PMID- 35854272 OWN - NLM STAT- MEDLINE DCOM- 20220721 LR - 20221026 IS - 1750-1172 (Electronic) IS - 1750-1172 (Linking) VI - 17 IP - 1 DP - 2022 Jul 19 TI - Short-term safety results from compassionate use of risdiplam in patients with spinal muscular atrophy in Germany. PG - 276 LID - 10.1186/s13023-022-02420-8 [doi] LID - 276 AB - BACKGROUND: The oral, selective SMN2-splicing modifier risdiplam obtained European approval in March 2021 for the treatment of patients >/= 2 months old with a clinical diagnosis of 5q-associated spinal muscular atrophy (SMA) 1/2/3 or with 1-4 SMN2 gene copies. For the preceding 12 months, this compassionate use program (CUP) made risdiplam available to patients with SMA1/2 in Germany who could not receive any approved SMA therapy. PATIENTS AND METHODS: Patients with SMA1/2, aged >/= 2 months at enrollment, could be included if they were not eligible for, no longer responsive to, or not able to tolerate nusinersen or not able to receive onasemnogene abeparvovec. Oral risdiplam dosing ranged from 0.2 mg/kg to 5 mg depending on age and weight. All treatment decisions were made by the attending physicians, who were required to report all adverse events (AEs). RESULTS: Between March 12, 2020 and March 30, 2021, 36 patients with SMA1 and 98 patients with SMA2 were enrolled, with 31 patients and 80 patients receiving >/= 1 risdiplam dose, respectively. The median (range) age was 10.5 (3-52) years in the SMA1 cohort, and 26.5 (3-60) years in the SMA2 cohort. 22.2% of patients with SMA1 and 48.0% with SMA2 were treatment-naive. Most patients were not eligible/could not continue to receive nusinersen due to scoliosis/safety risk (SMA1: 75.0%; SMA2: 96.9%), risks associated with sedation (77.8%; 63.3%), or loss of efficacy (30.6%; 12.2%). Safety data were generally in line with the safety profile of risdiplam in ongoing clinical studies. Gastrointestinal disorders were the most common AEs. For patients with SMA1, 30 AEs were reported in 13 cases with 2 serious AEs in 1 patient. For SMA2, 100 AEs were documented in 31 case reports, including 8 serious AEs in 2 patients. CONCLUSIONS: We present the first real-world safety data of risdiplam in patients with SMA in Germany. Our observations indicated no new safety signals under real-world conditions. Real-world SMA1/2 populations comprise considerable numbers of patients who are not eligible for gene therapy and cannot tolerate or have failed nusinersen treatment. This medical need may be addressed by oral risdiplam. CI - (c) 2022. The Author(s). FAU - Hahn, Andreas AU - Hahn A AD - Department of Child Neurology, University of Giessen, Giessen, Germany. FAU - Gunther, Rene AU - Gunther R AD - Department of Neurology, University Hospital Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany. FAU - Ludolph, Albert AU - Ludolph A AD - Department of Neurology, University of Ulm, Ulm, Germany. FAU - Schwartz, Oliver AU - Schwartz O AD - Department of Pediatric Neurology, Munster University Hospital, Munster, Germany. FAU - Trollmann, Regina AU - Trollmann R AD - Division of Pediatric Neurology, Department of Pediatrics, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany. FAU - Weydt, Patrick AU - Weydt P AD - Department of Neurodegenerative Diseases and Gerontopsychiatry/Neurology, University of Bonn Medical Center, Bonn, Germany. FAU - Weiler, Markus AU - Weiler M AD - Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany. FAU - Neuland, Kathrin AU - Neuland K AD - Roche Pharma AG, Grenzach-Wyhlen, Germany. FAU - Schwaderer, Martin Sebastian AU - Schwaderer MS AD - Roche Pharma AG, Grenzach-Wyhlen, Germany. FAU - Hagenacker, Tim AU - Hagenacker T AUID- ORCID: 0000-0002-3631-3450 AD - Department of Neurology, University Hospital Essen, Essen, Germany. tim.hagenacker@uk-essen.de. CN - Risdiplam Compassionate Use Program Group LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220719 PL - England TA - Orphanet J Rare Dis JT - Orphanet journal of rare diseases JID - 101266602 RN - 0 (Azo Compounds) RN - 0 (Pyrimidines) RN - 76RS4S2ET1 (Risdiplam) SB - IM EIN - Orphanet J Rare Dis. 2022 Oct 25;17(1):387. PMID: 36284315 MH - Azo Compounds MH - Compassionate Use Trials MH - Germany MH - Humans MH - Infant MH - *Muscular Atrophy, Spinal/drug therapy MH - Pyrimidines MH - *Spinal Muscular Atrophies of Childhood/drug therapy PMC - PMC9295446 OTO - NOTNLM OT - Compassionate use OT - Real-world data OT - Risdiplam OT - Spinal muscular atrophy OT - Splicing modifier OT - Survival of motor neuron 1 protein COIS- All authors received institutional support for their contribution to this CUP as well as medical writing support for publication of the data, both funded by Roche Pharma AG, Grenzach-Wyhlen, Germany. AH has received honoraria from Roche for participation at advisory boards and lectures. RG has received research grants from Biogen, personal fees and non-financial support from Biogen for lectures and for serving on advisory boards as well as personal fees from Hoffmann-La Roche for serving on advisory boards outside of the submitted work. AL has served on advisory boards for Roche Pharma AG. OS has declared no further competing interests. RT has received personal fees from Novartis, Sanofi, PTC, Biogen and Desitin for lectures and for serving on advisory boards outside of the submitted work. PW has received consulting fees from Roche, Biogen and ITF Pharma. MW advises for Akcea Therapeutics, Alnylam Pharmaceuticals, Biogen, Pfizer, Hoffmann-La Roche and Swedish Orphan Biovitrum, received lecture honoraria from Akcea Therapeutics, Alnylam Pharmaceuticals and Biogen, and received financial support for conference attendance from Biogen and Pfizer, all outside of the present work. KN and MSS are employees of Roche Pharma AG. TH has received research grants and personal fees for lectures from Biogen, Novartis Gene Therapies, Sanofi-Genzyme and Hoffmann-La Roche and for serving on advisory boards from Biogen, Sanofi-Genzyme, Hoffmann-La Roche, Alexion, Hormosan, Alnylam, Argenx and PTC outside the submitted work. EDAT- 2022/07/20 06:00 MHDA- 2022/07/22 06:00 PMCR- 2022/07/19 CRDT- 2022/07/19 23:44 PHST- 2022/02/07 00:00 [received] PHST- 2022/06/30 00:00 [accepted] PHST- 2022/07/19 23:44 [entrez] PHST- 2022/07/20 06:00 [pubmed] PHST- 2022/07/22 06:00 [medline] PHST- 2022/07/19 00:00 [pmc-release] AID - 10.1186/s13023-022-02420-8 [pii] AID - 2420 [pii] AID - 10.1186/s13023-022-02420-8 [doi] PST - epublish SO - Orphanet J Rare Dis. 2022 Jul 19;17(1):276. doi: 10.1186/s13023-022-02420-8.