Effectiveness and Safety of Risdiplam in Chinese Adolescents and Adults with Spinal Muscular Atrophy: A Prospective Real-World Study

Effectiveness and Safety of Risdiplam in Chinese Adolescents and Adults with Spinal Muscular Atrophy: A Prospective Real-World Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effectiveness and Safety of Risdiplam in Chinese Adolescents and Adults with Spinal Muscular Atrophy: A Prospective Real-World Study Hang Su, Bin Wang, Cong Tian, Yuan Sun, Han Zhang, Haotian Zhao, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7966590/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 19 You are reading this latest preprint version Abstract Background Evidence for the efficacy of risdiplam in adolescents and adults with 5q spinal muscular atrophy (SMA) has been demonstrated in clinical trials, but its sustained effectiveness and safety in real-world settings, particularly in Chinese populations, remains to be demonstrated. We evaluated the efficacy and safety of risdiplam in this population in a real-world setting. Methods This prospective observational study included adolescent and adult patients with genetically confirmed 5q SMA under standard clinical care (January 2023 to December 2024). Patients received risdiplam monotherapy (5 mg daily), with dosing adjusted based on clinical condition and tolerability. Primary outcomes were changes in Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM) scores, and 6-min walk test (6MWT). Results Fifteen patients (8 male, 7 female) were included, with a mean (SD) efficacy assessment time of 1.45 (0.38) years. The mean (SD) RULM score significantly improved from 17.60 (10.87) at baseline to 19.33 (11.11) at final follow-up (P = 0.043). The mean (SD) HFMSE score showed a non-significant increase (13.00 (16.21) to 13.60 (16.26), P = 0.159). The 6-minute walk test remained stable, with improvement observed in two patients. The mean (SD) ALSFRS-R scores were unchanged (31.47 (7.61) vs. 31.80 (7.59), P = 0.936). No adverse events were reported, indicating good tolerability. Conclusions Our real-world findings provide evidence supporting the sustained efficacy and safety of risdiplam in managing SMA in adolescent and adult patients. Longer-term and larger-scale studies remain warranted to further characterize its clinical sustainability. Spinal muscular atrophy risdiplam motor function real-world study the Hammersmith Functional Motor Scale Figures Figure 1 Background Spinal muscular atrophy (SMA) is an inherited motor neuron disorder caused by pathogenic variants in the SMN1 gene, typically involving homozygous deletions or compound heterozygous pathogenic variants [ 1 , 2 ]. These genetic alterations lead to degeneration of spinal anterior horn motor neurons and lower brainstem motor nuclei, resulting in progressive muscle weakness and atrophy in the innervated muscles [ 3 , 4 ]. The disease is characterized by reduced levels of functional SMN protein, which is essential for the survival and function of motor neurons across various tissues and organs [ 5 , 6 ]. Consequently, SMA manifests with a spectrum of symptoms, including proximal muscle weakness, respiratory insufficiency, scoliosis, joint contractures, and difficulties with swallowing and speech, causing substantial physical and psychological disability [ 7 – 9 ]. The incidence of SMA is approximately 1 in 10,000 live births, with a carrier frequency of 1 in 50, indicating a significant genetic burden [ 10 , 11 ]. Beyond its impact on patient health, SMA imposes considerable emotional and financial strain on families and society. The SMN2 gene, a homolog of SMN1 , carries a critical nucleotide variation in exon 7 that causes most transcripts to skip this exon during splicing. This results in insufficient SMN protein production, which cannot fully compensate for the loss of SMN1 function in SMA [ 12 ]. Enhancing SMN2 expression has thus emerged as a promising therapeutic strategy. Recent advances in disease-modifying therapies (DMTs), such as nusinersen and risdiplam, have expanded treatment options for patients with SMA [ 13 , 14 ]. Nusinersen, the first drug approved by the U.S. Food and Drug Administration (FDA) for SMA, significantly improved motor function and survival outcomes [ 15 , 16 ]. However, its administration requires intrathecal injection due to poor blood–brain barrier penetration. In addition, nusinersen is associated with side effects such as headache, back pain, and vomiting [ 17 ], which are factors that need to be considered in its clinical application. Risdiplam is a selective modulator of SMN2 pre-messenger RNA splicing that enhances exon 7 inclusion, thereby increasing the production of functional SMN protein [ 18 ]. In June 2021, risdiplam was approved in China for the treatment of patients with SMA aged 16 days or older. This oral therapy, which can be administered directly or via a gastric tube, has demonstrated significant improvements in motor function [ 14 ]. In the FIREFISH study, risdiplam significantly improved survival rates and milestones related to motor, respiratory, and swallowing functions in infants with type 1 SMA compared to historical controls [ 19 ]. The SUNFISH study confirmed its efficacy in improving motor function and independence in daily living among patients with type 2 and non-ambulatory type 3 SMA compared to placebo [ 20 ]. A European survey found that improvements in motor and respiratory function were top priorities for SMA patients, who strongly preferred oral over injectable treatments [ 21 ]. Furthermore, a real-world study in Germany demonstrated that risdiplam was a viable option for patients intolerant to nusinersen, with favorable safety outcomes [ 22 ]. While numerous real-world studies from various countries have confirmed the effectiveness and safety of risdiplam in SMA patients, despite these promising findings, real-world evidence on the effectiveness and safety of risdiplam in the Chinese SMA population remains limited. To address this gap, we conducted a prospective real-world study to evaluate the clinical outcomes of risdiplam treatment in Chinese adolescents and adults with SMA. Methods Study design and patients This single-center, prospective observational real-world study was conducted at Qilu Hospital, Shandong University, from January 2023 to December 2024. The study aimed to assess the real-world effectiveness and safety of risdiplam in patients with genetically confirmed 5q SMA treated in routine clinical practice, without interventions beyond standard care. The study protocol was approved by the Ethics Committee of Qilu Hospital (Approval No. [KYLL-2022B-051-1]). Written informed consent was obtained from all participants prior to the initiation of the study, and the study complied with the ethical principles of the Declaration of Helsinki. Patients were included if they had genetically confirmed 5q SMA and were aged 13 years or older at enrollment. Participants or their legally authorized representatives (e.g., caregivers) were required to understand the study’s purpose and risks and provide informed consent. Patients were excluded if they were unable or unwilling to provide informed consent or if they had other types of SMA (non–5q SMA). Treatment Risdiplam was administered as monotherapy at a recommended dose of 5 mg once daily orally. All patients received the standard dose of risdiplam (5 mg daily). The dosing schedule was individualized and adjusted by the treating physician based on clinical condition, therapeutic response, and tolerability for concomitant supportive therapies and medication management, such as temporary treatment interruption during acute illnesses. During treatment, some patients received supplementary supportive care, including rehabilitation therapy. Outcomes and assessments Primary Outcome Measure The primary outcome was motor function, evaluated using standardized clinical scales. Motor function was assessed with the Hammersmith Functional Motor Scale Expanded (HFMSE) and the RULM for SMA [ 4 ], both providing quantitative measures of motor abilities in SMA patients. Secondary Outcome Measure Secondary outcomes included respiratory function, activities of daily living, and overall functional capacity. Respiratory function was monitored using forced vital capacity (FVC), a key parameter for pulmonary function assessment in neuromuscular diseases. The 6-minute walk test (6MWT), a common measure of motor capacity and rehabilitation outcomes, assessed walking performance and functional mobility [ 4 ]. Overall functional status was evaluated using the Revised ALSFRS-R, which covers four domains: bulbar, upper limb, lower limb, and respiratory function. The scale includes 12 items scored 0–4, with a maximum score of 48; higher scores indicate better function. Although developed for ALS, the ALSFRS-R has been validated in adult SMA populations [ 23 ]. Laboratory Tests Laboratory assessments included serum creatine kinase (CK) levels, which are typically normal or mildly elevated in SMA patients (with the upper limit of normal defined as > 140 U/L at our center) [ 4 ]. Electrophysiological assessments included electromyography (EMG) to detect neurogenic changes, where nerve conduction velocities were generally normal but compound muscle action potential (CMAP) amplitudes were reduced. Some patients exhibited spontaneous potentials on EMG [ 4 ]. Clinical Overall Impression Assessment The Clinical Global Impression (CGI) scale [ 24 ] was used to assess clinical change, with scores recorded at baseline (CGI baseline) and post-treatment (CGI improvement, CGI-I). The CGI-I scale ranges from 1 ("very much improved") to 7 ("very much worse"), providing an overall evaluation of treatment impact as perceived by the physician. Safety Assessment Adverse events (AEs) were recorded throughout treatment and follow-up. Patients were followed up via telephone every 3 months to actively inquire about and document any potential adverse events. Each AE was evaluated for severity and potential causality related to the treatment by the attending physician. Baseline for all assessments was defined as the initiation of risdiplam treatment, with subsequent evaluations monitoring changes in clinical outcomes throughout the study. Treatment regimens were individualized by the attending physician following follow-up visits based on patient-specific factors. Statistical analysis Categorical variables were summarized as frequencies and percentages. Continuous variables were assessed for normality using the Shapiro-Wilk test. Normally distributed data were expressed as means ± standard deviation (SD). Between-group comparisons used independent-samples t-test (for independent samples) or paired t-test (for paired samples). Non-normally distributed data were presented as medians and ranges, with differences analyzed by Mann-Whitney U test (independent samples) or Wilcoxon signed-rank test (paired samples). Correlations were analyzed using Pearson’s or Spearman’s rank correlation coefficient, depending on data distribution. All tests were two-sided with α = 0.05, and P < 0.05 was considered statistically significant. Statistical analyses were performed using R software (Version 4.2.3). Results Baseline Characteristics of Patients A total of 15 patients with SMA were included, comprising 8 males (53.3%) and 7 females (46.7%). The median age at disease onset was 1.00 years (range, 1.00–17.00 years), and the mean (SD) age at diagnosis was 17.00 (15.18) years. The median diagnostic delay was 10.00 years (range, 0.00–42.00 years), and the mean (SD) age at initiation of risdiplam was 27.73 (10.37) years. Genetic analysis revealed that 12 patients (80%) had homozygous deletions in the SMN1 gene. The median copy number of SMN2 exon 7 was 3.00 years (range, 1.00–4.00 years), while the mean (SD) copy number of exon 8 was 2.71 (1.07). The distribution of SMN2 exon 7 copy numbers was as follows: two patients (14.3%) had one copies, eleven patients (78.6%) had three copies, and one patient (7.1%) had four copies. One patient had no record of SMN2 exon 7 copy number. Three patients had elevated serum CK levels above the normal range, measuring 278 U/L, 983 U/L, and 690 U/L, respectively. Further details of patient demographics and baseline characteristics are presented in Supplementary Table 1. Effectiveness The mean (SD) duration of efficacy assessment for the 15 patients was 1.45 (0.38) years. The mean (SD) HFMSE score increased from 13.00 (16.21) at baseline to 13.60 (16.26) at the final follow-up, though this change was not statistically significant (P = 0.159) (Fig. 1 A). In contrast, the mean (SD) Revised Upper Limb Module (RULM) score improved significantly from 17.60 (10.87) to 19.33 (11.11) (P = 0.043) (Fig. 1 B). The 6MWT results remained largely stable over the course of the study, with thirteen patients (86.7%) unable to walk (6MWT = 0 meters) at both baseline and follow-up assessments. Among the two ambulatory patients, one patient with type 4 SMA improved from 239 to 385 meters and the other with type 3 SMA improved from 450 to 537 meters, demonstrating a positive trend in walking capacity (Fig. 1 C). The mean (SD) Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score remained unchanged (31.47 (7.61) at baseline vs. 31.80 (7.59) at follow-up, P = 0.936) (Fig. 1 D). Respiratory function, measured by FVC, showed a slight increase from 2.23 (1.33) to 2.41 (1.77), which was not statistically significant (P = 0.401). Changes in effectiveness outcomes by SMA subtype are summarized in Table 1 . Among patients with type III–IV SMA, the mean (SD) HFMSE score increased from 15.30 (19.37) to 16.30 (19.15), though this change did not reach statistical significance (P = 0.074). Improvements in upper limb motor function were observed in both type II and type III–IV patients. For type II, the mean (SD) RULM score rose from 17.80 (7.09) to 19.40 (8.14) (P = 0.327), and for type III–IV, from 17.50 (12.71) to 19.30 (12.75) (P = 0.108). Patients with type III–IV SMA also demonstrated greater improvement in walking capacity (from 68.90 [153.53] meters to 92.20 [197.65] meters), although this was not statistically significant (P = 0.180). Both subgroups showed modest gains in overall functioning, as reflected in ALSFRS-R scores. Table 1 Changes in efficacy indicators by SMA classification. Measure Baseline (N = 15) Final follow-up (N = 15) P HFMSE Score Type II (n = 5) 8.40 ± 5.94 8.20 ± 6.80 0.706 Type III + IV (n = 10) 15.30 ± 19.37 16.30 ± 19.15 0.074 * RULM Score Type II (n = 5) 17.80 ± 7.09 19.40 ± 8.14 0.327 * Type III + IV (n = 10) 17.50 ± 12.71 19.30 ± 12.75 0.108 * 6MWT Type II (n = 5) 0.00 ± 0.00 0.00 ± 0.00 — Type III + IV (n = 10) 68.90 ± 153.53 92.20 ± 197.65 0.180 ALSFRS-r Type II (n = 5) 30.40 ± 4.88 30.80 ± 5.36 0.317 Type III + IV (n = 10) 32.00 ± 8.87 32.30 ± 8.72 0.884 HFMSE: Hammersmith Functional Motor Scale Expanded; RULM: Revised Upper Limb Module for SMA; 6MWT: 6-minute walk test; ALSFRS-r: Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. Due to the constraints of outpatient follow-up, only a subset of patients provided post-treatment CK data. The limited available data suggested a reduction in CK levels in two patients after treatment (Supplementary Table 1). Clinical Global Impression All patients reported either improvement or stabilization in their condition, as assessed by the Clinical Global Impression improvement (CGI-I) scale. No patients rated their condition as “much worse” or “very much worse” (CGI-I scores of 6 or 7) during follow-up. Notably, 40% of patients reported significant subjective improvement in their overall condition. Correlation Analysis The correlations between diagnostic delay, SMN2 gene copy number, and changes in efficacy outcomes are summarized in Table 2 . A significant positive correlation was observed between the SMN2 exon 7 copy number and changes in RULM scores (R = 0.659, P = 0.010). In contrast, no significant correlations were found between diagnostic delay and changes in any of the assessed outcomes (P > 0.05). Additionally, SMN1 exons 7 copy number were not significantly associated with changes in any outcome measures (P > 0.05). Table 2 Correlation of diagnostic delay and SMN2 gene copy numbers with changes in efficacy outcomes Variable ΔHFMSE ΔRULM Δ6MWT ΔALSFRS-r Diagnostic delay R=-0.212, P = 0.448 R=-0.018, P = 0.950 R = 0.393, P = 0.147 R=-0.123, P = 0.662 SMN2 gene exon 7 copies R = 0.452, P = 0.104 R = 0.659, P = 0.010 R = 0.523, P = 0.055 R=-0.100, P = 0.735 SMN2 gene exon 8 copies R = 0.155, P = 0.597 R = 0.099, P = 0.736 R = 0.395, P = 0.162 R=-0.447, P = 0.109 Δ represents the change in scores from baseline to the last follow-up. Safety No adverse events were reported during the follow-up period among patients receiving risdiplam. Discussion This observational study provides valuable real-world evidence on the effectiveness and safety of risdiplam in Chinese adolescents and adults with 5q SMA under routine clinical practice. Overall, the findings suggest that risdiplam is both well-tolerated and effective. Improvements in motor function were observed, most notably in the RULM scores, which increased significantly from 17.50 (12.71) at baseline to 19.30 (12.75) at the final follow-up (P = 0.043). Although HFMSE scores did not improve significantly, the positive trend in RULM scores—particularly among patients with type III-IV SMA, a population typically less responsive to treatment—indicates clinical benefit. Among the three patients with elevated baseline serum CK levels, one exhibited a marked reduction from 690 U/L to 306 U/L following treatment. Importantly, no adverse events were reported throughout the follow-up period, further supporting the favorable safety profile of risdiplam. Our study contributed to the growing evidence supporting risdiplam’s efficacy in treating SMA. Previous clinical trials consistently demonstrated improvements in motor function, a key endpoint in SMA treatment. For example, the FIREFISH study [ 25 ] showed that risdiplam treatment in infants with type 1 SMA resulted in significant motor function gains, with 29% achieving the milestone of sitting unsupported for at least 5 seconds after 12 months. These findings were confirmed in a subsequent analysis [ 19 ], where infants treated with risdiplam showed improved motor milestones, including unsupported sitting. Similarly, the SUNFISH study [ 20 ] reported that risdiplam treatment in patients with type 2 and non-ambulant type 3 SMA led to a 1.55-point increase in the 32-item Motor Function Measure (MFM32) at 12 months compared with placebo. This improvement was more pronounced in younger patients, whereas older patients exhibited more stabilized motor function, suggesting that earlier risdiplam initiation may yield better long-term functional outcomes. The FIREFISH study [ 26 ] further supported this, showing continued motor function improvement over 24 months in risdiplam-treated infants, including longer durations of unsupported sitting. Our findings aligned with these trials, showing risdiplam-induced improvements in motor function and daily activity capacity. However, although RULM scores improved significantly in our cohort, changes in HFMSE scores and 6MWT values were less marked than in other studies [ 20 ], possibly due to our limited sample size. Future studies with larger cohorts and longer follow-up will be essential to fully establish risdiplam’s long-term efficacy and safety in SMA patients. In addition to pivotal clinical trials, real-world evidence further reinforced risdiplam’s positive impact. A real-world study [ 27 ] showed that adult SMA patients treated with risdiplam experienced stabilized motor function, with some reporting clinically meaningful improvements, particularly in bulbar function. Notably, improvements in RULM scores have also been documented in adult SMA patients receiving risdiplam in previous real-world studies [ 28 , 29 ], providing external validation for our findings. While the open-label design introduces the possibility of training or placebo effects, the observed gradual and sustained improvement in RULM scores is more consistent with a treatment response pattern than a training effect, which typically manifests as rapid initial gains followed by a plateau. Additionally, recent real-world studies across diverse populations, including those from America and Iran, have consistently demonstrated the efficacy and safety of risdiplam in pediatric SMA patients, highlighting its role in stabilizing or improving motor and respiratory function [ 30 – 32 ]. However, our study distinctively focuses on Chinese adolescents and adults with type 2, 3, and 4 SMA, a population that remains under-represented in existing real-world evidence. Our comprehensive outcome assessment, which emphasizes activities of daily living and overall functional capacity, further differentiates this work by providing a holistic view of risdiplam’s impact in real-world clinical practice. Although our study focused on adolescent and adult patients, the improvements observed aligned with these real-world findings. Our study confirmed that risdiplam was generally well tolerated in SMA patients, with a safety profile consistent with previous trials and real-world data. In the FIREFISH study [ 25 ], risdiplam treatment in infants with type 1 SMA was associated with gastrointestinal disturbances, including diarrhea, and common respiratory issues like pneumonia. Similarly, the SUNFISH study [ 20 ] reported side effects such as pyrexia and gastrointestinal complaints in risdiplam-treated patients. Notably, our study found no adverse events during follow-up, supporting risdiplam’s established safety in clinical practice. A key advantage of risdiplam is its oral administration, which facilitates better adherence compared to intrathecal therapies like nusinersen. In a real-world analysis [ 33 ], 93% of patients demonstrated good adherence to risdiplam at 12 months. This finding was consistent with our study, which showed high adherence and no significant treatment discontinuations. Oral administration likely contributes to improved persistence and adherence compared to treatments requiring intrathecal injections, which have been linked to injection-related complications and discomfort. This was further supported by a German study [ 22 ], where risdiplam was well tolerated, especially among patients ineligible for or intolerant to other therapies such as nusinersen. This study had several limitations. The small sample size of 15 patients limited the generalizability of the findings. As a preliminary and exploratory real-world experience summary, further validation through larger multicenter studies is warranted to confirm the observed outcomes. Additionally, the relatively short follow-up duration of 1.47 years restricted the assessment of risdiplam’s long-term benefits and risks. Another limitation was the incomplete collection of post-treatment laboratory biomarker data, such as CK levels, which may affect the comprehensive evaluation of treatment safety. Future prospective studies should incorporate stricter follow-up protocols to ensure complete collection of these data. The cohort was also heterogeneous in terms of age and SMA subtype, which may have introduced variability in treatment responses. Without a control group, direct comparisons between risdiplam and other therapies were not possible. Larger, more homogeneous studies with longer follow-up are needed to validate these findings. Conclusion Our study provided preliminary clinical evidence supporting risdiplam’s therapeutic effectiveness in patients with various SMA subtypes. The treatment was well tolerated across the cohort, with no new safety signals identified. Risdiplam’s oral administration offered a significant advantage over other SMA therapies by facilitating better adherence. While the results indicated improvements in motor function and quality of life, further large-scale, long-term studies are necessary to confirm these findings. Abbreviations AEs Adverse events ALS amyotrophic lateral sclerosis ALSFRS-R Amyotrophic Lateral Sclerosis Functional Rating Scale CGI Clinical Global Impression CK creatine kinase CMAP compound muscle action potential DMTs disease-modifying therapies EMG electromyography FDA Food and Drug Administration FVC forced vital capacity HFMSE Hammersmith Functional Motor Scale Expanded SMA spinal muscular atrophy RULM Revised Upper Limb Module for SMA 6MWT 6-minute walk test MFM32 32-item Motor Function Measure Declarations Ethics approval and consent to participate The study protocol was approved by the Ethics Committee of Qilu Hospital (Approval No. [KYLL-2022B-051-1]). Written informed consent was obtained from all participants, and the study adhered to the ethical principles of the Declaration of Helsinki. Consent for publication Not applicable. Availability of data and materials Anonymized data not published within this article will be made available by request from any qualified investigator. Competing interests The authors report no relevant disclosures. Funding The study was supported by the National Natural Science Foundation of China (82371410). Author contributions Hang Su: Data curation; Formal analysis, Writing - original draft, Writing - review & editing, Project administration. Bin Wang: Data curation; Formal analysis, Investigation. Cong Tian: Data curation; Investigation. Yuan Sun: Formal analysis, Writing - review & editing. Han Zhang: Data curation; Investigation. Haotian Zhao: Data curation; Investigation. Cuiping Zhao: Project administration. Chuanzhu Yan: Project administration, Funding acquisition, Methodology, Supervision. Yuying Zhao: Conceptualization, Funding acquisition, Methodology, Resources, Writing - review & editing. Acknowledgements Not applicable. Clinical trial number Not applicable. 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BMC Neurol. 2025;25:283. Barzegar M, Poorshiri B, Rezazadeh K, Toopchizadeh V, Shiva S, Motamedi A. Risdiplam and nusinersen in spinal muscular atrophy: a descriptive real-world study on motor function outcomes in northwestern Iran. Neuromuscul Disord. 2025;54:106210. Ashrafi MR, Babaee M, Hashemi Nazari SS, Barzegar M, Ghazavi M, Beiraghi Toosi M, et al. Comparative efficacy of risdiplam and nusinersen in Type 2 and 3 spinal muscular atrophy patients: A cohort study using real-world data. J Neuromuscul Dis. 2024;11:1190-9. Pineda ED, To TM, Dickendesher TL, Shapouri S, Iannaccone ST. Adherence and Persistence Among Risdiplam-Treated Individuals with Spinal Muscular Atrophy: A Retrospective Claims Analysis. Adv Ther. 2024;41:2446-59. Additional Declarations No competing interests reported. Supplementary Files SupplementaryTable1.doc Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 16 Dec, 2025 Reviewers agreed at journal 22 Nov, 2025 Reviewers agreed at journal 20 Nov, 2025 Reviewers agreed at journal 19 Nov, 2025 Reviews received at journal 17 Nov, 2025 Reviewers agreed at journal 17 Nov, 2025 Reviewers agreed at journal 16 Nov, 2025 Reviews received at journal 16 Nov, 2025 Reviewers agreed at journal 16 Nov, 2025 Reviews received at journal 16 Nov, 2025 Reviewers agreed at journal 16 Nov, 2025 Reviews received at journal 16 Nov, 2025 Reviewers agreed at journal 16 Nov, 2025 Reviewers agreed at journal 15 Nov, 2025 Reviewers invited by journal 14 Nov, 2025 Editor invited by journal 14 Nov, 2025 Editor assigned by journal 03 Nov, 2025 Submission checks completed at journal 03 Nov, 2025 First submitted to journal 28 Oct, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7966590","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":550135713,"identity":"f0efdef3-a79a-4e5b-8827-f076f58b08ed","order_by":0,"name":"Hang Su","email":"","orcid":"","institution":"Qilu Hospital of Shandong University","correspondingAuthor":false,"prefix":"","firstName":"Hang","middleName":"","lastName":"Su","suffix":""},{"id":550135714,"identity":"a3fdd74e-1ce8-4d65-b79c-cc3e2c781c01","order_by":1,"name":"Bin Wang","email":"","orcid":"","institution":"Zibo Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Bin","middleName":"","lastName":"Wang","suffix":""},{"id":550135715,"identity":"75a472b3-3d0a-448a-a6f7-2996ee8f1863","order_by":2,"name":"Cong Tian","email":"","orcid":"","institution":"Qilu Hospital of Shandong University","correspondingAuthor":false,"prefix":"","firstName":"Cong","middleName":"","lastName":"Tian","suffix":""},{"id":550135716,"identity":"05fcba0a-667e-4b81-bc5b-e43480d08085","order_by":3,"name":"Yuan Sun","email":"","orcid":"","institution":"Qilu Hospital, Shandong University","correspondingAuthor":false,"prefix":"","firstName":"Yuan","middleName":"","lastName":"Sun","suffix":""},{"id":550135717,"identity":"55cac83c-0bae-4650-9f07-d03ccf80a873","order_by":4,"name":"Han Zhang","email":"","orcid":"","institution":"Qilu Hospital, Shandong University","correspondingAuthor":false,"prefix":"","firstName":"Han","middleName":"","lastName":"Zhang","suffix":""},{"id":550135718,"identity":"d2845fb6-7958-4470-924b-9e88de685b94","order_by":5,"name":"Haotian Zhao","email":"","orcid":"","institution":"Jining No 1. People’s Hosptial","correspondingAuthor":false,"prefix":"","firstName":"Haotian","middleName":"","lastName":"Zhao","suffix":""},{"id":550135719,"identity":"4caa5371-0911-423d-92f7-b4f83246f015","order_by":6,"name":"Cuiping Zhao","email":"","orcid":"","institution":"Qilu Hospital, Shandong University","correspondingAuthor":false,"prefix":"","firstName":"Cuiping","middleName":"","lastName":"Zhao","suffix":""},{"id":550135720,"identity":"55e7271e-ca42-42fc-9785-c6542eca36b5","order_by":7,"name":"Chuanzhu Yan","email":"","orcid":"","institution":"Qilu Hospital of Shandong University","correspondingAuthor":false,"prefix":"","firstName":"Chuanzhu","middleName":"","lastName":"Yan","suffix":""},{"id":550135721,"identity":"a0d7598c-a9bf-454f-b4a0-8e4a2b7fc4d6","order_by":8,"name":"Yuying Zhao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAr0lEQVRIiWNgGAWjYHAC9h8fKiTk+EnSIznjjIWxZAMpWqR52yoSNxCtRX5GjoEB7zwJxg0MzA8f3SBGCyNQS4LkNglmcwY2Y+McYrQwS+QYHDDcJsFm2cDDJk2UFjaJHMOGxDkSPAYHiNXCI5FjzHCwQUKCeC0SPM/KGBuOSRhINhPrF/n25G3Mf2rq6vvZmx8+JkoLg0CGAYTBTJRyEOA//oBotaNgFIyCUTBCAQBhVCrcSrFh7wAAAABJRU5ErkJggg==","orcid":"","institution":"Qilu Hospital of Shandong University","correspondingAuthor":true,"prefix":"","firstName":"Yuying","middleName":"","lastName":"Zhao","suffix":""}],"badges":[],"createdAt":"2025-10-28 16:27:56","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7966590/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7966590/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":96804121,"identity":"b9e1bd74-ba35-4db5-9b5c-2aec8a78b871","added_by":"auto","created_at":"2025-11-26 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09:05:35","extension":"html","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":100626,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7966590/v1/14c5a7c92c3264fca0de0439.html"},{"id":96916940,"identity":"7e0edc14-f466-4adf-b615-842b7018826e","added_by":"auto","created_at":"2025-11-27 14:09:05","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":3855978,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in efficacy outcomes following risdiplam treatment. (A) Hammersmith Functional Motor Scale Expanded (HFMSE) scores at baseline and final follow-up. (B) Revised Upper Limb Module (RULM) scores showing significant improvement over the study period. (C) 6-minute walk test (6MWT) values throughout the study. (D) Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores before and after risdiplam treatment.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7966590/v1/02cac5a58a0cb01d14f1ee1d.png"},{"id":96923064,"identity":"7ba27382-9f28-4656-82c1-56f38847a5a5","added_by":"auto","created_at":"2025-11-27 14:20:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4430041,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7966590/v1/a4dfd452-2b56-4091-b660-c1c3452d61de.pdf"},{"id":96804122,"identity":"d93e7458-3854-4faa-8212-f84054914d1b","added_by":"auto","created_at":"2025-11-26 09:05:35","extension":"doc","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":72192,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1.doc","url":"https://assets-eu.researchsquare.com/files/rs-7966590/v1/3bd247145d1f466607e0b098.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effectiveness and Safety of Risdiplam in Chinese Adolescents and Adults with Spinal Muscular Atrophy: A Prospective Real-World Study","fulltext":[{"header":"Background","content":"\u003cp\u003eSpinal muscular atrophy (SMA) is an inherited motor neuron disorder caused by pathogenic variants in the SMN1 gene, typically involving homozygous deletions or compound heterozygous pathogenic variants [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. These genetic alterations lead to degeneration of spinal anterior horn motor neurons and lower brainstem motor nuclei, resulting in progressive muscle weakness and atrophy in the innervated muscles [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The disease is characterized by reduced levels of functional SMN protein, which is essential for the survival and function of motor neurons across various tissues and organs [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Consequently, SMA manifests with a spectrum of symptoms, including proximal muscle weakness, respiratory insufficiency, scoliosis, joint contractures, and difficulties with swallowing and speech, causing substantial physical and psychological disability [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The incidence of SMA is approximately 1 in 10,000 live births, with a carrier frequency of 1 in 50, indicating a significant genetic burden [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Beyond its impact on patient health, SMA imposes considerable emotional and financial strain on families and society.\u003c/p\u003e\u003cp\u003eThe \u003cem\u003eSMN2\u003c/em\u003e gene, a homolog of \u003cem\u003eSMN1\u003c/em\u003e, carries a critical nucleotide variation in exon 7 that causes most transcripts to skip this exon during splicing. This results in insufficient SMN protein production, which cannot fully compensate for the loss of SMN1 function in SMA [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Enhancing \u003cem\u003eSMN2\u003c/em\u003e expression has thus emerged as a promising therapeutic strategy. Recent advances in disease-modifying therapies (DMTs), such as nusinersen and risdiplam, have expanded treatment options for patients with SMA [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Nusinersen, the first drug approved by the U.S. Food and Drug Administration (FDA) for SMA, significantly improved motor function and survival outcomes [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, its administration requires intrathecal injection due to poor blood\u0026ndash;brain barrier penetration. In addition, nusinersen is associated with side effects such as headache, back pain, and vomiting [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], which are factors that need to be considered in its clinical application.\u003c/p\u003e\u003cp\u003eRisdiplam is a selective modulator of SMN2 pre-messenger RNA splicing that enhances exon 7 inclusion, thereby increasing the production of functional SMN protein [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In June 2021, risdiplam was approved in China for the treatment of patients with SMA aged 16 days or older. This oral therapy, which can be administered directly or via a gastric tube, has demonstrated significant improvements in motor function [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In the FIREFISH study, risdiplam significantly improved survival rates and milestones related to motor, respiratory, and swallowing functions in infants with type 1 SMA compared to historical controls [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The SUNFISH study confirmed its efficacy in improving motor function and independence in daily living among patients with type 2 and non-ambulatory type 3 SMA compared to placebo [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. A European survey found that improvements in motor and respiratory function were top priorities for SMA patients, who strongly preferred oral over injectable treatments [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Furthermore, a real-world study in Germany demonstrated that risdiplam was a viable option for patients intolerant to nusinersen, with favorable safety outcomes [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. While numerous real-world studies from various countries have confirmed the effectiveness and safety of risdiplam in SMA patients, despite these promising findings, real-world evidence on the effectiveness and safety of risdiplam in the Chinese SMA population remains limited. To address this gap, we conducted a prospective real-world study to evaluate the clinical outcomes of risdiplam treatment in Chinese adolescents and adults with SMA.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy design and patients\u003c/h2\u003e\u003cp\u003eThis single-center, prospective observational real-world study was conducted at Qilu Hospital, Shandong University, from January 2023 to December 2024. The study aimed to assess the real-world effectiveness and safety of risdiplam in patients with genetically confirmed 5q SMA treated in routine clinical practice, without interventions beyond standard care. The study protocol was approved by the Ethics Committee of Qilu Hospital (Approval No. [KYLL-2022B-051-1]). Written informed consent was obtained from all participants prior to the initiation of the study, and the study complied with the ethical principles of the Declaration of Helsinki.\u003c/p\u003e\u003cp\u003ePatients were included if they had genetically confirmed 5q SMA and were aged 13 years or older at enrollment. Participants or their legally authorized representatives (e.g., caregivers) were required to understand the study\u0026rsquo;s purpose and risks and provide informed consent.\u003c/p\u003e\u003cp\u003ePatients were excluded if they were unable or unwilling to provide informed consent or if they had other types of SMA (non\u0026ndash;5q SMA).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eTreatment\u003c/h3\u003e\n\u003cp\u003eRisdiplam was administered as monotherapy at a recommended dose of 5 mg once daily orally. All patients received the standard dose of risdiplam (5 mg daily). The dosing schedule was individualized and adjusted by the treating physician based on clinical condition, therapeutic response, and tolerability for concomitant supportive therapies and medication management, such as temporary treatment interruption during acute illnesses. During treatment, some patients received supplementary supportive care, including rehabilitation therapy.\u003c/p\u003e\n\u003ch3\u003eOutcomes and assessments\u003c/h3\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003ePrimary Outcome Measure\u003c/h2\u003e\u003cp\u003eThe primary outcome was motor function, evaluated using standardized clinical scales. Motor function was assessed with the Hammersmith Functional Motor Scale Expanded (HFMSE) and the RULM for SMA [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], both providing quantitative measures of motor abilities in SMA patients.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eSecondary Outcome Measure\u003c/h3\u003e\n\u003cp\u003eSecondary outcomes included respiratory function, activities of daily living, and overall functional capacity. Respiratory function was monitored using forced vital capacity (FVC), a key parameter for pulmonary function assessment in neuromuscular diseases. The 6-minute walk test (6MWT), a common measure of motor capacity and rehabilitation outcomes, assessed walking performance and functional mobility [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Overall functional status was evaluated using the Revised ALSFRS-R, which covers four domains: bulbar, upper limb, lower limb, and respiratory function. The scale includes 12 items scored 0\u0026ndash;4, with a maximum score of 48; higher scores indicate better function. Although developed for ALS, the ALSFRS-R has been validated in adult SMA populations [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eLaboratory Tests\u003c/h2\u003e\u003cp\u003eLaboratory assessments included serum creatine kinase (CK) levels, which are typically normal or mildly elevated in SMA patients (with the upper limit of normal defined as \u0026gt;\u0026thinsp;140 U/L at our center) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Electrophysiological assessments included electromyography (EMG) to detect neurogenic changes, where nerve conduction velocities were generally normal but compound muscle action potential (CMAP) amplitudes were reduced. Some patients exhibited spontaneous potentials on EMG [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eClinical Overall Impression Assessment\u003c/h3\u003e\n\u003cp\u003eThe Clinical Global Impression (CGI) scale [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] was used to assess clinical change, with scores recorded at baseline (CGI baseline) and post-treatment (CGI improvement, CGI-I). The CGI-I scale ranges from 1 (\"very much improved\") to 7 (\"very much worse\"), providing an overall evaluation of treatment impact as perceived by the physician.\u003c/p\u003e\n\u003ch3\u003eSafety Assessment\u003c/h3\u003e\n\u003cp\u003eAdverse events (AEs) were recorded throughout treatment and follow-up. Patients were followed up via telephone every 3 months to actively inquire about and document any potential adverse events. Each AE was evaluated for severity and potential causality related to the treatment by the attending physician.\u003c/p\u003e\u003cp\u003eBaseline for all assessments was defined as the initiation of risdiplam treatment, with subsequent evaluations monitoring changes in clinical outcomes throughout the study. Treatment regimens were individualized by the attending physician following follow-up visits based on patient-specific factors.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eCategorical variables were summarized as frequencies and percentages. Continuous variables were assessed for normality using the Shapiro-Wilk test. Normally distributed data were expressed as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD). Between-group comparisons used independent-samples t-test (for independent samples) or paired t-test (for paired samples). Non-normally distributed data were presented as medians and ranges, with differences analyzed by Mann-Whitney U test (independent samples) or Wilcoxon signed-rank test (paired samples). Correlations were analyzed using Pearson\u0026rsquo;s or Spearman\u0026rsquo;s rank correlation coefficient, depending on data distribution. All tests were two-sided with α\u0026thinsp;=\u0026thinsp;0.05, and P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Statistical analyses were performed using R software (Version 4.2.3).\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eBaseline Characteristics of Patients\u003c/h2\u003e\u003cp\u003eA total of 15 patients with SMA were included, comprising 8 males (53.3%) and 7 females (46.7%). The median age at disease onset was 1.00 years (range, 1.00\u0026ndash;17.00 years), and the mean (SD) age at diagnosis was 17.00 (15.18) years. The median diagnostic delay was 10.00 years (range, 0.00\u0026ndash;42.00 years), and the mean (SD) age at initiation of risdiplam was 27.73 (10.37) years. Genetic analysis revealed that 12 patients (80%) had homozygous deletions in the SMN1 gene. The median copy number of SMN2 exon 7 was 3.00 years (range, 1.00\u0026ndash;4.00 years), while the mean (SD) copy number of exon 8 was 2.71 (1.07). The distribution of SMN2 exon 7 copy numbers was as follows: two patients (14.3%) had one copies, eleven patients (78.6%) had three copies, and one patient (7.1%) had four copies. One patient had no record of SMN2 exon 7 copy number. Three patients had elevated serum CK levels above the normal range, measuring 278 U/L, 983 U/L, and 690 U/L, respectively. Further details of patient demographics and baseline characteristics are presented in Supplementary Table\u0026nbsp;1.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eEffectiveness\u003c/h2\u003e\u003cp\u003eThe mean (SD) duration of efficacy assessment for the 15 patients was 1.45 (0.38) years. The mean (SD) HFMSE score increased from 13.00 (16.21) at baseline to 13.60 (16.26) at the final follow-up, though this change was not statistically significant (P\u0026thinsp;=\u0026thinsp;0.159) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). In contrast, the mean (SD) Revised Upper Limb Module (RULM) score improved significantly from 17.60 (10.87) to 19.33 (11.11) (P\u0026thinsp;=\u0026thinsp;0.043) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). The 6MWT results remained largely stable over the course of the study, with thirteen patients (86.7%) unable to walk (6MWT\u0026thinsp;=\u0026thinsp;0 meters) at both baseline and follow-up assessments. Among the two ambulatory patients, one patient with type 4 SMA improved from 239 to 385 meters and the other with type 3 SMA improved from 450 to 537 meters, demonstrating a positive trend in walking capacity (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). The mean (SD) Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score remained unchanged (31.47 (7.61) at baseline vs. 31.80 (7.59) at follow-up, P\u0026thinsp;=\u0026thinsp;0.936) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD). Respiratory function, measured by FVC, showed a slight increase from 2.23 (1.33) to 2.41 (1.77), which was not statistically significant (P\u0026thinsp;=\u0026thinsp;0.401).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eChanges in effectiveness outcomes by SMA subtype are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Among patients with type III\u0026ndash;IV SMA, the mean (SD) HFMSE score increased from 15.30 (19.37) to 16.30 (19.15), though this change did not reach statistical significance (P\u0026thinsp;=\u0026thinsp;0.074). Improvements in upper limb motor function were observed in both type II and type III\u0026ndash;IV patients. For type II, the mean (SD) RULM score rose from 17.80 (7.09) to 19.40 (8.14) (P\u0026thinsp;=\u0026thinsp;0.327), and for type III\u0026ndash;IV, from 17.50 (12.71) to 19.30 (12.75) (P\u0026thinsp;=\u0026thinsp;0.108). Patients with type III\u0026ndash;IV SMA also demonstrated greater improvement in walking capacity (from 68.90 [153.53] meters to 92.20 [197.65] meters), although this was not statistically significant (P\u0026thinsp;=\u0026thinsp;0.180). Both subgroups showed modest gains in overall functioning, as reflected in ALSFRS-R scores.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eChanges in efficacy indicators by SMA classification.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMeasure\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBaseline\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;15)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFinal follow-up\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;15)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHFMSE Score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eType II (n\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e8.40\u0026thinsp;\u0026plusmn;\u0026thinsp;5.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e8.20\u0026thinsp;\u0026plusmn;\u0026thinsp;6.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.706\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eType III\u0026thinsp;+\u0026thinsp;IV (n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e15.30\u0026thinsp;\u0026plusmn;\u0026thinsp;19.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e16.30\u0026thinsp;\u0026plusmn;\u0026thinsp;19.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.074\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRULM Score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eType II (n\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e17.80\u0026thinsp;\u0026plusmn;\u0026thinsp;7.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e19.40\u0026thinsp;\u0026plusmn;\u0026thinsp;8.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.327\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eType III\u0026thinsp;+\u0026thinsp;IV (n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e17.50\u0026thinsp;\u0026plusmn;\u0026thinsp;12.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e19.30\u0026thinsp;\u0026plusmn;\u0026thinsp;12.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.108\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6MWT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eType II (n\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e0.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e0.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e\u0026mdash;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eType III\u0026thinsp;+\u0026thinsp;IV (n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e68.90\u0026thinsp;\u0026plusmn;\u0026thinsp;153.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e92.20\u0026thinsp;\u0026plusmn;\u0026thinsp;197.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.180\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eALSFRS-r\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eType II (n\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e30.40\u0026thinsp;\u0026plusmn;\u0026thinsp;4.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e30.80\u0026thinsp;\u0026plusmn;\u0026thinsp;5.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.317\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eType III\u0026thinsp;+\u0026thinsp;IV (n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e32.00\u0026thinsp;\u0026plusmn;\u0026thinsp;8.87\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e32.30\u0026thinsp;\u0026plusmn;\u0026thinsp;8.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.884\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eHFMSE: Hammersmith Functional Motor Scale Expanded; RULM: Revised Upper Limb Module for SMA; 6MWT: 6-minute walk test; ALSFRS-r: Revised Amyotrophic Lateral Sclerosis Functional Rating Scale.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eDue to the constraints of outpatient follow-up, only a subset of patients provided post-treatment CK data. The limited available data suggested a reduction in CK levels in two patients after treatment (Supplementary Table\u0026nbsp;1).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eClinical Global Impression\u003c/h2\u003e\u003cp\u003eAll patients reported either improvement or stabilization in their condition, as assessed by the Clinical Global Impression improvement (CGI-I) scale. No patients rated their condition as \u0026ldquo;much worse\u0026rdquo; or \u0026ldquo;very much worse\u0026rdquo; (CGI-I scores of 6 or 7) during follow-up. Notably, 40% of patients reported significant subjective improvement in their overall condition.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eCorrelation Analysis\u003c/h2\u003e\u003cp\u003eThe correlations between diagnostic delay, SMN2 gene copy number, and changes in efficacy outcomes are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. A significant positive correlation was observed between the SMN2 exon 7 copy number and changes in RULM scores (R\u0026thinsp;=\u0026thinsp;0.659, P\u0026thinsp;=\u0026thinsp;0.010). In contrast, no significant correlations were found between diagnostic delay and changes in any of the assessed outcomes (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Additionally, SMN1 exons 7 copy number were not significantly associated with changes in any outcome measures (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCorrelation of diagnostic delay and SMN2 gene copy numbers with changes in efficacy outcomes\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eΔHFMSE\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eΔRULM\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eΔ6MWT\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eΔALSFRS-r\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiagnostic delay\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eR=-0.212,\u003c/p\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.448\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eR=-0.018,\u003c/p\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.950\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eR\u0026thinsp;=\u0026thinsp;0.393,\u003c/p\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.147\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eR=-0.123,\u003c/p\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.662\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSMN2 gene exon 7 copies\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eR\u0026thinsp;=\u0026thinsp;0.452,\u003c/p\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.104\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eR\u0026thinsp;=\u0026thinsp;0.659,\u003c/p\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eR\u0026thinsp;=\u0026thinsp;0.523,\u003c/p\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.055\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eR=-0.100,\u003c/p\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.735\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSMN2 gene exon 8 copies\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eR\u0026thinsp;=\u0026thinsp;0.155,\u003c/p\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.597\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eR\u0026thinsp;=\u0026thinsp;0.099,\u003c/p\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.736\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eR\u0026thinsp;=\u0026thinsp;0.395,\u003c/p\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.162\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eR=-0.447,\u003c/p\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.109\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eΔ represents the change in scores from baseline to the last follow-up.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eSafety\u003c/h2\u003e\u003cp\u003eNo adverse events were reported during the follow-up period among patients receiving risdiplam.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis observational study provides valuable real-world evidence on the effectiveness and safety of risdiplam in Chinese adolescents and adults with 5q SMA under routine clinical practice. Overall, the findings suggest that risdiplam is both well-tolerated and effective. Improvements in motor function were observed, most notably in the RULM scores, which increased significantly from 17.50 (12.71) at baseline to 19.30 (12.75) at the final follow-up (P\u0026thinsp;=\u0026thinsp;0.043). Although HFMSE scores did not improve significantly, the positive trend in RULM scores\u0026mdash;particularly among patients with type III-IV SMA, a population typically less responsive to treatment\u0026mdash;indicates clinical benefit. Among the three patients with elevated baseline serum CK levels, one exhibited a marked reduction from 690 U/L to 306 U/L following treatment. Importantly, no adverse events were reported throughout the follow-up period, further supporting the favorable safety profile of risdiplam.\u003c/p\u003e\u003cp\u003eOur study contributed to the growing evidence supporting risdiplam\u0026rsquo;s efficacy in treating SMA. Previous clinical trials consistently demonstrated improvements in motor function, a key endpoint in SMA treatment. For example, the FIREFISH study [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] showed that risdiplam treatment in infants with type 1 SMA resulted in significant motor function gains, with 29% achieving the milestone of sitting unsupported for at least 5 seconds after 12 months. These findings were confirmed in a subsequent analysis [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], where infants treated with risdiplam showed improved motor milestones, including unsupported sitting. Similarly, the SUNFISH study [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] reported that risdiplam treatment in patients with type 2 and non-ambulant type 3 SMA led to a 1.55-point increase in the 32-item Motor Function Measure (MFM32) at 12 months compared with placebo. This improvement was more pronounced in younger patients, whereas older patients exhibited more stabilized motor function, suggesting that earlier risdiplam initiation may yield better long-term functional outcomes. The FIREFISH study [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] further supported this, showing continued motor function improvement over 24 months in risdiplam-treated infants, including longer durations of unsupported sitting. Our findings aligned with these trials, showing risdiplam-induced improvements in motor function and daily activity capacity. However, although RULM scores improved significantly in our cohort, changes in HFMSE scores and 6MWT values were less marked than in other studies [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], possibly due to our limited sample size. Future studies with larger cohorts and longer follow-up will be essential to fully establish risdiplam\u0026rsquo;s long-term efficacy and safety in SMA patients.\u003c/p\u003e\u003cp\u003eIn addition to pivotal clinical trials, real-world evidence further reinforced risdiplam\u0026rsquo;s positive impact. A real-world study [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] showed that adult SMA patients treated with risdiplam experienced stabilized motor function, with some reporting clinically meaningful improvements, particularly in bulbar function. Notably, improvements in RULM scores have also been documented in adult SMA patients receiving risdiplam in previous real-world studies [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], providing external validation for our findings. While the open-label design introduces the possibility of training or placebo effects, the observed gradual and sustained improvement in RULM scores is more consistent with a treatment response pattern than a training effect, which typically manifests as rapid initial gains followed by a plateau. Additionally, recent real-world studies across diverse populations, including those from America and Iran, have consistently demonstrated the efficacy and safety of risdiplam in pediatric SMA patients, highlighting its role in stabilizing or improving motor and respiratory function [\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. However, our study distinctively focuses on Chinese adolescents and adults with type 2, 3, and 4 SMA, a population that remains under-represented in existing real-world evidence. Our comprehensive outcome assessment, which emphasizes activities of daily living and overall functional capacity, further differentiates this work by providing a holistic view of risdiplam\u0026rsquo;s impact in real-world clinical practice. Although our study focused on adolescent and adult patients, the improvements observed aligned with these real-world findings.\u003c/p\u003e\u003cp\u003eOur study confirmed that risdiplam was generally well tolerated in SMA patients, with a safety profile consistent with previous trials and real-world data. In the FIREFISH study [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], risdiplam treatment in infants with type 1 SMA was associated with gastrointestinal disturbances, including diarrhea, and common respiratory issues like pneumonia. Similarly, the SUNFISH study [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] reported side effects such as pyrexia and gastrointestinal complaints in risdiplam-treated patients. Notably, our study found no adverse events during follow-up, supporting risdiplam\u0026rsquo;s established safety in clinical practice. A key advantage of risdiplam is its oral administration, which facilitates better adherence compared to intrathecal therapies like nusinersen. In a real-world analysis [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], 93% of patients demonstrated good adherence to risdiplam at 12 months. This finding was consistent with our study, which showed high adherence and no significant treatment discontinuations. Oral administration likely contributes to improved persistence and adherence compared to treatments requiring intrathecal injections, which have been linked to injection-related complications and discomfort. This was further supported by a German study [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], where risdiplam was well tolerated, especially among patients ineligible for or intolerant to other therapies such as nusinersen.\u003c/p\u003e\u003cp\u003eThis study had several limitations. The small sample size of 15 patients limited the generalizability of the findings. As a preliminary and exploratory real-world experience summary, further validation through larger multicenter studies is warranted to confirm the observed outcomes. Additionally, the relatively short follow-up duration of 1.47 years restricted the assessment of risdiplam\u0026rsquo;s long-term benefits and risks. Another limitation was the incomplete collection of post-treatment laboratory biomarker data, such as CK levels, which may affect the comprehensive evaluation of treatment safety. Future prospective studies should incorporate stricter follow-up protocols to ensure complete collection of these data. The cohort was also heterogeneous in terms of age and SMA subtype, which may have introduced variability in treatment responses. Without a control group, direct comparisons between risdiplam and other therapies were not possible. Larger, more homogeneous studies with longer follow-up are needed to validate these findings.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur study provided preliminary clinical evidence supporting risdiplam\u0026rsquo;s therapeutic effectiveness in patients with various SMA subtypes. The treatment was well tolerated across the cohort, with no new safety signals identified. Risdiplam\u0026rsquo;s oral administration offered a significant advantage over other SMA therapies by facilitating better adherence. While the results indicated improvements in motor function and quality of life, further large-scale, long-term studies are necessary to confirm these findings.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAEs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAdverse events\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eALS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eamyotrophic lateral sclerosis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eALSFRS-R\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAmyotrophic Lateral Sclerosis Functional Rating Scale\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCGI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eClinical Global Impression\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCK\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecreatine kinase\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCMAP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecompound muscle action potential\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDMTs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003edisease-modifying therapies\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eEMG\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eelectromyography\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eFDA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eFood and Drug Administration\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eFVC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eforced vital capacity\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHFMSE\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHammersmith Functional Motor Scale Expanded\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSMA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003espinal muscular atrophy\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRULM\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eRevised Upper Limb Module for SMA\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e6MWT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003e6-minute walk test\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMFM32\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003e32-item Motor Function Measure\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the Ethics Committee of Qilu Hospital (Approval No. [KYLL-2022B-051-1]). Written informed consent was obtained from all participants, and the study adhered to the ethical principles of the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnonymized data not published within this article will be made available by request from any qualified investigator.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors report no relevant disclosures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was supported by the National Natural Science Foundation of China (82371410).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHang Su: Data curation; Formal analysis, Writing - original draft, Writing - review \u0026amp; editing, Project administration. Bin Wang: Data curation; Formal analysis, Investigation. Cong Tian: Data curation; Investigation. Yuan Sun: Formal analysis, Writing - review \u0026amp; editing. Han Zhang: Data curation; Investigation. Haotian Zhao: Data curation; Investigation. Cuiping Zhao: Project administration. Chuanzhu Yan: Project administration, Funding acquisition, Methodology, Supervision. Yuying Zhao: Conceptualization, Funding acquisition, Methodology, Resources, Writing - review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKeinath MC, Prior DE, Prior TW. Spinal Muscular Atrophy: Mutations, Testing, and Clinical Relevance. Appl Clin Genet. 2021;14:11-25.\u003c/li\u003e\n\u003cli\u003eKato T, Yokomura M, Osawa Y, Matsuo K, Kubo Y, Homma T, et al. Genomic analysis of the SMN1 gene region in patients with clinically diagnosed spinal muscular atrophy: a retrospective observational study. Orphanet J Rare Dis. 2025;20:55.\u003c/li\u003e\n\u003cli\u003eMercuri E, Finkel RS, Muntoni F, Wirth B, Montes J, Main M, et al. Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018;28:103-15.\u003c/li\u003e\n\u003cli\u003eRare Disease Society of Chinese Research Hospital A, China Alliance for Rare D, Beijing Society of Rare Disease Clinical C, Accessibility, China Expert Group for Clinical Practice Guideline for A, Adult Patients with Spinal Muscular A. Clinical Practice Guideline for Adolescent \u0026amp;amp; Adult Patients with Spinal Muscular Atrophy. 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N Engl J Med. 2021;385:427-35.\u003c/li\u003e\n\u003cli\u003eMercuri E, Deconinck N, Mazzone ES, Nascimento A, Oskoui M, Saito K, 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.\u003c/li\u003e\n\u003cli\u003eLo SH, Lawrence C, Marti Y, Cafe A, Lloyd AJ. Patient and Caregiver Treatment Preferences in Type 2 and Non-ambulatory Type 3 Spinal Muscular Atrophy: A Discrete Choice Experiment Survey in Five European Countries. Pharmacoeconomics. 2022;40:103-15.\u003c/li\u003e\n\u003cli\u003eHahn A, Gunther R, Ludolph A, Schwartz O, Trollmann R, Weydt P, et al. Short-term safety results from compassionate use of risdiplam in patients with spinal muscular atrophy in Germany. Orphanet J Rare Dis. 2022;17:276.\u003c/li\u003e\n\u003cli\u003eVazquez-Costa JF, Povedano M, Nascimiento-Osorio AE, Moreno Escribano A, Kapetanovic Garcia S, Dominguez R, et al. Validation of motor and functional scales for the evaluation of adult patients with 5q spinal muscular atrophy. Eur J Neurol. 2022;29:3666-75.\u003c/li\u003e\n\u003cli\u003eVazquez-Costa JF, Povedano M, Nascimiento-Osorio AE, Moreno Escribano A, Kapetanovic Garcia S, Dominguez R, et al. Nusinersen in adult patients with 5q spinal muscular atrophy: A multicenter observational cohorts\u0026apos; study. Eur J Neurol. 2022;29:3337-46.\u003c/li\u003e\n\u003cli\u003eBaranello G, Darras BT, Day JW, Deconinck N, Klein A, Masson R, et al. Risdiplam in Type 1 Spinal Muscular Atrophy. N Engl J Med. 2021;384:915-23.\u003c/li\u003e\n\u003cli\u003eMasson R, Mazurkiewicz-Beldzinska M, Rose K, Servais L, Xiong H, Zanoteli E, et al. Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): secondary analyses from an open-label trial. Lancet Neurol. 2022;21:1110-9.\u003c/li\u003e\n\u003cli\u003eSitas B, Hancevic M, Bilic K, Bilic H, Bilic E. Risdiplam Real World Data - Looking Beyond Motor Neurons and Motor Function Measures. J Neuromuscul Dis. 2024;11:75-84.\u003c/li\u003e\n\u003cli\u003eBrakemeier S, Lipka J, Schlag M, Kleinschnitz C, Hagenacker T. Risdiplam improves subjective swallowing quality in non-ambulatory adult patients with 5q-spinal muscular atrophy despite advanced motor impairment. J Neurol. 2024;271:2649-57.\u003c/li\u003e\n\u003cli\u003eBjelica B, Wohnrade C, Cespedes I, Osmanovic A, Schreiber-Katz O, Petri S. Risdiplam therapy in adults with 5q-SMA: observational study on motor function and treatment satisfaction. BMC Neurol. 2024;24:67.\u003c/li\u003e\n\u003cli\u003eSvoboda MD, Kuntz N, Leon-Astudillo C, Byrne BJ, Krueger J, Kwon JM, et al. Risdiplam treatment following onasemnogene abeparvovec in individuals with spinal muscular atrophy: a multicenter case series. BMC Neurol. 2025;25:283.\u003c/li\u003e\n\u003cli\u003eBarzegar M, Poorshiri B, Rezazadeh K, Toopchizadeh V, Shiva S, Motamedi A. Risdiplam and nusinersen in spinal muscular atrophy: a descriptive real-world study on motor function outcomes in northwestern Iran. Neuromuscul Disord. 2025;54:106210.\u003c/li\u003e\n\u003cli\u003eAshrafi MR, Babaee M, Hashemi Nazari SS, Barzegar M, Ghazavi M, Beiraghi Toosi M, et al. Comparative efficacy of risdiplam and nusinersen in Type 2 and 3 spinal muscular atrophy patients: A cohort study using real-world data. J Neuromuscul Dis. 2024;11:1190-9.\u003c/li\u003e\n\u003cli\u003ePineda ED, To TM, Dickendesher TL, Shapouri S, Iannaccone ST. Adherence and Persistence Among Risdiplam-Treated Individuals with Spinal Muscular Atrophy: A Retrospective Claims Analysis. Adv Ther. 2024;41:2446-59.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Spinal muscular atrophy, risdiplam, motor function, real-world study, the Hammersmith Functional Motor Scale","lastPublishedDoi":"10.21203/rs.3.rs-7966590/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7966590/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eEvidence for the efficacy of risdiplam in adolescents and adults with 5q spinal muscular atrophy (SMA) has been demonstrated in clinical trials, but its sustained effectiveness and safety in real-world settings, particularly in Chinese populations, remains to be demonstrated. We evaluated the efficacy and safety of risdiplam in this population in a real-world setting.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis prospective observational study included adolescent and adult patients with genetically confirmed 5q SMA under standard clinical care (January 2023 to December 2024). Patients received risdiplam monotherapy (5 mg daily), with dosing adjusted based on clinical condition and tolerability. Primary outcomes were changes in Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM) scores, and 6-min walk test (6MWT).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eFifteen patients (8 male, 7 female) were included, with a mean (SD) efficacy assessment time of 1.45 (0.38) years. The mean (SD) RULM score significantly improved from 17.60 (10.87) at baseline to 19.33 (11.11) at final follow-up (P\u0026thinsp;=\u0026thinsp;0.043). The mean (SD) HFMSE score showed a non-significant increase (13.00 (16.21) to 13.60 (16.26), P\u0026thinsp;=\u0026thinsp;0.159). The 6-minute walk test remained stable, with improvement observed in two patients. The mean (SD) ALSFRS-R scores were unchanged (31.47 (7.61) vs. 31.80 (7.59), P\u0026thinsp;=\u0026thinsp;0.936). No adverse events were reported, indicating good tolerability.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eOur real-world findings provide evidence supporting the sustained efficacy and safety of risdiplam in managing SMA in adolescent and adult patients. Longer-term and larger-scale studies remain warranted to further characterize its clinical sustainability.\u003c/p\u003e","manuscriptTitle":"Effectiveness and Safety of Risdiplam in Chinese Adolescents and Adults with Spinal Muscular Atrophy: A Prospective Real-World Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-26 09:05:30","doi":"10.21203/rs.3.rs-7966590/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-16T08:08:01+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"133817289775924873334599997836359013435","date":"2025-11-23T04:16:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"87780578320455745607813732529017025763","date":"2025-11-20T12:48:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"134219031430678458374963925408738781425","date":"2025-11-19T19:24:58+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-17T14:37:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"337441349734357751476728780318871326503","date":"2025-11-17T07:12:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"6093255330802534926455986100567452833","date":"2025-11-16T22:02:31+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-16T19:14:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"242264609296414193605068338642730158836","date":"2025-11-16T19:06:20+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-16T18:37:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"96900505581037695024098553185000022476","date":"2025-11-16T18:35:57+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-16T11:29:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"308563184412073231001695665005902919998","date":"2025-11-16T10:50:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"329682565897460519291303833566820636677","date":"2025-11-15T11:31:03+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-14T18:37:13+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-11-14T17:08:51+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-03T11:26:20+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-03T11:26:10+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Neurology","date":"2025-10-28T07:32:17+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"532fdeda-a9a4-4662-afd5-119cb3d53b09","owner":[],"postedDate":"November 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-12-30T05:53:07+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-26 09:05:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7966590","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7966590","identity":"rs-7966590","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}