{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T10:03:07Z","timestamp":1784887387676,"version":"3.55.0"},"reference-count":36,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R00DK1208689"],"award-info":[{"award-number":["R00DK1208689"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["P30DK045735"],"award-info":[{"award-number":["P30DK045735"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cancer cachexia is a debilitating syndrome marked by involuntary weight loss resulting from reduced food intake and intricate metabolic reprogramming. Despite its high prevalence, cancer cachexia remains undertreated, with a lack of effective and approved pharmacotherapies. Ghrelin has emerged as a therapeutic target for cancer cachexia due to its beneficial effects on energy balance. However, the clinical application of ghrelin is hampered by its short half\u2010life. In this study, we introduce PEP\u2010064, a novel stabilized, long\u2010acting and efficacious ghrelin analogue and assess its effects on C26\u2010induced and Lewis lung carcinoma (LLC)\u2013induced cachexia in mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The in\u00a0vivo efficacy of PEP\u2010064 was evaluated in healthy CD\u20101 mice after repeated dosing for 7\u2009days and in the C26 and LLC cancer cachexia mouse models. Additionally, the pharmacokinetic profile and whole brain neuronal activity mapping were conducted in healthy mice following a single subcutaneous injection of PEP\u2010064. Growth hormone secretion was measured in healthy rats following a single administration of PEP\u2010064.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In healthy mice, PEP\u2010064 exhibited a dose\u2010dependent (100, 300 and 1000\u2009nmol\/kg) increase in both delta body weight (BW) and total food intake (FI) compared to the vehicle (BW: 2.7\u2009g vs. 3.5, 4.8 and 5.3\u2009g; FI: 50\u2009g vs. 57\u2009g, 60 and 70\u2009g). In the C26 model, PEP\u2010064 protected against loss of tumour\u2010free (TF) BW (\u22121.2\u2009g vs. 1.7\u2009g,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001), increased food intake (33\u2009g vs. 41\u2009g,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01), prevented losses in fat (\u22121.1\u2009g vs. 0.9\u2009g,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001) and lean mass (\u22120.07\u2009g vs. 0.4\u2009g,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) without affecting tumour growth. In the LLC model, PEP\u2010064 induced hyperphagia (52.2\u2009g vs. 61.6\u2009g,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001) and protected against TF\u2010BW loss (\u22121.4\u2009g vs.\u2009\u2212\u20090.01\u2009g,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) and fat mass loss (\u22120.9\u2009g vs. 0.8\u2009g,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001). In mice, PEP\u2010064 had a T\n                      <jats:sub>1\/2<\/jats:sub>\n                      of 6.6\u2009h and a\n                      <jats:italic>T<\/jats:italic>\n                      <jats:sub>\n                        <jats:italic>max<\/jats:italic>\n                      <\/jats:sub>\n                      at 4\u2009h. PEP\u2010064 increased neuronal activity (c\u2010Fos) in the hypothalamic and amygdala regions, with the tuberal nucleus of the hypothalamus showing the highest increase compared to the vehicle (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). Lastly, circulating growth hormone was increased 20\u2009min after subcutaneous PEP\u2010064 dosing, peaking at 30\u2009min at 93\u2009ng\/mL and returning to approximately baseline by 120\u2009min.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The novel, long\u2010acting and efficacious ghrelin analogue, PEP\u2010064, restored energy balance in cancer cachexia by increasing food intake and body weight, preserving lean mass and increasing adiposity, without affecting tumour growth. Considering the unmet medical need for safe and effective treatments for cachexia, our study demonstrates the feasibility of a long\u2010acting ghrelin approach for treating cancer cachexia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70318","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T12:31:59Z","timestamp":1780317119000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel Long\u2010Acting Ghrelin Analogue PEP\u2010064 Restores Energy Balance in C26 and Lewis Lung Carcinoma\u2013Induced cachexia in Mice"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0508-7320","authenticated-orcid":false,"given":"J. E.","family":"Hunt","sequence":"first","affiliation":[{"name":"Pephexia Therapeutics ApS  Frederiksberg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Lund","sequence":"additional","affiliation":[{"name":"Pephexia Therapeutics ApS  Frederiksberg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Physiology Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. R.","family":"Diaz","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Physiology Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"O.","family":"Dmytriyeva","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Marcotorchino","sequence":"additional","affiliation":[{"name":"Biomeostasis  La Penne sur Huveaune France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"L\u00f6bner","sequence":"additional","affiliation":[{"name":"Faculty of Life Sciences Leipzig University  Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"M\u00f6rl","sequence":"additional","affiliation":[{"name":"Faculty of Life Sciences Leipzig University  Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N. R.","family":"Andersen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Medical and Health Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z. K. J.","family":"Ogueboule","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Medical and Health Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Frank","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Medical and Health Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"St\u00f6hr","sequence":"additional","affiliation":[{"name":"Apigenex sro  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"Meseguer","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Physiology Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V.","family":"Panajotova","sequence":"additional","affiliation":[{"name":"Apigenex sro  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Roux","sequence":"additional","affiliation":[{"name":"Biomeostasis  La Penne sur Huveaune France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2456-9667","authenticated-orcid":false,"given":"C.","family":"Clemmensen","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Sylow","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Medical and Health Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Schneeberger","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Physiology Yale University School of Medicine  New Haven Connecticut USA"},{"name":"Wu Tsai Institute for Mind and Brain Yale University  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4560-8020","authenticated-orcid":false,"given":"A. G.","family":"Beck\u2010Sickinger","sequence":"additional","affiliation":[{"name":"Faculty of Life Sciences Leipzig University  Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. L.","family":"Pedersen","sequence":"additional","affiliation":[{"name":"Pephexia Therapeutics ApS  Frederiksberg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Fosgerau","sequence":"additional","affiliation":[{"name":"Pephexia Therapeutics ApS  Frederiksberg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-024-01167-9"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(10)70218-7"},{"key":"e_1_2_10_4_1","first-page":"1","volume-title":"Encyclopedia of Molecular Pharmacology","author":"Burm 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