{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:42:57Z","timestamp":1790772177920,"version":"4.1.0"},"reference-count":36,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2022,6,6]],"date-time":"2022-06-06T00:00:00Z","timestamp":1654473600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Haemophilia"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Befovacimab (formerly BAY 1093884) is a fully human monoclonal antibody able to bind to tissue factor pathway inhibitor (TFPI) and developed as a non\u2010replacement therapy for individuals with haemophilia A\/B, with or without inhibitors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>To assess the safety of multiple escalating doses of befovacimab in individuals with severe haemophilia A\/B with or without inhibitors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this non\u2010randomised, open\u2010label Phase 2 study (NCT03597022), adult males with\u00a0&lt;1% factor VIII or\u00a0&lt;2% factor IX and \u22654 bleeds in the previous six months were enrolled in three dose cohorts (100\/225\/400\u00a0mg). Participants received befovacimab subcutaneously once weekly. The primary endpoint was safety; secondary endpoints included annualised bleeding rate (ABR) and pharmacokinetics\/pharmacodynamics (PK\/PD) of befovacimab.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 24 participants (<jats:italic>n<\/jats:italic>\u00a0=\u00a08 in each dose cohort) were treated for 2\u201347\u00a0weeks. Patients treated with 100\u00a0mg and 225\u00a0mg doses of befovacimab demonstrated improved bleeding control compared with pre\u2010study bleeding rates, with a dose\u2010dependent effect. Dosing was suspended and the study prematurely terminated following three drug\u2010related thrombotic serious adverse events (SAEs): two at the 225\u00a0mg dose and one at the 400\u00a0mg dose. These occurred in the absence of bleeding episodes or concomitant use of replacement\/bypass therapies. No laboratory abnormalities were observed, and PK\/PD data did not show correlation between SAE occurrence and levels of circulating befovacimab or free TFPI.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Despite favourable initial results from preclinical and clinical studies, a positive safety profile of befovacimab was not confirmed. The lack of SAE\u2010related laboratory abnormalities or differentiating PK\/PD characteristics in participants experiencing SAEs raises concerns about the predictability of thrombosis following befovacimab treatment and emphasises the need for further investigation into the therapeutic window of anti\u2010TFPI treatment.<\/jats:p><\/jats:sec>","DOI":"10.1111\/hae.14595","type":"journal-article","created":{"date-parts":[[2022,6,6]],"date-time":"2022-06-06T20:38:25Z","timestamp":1654547905000},"page":"702-712","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Befovacimab, an anti\u2010tissue factor pathway inhibitor antibody: Early termination of the multiple\u2010dose, dose\u2010escalating Phase 2 study due to thrombosis"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7113-4028","authenticated-orcid":false,"given":"Maria Elisa","family":"Mancuso","sequence":"first","affiliation":[{"name":"Center for Thrombosis and Hemorrhagic Diseases IRCCS Humanitas Research Hospital  Rozzano Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2072-1094","authenticated-orcid":false,"given":"Sheila J. M.","family":"Ingham","sequence":"additional","affiliation":[{"name":"Bayer SA  S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Kunze","sequence":"additional","affiliation":[{"name":"Bayer AG  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,6,6]]},"reference":[{"key":"e_1_2_10_2_1","first-page":"7","article-title":"Emerging therapies for hemophilia: controversies and unanswered questions","author":"Arruda VR","year":"2018","journal-title":"F1000Res"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.2147\/PPA.S139851"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.15256\/joc.2011.1.2"},{"issue":"5","key":"e_1_2_10_5_1","first-page":"457","article-title":"Non\u2010factor replacement therapy for haemophilia: a current update","volume":"16","author":"Franchini M","year":"2018","journal-title":"Blood Transfus"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2004.05168.x"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00563"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2019.239160"},{"issue":"6","key":"e_1_2_10_9_1","first-page":"344","article-title":"Diagnosis and treatment of hemophilia","volume":"17","author":"Kizilocak H","year":"2019","journal-title":"Clin Adv Hematol Oncol"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1213\/ane.0b013e31819bceb1"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0504240103"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.115.305996"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0049-3848(16)30359-0"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)68737-X"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.2741\/3926"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.12897"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-018-0922-6"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1310444110"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-017-0086-4"},{"key":"e_1_2_10_20_1","unstructured":"YegneswaranS MarquardtT EvansV et\u00a0al.BAY 1093884 binds to the Kunitz 1 and 2 domain interface of tissue factor pathway inhibitor and inhibits its function (PB 892).International Society on Thrombosis and Haemostasis \u2010 26th Congress. 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