{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T20:27:48Z","timestamp":1754598468878,"version":"3.33.0"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T00:00:00Z","timestamp":1733097600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T00:00:00Z","timestamp":1733097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"funder":[{"name":"NuNerve Pty Ltd"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Clin Drug Investig"],"published-print":{"date-parts":[[2025,1]]},"DOI":"10.1007\/s40261-024-01410-x","type":"journal-article","created":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T13:55:15Z","timestamp":1733147715000},"page":"17-28","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Evaluation of NUN-004, a Novel Engineered Ephrin Antagonist, in Healthy Volunteers and Patients with Amyotrophic Lateral Sclerosis: A Phase I\/Ib, Open-Label, Escalating Dose and Extended Access Study"],"prefix":"10.1007","volume":"45","clinical-trial-number":[{"clinical-trial-number":"actrn12621000514808","registry":"10.18810\/anzctr"}],"author":[{"given":"Michael","family":"Gerometta","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert D.","family":"Henderson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Friend","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leanne T.","family":"Cooper","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew W.","family":"Boyd","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Perry F.","family":"Bartlett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,12,2]]},"reference":[{"issue":"5\u20136","key":"1410_CR1","doi-asserted-by":"publisher","first-page":"310","DOI":"10.3109\/17482960802566824","volume":"10","author":"A Chi\u00f2","year":"2009","unstructured":"Chi\u00f2 A, Logroscino G, Hardiman O, Swingler R, Mitchell D, Beghi E, et al. Prognostic factors in ALS: a critical review. Amyotroph Lateral Scler. 2009;10(5\u20136):310\u201323. https:\/\/doi.org\/10.3109\/17482960802566824.","journal-title":"Amyotroph Lateral Scler"},{"issue":"4","key":"1410_CR2","doi-asserted-by":"publisher","first-page":"944","DOI":"10.1007\/s00415-019-09652-y","volume":"267","author":"L Xu","year":"2020","unstructured":"Xu L, Liu T, Liu L, Yao X, Chen L, Fan D, et al. Global variation in prevalence and incidence of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol. 2020;267(4):944\u201353. https:\/\/doi.org\/10.1007\/s00415-019-09652-y.","journal-title":"J Neurol"},{"key":"1410_CR3","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/1750-1326-8-28","volume":"8","author":"S Chen","year":"2013","unstructured":"Chen S, Sayana P, Zhang X, Le W. Genetics of amyotrophic lateral sclerosis: an update. Mol Neurodegener. 2013;8:28. https:\/\/doi.org\/10.1186\/1750-1326-8-28.","journal-title":"Mol Neurodegener"},{"issue":"9 Suppl","key":"1410_CR4","doi-asserted-by":"publisher","first-page":"S191","DOI":"10.7765\/ajmc.2020.88483","volume":"26","author":"JJ Chen","year":"2020","unstructured":"Chen JJ. Overview of current and emerging therapies for amytrophic lateral sclerosis. Am J Manag Care. 2020;26(9 Suppl):S191\u20137. https:\/\/doi.org\/10.7765\/ajmc.2020.88483.","journal-title":"Am J Manag Care"},{"key":"1410_CR5","doi-asserted-by":"publisher","first-page":"1310","DOI":"10.3389\/fnins.2019.01310","volume":"13","author":"R Mejzini","year":"2019","unstructured":"Mejzini R, Flynn LL, Pitout IL, Fletcher S, Wilton SD, Akkari PA. ALS genetics, mechanisms, and therapeutics: where are we now? Front Neurosci. 2019;13:1310. https:\/\/doi.org\/10.3389\/fnins.2019.01310.","journal-title":"Front Neurosci"},{"issue":"9","key":"1410_CR6","doi-asserted-by":"publisher","first-page":"1418","DOI":"10.1038\/nm.2901","volume":"18","author":"A Van Hoecke","year":"2012","unstructured":"Van Hoecke A, Schoonaert L, Lemmens R, Timmers M, Staats KA, Laird AS, et al. EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans. Nat Med. 2012;18(9):1418\u201322. https:\/\/doi.org\/10.1038\/nm.2901.","journal-title":"Nat Med"},{"issue":"1","key":"1410_CR7","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1038\/nrd4175","volume":"13","author":"AW Boyd","year":"2014","unstructured":"Boyd AW, Bartlett PF, Lackmann M. Therapeutic targeting of EPH receptors and their ligands. Nat Rev Drug Discov. 2014;13(1):39\u201362. https:\/\/doi.org\/10.1038\/nrd4175.","journal-title":"Nat Rev Drug Discov"},{"issue":"7","key":"1410_CR8","doi-asserted-by":"publisher","first-page":"3375","DOI":"10.1007\/s10571-023-01390-0","volume":"43","author":"M Verma","year":"2023","unstructured":"Verma M, Chopra M, Kumar H. Unraveling the potential of EphA4: a breakthrough target and beacon of hope for neurological diseases. Cell Mol Neurobiol. 2023;43(7):3375\u201391. https:\/\/doi.org\/10.1007\/s10571-023-01390-0.","journal-title":"Cell Mol Neurobiol"},{"issue":"22","key":"1410_CR9","doi-asserted-by":"publisher","first-page":"13248","DOI":"10.1073\/pnas.95.22.13248","volume":"95","author":"M Dottori","year":"1998","unstructured":"Dottori M, Hartley L, Galea M, Paxinos G, Polizzotto M, Kilpatrick T, et al. EphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract. Proc Natl Acad Sci U S A. 1998;95(22):13248\u201353. https:\/\/doi.org\/10.1073\/pnas.95.22.13248.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4","key":"1410_CR10","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1016\/j.neuroscience.2009.03.013","volume":"160","author":"SK Ho","year":"2009","unstructured":"Ho SK, Kovacevi\u0107 N, Henkelman RM, Boyd A, Pawson T, Henderson JT. EphB2 and EphA4 receptors regulate formation of the principal inter-hemispheric tracts of the mammalian forebrain. Neuroscience. 2009;160(4):784\u201395. https:\/\/doi.org\/10.1016\/j.neuroscience.2009.03.013.","journal-title":"Neuroscience"},{"issue":"5614","key":"1410_CR11","doi-asserted-by":"publisher","first-page":"1889","DOI":"10.1126\/science.1079641","volume":"299","author":"K Kullander","year":"2003","unstructured":"Kullander K, Butt SJ, Lebret JM, Lundfald L, Restrepo CE, Rydstr\u00f6m A, et al. Role of EphA4 and EphrinB3 in local neuronal circuits that control walking. Science. 2003;299(5614):1889\u201392. https:\/\/doi.org\/10.1126\/science.1079641.","journal-title":"Science"},{"issue":"2","key":"1410_CR12","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1038\/nn994","volume":"6","author":"KK Murai","year":"2003","unstructured":"Murai KK, Nguyen LN, Irie F, Yamaguchi Y, Pasquale EB. Control of hippocampal dendritic spine morphology through ephrin-A3\/EphA4 signaling. Nat Neurosci. 2003;6(2):153\u201360. https:\/\/doi.org\/10.1038\/nn994.","journal-title":"Nat Neurosci"},{"issue":"9","key":"1410_CR13","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0024636","volume":"6","author":"Y Goldshmit","year":"2011","unstructured":"Goldshmit Y, Spanevello MD, Tajouri S, Li L, Rogers F, Pearse M, et al. EphA4 blockers promote axonal regeneration and functional recovery following spinal cord injury in mice. PLoS ONE. 2011;6(9): e24636. https:\/\/doi.org\/10.1371\/journal.pone.0024636.","journal-title":"PLoS ONE"},{"issue":"12","key":"1410_CR14","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1089\/neu.2012.2729","volume":"30","author":"MD Spanevello","year":"2013","unstructured":"Spanevello MD, Tajouri SI, Mirciov C, Kurniawan N, Pearse MJ, Fabri LJ, et al. Acute delivery of EphA4-Fc improves functional recovery after contusive spinal cord injury in rats. J Neurotrauma. 2013;30(12):1023\u201334. https:\/\/doi.org\/10.1089\/neu.2012.2729.","journal-title":"J Neurotrauma"},{"issue":"1","key":"1410_CR15","doi-asserted-by":"publisher","first-page":"11393","DOI":"10.1038\/s41598-018-29845-1","volume":"8","author":"J Zhao","year":"2018","unstructured":"Zhao J, Cooper LT, Boyd AW, Bartlett PF. Decreased signalling of EphA4 improves functional performance and motor neuron survival in the SOD1G93A ALS mouse model. Sci Rep. 2018;8(1):11393. https:\/\/doi.org\/10.1038\/s41598-018-29845-1.","journal-title":"Sci Rep"},{"issue":"744","key":"1410_CR16","doi-asserted-by":"publisher","first-page":"eadg5768","DOI":"10.1126\/scitranslmed.adg5768","volume":"16","author":"N Khan","year":"2024","unstructured":"Khan N, Kumar V, Li P, Schlapbach LJ, Boyd AW, Coulthard MG, et al. Inhibiting Eph\/ephrin signaling reduces vascular leak and endothelial cell dysfunction in mice with sepsis. Sci Transl Med. 2024;16(744):eadg5768. https:\/\/doi.org\/10.1126\/scitranslmed.adg5768.","journal-title":"Sci Transl Med"},{"issue":"2","key":"1410_CR17","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1097\/SHK.0000000000000494","volume":"45","author":"TM Woodruff","year":"2016","unstructured":"Woodruff TM, Wu MC, Morgan M, Bain NT, Jeanes A, Lipman J, et al. EPhA4-Fc treatment reduces ischemia\/reperfusion-induced intestinal injury by inhibiting vascular permeability. Shock. 2016;45(2):184\u201391. https:\/\/doi.org\/10.1097\/SHK.0000000000000494.","journal-title":"Shock"},{"issue":"1","key":"1410_CR18","doi-asserted-by":"publisher","first-page":"6519","DOI":"10.1038\/s41598-017-06685-z","volume":"7","author":"CL Pegg","year":"2017","unstructured":"Pegg CL, Cooper LT, Zhao J, Gerometta M, Smith FM, Yeh M, et al. Glycoengineering of EphA4 Fc leads to a unique, long-acting and broad spectrum, Eph receptor therapeutic antagonist. Sci Rep. 2017;7(1):6519. https:\/\/doi.org\/10.1038\/s41598-017-06685-z.","journal-title":"Sci Rep"},{"issue":"3","key":"1410_CR19","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1007\/s11095-012-0921-3","volume":"30","author":"L Liu","year":"2013","unstructured":"Liu L, Gomathinayagam S, Hamuro L, Prueksaritanont T, Wang W, Stadheim TA, et al. The impact of glycosylation on the pharmacokinetics of a TNFR2: Fc fusion protein expressed in glycoengineered Pichia pastoris. Pharm Res. 2013;30(3):803\u201312. https:\/\/doi.org\/10.1007\/s11095-012-0921-3.","journal-title":"Pharm Res"},{"issue":"5","key":"1410_CR20","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1093\/glycob\/cwm017","volume":"17","author":"AJ Jones","year":"2007","unstructured":"Jones AJ, Papac DI, Chin EH, Keck R, Baughman SA, Lin YS, et al. Selective clearance of glycoforms of a complex glycoprotein pharmaceutical caused by terminal N-acetylglucosamine is similar in humans and cynomolgus monkeys. Glycobiology. 2007;17(5):529\u201340. https:\/\/doi.org\/10.1093\/glycob\/cwm017.","journal-title":"Glycobiology"},{"issue":"5","key":"1410_CR21","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1080\/146608200300079536","volume":"1","author":"BR Brooks","year":"2000","unstructured":"Brooks BR, Miller RG, Swash M, Munsat TL. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000;1(5):293\u20139. https:\/\/doi.org\/10.1080\/146608200300079536.","journal-title":"Amyotroph Lateral Scler Other Motor Neuron Disord"},{"issue":"1\u20132","key":"1410_CR22","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/s0022-510x(99)00210-5","volume":"169","author":"JM Cedarbaum","year":"1999","unstructured":"Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, et al. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci. 1999;169(1\u20132):13\u201321. https:\/\/doi.org\/10.1016\/s0022-510x(99)00210-5.","journal-title":"J Neurol Sci"},{"issue":"8","key":"1410_CR23","doi-asserted-by":"publisher","first-page":"870","DOI":"10.1136\/jnnp-2018-320106","volume":"90","author":"L Gaetani","year":"2019","unstructured":"Gaetani L, Blennow K, Calabresi P, Di Filippo M, Parnetti L, Zetterberg H. Neurofilament light chain as a biomarker in neurological disorders. J Neurol Neurosurg Psychiatry. 2019;90(8):870\u201381. https:\/\/doi.org\/10.1136\/jnnp-2018-320106.","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"12","key":"1410_CR24","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1212\/WNL.0000000000003741","volume":"88","author":"SR Shepheard","year":"2017","unstructured":"Shepheard SR, Wuu J, Cardoso M, Wiklendt L, Dinning PG, Chataway T, et al. Urinary p75ECD: a prognostic, disease progression, and pharmacodynamic biomarker in ALS. Neurology. 2017;88(12):1137\u201343. https:\/\/doi.org\/10.1212\/WNL.0000000000003741.","journal-title":"Neurology"},{"issue":"1\u20132","key":"1410_CR25","doi-asserted-by":"publisher","first-page":"178","DOI":"10.3109\/17482960903093710","volume":"11","author":"C Castrillo-Viguera","year":"2010","unstructured":"Castrillo-Viguera C, Grasso DL, Simpson E, Shefner J, Cudkowicz ME. Clinical significance in the change of decline in ALSFRS-R. Amyotroph Lateral Scler. 2010;11(1\u20132):178\u201380. https:\/\/doi.org\/10.3109\/17482960903093710.","journal-title":"Amyotroph Lateral Scler"},{"issue":"10","key":"1410_CR26","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1056\/NEJMoa1916945","volume":"383","author":"S Paganoni","year":"2020","unstructured":"Paganoni S, Macklin EA, Hendrix S, Berry JD, Elliott MA, Maiser S, et al. Trial of sodium phenylbutyrate-taurursodiol for amyotrophic lateral sclerosis. N Engl J Med. 2020;383(10):919\u201330. https:\/\/doi.org\/10.1056\/NEJMoa1916945.","journal-title":"N Engl J Med"},{"issue":"11","key":"1410_CR27","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1016\/S1474-4422(14)70222-4","volume":"13","author":"ME Cudkowicz","year":"2014","unstructured":"Cudkowicz ME, Titus S, Kearney M, Yu H, Sherman A, Schoenfeld D, et al. Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: a multi-stage, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2014;13(11):1083\u201391. https:\/\/doi.org\/10.1016\/S1474-4422(14)70222-4.","journal-title":"Lancet Neurol"},{"key":"1410_CR28","doi-asserted-by":"publisher","unstructured":"Writing Group; Edaravone (MCI-186) ALS 19 Study Group. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017;16(7):505\u201312. https:\/\/doi.org\/10.1016\/S1474-4422(17)30115-1.","DOI":"10.1016\/S1474-4422(17)30115-1"}],"container-title":["Clinical Drug Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40261-024-01410-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s40261-024-01410-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40261-024-01410-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T03:04:49Z","timestamp":1737687889000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s40261-024-01410-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,2]]},"references-count":28,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,1]]}},"alternative-id":["1410"],"URL":"https:\/\/doi.org\/10.1007\/s40261-024-01410-x","relation":{},"ISSN":["1173-2563","1179-1918"],"issn-type":[{"type":"print","value":"1173-2563"},{"type":"electronic","value":"1179-1918"}],"subject":[],"published":{"date-parts":[[2024,12,2]]},"assertion":[{"value":"4 November 2024","order":1,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 December 2024","order":2,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was funded by NuNerve Pty Ltd, the manufacturer of NUN-004. NuNerve Pty Ltd was involved in the study design, data collection, data analysis and preparation of the manuscript.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"Perry F. Bartlett, Andrew W. Boyd, Michael Gerometta and Leanne T. Cooper are inventors of NUN-004 and are thus listed inventors on granted patents. As such, they have a direct interest in the current clinical trial and a potential pecuniary interest if this drug is commercialised. Robert D. Henderson, Richard Friend and Jing Zhao have no relevant financial or non-financial interests that are directly relevant to the content of this article.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}},{"value":"The study was carried out in compliance with the clinical protocol and approved by an independent ethics committee (The Alfred Human Research Ethics Committee, project 743\/20 [HREC\/71737\/Alfred-2020], approved on 18 December, 2020). The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"Each participant signed and dated an informed consent form according to the local regulatory and legal requirements and Good Clinical Practices.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"Not applicable.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"The data that support the findings of this study are not openly available because of reasons of commercial sensitivity but may be available from the corresponding author upon reasonable request under an appropriate agreement.","order":7,"name":"Ethics","group":{"name":"EthicsHeading","label":"Availability of Data and Material"}},{"value":"Not applicable.","order":8,"name":"Ethics","group":{"name":"EthicsHeading","label":"Code Availability"}},{"value":"PFB, AWB, MG and JZ contributed to the study concept and design and provided ongoing advice to the clinical trial team when requested. RF and RH were involved in the acquisition of study data. LTC contributed to the custom assay design and development. All authors contributed towards the preparation of the manuscript, and read and approved the final submitted version.","order":9,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 Contributions"}}]}}