Safety Concerns with Nusinersen, Risdiplam, and Onasemnogene Abeparvovec in Spinal Muscular Atrophy: A Real-World Pharmacovigilance Study.

Background and objective: Spinal muscular atrophy (SMA) is a genetic disorder with limited treatment options. It is crucial to have a comprehensive understanding of drug safety in order to make informed clinical drug selections for patients with SMA. Assessing the safety profiles of therapeutic drugs for SMA has been challenging due to the limited number of patients included in clinical trials. This study aims to investigate and compare the potential safety concerns associated with three leading SMA therapeutic drugs: nusinersen, risdiplam, and onasemnogene abeparvovec.

Methods: The FDA Adverse Event Reporting System database was used to analyze drug safety, and a case (SMA drug)/noncase (all other drugs in the database) approach was employed to estimate safety signals through disproportionality analysis and reporting odds ratio (ROR). Veen analysis was conducted to compare and select the idiosyncratic adverse events (AEs) associated with each drug.

Results: The study included 5324 cases of nusinersen, 1184 cases of risdiplam, and 1277 cases of onasemnogene abeparvovec. Venn analysis revealed 27 common AEs among the three drugs, including cardiac, gastrointestinal, metabolism, musculoskeletal, renal, respiratory disorders, and infections. Additionally, 196 AEs exclusively found in nusinersen included post lumbar puncture syndrome [ROR (95% CI) = 6120.91 (5057.01-7408.64), n = 372], procedural pain [ROR (95% CI) = 54.86 (48.13-62.54), n = 234], idiopathic intracranial hypertension [ROR (95% CI) = 6.12 (2.29-16.33), n = 4], and hypokalemia [ROR (95% CI) = 2.02 (1.24-3.31), n = 16]. Additionally, transient deafness was identified as an unexpected and rare, yet severe, AE for nusinersen [ROR (95% CI) = 23.32 (8.71-62.44), n = 4]. Risdiplam exhibited 50 AEs exclusively, with notable idiosyncratic AEs including diarrhea [ROR (95% CI) = 4.55 (3.79-5.46), n = 121], fatigue [ROR (95% CI) = 2.03 (1.6-2.57), n = 70], photosensitivity reaction [ROR (95% CI) = 9.50 (4.25-21.13), n = 6], rash [ROR (95% CI) = 1.90 (1.36-2.67), n = 34], and [ROR (95% CI) = 4.3 (1.93-9.58), n = 6] in comparison with the other two drugs. Moreover, ileus [ROR (95% CI) = 11.11 (4.14-29.51), n = 4], gastrointestinal hemorrhage [ROR (95% CI) = 2.55 (1.15-5.69), n = 6], and hypoglycemic unconsciousness [ROR (95% CI) = 153.58 (62.98-374.54), n = 5] were rare but severe AEs associated with risdiplam. Onasemnogene abeparvovec had 143 exclusively identified AEs, with significant high signals for troponin I increase [ROR (95% CI) = 627.1 (492.2-798.99), n = 78], troponin T increase [ROR (95% CI) = 233.98 (153.29-357.15), n = 23], blood lactate dehydrogenase increase [ROR (95% CI) = 39.81 (28.88-54.87), n = 38], and transaminases increase [ROR (95% CI) = 36.88 (29.24-46.52), n = 73].

Conclusions: This study highlights the importance of monitoring injection-related injuries and transient deafness events in patients treated with nusinersen. For onasemnogene abeparvovec, careful monitoring for renal impairment, liver injury, and myocardial damage is necessary. Risdiplam requires attention to the potential risk of rare but severe gastrointestinal damage events and hypoglycemia. Importantly, risdiplam exhibited lower liver and renal toxicity, making it a potential consideration for patients with liver or renal insufficiency or for combined use with other drugs that possess high liver or renal toxicity. These findings can be a reference for drug selection and further prospective studies.