Short-term safety results from compassionate use of risdiplam in patients with spinal muscular atrophy in Germany

Abstract

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-naïve. 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.

Risdiplam for the treatment of adults with spinal muscular atrophy: Experience of the Northern Ireland neuromuscular service

“…There have been two recent studies on the safety of risdiplam in both children and adults outside of clinical trials with the most commonly reported treatment related adverse events being diarrhea, constipation, nausea, rash, and headache. 17,18 The studies did not report on the efficacy of treatment.…”

“…Minor rashes have commonly been reported with 14% and 17% of patients developing rashes in the FIREFISH study and SUNFISH part 2 study respectively 9,16 There were few other reported side effects in our cohort; none of these were serious. There have been two recent studies on the safety of risdiplam in both children and adults outside of clinical trials with the most commonly reported treatment related adverse events being diarrhea, constipation, nausea, rash, and headache 17,18 . The studies did not report on the efficacy of treatment.…”

Risdiplam in non‐sitter patients aged 16 years and older with 5q spinal muscular atrophy

“…The safety of risdiplam has been recently reported in two EAPbased studies, which included some patients not considered in the clinical trials. 11,12 However, data on risdiplam efficacy were not reported.…”

Gentherapien bei den Motoneuronerkrankungen ALS und SMA

“…Die Dosierung erfolgt alters-und körpergewichtsadaptiert (2 Monate bis < 2 Jahre: 0,20 mg/kg KG; ≥ 2 Jahre und < 20 kg: 0,25 mg/kg KG; ≥ 2 Jahre und ≥ 20 kg: 5 mg). Risdiplam wird insgesamt gut vertragen [104]. Nebenwirkungen wie Diarrhoe, Übelkeit, Mundgeschwüre oder aphthöse Geschwüre, Hautausschlag, Kopfschmerzen, Fieber, Gelenkschmerzen und Harnwegsinfektionen können auftreten.…”