{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T21:51:54Z","timestamp":1789681914200,"version":"4.0.1"},"reference-count":33,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2022,7,31]],"date-time":"2022-07-31T00:00:00Z","timestamp":1659225600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100004336","name":"Novartis","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004336","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:p>Asciminib (Scemblix) is a first\u2010in\u2010class BCR::ABL1 inhibitor that works by specifically targeting the ABL myristoyl pocket (STAMP) and has potent activity against the T315I mutation. This study aimed to characterize the effect of asciminib exposure on disease progression and to elucidate factors influencing efficacy. Our analysis included 303 patients with chronic myeloid leukemia in chronic phase recruited in a phase I study with dose ranging from 10 to 200\u2009mg twice a day (b.i.d.) or 40 to 200\u2009mg once a day (q.d.) (NCT02081378) and in the phase III ASCEMBL (Study of Efficacy of CML\u2010CP Patients Treated With ABL001 Versus Bosutinib, Previously Treated With 2 or More TKIs) study receiving asciminib 40\u2009mg b.i.d. (NCT03106779). A total of 67 patients harbored the T315I mutation. A longitudinal pharmacokinetic\/pharmacodynamic model was developed to characterize the exposure\u2013efficacy relationship, in which the efficacy was assessed through <jats:italic>BCR::ABL1<\/jats:italic> transcript levels over time. Specifically, a three\u2010compartment model representing quiescent leukemic stem cells, proliferating bone marrow cells, and resistant cells was developed. Drug killing of the proliferating cells by asciminib was characterized by a power model. A subgroup analysis was performed on the patients with the T315I mutation using a maximum drug effect model to characterize the drug effect. The model demonstrated the appropriateness of a total daily dose of asciminib 80\u2009mg in patients without the T315I mutation and 200\u2009mg b.i.d. in patients with the T315I mutation with further validation in light of safety data. This model captured key characteristics of patients' response to asciminib and helped inform dosing rationale for resistant and difficult\u2010to\u2010treat populations.<\/jats:p>","DOI":"10.1002\/cpt.2699","type":"journal-article","created":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T14:14:05Z","timestamp":1656684845000},"page":"1040-1050","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Exposure\u2013Efficacy Analysis of Asciminib in Philadelphia Chromosome\u2013Positive Chronic Myeloid Leukemia in Chronic Phase"],"prefix":"10.1111","volume":"112","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8637-7372","authenticated-orcid":false,"given":"Fran\u00e7ois Pierre","family":"Combes","sequence":"first","affiliation":[{"name":"Novartis Pharmaceuticals Corporation  East Hanover New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying Fei","family":"Li","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation  East Hanover New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Hoch","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastien","family":"Lorenzo","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu\u2010Yun","family":"Ho","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation  East Hanover New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6405-9130","authenticated-orcid":false,"given":"Sherwin K. B.","family":"Sy","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation  East Hanover New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,7,31]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-03-144790"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-11-466037"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.12187"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2020.106458"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1902328"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020009984"},{"key":"e_1_2_10_7_1","doi-asserted-by":"crossref","unstructured":"MauroM.J.et al.Efficacy and Safety Results from Ascembl a Multicenter Open\u2010Label Phase 3 Study of Asciminib a First\u2010in\u2010Class STAMP Inhibitor Vs Bosutinib in Patients with Chronic Myeloid Leukemia in Chronic Phase after \u22652 Prior Tyrosine Kinase Inhibitors: Update after 48\u2009Weeks<https:\/\/ash.confex.com\/ash\/2021\/webprogram\/Paper152561.html> (2021). Accessed December 20 2021.","DOI":"10.1182\/blood-2021-152561"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2152-2650(21)01785-7"},{"key":"e_1_2_10_9_1","unstructured":"FDA approves asciminib for Philadelphia chromosome\u2010positive chronic myeloid leukemia<https:\/\/www.fda.gov\/drugs\/resources\u2010information\u2010approved\u2010drugs\/fda\u2010approves\u2010asciminib\u2010philadelphia\u2010chromosome\u2010positive\u2010chronic\u2010myeloid\u2010leukemia> (2021). Accessed November 23 2021."},{"key":"e_1_2_10_10_1","unstructured":"CombesF.P.et al.Dose justification for asciminib in patients with Ph+ chronic myeloid leukemia in chronic phase with or without the T315I mutation previously treated with two or more tyrosine kinase inhibitors. In American Association of Pharmaceutical ScientistsPoster presented on October 19th 2021; 344572; poster no. T6107V."},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262\u2010022\u201001148\u20109"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2018.194522"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-1304-6_8"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-11-393041"},{"key":"e_1_2_10_15_1","unstructured":"R Core Team.R: a language and environment for statistical computing<https:\/\/www.R\u2010project.org\/> (2019). Accessed July 29 2022."},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.8b01040"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2014.326"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.00665"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-012-1385-4"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-011-1200-7"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-015-0143-7"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1097\/HS9.0000000000000077"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmi.2017.07.020"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-1516"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.18573"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2012.080234"},{"key":"e_1_2_10_27_1","first-page":"243","article-title":"Resistant mutations in CML and Ph(+)ALL \u2014 role of ponatinib","volume":"8","author":"Miller G.D.","year":"2014","journal-title":"Biol. Theory"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(07)70342-X"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.30558"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2010.08.026"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1487"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0000990"},{"key":"e_1_2_10_33_1","unstructured":"Scemblix [prescribing information]. (Novartis Pharmaceuticals East Hanover NJ 2021). <https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2021\/215358s000Orig1lbl.pdf> (2021). Accessed December 27 2021."}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.2699","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.2699","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.2699","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T13:37:22Z","timestamp":1699364242000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.2699"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,31]]},"references-count":33,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2022,11]]}},"alternative-id":["10.1002\/cpt.2699"],"URL":"https:\/\/doi.org\/10.1002\/cpt.2699","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,31]]},"assertion":[{"value":"2022-03-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-06-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-07-31","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}