Search

Introduction/aims: Persons with spinal muscular atrophy (pwSMA) report progressive muscle weakness but also reduced endurance when performing repetitive tasks in daily life, referred to as "performance fatigability" (PF). Data regarding the effects of the new disease-modifying drugs on PF are scarce. Thus, our main objective was to examine PF in adult ambulatory pwSMA treated long-term with nusinersen., Methods: Six-minute walk test (6MWT) data from 14 adult pwSMA treated with nusinersen for up to 70 months were retrospectively analyzed to determine PF. Performance fatigability was defined as the percentage change in the distance covered between the last and first minute of the 6MWT. In addition, relationships between PF and other clinical features were assessed., Results: Performance fatigability was found in 12/14 pwSMA (85.7%) prior to treatment. The mean distance walked in the sixth minute (71.1 m) was shorter than the distance covered in the first minute (81.8 m), corresponding to a mean PF of 13.1% (95% confidence interval (CI): 6.5-19.6, p = .0007). During treatment with nusinersen, there was a mean reduction in PF of 5.6% (95% CI: -10.0 to -1.3, p = .0148). We found no relationship between PF and fatigue as measured by the Fatigue Severity Scale., Discussion: This study demonstrates the presence of PF as an independent component of motor impairment and as a potential therapeutic target in our cohort of adult ambulatory pwSMA. Furthermore, the observations in our cohort suggest that nusinersen may have a beneficial effect on PF., (© 2024 The Author(s). Muscle & Nerve published by Wiley Periodicals LLC.)

Background: Evidence for the efficacy of nusinersen in adults with 5q-associated spinal muscular atrophy (SMA) has been demonstrated up to a period of 16 months in relatively large cohorts but whereas patients reach a plateau over time is still to be demonstrated. We investigated the efficacy and safety of nusinersen in adults with SMA over 38 months, the longest time period to date in a large cohort of patients from multiple clinical sites., Methods: Our prospective, observational study included adult patients with SMA from Germany, Switzerland, and Austria (July 2017 to May 2022). All participants had genetically-confirmed, 5q-associated SMA and were treated with nusinersen according to the label. The total Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM) scores, and 6-min walk test (6 MWT; metres), were recorded at baseline and 14, 26, and 38 months after treatment initiation, and pre and post values were compared. Adverse events were also recorded., Findings: Overall, 389 patients were screened for eligibility and 237 were included. There were significant increases in all outcome measures compared with baseline, including mean HFMSE scores at 14 months (mean difference 1.72 [95% CI 1.19-2.25]), 26 months (1.20 [95% CI 0.48-1.91]), and 38 months (1.52 [95% CI 0.74-2.30]); mean RULM scores at 14 months (mean difference 0.75 [95% CI 0.43-1.07]), 26 months (mean difference 0.65 [95% CI 0.27-1.03]), and 38 months (mean difference 0.72 [95% CI 0.25-1.18]), and 6 MWT at 14 months (mean difference 30.86 m [95% CI 18.34-43.38]), 26 months (mean difference 29.26 m [95% CI 14.87-43.65]), and 38 months (mean difference 32.20 m [95% CI 10.32-54.09]). No new safety signals were identified., Interpretation: Our prospective, observational, long-term (38 months) data provides further real-world evidence for the continuous efficacy and safety of nusinersen in a large proportion of adult patients with SMA., Funding: Financial support for the registry from Biogen, Novartis and Roche., Competing Interests: SB, ZU, MH, TK, KM, BI, JB, MTM, TB, BS, SF, CS, MTo, AG, MTue, MS, CR, PB, MFB, CK, KPS, SG, ST, JN, RS, MWeb, GW and OvV declare no conflicts of interest. RG has received personal fees from Biogen and Hoffmann-La Roche and served on advisory boards from Biogen, Hoffmann-La Roche, ITF Pharma, Zambon and research support from Biogen, outside of the submitted work. CDW has received personal fees from Biogen and Hoffmann–La Roche outside of the submitted work. AO has received speaker fees from Biogen outside of the submitted work. OSK received academic research support from the Hannover Medical School (MHH) and the German Neuromuscular Society “Deutsche Gesellschaft fuer Muskelkranke” (DGM e.V.), 2019–2021 (grant no. Sc 23/1); and received honoraria as a speaker and/or funding for travel expenses from the German Neuromuscular Society “Deutsche Gesellschaft fuer Muskelkranke (DGM e.V.), Biogen GmbH, Biermann Verlag GmbH, and MK + S—Medizin, Kommunikation & Service GmbH, outside the submitted work. SP has received speaker fees, non-financial support and research support from Biogen, Roche, AL-S Pharma, Amylyx, Cytokinetics, Ferrer, ITF-Pharma, Zambon, and Sanofi and served on advisory boards of Amylyx, Biogen, Roche, Zambon and ITF Pharma outside of the submitted work. MCW has served on advisory boards for Avexis, Biogen, Grünenthal, Novartis, Pfizer, PharNext, PTC Therapeutics, Roche, Santhera, Sarepta, Ultragenyx, Wave Sciences, received funding for Travel or Speaker Honoraria from Biogen, Novartis, PTC Therapeutics, Santhera, and worked as an ad-hoc consultant for Affinia, Audentes Therapeutics, Avexis, Biogen, BridgeBio, Edgewise, Fulcrum, Grünenthal, ML Bio, Novartis, Pfizer, PharNEXT, PTC Therapeutics, Roche. MWei has received advisory board and consultant honoraria from Biogen and Hoffmann-La Roche, and speaker honoraria and travel support for conference attendance from Biogen, outside of the submitted work. MW is a member of the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD). MF has received a speaker honorarium and non-financial support from Biogen outside the submitted work. HSL is receiving advisory fees from Biogen but has no financial or non-financial conflict of interest to declare related to the content of this manuscript. IC has received research grants and speaker fees from Biogen and Hoffmann-La Roche, outside of the submitted work. PL has received honoraria for advisory boards and consultancies from Stadapharm, Abbvie, Alexion, Bial, ITF Pharma, Desitin, Novartis, Woolsey Pharma outside the scope of this work. MD has received personal fees as speaker/consultant from Biogen and Roche, outside of the submitted work. Aha received research grants from Novartis Gene Therapies, and advisory board honoraria and speaker fees from Biogen, Roche, and Novartis. AR has received advisory board honoraria from Biogen outside of the submitted work. DZ received compensation from Biogen for participation on advisory boards, from Novartis for consultancy work, and travel compensation from Angelini Pharma outside of the submitted work. JCK has received personal fees from Biogen and Roche for advisory boards and development of educational material outside of this study. AHe has received personal fees and non-financial support from Biogen and Desitin for advisory board meetings outside the reported work. CK has received advisory board honoraria from Biogen, Roche and Ipsen Pharma, speaker honoraria from Biogen and unrestricted travel grants from Ipsen outside of the submitted work. SN has received financial support for consultancy and lecturing from Allergan, Hormosan, Lilly, Lundbeck, Novartis, Teva and Medscape, research support from Novartis, all outside of the submitted work. AM has received advisory board honoraria from Hormosan and Sanofi, outside of the submitted work. CN has received personal fees from Biogen and Hoffmann–La Roche outside of the submitted work. HCL received honoraria for speaking and advisory board engagements or academic research support Biogen. MG has received an advisory board honorarium from Hoffmann-La Roche and a speaker fee from Novartis outside of the submitted work. AP received compensation for advisory boards, training activities and research grants from Novartis and Biogen. JK received compensation for clinical research and/or consultancy activities from Biogen, Novartis, Roche and ScholarRock. GB has received research grants from PTC, advisory board honoraria and speaker fees from Biogen, Hoffmann-La Roche, Novartis, Pfizer, PTC and personal fees from Roche outside of the submitted work. PM has received honorary as an advisory board member from Biogen unrelated to this work. GMzH received compensation for serving on scientific advisory boards (Alexion, Roche, LFB) and speaker honoraria (Alexion). WL received advisory board honoraria and speaker fees from Biogen and Roche outside of the submitted work MFB has received honoraria from Biogen, Roche and Novartis as an advisory board member and for lectures from Novartis. US has received honoraria for counseling at advisory boards and invited talks for Biogen, Novartis and Roche. WMF has received compensation for scientific advisory boards for Biogen, Novartis, PTC, Sarepta, Sanofi-Aventis, Roche and Cytokinetics and received travel expenses and speaker fees from Biogen, Novartis, PTC, Roche, Sarepta and Sanofi-Aventis. HLo received support for research projects and clinical trials from Amplo Biotechnology, AMO Pharma, argenx, Biogen, Desitin, Fulcrum Therapeutics, Harmony Biosciences, KYE Pharmaceuticals, Milo Biotechnology, Novartis, Pfizer, PTC Therapeutics, Hoffman-La Roche Limited, Sanofi-Genzyme, Santhera, Sarepta, Satellos, Spark Therapeutics and Ultragenyx. HL is the Editor-in-chief for the Journal of Neuromuscular Diseases (IOS Press). CK has received compensation for lectures and advisory boards as well as research funds from Biogen, Roche and Novartis. ACL is a member of Advisory Boards of Roche Pharma AG, Biogen, Alector and Amylyx. He received compensation for talks from Biologix, the German Society of Neurology, Biogen, Springer Medicine, Amylyx and the company Streamed Up! GmbH. He is involved in trials which are sponsored by Amylyx, Ferrer International, Novartis Research and Development, Mitsubishi Tanabe, Apellis Pharmaceuticals, Alexion, Orion Pharma, the European Union, BMBF, Biogen and Orphazyme, Ionis Pharmaceuticals, QurAlis and Alector. TH has received research grants, advisory board honoraria and speaker fees from Biogen, Hoffmann-La Roche, Novartis and personal fees from Roche and Novartis outside of the submitted work., (© 2024 The Author(s).)

Background: In patients with coronary artery disease and concomitant asymptomatic severe carotid stenosis, combined simultaneous coronary artery bypass grafting (CABG) and carotid endarterectomy (CEA) has been widely performed despite lack of evidence from randomized trials. We recently showed that the risk of stroke or death within 30 days was higher following CABG+CEA compared with CABG alone. Here, we report long-term outcomes following CABG with versus without CEA., Methods: The CABACS (Coronary Artery Bypass Graft Surgery in Patients With Asymptomatic Carotid Stenosis Study) is a randomized, controlled, multicenter, open trial. Patients with asymptomatic severe (≥70%) carotid stenosis undergoing CABG were allocated either CABG+CEA or CABG alone, and follow-up was 5 years. Major secondary end points included nonfatal stroke or death, any death and any nonfatal stroke. Due to low recruitment, the study was stopped prematurely after randomization of 127 patients in 17 centers., Results: By 5 years, the rate of stroke or death did not significantly differ between groups (CABG+CEA 40.6% [95% CI, 0.285-0.536], CABG alone 35.0% [95% CI, 0.231-0.484]; P =0.58). Higher albeit statistically nonsignificant rates of nonfatal strokes occurred at any time following CABG+CEA versus CABG alone (1 year: 19.3% versus 7.1%, P =0.09; 5 years: 29.4% versus 18.8%, P =0.25). All-cause mortality up to 5 years was similar in both groups (CABG+CEA: 25.4% versus CABG alone: 23.3%, hazard ratio, 1.148 [95% CI, 0.560-2.353]; P =0.71). Subgroup analyses did not reveal any significant effect of age, sex, preoperative modified Rankin Scale and center on outcome events., Conclusions: During 5-years follow-up, combined simultaneous CABG+CEA was associated with a higher albeit statistically nonsignificant rate of stroke or death compared with CABG alone. This was mainly due to a nonsignificantly higher perioperative risk following CABG+CEA. Since the power of our study was not sufficient, no significant effect of either procedure could be observed at any time during follow-up., Registration: URL: http://www.controlled-trials.com; Unique identifier: ISRCTN13486906.

5q-associated spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder that leads to progressive muscle atrophy and weakness. The disease is caused by a homozygous deletion or mutation in the survival of motor neuron 1 ( SMN1 ) gene, resulting in insufficient levels of SMN protein. Onasemnogene abeparvovec-xioi (OA) is a nonreplicating vector based on adeno-associated virus serotype 9 (AAV9) that contains the full-length human SMN1 gene. Recently, OA was approved for the treatment of SMA by the U.S. Food and Drug Administration and the European Medicines Agency. Because the presence of neutralizing antibodies caused by previous natural exposure to wild-type adeno-associated viruses (AAVs) may impair the efficiency of AAV-mediated gene transfer and thus reduce the therapeutic benefit of the gene therapy, an AAV9-binding antibody titer of >1:50 was defined as a surrogate exclusion criterion in pivotal OA clinical trials. However, these studies were exclusively conducted in infants and children. Because data on anti-AAV9 antibody titers in adults are generally sparse and not available for adult patients with SMA, we determined the prevalence of anti-AAV9 antibodies in sera of adult individuals with SMA to evaluate the feasibility of AAV9-mediated gene therapy in this cohort. In our study population of 69 adult patients with SMA type 2 and type 3 from four German academic sites, only 3 patients (4.3%) had an elevated anti-AAV9 antibody titer of >1:50. The prevalence of anti-AAV9 antibodies did not increase with age. The low and age-independent prevalence of anti-AAV9 antibodies in our cohort provides evidence that gene therapy with intravenous administered recombinant AAV9 vectors (rAAV9) might be feasible in adult patients with SMA, regardless of the patients' sex, SMA type, walking ability, or ventilatory status. This could also apply to the treatment of other inherited neurological diseases with rAAV9.

Background: Nusinersen is approved for the treatment of 5q spinal muscular atrophy of all types and stages in patients of all ages. Although clinical trials have shown improvements in motor function in infants and children treated with the drug, data for adults are scarce. We aimed to assess the safety and efficacy of nusinersen in adults with 5q spinal muscular atrophy., Methods: We did an observational cohort study at ten academic clinical sites in Germany. Patients with genetically confirmed 5q spinal muscular atrophy (age 16-65 years) with a homozygous deletion of exons 7, 8, or both, or with compound heterozygous mutations were eligible for inclusion and received nusinersen treatment in accordance with the label for a minimum treatment time of 6 months to a follow-up of up to 14 months. The primary outcome was the change in the total Hammersmith Functional Motor Scale Expanded (HFMSE) score, assessed at months 6, 10, and 14, and based on pre-post comparisons. This study is registered with the German Clinical Trials Register (number DRKS00015702)., Findings: Between July 13, 2017, and May 1, 2019, 173 patients were screened, of whom 139 (80%) were eligible for data analysis. Of these, 124 (89%) were included in the 6-month analysis, 92 (66%) in the 10-month analysis, and 57 (41%) in the 14-month analysis; patients with missing baseline HFMSE scores were excluded from these analyses. Mean HFMSE scores were significantly increased compared with baseline at 6 months (mean difference 1·73 [95% CI 1·05-2·41], p<0·0001), 10 months (2·58 [1·76-3·39], p<0·0001), and 14 months (3·12 [2·06-4·19], p<0·0001). Clinically meaningful improvements (≥3 points increase) in HFMSE scores were seen in 35 (28%) of 124 patients at 6 months, 33 (35%) of 92 at 10 months, and 23 (40%) of 57 at 14 months. To 14-month follow-up, the most frequent adverse effects among 173 patients were headache (61 [35%] patients), back pain (38 [22%]), and nausea (19 [11%]). No serious adverse events were reported., Interpretation: Despite the limitations of the observational study design and a slow functional decline throughout the natural disease course, our data provide evidence for the safety and efficacy of nusinersen in the treatment of adults with 5q spinal muscular atrophy, with clinically meaningful improvements in motor function in a real-world cohort., Funding: None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)