{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T12:07:23Z","timestamp":1784549243222,"version":"3.55.0"},"reference-count":40,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100001003","name":"Boehringer Ingelheim","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001003","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>There are currently no approved pharmacotherapies to treat cognitive impairment associated with schizophrenia (CIAS). Iclepertin (BI 425809) is a selective glycine transporter\u20101 (GlyT1) inhibitor that was investigated for the treatment of CIAS. As hemoglobin reduction is considered a class effect of GlyT1 inhibitors, nonclinical studies and clinical trials were assessed to determine if this effect applied to iclepertin. Nonclinical studies of iclepertin\u2010treated rodents demonstrated a reversible reduction in hemoglobin versus vehicle\u2010control animals. Pooled Phase I data from healthy volunteers (N = 391) showed no clinically relevant changes in hemoglobin. Analysis of Phase II, 12\u2010week, randomized\u2010controlled trials in patients with CIAS (N = 709) receiving placebo or iclepertin 2, 5, 10, or 25 mg demonstrated a small hemoglobin decrease in the 10\u2010mg group and, in the 25\u2010mg group, a dose\u2010 and pharmacokinetic\u2010dependent, mild hemoglobin decrease that recovered slightly at post\u2010treatment follow\u2010up (Week 16). Pooled data from the Phase III CONNEX trial program, which included three 26\u2010week, randomized\u2010controlled trials (N = 1835), and one 52\u2010week open\u2010label extension (N = 1356) in patients with CIAS, showed that iclepertin was well\u2010tolerated. In placebo\u2010treated patients, hemoglobin concentration was stable, with small fluctuations over 26 weeks. In iclepertin\u2010treated patients, hemoglobin concentration dropped within the first 18 weeks (mean change vs baseline, \u22122.4 g\/L) and remained stable until the end of treatment (\u226478 weeks). As the primary and secondary CIAS efficacy endpoints were not met, the CONNEX trial program was terminated. Findings from these nonclinical studies and clinical trials suggest reversible mean hemoglobin reductions were of limited significance and iclepertin was well\u2010tolerated with a consistent safety profile.<\/jats:p>","DOI":"10.1002\/jcph.70184","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T14:13:42Z","timestamp":1777472022000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Effect of Iclepertin on Hematological Parameters: An Overview of Nonclinical Studies and Clinical Trials in Healthy Volunteers and Patients with Cognitive Impairment Associated with Schizophrenia"],"prefix":"10.1002","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-1731-4405","authenticated-orcid":false,"given":"Peter","family":"Nagy","sequence":"first","affiliation":[{"name":"Global Patient Safety &amp; Pharmacovigilance Boehringer Ingelheim International GmbH Ingelheim am Rhein Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin Corey","family":"Fowler","sequence":"additional","affiliation":[{"name":"Global Clinical Development MH and EH Boehringer Ingelheim Pharmaceuticals, Inc.  Ridgefield CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Rosenbrock","sequence":"additional","affiliation":[{"name":"Neuroscience &amp; Mental Health DR Boehringer Ingelheim Pharma GmbH &amp; Co. KG  Biberach Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbo","family":"Tang","sequence":"additional","affiliation":[{"name":"Global Biostatistics and Data Sciences Boehringer Ingelheim Pharmaceuticals, Inc.  Ridgefield CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Fu","sequence":"additional","affiliation":[{"name":"Global Biostatistics and Data Sciences Boehringer Ingelheim Pharmaceuticals, Inc.  Ridgefield CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie","family":"Fraser","sequence":"additional","affiliation":[{"name":"Global Clinical Development Operations Boehringer Ingelheim UK Ltd.  Bracknell UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly","family":"Dursema","sequence":"additional","affiliation":[{"name":"Global CPS Inflammation Boehringer Ingelheim Pharmaceuticals, Inc.  Ridgefield CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Schlichtiger","sequence":"additional","affiliation":[{"name":"Global CPS Mental and Eye Health and EA Boehringer Ingelheim Pharma GmbH &amp; Co. KG  Biberach Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Desch","sequence":"additional","affiliation":[{"name":"Global CPS Mental and Eye Health and EA Boehringer Ingelheim Pharma GmbH &amp; Co. KG  Biberach Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fredrik","family":"Gruenenfelder","sequence":"additional","affiliation":[{"name":"Global Patient Safety &amp; Pharmacovigilance Boehringer Ingelheim International GmbH Ingelheim am Rhein Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00406-023-01576-z"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2019.3360"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.books.9780890425596"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.24r15316"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.schres.2014.06.034"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.scog.2021.100233"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.22m14746"},{"key":"e_1_2_10_9_1","first-page":"10","article-title":"Glycine transport inhibitors for the treatment of schizophrenia","volume":"4","author":"Hashimoto K","year":"2010","journal-title":"Open Med Chem J"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.121.001071"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3405-11.2012"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-021-01196-w"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41537-016-0003-3"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40261-018-0660-2"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03274-z"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2016.07.003"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2016.155671"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12888-016-0778-9"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2016.11.014"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-023-01163-3"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(20)30513-7"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.scog.2024.100340"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13318-017-0440-z"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12578"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2019.03.014"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40261-021-01111-9"},{"key":"e_1_2_10_27_1","unstructured":"ClinicalTrials.gov.Effect of fluconazole on the pharmacokinetics of a single oral dose of BI 425809 in healthy male subjects (an open\u2010label two\u2010period fixed\u2010sequence design study). Accessed October 2024.https:\/\/clinicaltrials.gov\/study\/NCT05076409"},{"key":"e_1_2_10_28_1","unstructured":"ClinicalTrials.gov.Relative bioavailability of Batch 1 and Batch 2 of the intended commercial formulation of BI 425809 compared to each other and to TF 2 formulation of BI 425809 following oral administration in healthy male and female subjects (randomized open\u2010label single\u2010dose three\u2010treatment three\u2010period six\u2010sequence crossover study). Accessed October 2024.https:\/\/clinicaltrials.gov\/study\/NCT03817476"},{"key":"e_1_2_10_29_1","unstructured":"ClinicalTrials.gov.A study to investigate the effects of multiple doses of BI 425809 on the single dose pharmacokinetics of cytochrome P450 substrates (midazolam warfarin and Omeprazole) and a P glycoprotein substrate (digoxin) administered orally in an open\u2010label one\u2010sequence trial in healthy male subjects. Accessed October 2024.https:\/\/clinicaltrials.gov\/study\/NCT02783040"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13318-021-00723-y"},{"key":"e_1_2_10_31_1","unstructured":"ClinicalTrials.gov.A study to investigate the effects of donepezil on the pharmacokinetics of BI 425809 and vice versa in healthy male and female subjects (open\u2010label two\u2010treatment two\u2010period one fixed sequence cross\u2010over design). Accessed October 2024.https:\/\/clinicaltrials.gov\/study\/NCT03905096"},{"key":"e_1_2_10_32_1","unstructured":"ClinicalTrials.gov.The effect of multiple oral doses of BI 425809 on metabolism of midazolam administered orally in healthy male subjects (open\u2010label two\u2010period one\u2010sequence trial). Accessed October 2024.https:\/\/clinicaltrials.gov\/study\/NCT05258110."},{"key":"e_1_2_10_33_1","unstructured":"ClinicalTrials.gov.The effect of multiple doses of BI 425809 on the pharmacokinetics of multiple doses of a combination of ethinylestradiol and levonorgestrel following oral administration in healthy premenopausal female subjects (an open\u2010label two\u2010period fixed sequence design trial with run\u2010in period). Accessed October 2024.https:\/\/clinicaltrials.gov\/study\/NCT05613777"},{"key":"e_1_2_10_34_1","unstructured":"ClinicalTrials.gov.A study to investigate the effects of memantine on the pharmacokinetics of BI 425809 and vice versa in healthy male and female subjects (non\u2010randomized single\u2010arm open\u2010label three\u2010period one fixed sequence cross\u2010over study). 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Accessed October 2024.https:\/\/clinicaltrials.gov\/study\/NCT05347004"},{"key":"e_1_2_10_37_1","volume-title":"Safety data of iclepertin (BI 425809) from phase I healthy volunteers and phase II patients with cognitive impairment associated with schizophrenia","author":"Gruenenfelder F"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.books.9780890425596"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(25)00296-2"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2014.163"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.655393"}],"container-title":["The Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.70184","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jcph.70184","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.70184","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T11:36:05Z","timestamp":1784547365000},"score":1,"resource":{"primary":{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/10.1002\/jcph.70184"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,29]]},"references-count":40,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["10.1002\/jcph.70184"],"URL":"https:\/\/doi.org\/10.1002\/jcph.70184","archive":["Portico"],"relation":{},"ISSN":["0091-2700","1552-4604"],"issn-type":[{"value":"0091-2700","type":"print"},{"value":"1552-4604","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,29]]},"assertion":[{"value":"2025-10-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70184"}}