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Harold and Leila Y. Mathers Charitable Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001229","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013013","name":"Target ALS","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013013","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Medicinal Research Reviews"],"published-print":{"date-parts":[[2020,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive loss of muscle function. It is the most common adult\u2010onset form of motor neuron disease, affecting about 16\u2009000 people in the United States alone. The average survival is about 3 years. Only two interventional drugs, the antiglutamatergic small\u2010molecule riluzole and the more recent antioxidant edaravone, have been approved for the treatment of ALS to date. Therapeutic strategies under investigation in clinical trials cover a range of different modalities and targets, and more than 70 different drugs have been tested in the clinic to date. Here, we summarize and classify interventional therapeutic strategies based on their molecular targets and phenotypic effects. We also discuss possible reasons for the failure of clinical trials in ALS and highlight emerging preclinical strategies that could provide a breakthrough in the battle against this relentless disease.<\/jats:p>","DOI":"10.1002\/med.21661","type":"journal-article","created":{"date-parts":[[2020,2,11]],"date-time":"2020-02-11T07:25:37Z","timestamp":1581405937000},"page":"1352-1384","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":84,"title":["The clinical trial landscape in amyotrophic lateral sclerosis\u2014Past, present, and future"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9041-3241","authenticated-orcid":false,"given":"Heike J.","family":"Wobst","sequence":"first","affiliation":[{"name":"Neuroscience, BioPharmaceuticals R&amp;D AstraZeneca Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Korrie L.","family":"Mack","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania"},{"name":"Merck &amp; Co, Inc Kenilworth New Jersey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean G.","family":"Brown","sequence":"additional","affiliation":[{"name":"Hit Discovery, Discovery Sciences, BioPharmaceuticals R&amp;D AstraZeneca Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3917-0096","authenticated-orcid":false,"given":"Nicholas J.","family":"Brandon","sequence":"additional","affiliation":[{"name":"Neuroscience, BioPharmaceuticals R&amp;D AstraZeneca Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5269-8533","authenticated-orcid":false,"given":"James","family":"Shorter","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,2,11]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1177\/1049909111434635"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1159\/000351153"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm6746a1"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1603471"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2019.02.030"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2015.03.005"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.07.033"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a024554"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20160499"},{"key":"e_1_2_9_11_1","unstructured":"NCT02469896. A trial of tocilizumab in ALS subjects (TCZALS\u2010001).2015.https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02469896"},{"key":"e_1_2_9_12_1","first-page":"129","article-title":"Tocilizumab infusion therapy normalizes inflammation in sporadic ALS patients","volume":"2","author":"Fiala M","year":"2013","journal-title":"Am J Neurodegener Dis"},{"key":"e_1_2_9_13_1","doi-asserted-by":"crossref","first-page":"P5.327","DOI":"10.1212\/WNL.90.15_supplement.P5.327","article-title":"Post hoc analysis using PRO\u2010ACT database to evaluate repository corticotropin injection (H.P. Acthar\u00ae Gel) as a potential treatment for ALS (P5.327)","volume":"90","author":"VanMeter S","year":"2018","journal-title":"Neurology"},{"key":"e_1_2_9_14_1","unstructured":"Mallinckrodt. (Press release).2019.http:\/\/www.mallinckrodt.com\/about\/news\u2010and\u2010media\/news\u2010detail\/?id=25976"},{"key":"e_1_2_9_15_1","unstructured":"NCT03039673. 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