Switching from Nusinersen to Risdiplam in Spinal Muscular Atrophy: A Comparative Analysis of Safety, Efficacy, and Economic Impact

Dear Editor,

The article by Belančić A et al., “Switching from Nusinersen to Risdiplam: A Croatian Real-World Experience on Effectiveness and Safety,” ¹ investigates the safety of switching from Nusinersen to Risdiplam. This topic is, in my opinion, particularly interesting as it is underexplored and highly relevant given that the deteriorating conditions of patients with Spinal Muscular Atrophy (SMA) often lead to such a switch in clinical practice. This publication prompted me to delve deeper into the subject. Specifically, I have reviewed the literature on both drugs, with particular emphasis on clinical aspects, administration, and costs, all evaluated from the perspective of the Italian National Health System. Additionally, I analyzed and compared the adverse drug reactions (ADRs) reported in EudraVigilance (EV).

The analysis covered the period from the commercialization of the two drugs in Europe, starting from 2020 for Risdiplam and 2018 for Nusinersen, up until 07/07/2024. To collect the majority of the data, ADRs were classified according to System Organ Class (SOC). To determine if there was a significant difference in the frequency of event reporting, Reporting Odds Ratios (RORs) with 95% confidence intervals and significance levels (P-values) were used. Statistical analysis was conducted using MedCalc software, Version 22.032. ²

Nusinersen, administered via intrathecal injections, has shown significant improvements in motor function in patients with SMA types 1 and 2 up to 12 years of age.^3,4 Moreover, in the ENDEAR study (NCT02193074), children with SMA type 1 treated with Nusinersen demonstrated significant improvements in event-free survival and overall survival. ³ Risdiplam, an oral drug, has shown comparable efficacy. In the FIREFISH study (NCT02913482), it led to significant improvements in motor skills in patients with SMA type 1. After 12 months of treatment, approximately 41% of patients achieved the ability to sit without support for at least 5 seconds.^5,6

The 2 drugs exhibit significant differences in treatment costs, influenced by the mode of administration, dosage, and duration of treatment. Nusinersen incurs high costs primarily due to repeated intrathecal injections, which require administration in a hospital or specialized center. The ex-factory price for a single dose ⁷ is approximately €63 175, totaling €379 050 for the first year of treatment, including 4 loading doses and 2 maintenance doses. Additional costs may arise from managing intrathecal procedures and related medical complications. The estimated cost per intrathecal injection is €1470. ⁸ Risdiplam, administered orally, reduces both drug costs and those associated with intrathecal administration and related healthcare services. The ex-factory price is €7477, and the annual cost, simulated for patients aged 2 years or older and weighing 20 kg or more, is €224 310. ⁹ There are no administration costs.

Regarding pharmacovigilance analysis, 856 ADR reports for Risdiplam and 3098 for Nusinersen were collected. Risdiplam shows a higher incidence of reports in females compared to males (ROR: 1.5, 95% CI: 1.28-1.74, P < .0001), with a higher incidence of gastrointestinal disorders (27.3% vs 10.2%; ROR: 3.35, 95% CI: 2.76-4.04, P < .0001) and general disorders related to the administration site (24.8% vs 20%; ROR: 1.32, 95% CI: 1.10-1.5, P = .0022). On the other hand, Nusinersen shows a higher prevalence of injury and procedural complications (26.2% vs 8%; ROR: 4.04, 95% CI: 3.12-5.23, P < .0001) and musculoskeletal disorders (14.0% vs 7.3%; ROR: 2.05, 95% CI: 1.56-2.70, P < .0001). Additionally, Nusinersen presents a higher percentage of nervous system disorders (17.8%) compared to Risdiplam (12.9%) (ROR: 1.46, 95% CI: 1.17-1.82, P = .0007).

According to my analysis, both drugs demonstrate positive clinical effects in managing the condition, but the oral administration of Risdiplam may offer benefits in terms of accessibility, ease of use, and overall economic impact. These different routes of administration seem closely related to the different ADRs reported in EudraVigilance, with Risdiplam, despite having 2 years less monitoring, showing fewer adverse reactions. The switch from Nusinersen to Risdiplam, based on pharmacovigilance data and the literature, can be considered favorable, taking into account various clinical factors and the individual needs of the patients.