{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T15:28:54Z","timestamp":1785338934155,"version":"3.55.0"},"reference-count":36,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T00:00:00Z","timestamp":1742342400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Muscle and Nerve"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Introduction\/Aims<\/jats:title><jats:p>Akt intracellular signal transduction pathway dysfunction has been reported in people with amyotrophic lateral sclerosis (ALS) providing a novel target for intervention in this devastating progressive disease. This first\u2010in\u2010human study evaluated the safety, tolerability, and preliminary efficacy of the Akt pathway activator, IPL344, in people with ALS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Nine participants with ALS and a progression rate &gt;\u20090.55 points\/month on the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS\u2010R) received open\u2010label IPL344 treatment (once\u2010daily) for up to 36\u2009months. Safety was assessed through adverse event (AE) reporting. Plasma neurofilament light chain (NfL) concentrations were measured before and after treatment. Clinical outcomes were compared to historical data.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The mean\u2009\u00b1\u2009SD duration of IPL344 follow\u2010up was 14.0\u2009\u00b1\u200912.5\u2009months. One participant developed drug hypersensitivity, two had central venous catheter\u2010related AEs, and two had serious pneumonia AEs. The unadjusted mean\u2009\u00b1\u2009SE slope of decline in ALSFRS\u2010R was \u22120.53\u2009\u00b1\u20090.15 (48% slower progression vs. historical controls, <jats:italic>p<\/jats:italic>\u2009=\u20090.028). Adjustment for disease stage and rate\u2010indicating covariates indicated a 64% slower ALSFRS\u2010R progression (<jats:italic>p<\/jats:italic>\u2009=\u20090.034), with increased rather than reduced body weight (<jats:italic>p<\/jats:italic>\u2009=\u20090.02). Eight of nine IPL344\u2010treated participants had a significantly improved slope compared to the median slope of a matched control group (<jats:italic>p<\/jats:italic>\u2009=\u20090.04). Plasma NfL concentrations were lowered by 27% (<jats:italic>n<\/jats:italic>\u2009=\u20096). Unadjusted median survival for participants in the IPL344 group was 43.4\u2009months [95% CI: 20.5, NA] compared with 19.1\u2009months [17.4, 23.0] in the historical control group.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These preliminary data indicate that IPL344 was safe and well\u2010tolerated, and possibly effective. Our findings may merit further investigation in a larger placebo\u2010controlled clinical trial.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mus.28393","type":"journal-article","created":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T11:44:22Z","timestamp":1742384662000},"page":"1032-1042","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Akt Activation With <scp>IPL344<\/scp> Treatment for Amyotrophic Lateral Sclerosis: First in Human, Open\u2010Label Study"],"prefix":"10.1002","volume":"71","author":[{"given":"Marc","family":"Gotkine","sequence":"first","affiliation":[{"name":"Neuromuscular Unit, Department of Neurology Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Schoenfeld","sequence":"additional","affiliation":[{"name":"Department of Biostatistics Massachusetts General Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4548-796X","authenticated-orcid":false,"given":"Ilana","family":"Cohen","sequence":"additional","affiliation":[{"name":"Immunity Pharma Ltd.  Mevasseret Zion Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy M.","family":"Shefner","sequence":"additional","affiliation":[{"name":"Department of Neurology Barrow Neurological Institute  Phoenix Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yossef","family":"Lerner","sequence":"additional","affiliation":[{"name":"Neuromuscular Unit, Department of Neurology Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irun R.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Immunology and Regenerative Biology Weizmann Institute of Science  Rehovot Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin","family":"Klein","sequence":"additional","affiliation":[{"name":"Department of Neurology Meir Medical Center  Kfar Saba Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eran","family":"Ovadia","sequence":"additional","affiliation":[{"name":"Immunity Pharma Ltd.  Mevasseret Zion Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7075-1681","authenticated-orcid":false,"given":"Merit E.","family":"Cudkowicz","sequence":"additional","affiliation":[{"name":"Department of Neurology Healey &amp; AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the Pooled Resource Open\u2010Access ALS Clinical Trials Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,19]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2022.786420"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.abh2290"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.04.001"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.06.009"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.2174\/092986712801661130"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12640-019-0003-y"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2017.06.009"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2990.2007.00850.x"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0603670103"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.05-5249fje"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12283"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0024-3205(02)02249-X"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1011334018804"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.23411"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2019.04.009"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/imm.12745"},{"key":"e_1_2_11_18_1","unstructured":"I.Cohen E.Ovadia R.Margalit andI. 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