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. 2025 Sep 26:88:103536.
doi: 10.1016/j.eclinm.2025.103536. eCollection 2025 Oct.

Efficacy and safety of risdiplam in adults with 5q-associated spinal muscular atrophy: a nationwide observational cohort study in Austria

Omar Keritam  1   2 , Marcus Erdler  3 , Bernhard Fasching  1   2 , Gudrun Zulehner  1   2 , Jakob Rath  1   2 , Martin Krenn  1   2 , Thomas Waldhör  4 , Victoria Anna Gruber  2   5 , Nadine Langweil  2   5 , Christian Kiss  6 , Theresa Antonia Griedl  6 , Valeriu Gold  6 , Julia Wanschitz  7 , Anna Hotter  7 , Vera E A Kleinveld  7 , Corinne G C Horlings  7 , Astrid Erber  4 , Eva Schernhammer  4   8 , Johannes Troger  9 , Susanne Grinzinger  10 , Petra Müller  11 , Dieter Langenscheidt  12 , Mika Rappold  13 , Anna Wiesenhofer  13 , Magdalena Gosk-Tomek  13 , Florian Knipp  13 , Simone Mahal  13 , Günther Bernert  13 , Matthias Baumann  14 , Fritz Zimprich  1   2 , Raffi Topakian  11 , Christian Eggers  15 , Stefan Quasthoff  6 , Wolfgang Löscher  7 , Hakan Cetin  1   2
Affiliations

Efficacy and safety of risdiplam in adults with 5q-associated spinal muscular atrophy: a nationwide observational cohort study in Austria

Omar Keritam et al. EClinicalMedicine. .

Abstract

Background: Spinal muscular atrophy (SMA) is a genetic motor neuron disease marked by the progressive decline of motor function. Risdiplam, an orally administered SMN2 splicing modifier, was approved for the treatment of 5q-associated SMA (5q-SMA) across all age groups. However, clinical trial data have primarily focused on paediatric populations, with limited evidence available for adult patients. This study aimed to evaluate the efficacy and safety of risdiplam in treatment-naïve adults with 5q-SMA in a real-world, multicentre setting.

Methods: We conducted a nationwide, observational cohort study across eight neuromuscular centres in Austria. Patients aged ≥16 years at treatment initiation with genetically confirmed 5q-SMA, who were previously untreated and initiated risdiplam between December 2020 and September 2024 were eligible for inclusion if they had received risdiplam for ≥3 months and had functional motor assessments available at baseline (T0) and at least one follow-up. Functional outcomes were assessed at four predefined intervals after baseline: 3-<6 months (T1), 6-<12 months (T2), 12-<18 months (T3), and ≥18 months (T4). The primary outcome was the change from baseline in the Hammersmith Functional Motor Scale Expanded (HFMSE). Secondary outcomes included changes in the Revised Upper Limb Module (RULM), Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), and 6-min walk test (6MWT). Adverse events were extracted from medical records.

Findings: A total of 87 patients had received risdiplam, of whom 57 fulfilled the inclusion criteria and were included in this study. The median age at treatment initiation was 35.7 years (IQR 28.8-43.4), with a median disease duration of 29.6 years (IQR 24.2-36.3). Most individuals had SMA type II (40.4%) or III (47.4%). Mean HFMSE changes from baseline were +1.00 (95% CI 0.05-1.95, p = 0.0100) at T1, +0.97 (95% CI 0.22-1.72, p = 0.0132) at T2, +1.78 (0.66-2.89, p = 0.0008) at T3, and +1.73 (0.49-2.97, p = 0.0049) at T4. Clinically meaningful improvements in motor function (≥3 points in HFMSE and/or ≥2 in RULM) were observed in 63.9% of patients at T4. Improvements were more pronounced in patients with higher baseline function, ambulatory status, or without a history of spinal surgery. Risdiplam was generally well tolerated, with predominantly mild and non-specific adverse events reported in 14.0% of patients.

Interpretation: In this nationwide observational study in a real-world setting, adult patients with 5q-SMA demonstrated consistent and clinically meaningful functional improvements with risdiplam over time, particularly by 18 months and beyond. These findings support the long-term use of risdiplam in adults with SMA and help close a critical evidence gap in this underrepresented population.

Funding: This study was financially supported by F. Hoffmann-La Roche Ltd.

Keywords: Observational study; Risdiplam; SMA; Spinal muscular atrophy.

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Conflict of interest statement

OK received support to attend scientific conferences or meetings from Roche and Biogen and speaker's honoraria from Biogen. ME received honoraria for lectures from Roche and for advisory boards from Roche, ScholarRock and Biogen, as well as support to attend a scientific conference from Roche. MK received travel support from Roche to attend scientific conferences. CK received support to attend scientific meetings as well as travel fees from Roche. TAG received travel compensation and compensation to attend scientific meetings from Biogen and Roche. CGH received support to attend scientific meetings from Biogen, Amicus Therapeutics, and speakers's honoraria from Grünenthal. JT received travel support from Roche to attend scientific conferences. SG received fees for advisory boards from Roche. PM received compensation from Roche to attend an advisory board, and support to attend a scientific meeting from Lundbeck Pharma. MR received consultation fees from Roche. AW received speaker's honoraria as well as conference and travel fees from Roche. MGT received advisory board fees and speaker's honoraria from Novartis and Roche, and support to attend scientific conferences from Roche. SM received consultation fees, speaker's or advisory board honoraria from Novartis, Roche and ScholarRock, and support for attending scientific conferences from Roche. GB received fees for advisory boards and consultations, and support to attend scientific conferences from Novartis, Biogen and Roche. MB received compensation for advisory boards and speaker's honoraria from Novartis, Biogen and Roche and travel compensation to meetings from Roche. RT received support to attend scientific meetings from Angelini, AstraZeneca, Janssen-Cilag, Merz, Pfizer, Sanofi, Biogen and Roche, speaker's honoraria from Abbvie, Alexion, ArgenX, BMS, Daiichi-Sankyo and Teva-ratiopharm. as well as advisory board fees from Alexion, ArgenX, Grünenthal, Janssen-Cilag, Sanofi, UCB, Biogen, Novartis and Roche. CE received fees for advisory boards from Roche and Biogen, and owns stock options from Roche. WL received fees for advisory boards or speaker's honoraria from Novartis, Biogen and Roche, and payments for patents from Roche and Novartis. WL also owns stock options from Novartis. HC received fees for advisory boards and speaker's honoraria from Biogen, Novartis and Roche, and also received funding for research projects from these companies. All other authors declared no conflicts of interest.

Figures

Fig. 1
Fig. 1
Inclusion flow chart. SMA, Spinal Muscular Atrophy; HFMSE, Hammersmith Functional Motor Scale Expanded; RULM, Revised Upper Limb Module; ALSFRS-R, Amyotrophic Lateral Sclerosis Functional Rating Scale Revised; 6MWT, 6 Minute Walk Test; DMT, Disease Modifying Therapy; w/o, without.
Fig. 2
Fig. 2
(A–D) Changes in HFMSE from baseline at the predefined timepoints, with bars representing individual patients. Dotted lines mark the threshold for clinically meaningful improvement. Reported p-values correspond to the Wilcoxon signed rank test. (E) Mean pre-post changes (with standard error) in HFMSE at each predefined timepoint. (F) Individual HFMSE trajectories (red) after treatment initiation, with baseline scores normalised to 0. The LOESS smoothing line (black) estimates average HFMSE change over time. HFMSE, Hammersmith Functional Motor Scale Expanded; 95% CI, 95% Confidence Interval; LOESS, Locally Estimated Scatterplot Smoothing.
Fig. 3
Fig. 3
(A–D) Changes in RULM from baseline at the predefined timepoints, with bars representing individual patients. Dotted lines mark the threshold for clinically meaningful improvement. Reported p-values correspond to the Wilcoxon signed rank test. (E) Mean pre-post changes (with standard error) in RULM at each predefined timepoint. (F) Individual RULM trajectories (red) after treatment initiation, with baseline scores normalised to 0. The LOESS smoothing line (black) estimates average RULM change over time. RULM, Revised Upper Limb Module; 95% CI, 95% Confidence Interval; LOESS, Locally Estimated Scatterplot Smoothing.
See this image and copyright information in PMC

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