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

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Abstract

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.

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Acknowledgments

We thank Dr. Feinan He (Department of Otorhinolaryngology Head and Neck Surgery, The Second Hospital of Jilin University, China) for her participation and contributions to this study.

Funding

This work was supported by the National Natural Science Foundation of China [grant number 82304629], the Natural Science Foundation of Xiamen, China [grant number 3502Z202371048], the Basic and Applied Basic Research Fund of Guangdong Province grant [grant numbers 2022A1515012549, 2023A1515012667].

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Author notes

  1. Wei Zhuang, Mei Lu have contribution equally.

Authors and Affiliations

  1. Department of Pharmacy, Women and Children’s Hospital, School of Medicine, Xiamen University, 10# Zhenhai Road, Xiamen, China

    Wei Zhuang & Wanlong Lin

  2. Department of Pediatrics, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen, China

    Mei Lu, Zhehui Chen & Minying Wang

  3. Department of Ultrasound, The First Affiliated Hospital of Xiamen University, Xiamen, China

    Ye Wu

  4. Department of Xiamen Newborn Screening Center, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen, China

    Xudong Wang

  5. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China

    Shaoxing Guan

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  1. Wei Zhuang
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Correspondence to Wanlong Lin.

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Competing Interests

The authors have no relevant conflicts of interest to disclose. There is no financial/nonfinancial need to disclosures of all authors.

Ethics Statement

The present pharmacovigilance study was conducted using a public database of spontaneous reports. Given the use of deidentified data, ethical approval was not considered necessary.

Data Availability

The data are openly available in the FDA Adverse Event Reporting System Public Dashboard at: https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html.

Consent to Participate

FDA Adverse Event Reporting System is a spontaneous reporting system, the publicly available data are anonymized, and therefore, obtaining consent to participate is not applicable.

Consent for Publication

Not applicable.

Code Availability

The custom code used in this study have been made available upon request. Please contact Dr. Wei Zhuang (zhuangw8@mail.sysu.edu.cn) for access to the code.

Author Contributions

WZ performed the main data analysis and statistics work, and wrote this manuscript. ML participated a part of data mining, gave the constructive suggestion and revised this manuscript. YW, ZC, MW, XW and SG participated the data cleaning and analysis. WL designed this study, critically reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

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Zhuang, W., Lu, M., Wu, Y. et al. Safety Concerns with Nusinersen, Risdiplam, and Onasemnogene Abeparvovec in Spinal Muscular Atrophy: A Real-World Pharmacovigilance Study. Clin Drug Investig 43, 949–962 (2023). https://doi.org/10.1007/s40261-023-01320-4

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