

      4.5.3 Safety endpoints

      Eight serious adverse events were reported in one study, none of which were categorized as treatment-related and resulted in study discontinuation [
      • Mendell J.R.
      • Al-Zaidy S.A.
      • Lehman K.J.
      • et al.
      Five-Year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy.
      ]. In the other study, however, liver enzyme elevation and liver injury were reported, which were drug-related, caused by onasemnogene abeparvovec use. Nusinersen demonstrated a favourable safety profile with no evidence that treatment caused drug-related adverse events [
      • Harada Y.
      • Rao V.K.
      • Arya K.
      • et al.
      Combination molecular therapies for type 1 spinal muscular atrophy.
      ].

      4.6 Risdiplam

      No evidence on risdiplam that met the inclusion criteria could be identified in the systematic search.

      5. Discussion

      To our knowledge, this is the first systematic review on SMA-therapies focusing on mid- and long-term (at least 12 months) real-world follow-up study data of all approved drug therapies and their combinations. Our findings, based on 22 studies (in 26 publications), show that nusinersen improved motor functions in SMA type 1 patients, while in SMA type 2 to type 4 patients stabilisation or small improvements (mostly under the MCID in HFSME and in RULM), but also some deterioration could be observed. Onasemnogene abeparvovec in SMA type 1 patients improved motor endpoints (the ability to sit for at least 30 s, or stand without support). Combination therapies in SMA type 1 patients improved motor endpoints (over the MCID in CHOP INTEND, the ability to sit without support, and hold the head or stand). Pulmonary outcomes, such as the incidence of respiratory failure and the need for ventilation support, and the need for nutritional support were poorly reported on or were often not defined as study outcome measures. However, the additional bulbar dysfunction and nutritional support would be important, since they reflect the risk of aspiration and the overall ability of these children to thrive [
      • Paul G.
      • Gushue C.
      • Kotha K.
      • Shell R.
      The respiratory impact of novel therapies for spinal muscular atrophy.
      ]. Drug-related adverse events occurred rarely, procedure-related adverse events occurred more often and mostly due to the lumbar puncture. These findings are in line with results of the pivotal trials on nusinersen and onasemnogene abeparvovec, which show clinically meaningful improvements in motor skills but no improvements in the need for invasive or non-invasive ventilation support and in the need for nutritional support in SMA type 1 patients. For SMA types 2 to 4 a stabilisation of health status could be observed both in the pivotal trials on nusinersen and in the included evidence.
      Although stability and further improvement on the long-term is still uncertain, the results from the included evidence, as well as from pivotal trials show a striking contrast to the natural progression of the disease. Infants with genetically diagnosed SMA without a functioning copy of the SMN1 gene and with two or three copies of the SMN2 gene will develop fatal or severe symptoms, on average, by 13.5 months of age [
      • Finkel R.S.
      • McDermott M.P.
      • Kaufmann P.
      • et al.
      Observational study of spinal muscular atrophy type I and implications for clinical trials.
      ], if untreated. Interim findings from an ongoing trial (NURTURE), which aims to evaluate the long-term safety and efficacy of nusinersen in infants who initiate treatment prior to the onset of clinical signs of SMA, show considerable contrast to the natural history of untreated SMA, as well as to treatment with nusinersen which was initiated in a symptomatic period (ENDEAR trial), supporting the importance of early treatment initiation to maximise treatment success [
      • De Vivo D.C.
      • Bertini E.
      • Swoboda K.J.
      • et al.
      Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: interim efficacy and safety results from the Phase 2 NURTURE study.
      ]. Long-term follow-up trials are also ongoing (onasemnogene abeparvovec: NCT04042025, NCT03421977; risdiplam: NCT05232929) for pre-symptomatic as well as for symptomatic SMA patients. Study results are expected to be published in the near future.
      Two other systematic reviews on nusinersen [
      • Albrechtsen S.
      • Born A.
      • Boesen M.
      Nusinersen treatment of spinal muscular atrophy - a systematic review.
      ,
      • Wadman R.
      • van der Pol W.
      • Bosboom W.
      • et al.
      Drug treatment for spinal muscular atrophy type I.
      ] conclude that SMA type 1 patients show improvements in survival and motor function, however, regarding the benefits for SMA type 2 and type 3 patients they come to different conclusions. One found that the benefits are less evident [
      • Albrechtsen S.
      • Born A.
      • Boesen M.
      Nusinersen treatment of spinal muscular atrophy - a systematic review.
      ], whereas the other one [
      • Wadman R.
      • van der Pol W.
      • Bosboom W.
      • et al.
      Drug treatment for spinal muscular atrophy types II and III.
      ] conclude that nusinersen improves motor function in SMA type 2, based on moderate-certainty evidence.
      Due to several major limitations of the included evidence, the effectiveness and safety results have to be treated with caution. Small patient numbers in the studies, study designs (single-arm, open-label trials) and the quality of the studies are prone to numerous biases. Additionally, the interpretation of the results is severely hampered by the many missing data on patients at follow-up. This normally favours the intervention, as patients who do not do well on the intervention tend to withdraw from the study. Some clinically relevant quality of life outcomes (e.g. respiratory and nutritional support) were often not measured, and only positive data were reported. This, in particular could be observed in the majority of the studies.
      Heterogeneity in the reported outcomes, the length of follow-up and the chosen outcome measures across studies are major concerns, often acknowledged by study authors themselves, and hamper comparability of study results. The included populations and definitions of certain patient characteristics (e.g. ambulatory patients or the ability to walk) were also heterogeneous. Although SMA type 1 and SMA type 2 to type 4 patients have vastly different baseline characteristics, as well as different outlook of improvements in any type of outcome, they were often included jointly in the studies. These publications on mixed SMA populations, which do not report detailed data per SMA type, are not very informative.
      Furthermore, five of 19 studies (six of 21 publications) on nusinersen were financed by Biogen, the one study on onasemnogene abeparvovec by Avexis; the majority of authors of the 26 publications declared multiple conflicts of interests with the manufacturer in question (Biogen & Ionis Pharmaceuticals for nusinersen, AveXis & Roche for onasemnogene abeparvovec). Only few authors have no conflict of interest. Independent studies and publications are needed, since industry-funded studies and their reporting tend to focus on positive results [
      • Dwan K.
      • Gamble C.
      • Williamson P.
      • Kirkham J.
      For the reporting bias group. Systematic review of the empirical evidence of study publication bias and outcome reporting bias — an updated review.
      ].
      Between the systematic search and this publication another seven observational studies reporting results with at least 12 months follow-up after initial treatment were published. One is based on the data from the patient population of the extension study SHINE of the pivotal trial ENDEAR for the approval of nusinersen [
      • Finkel R.S.
      • Chiriboga C.A.
      • Vajsar J.
      • et al.
      Treatment of infantile-onset spinal muscular atrophy with nusinersen: final report of a phase 2, open-label, multicentre, dose-escalation study.
      ], two are based on the data from the pivotal trials for the approval of onasemnogene abeparvovec STR1VE [
      • Day J.W.
      • Finkel R.S.
      • Chiriboga C.A.
      • et al.
      Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial.
      ] and STR1VE–EU [
      • Mercuri E.
      • Muntoni F.
      • Baranello G.
      • et al.
      Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy type 1 (STR1VE-EU): an open-label, single-arm, multicentre, phase 3 trial.
      ], two are based on the data from the pivotal trials for the approval of risdiplam FIREFISH [
      • Darras B.T.
      • Masson R.
      • Mazurkiewicz-Bełdzińska M.
      • et al.
      Risdiplam-treated infants with type 1 spinal muscular atrophy versus historical controls.
      ] and SUNFISH [
      • Mercuri E.
      • Deconinck N.
      • Mazzone E.S.
      • et al.
      Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial.
      ]. These five and two additional independent studies on SMA type 1 [
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • et al.
      Type I SMA "new natural history": long-term data in nusinersen-treated patients.
      ] and SMA type 1 to type 3 [
      • Konersman C.G.
      • Ewing E.
      • Yaszay B.
      • Naheedy J.
      • Murphy S.
      • Skalsky A.
      Nusinersen treatment of older children and adults with spinal muscular atrophy.
      ] treated with nusinersen confirm the results from our systematic review that some improvement of motor function can be observed and this is more obvious in those treated earlier, but that the need for respiratory and nutritional support increased slightly over time [
      • Finkel R.S.
      • Chiriboga C.A.
      • Vajsar J.
      • et al.
      Treatment of infantile-onset spinal muscular atrophy with nusinersen: final report of a phase 2, open-label, multicentre, dose-escalation study.
      ,
      • Pane M.
      • Coratti G.
      • Sansone V.A.
      • et al.
      Type I SMA "new natural history": long-term data in nusinersen-treated patients.
      ], an endpoint that is not reported in some publications. It is a major limitation of this systematic review that these new trial results are not included due to the time lag between the database search and the publication of the results of the systematic review. This limitation can only be overcome by regular (annual) updates on the available clinical data: the next is planned for mid-2022 and will include longer-term (at least 24 months) follow-up data.

      6. Conclusions

      Long-term clinical data published by independent clinicians are lacking. Some questions remain unanswered, such as uncertainties around disease stabilisation or further improvement over time, persistence of gained abilities, and additional patient characteristics for clinical decision-making. Periodic assessment of patient outcomes over many years is of utmost necessity to answer these questions [
      • Paul G.
      • Gushue C.
      • Kotha K.
      • Shell R.
      The respiratory impact of novel therapies for spinal muscular atrophy.
      ] and to ascertain that missing data will not introduce bias in the results through the publication and generalization of outcomes from the patients who were not lost to follow-up. Many countries already require patient data documentation in the reimbursement process, which could reinforce multicentre studies across jurisdictions and health care systems and hence substantial information on larger patient cohorts and the effectiveness in subgroups of patients could be gathered. This could also be used to back up the initial findings of the pivotal studies and understand the effects in real-world settings. Nevertheless, the existing clinical data show that early treatment in SMA type 1 children seem to lead to the best outcomes; hence newborn screening is of particular importance. The evidence for later onset SMA types (SMA type 2 to type 4) is less convincing. Since all three approved therapies are cost-intensive, reimbursement should be based on clinical data and clear criteria for discontinuation in case patients do not respond to the therapy.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Declaration of competing interest

      The authors declare that they have no conflict of interest.

      Acknowledgements

      We would like to acknowledge Tarquin Mittermayr and Ozren Sehic for assisting with the literature search.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

      References

        • Calucho M.
        • Bernal S.
        • Alías L.
        • March F.
        • Venceslá A.
        • Rodríguez-Álvarez Fea
        Correlation between SMA type and SMN2 copy number revisited: an analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases.
        Neuromuscul. Disord. 2018; 28: 208-215
        • Gemeinsamer Bundesausschuss (G-BA)
        Nusinersen (Spinraza®) modul 3 A 5q-assoziierte spinale muskelatrophie (SMA).
        in: Dossier zur Nutzenbewertung gemäß § 35a SGB V. Gemeinsamer Bundesausschuss (G-BA), 2020 (Berlin)
        • European Medicines Agency (EMA)
        Spinraza (Nusinersen).
        2017 ([cited 18.08.2021]; Available from:)
        • European Medicines Agency (EMA)
        Zolgensma (onasemnogene abeparvovec).
        2020 ([cited: 18.08.2021]; Available from:)
        • Food and Drug Administration (FDA)
        Zolgensma.
        2019 ([cited 10.03.2022]; Available from:)
        • European Medicines Agency (EMA)
        Evrysdi (Risdiplam).
        2021 ([cited 18.08. 2021]; Available from:)
        • Finkel R.S.
        • Mercuri E.
        • Darras B.T.
        • et al.
        Nusinersen versus sham control in infantile-onset spinal muscular atrophy.
        N. Engl. J. Med. 2017; 377: 1723-1732
        • Mercuri E.
        • Darras B.T.
        • Chiriboga C.A.
        • et al.
        Nusinersen versus sham control in later-onset spinal muscular atrophy.
        N. Engl. J. Med. 2018; 378: 625-635
        • Darras B.T.
        • Masson R.
        • Mazurkiewicz-Bełdzińska M.
        • et al.
        Risdiplam-treated infants with type 1 spinal muscular atrophy versus historical controls.
        N. Engl. J. Med. 2021; 385: 427-435
        • Servais L.
        • Baranello G.
        • Masson R.
        • Mazurkiewicz-Bełdzińska M.
        • Rose K.
        • Vlodavets D.
        Firefish part 2: efficacy and safety of risdiplam (rg7916) in infants with type 1 spinal muscular atrophy (SMA).
        Eur. J. Neurol. 2020; 27: 166-167
        • Day J.W.
        • Finkel R.S.
        • Chiriboga C.A.
        • et al.
        Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial.
        Lancet Neurol. 2021; 20: 284-293
        • Mendell J.
        • Shell R.
        • Lehman K.
        • et al.
        Gene-replacement therapy (GRT) in spinal muscular atrophy type 1 (SMA1): long-term follow-up from the onasemnogene abeparvovec phase 1/2a clinical trial.
        Ann. Neurol. 2019; 86: S126
        • Mendell J.R.
        • Al-Zaidy S.A.
        • Lehman K.J.
        • et al.
        Five-Year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy.
        JAMA Neurol. 2021; 78: 834-841
        • Institute of Health Economics (IHE)
        Quality Appraisal of Case Series Studies Checklist.
        2014 ([cited 20.08.2021]; Available from:)
      1. CHOP INTEND Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders.
        ([cited 01.09.2021]; Avaialble from:)
        • HINE - Hammersmith Infant Neurological Examination
        ([cited 01.09.2021]; Available from:)
        • HMFSE - Hammersmith Functional Motor Sclae Expanded
        ([cited 01.09.2021]; Available from:)
        • MRC Muscle Scale
        ([cited 03.09.2021]; Available from:)
        • European Medicines Agency (EMA)
        Briefing Document to the Clinical Trial Readiness in Spinal Muscular Atrophy (SMA) SMA Europe.
        TREAT-NMD and European Medicines Agency meeting, 2016 ([cited 01.09.2021]; Available from:)
        • Finkel R.
        • Bertini E.
        • Muntoni F.
        • Mercuri E.
        209th ENMC International Workshop: Outcome Measures and Clinical Trial Readiness in Spinal Muscular Atrophy 7–9 November 2014. vol. 25. Neuromuscular Disorders, Heemskerk, The Netherlands2015: 593-602
        • Krosschell K.
        • Young S.
        • Cruz R.
        • Mazzella A.
        • Curry M.
        • Peterson I.
        Best Practices for Physical Therapists & Clinical Evaluators in Spinal Muscular Atrophy (SMA). Recommendations to Support the Effective Conduct of Clinical Trials in SMA.
        Cure SMA, 2019
        • Pierzchlewicz K.
        • Kepa I.
        • Podogrodzki J.
        • Kotulska K.
        Spinal muscular atrophy: the use of functional motor scales in the era of disease-modifying treatment.
        Child Neurol. Open. 2021; 82329048X211008725
        • Audic F.
        • de la Banda M.G.G.
        • Bernoux D.
        • et al.
        Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.
        Orphanet J. Rare Dis. 2020; 15: 148
        • Gómez-García de la Banda M.
        • Amaddeo A.
        • Khirani S.
        • et al.
        Assessment of respiratory muscles and motor function in children with SMA treated by nusinersen.
        Pediatr. Pulmonol. 2021; 56: 299-306
        • Al-Zaidy S.
        • Pickard A.S.
        • Kotha K.
        • et al.
        Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy.
        Pediatr. Pulmonol. 2019; 54: 179-185
        • Al-Zaidy S.A.
        • Kolb S.J.
        • Lowes L.
        • et al.
        AVXS-101 (onasemnogene abeparvovec) for SMA1: comparative study with a prospective natural history cohort.
        J. Neuromuscul. Dis. 2019; 6: 307-317
        • Lowes L.P.
        • Alfano L.N.
        • Arnold W.D.
        • et al.
        Impact of age and motor function in a phase 1/2A study of infants with SMA type 1 receiving single-dose gene replacement therapy.
        Pediatr. Neurol. 2019; 98: 39-45
        • Darras B.T.
        • Chiriboga C.A.
        • Iannaccone S.T.
        • et al.
        Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies.
        Neurology. 2019; 92: e2492-e2506
        • Montes J.
        • Dunaway Young S.
        • Mazzone E.S.
        • et al.
        Nusinersen improves walking distance and reduces fatigue in later-onset spinal muscular atrophy.
        Muscle Nerve. 2019; 60: 409-414
        • Acsadi G.
        • Crawford T.
        • Muller-Felber W.
        • et al.
        Safety and efficacy of nusinersen in spinal muscular atrophy: the EMBRACE study.
        Muscle Nerve. 2021; 63: 668-677
        • Aragon-Gawinska K.
        • Daron A.
        • Ulinici A.
        • et al.
        Sitting in patients with spinal muscular atrophy type 1 treated with nusinersen.
        Dev. Med. Child Neurol. 2020; 62: 310-314
        • Lavie M.
        • Diamant N.
        • Cahal M.
        • et al.
        Nusinersen for spinal muscular atrophy type 1: real-world respiratory experience.
        Pediatr. Pulmonol. 2021; 56: 291-298
        • de Holanda Mendonça R.
        • Jorge Polido G.
        • Ciro M.
        • Jorge Fontoura Solla D.
        • Conti Reed U.
        • Zanoteli E.
        Clinical outcomes in patients with spinal muscular atrophy type 1 treated with nusinersen.
        J. Neuromuscul. Dis. 2021; 8: 217-224
        • Modrzejewska1 S.
        • Kotulska K.
        • Kopyta I.
        • et al.
        Nusinersen treatment of spinal muscular atrophy type 1— results of expanded access programme in Poland.
        Neurol. Neurochir. Pol. 2021; 55: 289-294
        • Pane M.
        • Coratti G.
        • Sansone V.A.
        • et al.
        Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data.
        Ann. Neurol. 2019; 86: 443-451
        • Chacko A.
        • Sly P.D.
        • Ware R.S.
        • et al.
        Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3.
        Thorax. 2021; 77: 40-46
        • Kariyawasam D.
        • D'Silva A.
        • Howells J.
        • et al.
        Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen.
        J. Neurol. Neurosurg. Psychiatry. 2020; 92: 78-85
        • Osredkar D.
        • Jilkova M.
        • Butenko T.
        • et al.
        Children and young adults with spinal muscular atrophy treated with nusinersen.
        Eur. J. Paediatr. Neurol. 2021; 30: 1-8
        • Veerapandiyan A.
        • Eichinger K.
        • Guntrum D.
        • et al.
        Nusinersen for older patients with spinal muscular atrophy: a real-world clinical setting experience.
        Muscle Nerve. 2020; 61: 222-226
        • Hagenacker T.
        • Wurster C.D.
        • Gunther R.
        • et al.
        Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study.
        Lancet Neurol. 2020; 19: 317-325
        • Maggi L.
        • Bello L.
        • Bonanno S.
        • et al.
        Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3.
        J. Neurol. Neurosurg. Psychiatr. 2020; 91: 1166-1174
        • Mendonca R.H.
        • Polido G.J.
        • Matsui C.
        • et al.
        Real-world data from nusinersen treatment for patients with later-onset spinal muscular atrophy: a single center experience.
        J. Neuromuscul. Dis. 2021; 8: 101-108
        • Moshe-Lilie O.
        • Visser A.
        • Chahin N.
        • Ragole T.
        • Dimitrova D.
        • Karam C.
        Nusinersen in adult patients with spinal muscular atrophy: observations from a single center.
        Neurology. 2020; 95: e413-e416
        • Yeo C.J.J.
        • Simeone S.D.
        • Townsend E.L.
        • Zhang R.Z.
        • Swoboda K.J.
        Prospective cohort study of nusinersen treatment in adults with spinal muscular atrophy.
        J. Neuromuscul. Dis. 2020; 7: 257-268
        • Binz C.
        • Schreiber-Katz O.
        • Kumpe M.
        • et al.
        An observational cohort study on impact, dimensions and outcome of perceived fatigue in adult 5q-spinal muscular atrophy patients receiving nusinersen treatment.
        J. Neurol. 2020; 268: 950-962
        • De Wel B.
        • Goosens V.
        • Sobota A.
        • et al.
        Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4.
        J. Neurol. 2020; 268: 923-935
        • Harada Y.
        • Rao V.K.
        • Arya K.
        • et al.
        Combination molecular therapies for type 1 spinal muscular atrophy.
        Muscle Nerve. 2020; 62: 550-554
        • Paul G.
        • Gushue C.
        • Kotha K.
        • Shell R.
        The respiratory impact of novel therapies for spinal muscular atrophy.
        Pediatr. Pulmonol. 2021; 56: 721-728
        • Finkel R.S.
        • McDermott M.P.
        • Kaufmann P.
        • et al.
        Observational study of spinal muscular atrophy type I and implications for clinical trials.
        Neurology. 2014; 83: 810-817
        • De Vivo D.C.
        • Bertini E.
        • Swoboda K.J.
        • et al.
        Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: interim efficacy and safety results from the Phase 2 NURTURE study.
        Neuromuscul. Disord. : NMD. 2019; 29: 842-856
        • Albrechtsen S.
        • Born A.
        • Boesen M.
        Nusinersen treatment of spinal muscular atrophy - a systematic review.
        Dan. Med. J. 2020; 67
        • Wadman R.
        • van der Pol W.
        • Bosboom W.
        • et al.
        Drug treatment for spinal muscular atrophy type I.
        Cochrane Database Syst. Rev. 2019; 12Cd006281
        • Wadman R.
        • van der Pol W.
        • Bosboom W.
        • et al.
        Drug treatment for spinal muscular atrophy types II and III.
        Cochrane Database Syst. Rev. 2020; 1Cd006282
        • Dwan K.
        • Gamble C.
        • Williamson P.
        • Kirkham J.
        For the reporting bias group. Systematic review of the empirical evidence of study publication bias and outcome reporting bias — an updated review.
        PLoS One. 2013; 8e66844
        • Finkel R.S.
        • Chiriboga C.A.
        • Vajsar J.
        • et al.
        Treatment of infantile-onset spinal muscular atrophy with nusinersen: final report of a phase 2, open-label, multicentre, dose-escalation study.
        Lancet Child Adolesc. Health. 2021; 5: 491-500
        • Mercuri E.
        • Muntoni F.
        • Baranello G.
        • et al.
        Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy type 1 (STR1VE-EU): an open-label, single-arm, multicentre, phase 3 trial.
        Lancet Neurol. 2021; 20: 832-841
        • Mercuri E.
        • Deconinck N.
        • Mazzone E.S.
        • et al.
        Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial.
        Lancet Neurol. 2022; 21: 42-52
        • Pane M.
        • Coratti G.
        • Sansone V.A.
        • et al.
        Type I SMA "new natural history": long-term data in nusinersen-treated patients.
        Ann. Clin. Transl. Neurol. 2021; 8: 548-557