Michael Tymianski, Michael D Hill, Mayank Goyal, Jim Christenson, Bijoy K Menon, Richard H Swartz, Corey Adams, Kathy Heard, Yatika Kohli
{"title":"Safety and efficacy of nerinetide in patients with acute ischaemic stroke enrolled in the early window: a post-hoc meta-analysis of individual patient data from three randomised trials","authors":"Michael Tymianski, Michael D Hill, Mayank Goyal, Jim Christenson, Bijoy K Menon, Richard H Swartz, Corey Adams, Kathy Heard, Yatika Kohli","doi":"10.1016/s1474-4422(24)00515-5","DOIUrl":"https://doi.org/10.1016/s1474-4422(24)00515-5","url":null,"abstract":"<h3>Background</h3>In three neuroprotection trials of nerinetide for acute ischaemic stroke, inconclusive results have been reported with respect to the prespecified primary outcome. However, none of the trials faithfully replicated the inclusion criteria of the animal studies that provided the rationale for the clinical trials—ie, treatment within 3 h of stroke onset and selected for reperfusion without previous thrombolysis. We aimed to investigate whether a clinical benefit of nerinetide might be seen in the subgroup of patients enrolled in these three clinical trials who met the criteria used in the animal studies.<h3>Methods</h3>In this post-hoc individual patient data meta-analysis, we pooled data from the ESCAPE-NA1, ESCAPE-NEXT, and FRONTIER trials, which were done at 135 stroke centres in 13 countries (Canada, Australia, Germany, Ireland, Italy, the Netherlands, Norway, Singapore, South Korea, Sweden, Switzerland, the UK, and the USA). We included all participants who were enrolled within 3 h of acute ischaemic stroke onset, treated with study drug (nerinetide or placebo; randomised 1:1), and selected for reperfusion with thrombolysis, endovascular thrombectomy, or both. The primary endpoint was the number of responders at day 90, which was defined as people with a favourable outcome as per the primary endpoint prespecified in their respective trial. The primary endpoint was analysed by logistic regression, adjusted for age, stroke severity, and trial.<h3>Findings</h3>Between March 26, 2015, and Jan 31, 2023, 2487 participants were enrolled in the three trials, of whom 690 met criteria for this pooled analysis (389 participants in the nerinetide group and 301 participants in the placebo group). 364 (53%) of 690 participants were men and 326 (47%) were women. The median age of participants was 76 years (IQR 66–83) and median baseline National Institutes of Health Stroke Scale score was 17 (11–21). 216 (56%) of 389 participants were responders at day 90 in the nerinetide group compared with 144 (48%) of 301 in the placebo group (adjusted odds ratio [aOR] 1·48, 95% CI 1·07–2·06; p=0·017). 62 (16%) of 389 people in the nerinetide group died compared with 55 (18%) of 301 people in the placebo group (aOR 0·81, 95% CI 0·53–1·24; p=0·34). No safety concerns were identified in either group.<h3>Interpretation</h3>Nerinetide showed a clinically significant benefit over several outcome measures, including the modified Rankin Scale score, the incidence of stroke worsening, and infarction volumes. Neuroprotection with nerinetide might, therefore, be indicated for patients within 3 h of stroke onset and who are selected for reperfusion. These inclusion criteria should be tested in a future trial.<h3>Funding</h3>None.","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"85 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
William A Banks, Michelle A Erickson, Elizabeth M Rhea
{"title":"Delivery of drugs through the blood–brain barrier: need for trials","authors":"William A Banks, Michelle A Erickson, Elizabeth M Rhea","doi":"10.1016/s1474-4422(24)00525-8","DOIUrl":"https://doi.org/10.1016/s1474-4422(24)00525-8","url":null,"abstract":"No Abstract","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"32 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thomas G Moens, Sandrine Da Cruz, Manuela Neumann, Tatyana A Shelkovnikova, Neil A Shneider, Ludo Van Den Bosch
{"title":"Amyotrophic lateral sclerosis caused by FUS mutations: advances with broad implications","authors":"Thomas G Moens, Sandrine Da Cruz, Manuela Neumann, Tatyana A Shelkovnikova, Neil A Shneider, Ludo Van Den Bosch","doi":"10.1016/s1474-4422(24)00517-9","DOIUrl":"https://doi.org/10.1016/s1474-4422(24)00517-9","url":null,"abstract":"Autosomal dominant mutations in the gene encoding the DNA and RNA binding protein FUS are a cause of amyotrophic lateral sclerosis (ALS), and about 0·3–0·9% of patients with ALS are <em>FUS</em> mutation carriers. <em>FUS</em>-mutation-associated ALS (<em>FUS</em>-ALS) is characterised by early onset and rapid progression, compared with other forms of ALS. However, different pathogenic mutations in <em>FUS</em> can result in markedly different age at symptom onset and rate of disease progression. Most <em>FUS</em> mutations disrupt its nuclear localisation, leading to its cytoplasmic accumulation in the CNS. FUS also forms inclusions in around 5% of patients with the related neurodegenerative condition frontotemporal dementia. However, there are key differences between the two diseases at the genetic and neuropathological level, which suggest distinct pathogenic processes. Experimental models have uncovered potential pathogenic mechanisms in <em>FUS</em>-ALS and informed therapeutic strategies that are currently in development, including the silencing of <em>FUS</em> expression using an intrathecally administered antisense oligonucleotide.","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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