{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T21:08:51Z","timestamp":1791234531605,"version":"4.1.0"},"reference-count":20,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100007705","name":"Astellas Pharma Global Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007705","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>ASP1617 is a novel, highly selective inhibitor of cathepsin\u2010S, an important protease for antigen peptide loading onto major histocompatibility complex class II molecules. Preclinically, ASP1617 prevented progression of lupus\u2010like glomerulonephritis in an NZB\/W F1 mouse model of systemic lupus erythematosus. In this double\u2010blind, randomized, placebo\u2010controlled, first\u2010in\u2010human study in healthy subjects, ASP1617 was generally well tolerated. Treatment\u2010emergent adverse events of rash and throat tightness were reported in two subjects receiving the highest doses of 110\u2009mg BID in multiple ascending dose (MAD) cohorts, leading to withdrawal of ASP1617 in both subjects. Mean elimination half\u2010life was 10.4\u201315.9\u2009h in single ascending dose (SAD) cohorts and 13.7\u201320.5\u2009h in MAD cohorts. ASP1617 exposure increased slightly greater than dose proportionally between SAD cohorts and dose proportionally between MAD cohorts and was similar between Japanese and non\u2010Asian subjects. A high\u2010fat, high\u2010calorie meal slightly decreased peak and total exposure and delayed absorption. Both single and multiple dosing of ASP1617 led to rapid and maximal inhibition (&gt;\u200980% at 3\u2009h post\u2010dose) of cathepsin\u2010S activity as well as the downstream increase of invariant chain p10 (Lip10) in B cells, indicating target engagement. However, in all MAD cohorts, cathepsin\u2010S activity gradually rebounded during treatment, surpassing baseline levels after the last dose, and cathepsin\u2010S mass increased significantly, fivefold above baseline, and prolonged after treatment. Due to the observed safety events, induction of the cathepsin\u2010S target, and gradual loss of pharmacodynamic effects during repeated dosing, appropriate mitigation strategies are necessary for the further clinical development of ASP1617.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Trial Registration:<\/jats:bold>\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link>\n                    Identifier: NCT04077879\n                  <\/jats:p>","DOI":"10.1111\/cts.70460","type":"journal-article","created":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T03:02:42Z","timestamp":1769223762000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["First\u2010in\u2010Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ASP1617, a Cathepsin\u2010S Inhibitor, in Healthy Adult Subjects"],"prefix":"10.1111","volume":"19","author":[{"given":"Tomoki","family":"Kojima","sequence":"first","affiliation":[{"name":"Astellas Pharma, Inc.  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