Befovacimab, an anti‐tissue factor pathway inhibitor antibody: Early termination of the multiple‐dose, dose‐escalating Phase 2 study due to thrombosis
Introduction Befovacimab (formerly BAY 1093884) is a fully human monoclonal antibody able to bind to tissue factor pathway inhibitor (TFPI) and developed as a non‐replacement therapy for individuals with haemophilia A/B, with or without inhibitors. Aim To assess the safety of multiple escalating dos...
Gespeichert in:
| Veröffentlicht in: | Haemophilia : the official journal of the World Federation of Hemophilia 2022-09, Vol.28 (5), p.702-712 |
|---|---|
| Hauptverfasser: | , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 712 |
|---|---|
| container_issue | 5 |
| container_start_page | 702 |
| container_title | Haemophilia : the official journal of the World Federation of Hemophilia |
| container_volume | 28 |
| creator | Mancuso, Maria Elisa Ingham, Sheila J. M. Kunze, Marc |
| description | Introduction
Befovacimab (formerly BAY 1093884) is a fully human monoclonal antibody able to bind to tissue factor pathway inhibitor (TFPI) and developed as a non‐replacement therapy for individuals with haemophilia A/B, with or without inhibitors.
Aim
To assess the safety of multiple escalating doses of befovacimab in individuals with severe haemophilia A/B with or without inhibitors.
Methods
In this non‐randomised, open‐label Phase 2 study (NCT03597022), adult males with |
| doi_str_mv | 10.1111/hae.14595 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2674004573</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2712030538</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3885-51cc132ac0e45d21844363c5947aaa921a936a15b855f0c8f01301d03814b9133</originalsourceid><addsrcrecordid>eNp1kUFu1TAQhi0EoqWw4ALIEhuQmtZjx07CrlQPilQJFrC2Jo5DXCXxw3aosuMIHIDTcRIcXmGBhDWyx9Y3v-35CXkK7AzyOB_QnkEpG3mPHINQsuAS1P0tl1DUHNQReRTjDWMgOFMPyZGQSlUM1DH58dr2_isaN2F7SnHOkdzPb9-Ti3GxtEeTfKB7TMMtrtTNg2vddrJhre_WV3SHYVxpsmFyMybnZ-p7mgZLp2VMbj_arNb5aE_pNueNjQbHTM6f6YcBo6WcxrR0K-3yhcnn2uCn1kcXH5MHPY7RPrlbT8inN7uPl1fF9fu37y4vrgsj6loWEozJP0PDbCk7DnVZCiWMbMoKERsO2AiFINtayp6Zus99YNAxUUPZNiDECXlx0N0H_2WxMenJRWPHEWfrl6i5qkrGSllt6PN_0Bu_hDm_TvMKOBNMijpTLw-UCT7GYHu9D7nDYdXA9GaZzpbp35Zl9tmd4tJOtvtL_vEoA-cH4NaNdv2_kr662B0kfwFB26Nl</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2712030538</pqid></control><display><type>article</type><title>Befovacimab, an anti‐tissue factor pathway inhibitor antibody: Early termination of the multiple‐dose, dose‐escalating Phase 2 study due to thrombosis</title><source>MEDLINE</source><source>Access via Wiley Online Library</source><creator>Mancuso, Maria Elisa ; Ingham, Sheila J. M. ; Kunze, Marc</creator><creatorcontrib>Mancuso, Maria Elisa ; Ingham, Sheila J. M. ; Kunze, Marc</creatorcontrib><description>Introduction
Befovacimab (formerly BAY 1093884) is a fully human monoclonal antibody able to bind to tissue factor pathway inhibitor (TFPI) and developed as a non‐replacement therapy for individuals with haemophilia A/B, with or without inhibitors.
Aim
To assess the safety of multiple escalating doses of befovacimab in individuals with severe haemophilia A/B with or without inhibitors.
Methods
In this non‐randomised, open‐label Phase 2 study (NCT03597022), adult males with <1% factor VIII or <2% factor IX and ≥4 bleeds in the previous six months were enrolled in three dose cohorts (100/225/400 mg). 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.
Results
A total of 24 participants (n = 8 in each dose cohort) were treated for 2–47 weeks. Patients treated with 100 mg and 225 mg doses of befovacimab demonstrated improved bleeding control compared with pre‐study bleeding rates, with a dose‐dependent effect. Dosing was suspended and the study prematurely terminated following three drug‐related thrombotic serious adverse events (SAEs): two at the 225 mg dose and one at the 400 mg 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.
Conclusion
Despite favourable initial results from preclinical and clinical studies, a positive safety profile of befovacimab was not confirmed. The lack of SAE‐related 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‐TFPI treatment.</description><identifier>ISSN: 1351-8216</identifier><identifier>ISSN: 1365-2516</identifier><identifier>EISSN: 1365-2516</identifier><identifier>DOI: 10.1111/hae.14595</identifier><identifier>PMID: 35667016</identifier><language>eng</language><publisher>England: Wiley Subscription Services, Inc</publisher><subject>Adult ; Antibodies, Monoclonal - therapeutic use ; Bleeding ; blood coagulation factor inhibitors ; Coagulation factors ; Dosage ; Factor IX - therapeutic use ; Factor VIII - therapeutic use ; haemophilia A ; haemophilia B ; Hemophilia ; Hemophilia A - complications ; Hemophilia A - drug therapy ; Hemophilia B - drug therapy ; Hemorrhage - complications ; Humans ; Laboratories ; Male ; Monoclonal antibodies ; Pharmacodynamics ; Pharmacokinetics ; Safety ; Thrombosis ; Thrombosis - complications ; Thrombosis - etiology ; Tissue factor ; tissue factor pathway inhibitor</subject><ispartof>Haemophilia : the official journal of the World Federation of Hemophilia, 2022-09, Vol.28 (5), p.702-712</ispartof><rights>2022 The Authors. published by John Wiley & Sons Ltd.</rights><rights>2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.</rights><rights>2022. This article is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3885-51cc132ac0e45d21844363c5947aaa921a936a15b855f0c8f01301d03814b9133</citedby><cites>FETCH-LOGICAL-c3885-51cc132ac0e45d21844363c5947aaa921a936a15b855f0c8f01301d03814b9133</cites><orcidid>0000-0003-2072-1094 ; 0000-0002-7113-4028</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fhae.14595$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fhae.14595$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>315,781,785,1418,27928,27929,45578,45579</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35667016$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mancuso, Maria Elisa</creatorcontrib><creatorcontrib>Ingham, Sheila J. M.</creatorcontrib><creatorcontrib>Kunze, Marc</creatorcontrib><title>Befovacimab, an anti‐tissue factor pathway inhibitor antibody: Early termination of the multiple‐dose, dose‐escalating Phase 2 study due to thrombosis</title><title>Haemophilia : the official journal of the World Federation of Hemophilia</title><addtitle>Haemophilia</addtitle><description>Introduction
Befovacimab (formerly BAY 1093884) is a fully human monoclonal antibody able to bind to tissue factor pathway inhibitor (TFPI) and developed as a non‐replacement therapy for individuals with haemophilia A/B, with or without inhibitors.
Aim
To assess the safety of multiple escalating doses of befovacimab in individuals with severe haemophilia A/B with or without inhibitors.
Methods
In this non‐randomised, open‐label Phase 2 study (NCT03597022), adult males with <1% factor VIII or <2% factor IX and ≥4 bleeds in the previous six months were enrolled in three dose cohorts (100/225/400 mg). 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.
Results
A total of 24 participants (n = 8 in each dose cohort) were treated for 2–47 weeks. Patients treated with 100 mg and 225 mg doses of befovacimab demonstrated improved bleeding control compared with pre‐study bleeding rates, with a dose‐dependent effect. Dosing was suspended and the study prematurely terminated following three drug‐related thrombotic serious adverse events (SAEs): two at the 225 mg dose and one at the 400 mg 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.
Conclusion
Despite favourable initial results from preclinical and clinical studies, a positive safety profile of befovacimab was not confirmed. The lack of SAE‐related 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‐TFPI treatment.</description><subject>Adult</subject><subject>Antibodies, Monoclonal - therapeutic use</subject><subject>Bleeding</subject><subject>blood coagulation factor inhibitors</subject><subject>Coagulation factors</subject><subject>Dosage</subject><subject>Factor IX - therapeutic use</subject><subject>Factor VIII - therapeutic use</subject><subject>haemophilia A</subject><subject>haemophilia B</subject><subject>Hemophilia</subject><subject>Hemophilia A - complications</subject><subject>Hemophilia A - drug therapy</subject><subject>Hemophilia B - drug therapy</subject><subject>Hemorrhage - complications</subject><subject>Humans</subject><subject>Laboratories</subject><subject>Male</subject><subject>Monoclonal antibodies</subject><subject>Pharmacodynamics</subject><subject>Pharmacokinetics</subject><subject>Safety</subject><subject>Thrombosis</subject><subject>Thrombosis - complications</subject><subject>Thrombosis - etiology</subject><subject>Tissue factor</subject><subject>tissue factor pathway inhibitor</subject><issn>1351-8216</issn><issn>1365-2516</issn><issn>1365-2516</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNp1kUFu1TAQhi0EoqWw4ALIEhuQmtZjx07CrlQPilQJFrC2Jo5DXCXxw3aosuMIHIDTcRIcXmGBhDWyx9Y3v-35CXkK7AzyOB_QnkEpG3mPHINQsuAS1P0tl1DUHNQReRTjDWMgOFMPyZGQSlUM1DH58dr2_isaN2F7SnHOkdzPb9-Ti3GxtEeTfKB7TMMtrtTNg2vddrJhre_WV3SHYVxpsmFyMybnZ-p7mgZLp2VMbj_arNb5aE_pNueNjQbHTM6f6YcBo6WcxrR0K-3yhcnn2uCn1kcXH5MHPY7RPrlbT8inN7uPl1fF9fu37y4vrgsj6loWEozJP0PDbCk7DnVZCiWMbMoKERsO2AiFINtayp6Zus99YNAxUUPZNiDECXlx0N0H_2WxMenJRWPHEWfrl6i5qkrGSllt6PN_0Bu_hDm_TvMKOBNMijpTLw-UCT7GYHu9D7nDYdXA9GaZzpbp35Zl9tmd4tJOtvtL_vEoA-cH4NaNdv2_kr662B0kfwFB26Nl</recordid><startdate>202209</startdate><enddate>202209</enddate><creator>Mancuso, Maria Elisa</creator><creator>Ingham, Sheila J. M.</creator><creator>Kunze, Marc</creator><general>Wiley Subscription Services, Inc</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-2072-1094</orcidid><orcidid>https://orcid.org/0000-0002-7113-4028</orcidid></search><sort><creationdate>202209</creationdate><title>Befovacimab, an anti‐tissue factor pathway inhibitor antibody: Early termination of the multiple‐dose, dose‐escalating Phase 2 study due to thrombosis</title><author>Mancuso, Maria Elisa ; Ingham, Sheila J. M. ; Kunze, Marc</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3885-51cc132ac0e45d21844363c5947aaa921a936a15b855f0c8f01301d03814b9133</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Adult</topic><topic>Antibodies, Monoclonal - therapeutic use</topic><topic>Bleeding</topic><topic>blood coagulation factor inhibitors</topic><topic>Coagulation factors</topic><topic>Dosage</topic><topic>Factor IX - therapeutic use</topic><topic>Factor VIII - therapeutic use</topic><topic>haemophilia A</topic><topic>haemophilia B</topic><topic>Hemophilia</topic><topic>Hemophilia A - complications</topic><topic>Hemophilia A - drug therapy</topic><topic>Hemophilia B - drug therapy</topic><topic>Hemorrhage - complications</topic><topic>Humans</topic><topic>Laboratories</topic><topic>Male</topic><topic>Monoclonal antibodies</topic><topic>Pharmacodynamics</topic><topic>Pharmacokinetics</topic><topic>Safety</topic><topic>Thrombosis</topic><topic>Thrombosis - complications</topic><topic>Thrombosis - etiology</topic><topic>Tissue factor</topic><topic>tissue factor pathway inhibitor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mancuso, Maria Elisa</creatorcontrib><creatorcontrib>Ingham, Sheila J. M.</creatorcontrib><creatorcontrib>Kunze, Marc</creatorcontrib><collection>Wiley-Blackwell Open Access Titles</collection><collection>Wiley Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Haemophilia : the official journal of the World Federation of Hemophilia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mancuso, Maria Elisa</au><au>Ingham, Sheila J. M.</au><au>Kunze, Marc</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Befovacimab, an anti‐tissue factor pathway inhibitor antibody: Early termination of the multiple‐dose, dose‐escalating Phase 2 study due to thrombosis</atitle><jtitle>Haemophilia : the official journal of the World Federation of Hemophilia</jtitle><addtitle>Haemophilia</addtitle><date>2022-09</date><risdate>2022</risdate><volume>28</volume><issue>5</issue><spage>702</spage><epage>712</epage><pages>702-712</pages><issn>1351-8216</issn><issn>1365-2516</issn><eissn>1365-2516</eissn><abstract>Introduction
Befovacimab (formerly BAY 1093884) is a fully human monoclonal antibody able to bind to tissue factor pathway inhibitor (TFPI) and developed as a non‐replacement therapy for individuals with haemophilia A/B, with or without inhibitors.
Aim
To assess the safety of multiple escalating doses of befovacimab in individuals with severe haemophilia A/B with or without inhibitors.
Methods
In this non‐randomised, open‐label Phase 2 study (NCT03597022), adult males with <1% factor VIII or <2% factor IX and ≥4 bleeds in the previous six months were enrolled in three dose cohorts (100/225/400 mg). 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.
Results
A total of 24 participants (n = 8 in each dose cohort) were treated for 2–47 weeks. Patients treated with 100 mg and 225 mg doses of befovacimab demonstrated improved bleeding control compared with pre‐study bleeding rates, with a dose‐dependent effect. Dosing was suspended and the study prematurely terminated following three drug‐related thrombotic serious adverse events (SAEs): two at the 225 mg dose and one at the 400 mg 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.
Conclusion
Despite favourable initial results from preclinical and clinical studies, a positive safety profile of befovacimab was not confirmed. The lack of SAE‐related 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‐TFPI treatment.</abstract><cop>England</cop><pub>Wiley Subscription Services, Inc</pub><pmid>35667016</pmid><doi>10.1111/hae.14595</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-2072-1094</orcidid><orcidid>https://orcid.org/0000-0002-7113-4028</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1351-8216 |
| ispartof | Haemophilia : the official journal of the World Federation of Hemophilia, 2022-09, Vol.28 (5), p.702-712 |
| issn | 1351-8216 1365-2516 1365-2516 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2674004573 |
| source | MEDLINE; Access via Wiley Online Library |
| subjects | Adult Antibodies, Monoclonal - therapeutic use Bleeding blood coagulation factor inhibitors Coagulation factors Dosage Factor IX - therapeutic use Factor VIII - therapeutic use haemophilia A haemophilia B Hemophilia Hemophilia A - complications Hemophilia A - drug therapy Hemophilia B - drug therapy Hemorrhage - complications Humans Laboratories Male Monoclonal antibodies Pharmacodynamics Pharmacokinetics Safety Thrombosis Thrombosis - complications Thrombosis - etiology Tissue factor tissue factor pathway inhibitor |
| title | Befovacimab, an anti‐tissue factor pathway inhibitor antibody: Early termination of the multiple‐dose, dose‐escalating Phase 2 study due to thrombosis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-16T17%3A22%3A18IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Befovacimab,%20an%20anti%E2%80%90tissue%20factor%20pathway%20inhibitor%20antibody:%20Early%20termination%20of%20the%20multiple%E2%80%90dose,%20dose%E2%80%90escalating%20Phase%202%20study%20due%20to%20thrombosis&rft.jtitle=Haemophilia%20:%20the%20official%20journal%20of%20the%20World%20Federation%20of%20Hemophilia&rft.au=Mancuso,%20Maria%20Elisa&rft.date=2022-09&rft.volume=28&rft.issue=5&rft.spage=702&rft.epage=712&rft.pages=702-712&rft.issn=1351-8216&rft.eissn=1365-2516&rft_id=info:doi/10.1111/hae.14595&rft_dat=%3Cproquest_cross%3E2712030538%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2712030538&rft_id=info:pmid/35667016&rfr_iscdi=true |