{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T06:50:34Z","timestamp":1792479034786,"version":"4.5.0"},"reference-count":36,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T00:00:00Z","timestamp":1641772800000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004328","name":"Genentech","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004328","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Dual leucine zipper kinase (DLK), which regulates the c\u2010Jun N\u2010terminal kinase pathway involved in axon degeneration and apoptosis following neuronal injury, is a potential therapeutic target in amyotrophic lateral sclerosis (ALS). This first\u2010in\u2010human study investigated safety, tolerability, and pharmacokinetics (PK) of oral GDC\u20100134, a small\u2010molecule DLK inhibitor. Plasma neurofilament light chain (NFL) levels were explored in GDC\u20100134\u2010treated ALS patients and DLK conditional knockout (cKO) mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The study included placebo\u2010controlled, single and multiple ascending\u2010dose (SAD; MAD) stages, and an open\u2010label safety expansion (OLE) with adaptive dosing for up to 48\u2009weeks.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Forty\u2010nine patients were enrolled. GDC\u20100134 (up to 1200\u2009mg daily) was well tolerated in the SAD and MAD stages, with no serious adverse events (SAEs). In the OLE, three study drug\u2010related SAEs occurred: thrombocytopenia, dysesthesia (both Grade 3), and optic ischemic neuropathy (Grade 4); Grade \u22642 sensory neurological AEs led to dose reductions\/discontinuations. GDC\u20100134 exposure was dose\u2010proportional (median half\u2010life\u2009=\u200984\u2009h). Patients showed GDC\u20100134 exposure\u2010dependent plasma NFL elevations; DLK cKO mice also exhibited plasma NFL compared to wild\u2010type littermates.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>This trial characterized GDC\u20100134 safety and PK, but no adequately tolerated dose was identified. NFL elevations in GDC\u20100134\u2010treated patients and DLK cKO mice raised questions about interpretation of biomarkers affected by both disease and on\u2010target drug effects. The safety profile of GDC\u20100134 was considered unacceptable and led to discontinuation of further drug development for ALS. Further work is necessary to understand relationships between neuroprotective and potentially therapeutic effects of DLK knockout\/inhibition and NFL changes in patients with ALS.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51491","type":"journal-article","created":{"date-parts":[[2022,1,11]],"date-time":"2022-01-11T07:16:29Z","timestamp":1641885389000},"page":"50-66","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["A Phase 1 study of <scp>GDC<\/scp>\u20100134, a dual leucine zipper kinase inhibitor, in <scp>ALS<\/scp>"],"prefix":"10.1002","volume":"9","author":[{"given":"Jonathan S.","family":"Katz","sequence":"first","affiliation":[{"name":"Forbes Norris MDA\/ALS Research Center, California Pacific Medical Center San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey D.","family":"Rothstein","sequence":"additional","affiliation":[{"name":"Johns Hopkins Hospital Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merit E.","family":"Cudkowicz","sequence":"additional","affiliation":[{"name":"Sean M. 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