Real-world safety of nusinersen in Japan: results from an interim analysis of a post-marketing surveillance and safety database

Wataya, Takafumi; Takasaki, Sakura; Hoshino, Misuzu; Makioka, Haruki; Nakamura, Genshu; Matsuda, Naoto

doi:10.1080/00207454.2021.1995382

Cited by 8 publications

(4 citation statements)

References 41 publications

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“…Good safety record of nusinersen over more than 5 years in the clinic is particularly notable because of its IT route of administration that potentially is an independent source of adverse events, especially in SMA where scoliosis and osseous fusion are frequent. In fact, most commonly reported adverse events during treatment with nusinersen were consistent with symptoms of SMA and lumbar puncture (Stolte et al, 2021;Wataya et al, 2021). Notably, retrospective claims database analysis of more than 300 SMA patients for years 2016-2019 indicated that fewer than 50% of patients who completed the loading phase of nusinersen treatment remained in treatment 24 months after start, likely due to logistical and medical challenges of the IT administration route, which highlights the importance of a non-invasive route of administration for wide acceptance of NBTs (Gauthier-Loiselle et al, 2021).…”

Section: Clinical Experience With Rnatargeting Therapiesmentioning

confidence: 97%

“…Meta-analysis of more than 20 clinical studies evaluating motor function in type 2 and 3 SMA patients treated with nusinersen revealed consistently positive outcomes (Coratti et al, 2021). Review of 271 SMA patients showed motor function improvements in 26.2% and overall improvement in 99.6-100.0% of patients treated with nusinersen in Japan between 2017 and 2019 (Wataya et al, 2021).…”

Section: Clinical Experience With Rnatargeting Therapiesmentioning

confidence: 99%

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Natural antisense transcripts as drug targets

Khorkova

Stahl

Joji

et al. 2022

Front. Mol. Biosci.

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The recent discovery of vast non-coding RNA-based regulatory networks that can be easily modulated by nucleic acid-based drugs has opened numerous new therapeutic possibilities. Long non-coding RNA, and natural antisense transcripts (NATs) in particular, play a significant role in networks that involve a wide variety of disease-relevant biological mechanisms such as transcription, splicing, translation, mRNA degradation and others. Currently, significant efforts are dedicated to harnessing these newly emerging NAT-mediated biological mechanisms for therapeutic purposes. This review will highlight the recent clinical and pre-clinical developments in this field and survey the advances in nucleic acid-based drug technologies that make these developments possible.

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Section: Clinical Experience With Rnatargeting Therapiesmentioning

confidence: 97%

Section: Clinical Experience With Rnatargeting Therapiesmentioning

confidence: 99%

Natural antisense transcripts as drug targets

Khorkova

Stahl

Joji

et al. 2022

Front. Mol. Biosci.

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“…As the pharmacokinetic and pharmacodynamic characteristics of ASO drugs are similar, results obtained with nusinersen can help evaluate future prospects of the protein-upregulating NBT field in general. Overall, the long-term efficacy and safety data for nusinersen are positive 44 – 46 , although the intrathecal route of administration may be associated with adverse events 47 , 48 and has potentially reduced treatment adherence, highlighting the need to develop non-invasive methods for NBT delivery 49 .…”

Section: Nbts For Protein Upregulationmentioning

confidence: 99%

Amplifying gene expression with RNA-targeted therapeutics

Khorkova

Stahl

Joji

et al. 2023

Nat Rev Drug Discov

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Many diseases are caused by insufficient expression of mutated genes and would benefit from increased expression of the corresponding protein. However, in drug development, it has been historically easier to develop drugs with inhibitory or antagonistic effects. Protein replacement and gene therapy can achieve the goal of increased protein expression but have limitations. Recent discoveries of the extensive regulatory networks formed by non-coding RNAs offer alternative targets and strategies to amplify the production of a specific protein. In addition to RNA-targeting small molecules, new nucleic acid-based therapeutic modalities that allow highly specific modulation of RNA-based regulatory networks are being developed. Such approaches can directly target the stability of mRNAs or modulate non-coding RNA-mediated regulation of transcription and translation. This Review highlights emerging RNA-targeted therapeutics for gene activation, focusing on opportunities and challenges for translation to the clinic.

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“…After reading the titles and abstracts, 148 non-conforming articles were excluded, and 57 articles were included for double screening. After reading the full text, 15 articles (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) were included in the final review. The process and results of literature screening are shown in Figure 1.…”

Section: Literature Searchmentioning

confidence: 99%

Adverse events in the treatment of spinal muscular atrophy in children and adolescents with nusinersen: A systematic review and meta-analysis

2023

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ObjectivesTo systematically analyze adverse events (AEs) in treatment of spinal muscular atrophy (SMA) with Nusinersen in children and adolescents.MethodsThe study is registered on PROSPERO (CRD42022345589). Databases were searched and literature relating to Nusinersen in the treatment of spinal muscular atrophy in children from the start of database establishment to December 1, 2022, was retrospectively analyzed. R.3.6.3 statistical software was used, and random effects meta-analysis was performed to calculate weighted mean prevalence and 95% confidence intervals (CI).ResultsIn total, 15 eligible studies were included, with a total of 967 children. Rate of definite Nusinersen-related AEs was 0.57% (95% CI: 0%–3.97%), and probable Nusinersen-related AEs 7.76% (95% CI: 1.85%–17.22%). Overall rate of AEs was 83.51% (95% CI: 73.55%–93.46%), and serious AEs 33.04% (95% CI: 18.15%–49.91%). For main specific AEs, fever was most common, 40.07% (95% CI: 25.14%–56.02%), followed by upper respiratory tract infection 39.94% (95% CI: 29.43%–50.94%), and pneumonia 26.62% (95% CI: 17.99%–36.25%).The difference in overall AE rates between the two groups (Nusinersen group and placebo group) was significant (OR = 0.27,95% CI: 0.08–0.95, P = 0.042). Moreover, incidence of serious adverse events, and fatal adverse events were both significantly lower than in the placebo group (OR = 0.47, 95%CI: 0.32–0.69, P < 0.01), and (OR = 0.37, 95%CI: 0.23–0.59, P < 0.01), respectively.ConclusionNusinersen direct adverse events are rare, and it can effectively reduces common, serious, and fatal adverse events in children and adolescents with spinal muscular atrophy.

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Real-world safety of nusinersen in Japan: results from an interim analysis of a post-marketing surveillance and safety database

Cited by 8 publications

References 41 publications

Natural antisense transcripts as drug targets

Natural antisense transcripts as drug targets

Amplifying gene expression with RNA-targeted therapeutics

Adverse events in the treatment of spinal muscular atrophy in children and adolescents with nusinersen: A systematic review and meta-analysis

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