{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T13:19:02Z","timestamp":1769087942347,"version":"3.49.0"},"reference-count":17,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T00:00:00Z","timestamp":1740009600000},"content-version":"vor","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Omaveloxolone is approved for the treatment of Friedreich ataxia (FA) in patients aged \u2265\u200916\u2009years at a dose of 150\u2009mg once daily. This double\u2010blind, randomized, placebo\u2010 and active\u2010controlled, three\u2010way crossover, thorough corrected QT interval (QTc) study (NCT05927649) evaluated the effect of supratherapeutic omaveloxolone exposure on QTc to exclude a clinically significant prolongation (defined as &gt;\u200910\u2009ms). Healthy adults were randomized to one of six sequences of three single oral doses (omaveloxolone 450\u2009mg, placebo, or moxifloxacin 400\u2009mg [open\u2010label positive control]) administered with an FDA high\u2010fat meal. Serial pharmacokinetic blood sampling and time\u2010matched electrocardiogram assessments were performed. The primary endpoint was placebo\u2010corrected change from baseline in QTcF (\u0394\u0394QTcF) following omaveloxolone administration. Secondary endpoints included pharmacokinetic parameters of omaveloxolone and its major plasma metabolites (M17 and M22) and safety. All 30 enrolled participants completed the study. The mean omaveloxolone <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> was 319\u2009ng\/mL in this study (4.5\u2010fold the mean steady\u2010state <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> [71.5\u2009ng\/mL] with the approved dose). The mean QTcF intervals were &lt;\u2009450\u2009ms, and mean changes from baseline were &lt;\u200910\u2009ms at all timepoints following all doses. The upper limit of the 90% CIs of \u0394\u0394QTcF following omaveloxolone administration was &lt;\u200910\u2009ms at all timepoints. At the <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> of omaveloxolone, M17, and M22, alone or combined, the upper limits of the 90% CIs of the model\u2010predicted \u0394\u0394QTcF were all &lt;\u200910\u2009ms. No safety concerns were identified. Supratherapeutic omaveloxolone exposure that covers the worst\u2010case clinical exposure did not cause a clinically significant QTc prolongation and was generally well tolerated.<\/jats:p>","DOI":"10.1111\/cts.70139","type":"journal-article","created":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T07:50:46Z","timestamp":1740037846000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Effect of a Supratherapeutic Dose of Omaveloxolone on the Corrected <scp>QT<\/scp> Interval in Healthy Participants: A Randomized, Double\u2010Blind, Placebo\u2010 and Active\u2010Controlled, Three\u2010Way Crossover Study"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7281-0166","authenticated-orcid":false,"given":"Hamim","family":"Zahir","sequence":"first","affiliation":[{"name":"Biogen Inc.  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7951-8321","authenticated-orcid":false,"given":"Masako","family":"Murai","sequence":"additional","affiliation":[{"name":"Biogen Inc.  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucy","family":"Wu","sequence":"additional","affiliation":[{"name":"Biogen Inc.  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3173-8791","authenticated-orcid":false,"given":"Michelle","family":"Valentine","sequence":"additional","affiliation":[{"name":"Celerion Inc.  Tempe Arizona USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott M.","family":"Hynes","sequence":"additional","affiliation":[{"name":"Biogen Inc.  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,2,20]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.2147\/JMDH.S292945"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.12317"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-022-06360-w"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1177\/0883073812448230"},{"key":"e_1_2_10_6_1","unstructured":"Skyclarys (Omaveloxolone) \u201c[Prescribing Information]\u201d(Reata Pharmaceuticals Inc. 2024) accessed January 29 2025 https:\/\/www.skyclarys.com\/docs\/skyclarys_us_prescribing_information\/."},{"key":"e_1_2_10_7_1","unstructured":"Skyclarys (Omaveloxolone) \u201c[Summary of Product Characteristics]\u201d(Reata Ireland Ltd. 2025) accessed January 29 2025 https:\/\/www.ema.europa.eu\/en\/documents\/product\u2010information\/skyclarys\u2010epar\u2010product\u2010information_en.pdf."},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.2482"},{"key":"e_1_2_10_9_1","unstructured":"Center for Drug Evaluation and Research \u201c216718Orig1s000 Clinical Pharmacology Review(s)\u201d(2023) accessed June 10 2024 https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2023\/216718Orig1s000ClinPharmR.pdf."},{"key":"e_1_2_10_10_1","first-page":"61134","article-title":"International Conference on Harmonisation; Guidance on E14 Clinical Evaluation of QT\/QTc Interval Prolongation and Proarrhythmic Potential for Non\u2010Antiarrhythmic Drugs; Availability. Notice","volume":"70","author":"US Food and Drug Administration","year":"2005","journal-title":"Federal Register"},{"key":"e_1_2_10_11_1","unstructured":"International Council for Harmonisation of Technical Requirements for Human Use \u201cICH Harmonised Tripartite Guideline: The Clinical Evaluation Of QT\/QTc Interval Prolongation and Proarrhythmic Potential for Nonantiarrhythmic Drugs E14\u201d(2005) accessed April 24 2024 https:\/\/database.ich.org\/sites\/default\/files\/E14_Guideline.pdf."},{"key":"e_1_2_10_12_1","unstructured":"Center for Drug Evaluation and Research \u201c216718Orig1s000 Other Review(s)\u201d(2023) accessed June 10 2024 https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2023\/216718Orig1s000OtherR.pdf."},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13221"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.2307\/2533558"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfac013"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.2147\/DHPS.S133286"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25934"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.4330\/wjc.v11.i1.1"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.70139","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:05:17Z","timestamp":1760162717000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.70139"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2]]},"references-count":17,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,2]]}},"alternative-id":["10.1111\/cts.70139"],"URL":"https:\/\/doi.org\/10.1111\/cts.70139","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2]]},"assertion":[{"value":"2024-10-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70139"}}