A randomized, placebo-controlled trial of the BTK inhibitor zanubrutinib in hospitalized patients with COVID-19 respiratory distress: immune biomarker and clinical findings
BackgroundCytokine release triggered by a hyperactive immune response is thought to contribute to severe acute respiratory syndrome coronavirus 2019 (SARS-CoV-2)–related respiratory failure. Bruton tyrosine kinase (BTK) is involved in innate immunity, and BTK inhibitors block cytokine release. We as...
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2025-01-01
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| author | Steven P. Treon Camille N. Kotton David J. Park Giorgia Moranzoni Camilla K. Lemvigh Joseph C. Gathe Tilly A. Varughese Christopher F. Barnett Johnny M. Belenchia Nina M. Clark Charles M. Farber Muhammad Bilal Abid Gulrayz Ahmed Christopher J. Patterson Maria L. Guerrera Jacob D. Soumerai Vipheaviny A. Chea Isabel P. Carulli Jackson Southard Shuqiang Li Catherine J. Wu Kenneth J. Livak Eric Holmgren Pil Kim Carrie Shi Holly Lin Vanitha Ramakrishnan Ying Ou Scott Olszewski Lars Rønn Olsen Derin B. Keskin Derin B. Keskin Zachary R. Hunter Christopher Tankersley Todd Zimmerman Binod Dhakal |
| author_facet | Steven P. Treon Camille N. Kotton David J. Park Giorgia Moranzoni Camilla K. Lemvigh Joseph C. Gathe Tilly A. Varughese Christopher F. Barnett Johnny M. Belenchia Nina M. Clark Charles M. Farber Muhammad Bilal Abid Gulrayz Ahmed Christopher J. Patterson Maria L. Guerrera Jacob D. Soumerai Vipheaviny A. Chea Isabel P. Carulli Jackson Southard Shuqiang Li Catherine J. Wu Kenneth J. Livak Eric Holmgren Pil Kim Carrie Shi Holly Lin Vanitha Ramakrishnan Ying Ou Scott Olszewski Lars Rønn Olsen Derin B. Keskin Derin B. Keskin Zachary R. Hunter Christopher Tankersley Todd Zimmerman Binod Dhakal |
| author_sort | Steven P. Treon |
| collection | DOAJ |
| description | BackgroundCytokine release triggered by a hyperactive immune response is thought to contribute to severe acute respiratory syndrome coronavirus 2019 (SARS-CoV-2)–related respiratory failure. Bruton tyrosine kinase (BTK) is involved in innate immunity, and BTK inhibitors block cytokine release. We assessed the next-generation BTK inhibitor zanubrutinib in SARS-CoV-2–infected patients with respiratory distress.MethodCohort 1 had a prospective, randomized, double-blind, placebo-controlled design; cohort 2 had a single-arm design. Adults with SARS-CoV-2 requiring hospitalization (without mechanical ventilation) were randomized in cohort 1. Those on mechanical ventilation ≤24 hours were enrolled in cohort 2. Patients were randomized 1:1 to zanubrutinib 320 mg once daily or placebo (cohort 1), or received zanubrutinib 320 mg once daily (cohort 2). Co-primary endpoints were respiratory failure-free survival rate and time to return to breathing room air at 28 days. Corollary studies to assess zanubrutinib’s impact on immune response were performed.ResultsSixty-three patients in cohort 1 received zanubrutinib (n=30) or placebo (n=33), with median treatment duration of 8.5 and 7.0 days, respectively. The median treatment duration in cohort 2 (n=4) was 13 days; all discontinued treatment early. In cohort 1, respiratory failure-free survival and the estimated rates of not returning to breathing room air by day 28 were not significantly different between treatments. Importantly, serological response to coronavirus disease 2019 (COVID-19) was not impacted by zanubrutinib. Lower levels of granulocyte colony-stimulating factor, interleukin (IL)-10, monocyte chemoattractant protein-1, IL-4, and IL-13 were observed in zanubrutinib-treated patients. Moreover, single-cell transcriptome analysis showed significant downregulation of inflammatory mediators (IL-6, IL-8, macrophage colony-stimulating factor, macrophage inflammatory protein-1α, IL-1β) and signaling pathways (JAK1, STAT3, TYK2), and activation of gamma-delta T cells in zanubrutinib-treated patients.ConclusionsMarked reduction in inflammatory signaling with preserved SARS-CoV-2 serological response was observed in hospitalized patients with COVID-19 respiratory distress receiving zanubrutinib. Despite these immunological findings, zanubrutinib did not show improvement over placebo in clinical recovery from respiratory distress. Concurrent administration of steroids and antiviral therapy to most patients may have contributed to these results. Investigation of zanubrutinib may be warranted in other settings where cytokine release and immune cell exhaustion are important.Clinical Trial Registrationhttps://www.clinicaltrials.gov/study/NCT04382586, identifier NCT04382586. |
| format | Article |
| id | doaj-art-aae234f3ed27470684afd09f13ffcddf |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-aae234f3ed27470684afd09f13ffcddf2025-01-21T11:21:58ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011510.3389/fimmu.2024.13696191369619A randomized, placebo-controlled trial of the BTK inhibitor zanubrutinib in hospitalized patients with COVID-19 respiratory distress: immune biomarker and clinical findingsSteven P. Treon0Camille N. Kotton1David J. Park2Giorgia Moranzoni3Camilla K. Lemvigh4Joseph C. Gathe5Tilly A. Varughese6Christopher F. Barnett7Johnny M. Belenchia8Nina M. Clark9Charles M. Farber10Muhammad Bilal Abid11Gulrayz Ahmed12Christopher J. Patterson13Maria L. Guerrera14Jacob D. Soumerai15Vipheaviny A. Chea16Isabel P. Carulli17Jackson Southard18Shuqiang Li19Catherine J. Wu20Kenneth J. Livak21Eric Holmgren22Pil Kim23Carrie Shi24Holly Lin25Vanitha Ramakrishnan26Ying Ou27Scott Olszewski28Lars Rønn Olsen29Derin B. Keskin30Derin B. Keskin31Zachary R. Hunter32Christopher Tankersley33Todd Zimmerman34Binod Dhakal35Dana-Farber Cancer Institute, Boston, MA, United StatesMassachusetts General Hospital, Boston, MA, United StatesProvidence St. Jude Medical Center/Providence Medical Foundation, Fullerton, CA, United StatesDepartment of Health Technology, Technical University of Denmark, Kongens Lyngby, DenmarkDepartment of Health Technology, Technical University of Denmark, Kongens Lyngby, DenmarkTherapeutic Concepts, PA, Houston, TX, United StatesRutgers New Jersey Medical School, Newark, NJ, United StatesMedStar Washington Hospital Center, Washington, DC, United StatesArchbold Medical Center, Thomasville, GA, United StatesLoyola University Stritch School of Medicine, Chicago, IL, United States0Atlantic Health System, Morristown, NJ, United States1Medical College of Wisconsin, Milwaukee, WI, United States1Medical College of Wisconsin, Milwaukee, WI, United StatesDana-Farber Cancer Institute, Boston, MA, United StatesDana-Farber Cancer Institute, Boston, MA, United StatesMassachusetts General Hospital, Boston, MA, United StatesDana-Farber Cancer Institute, Boston, MA, United StatesDana-Farber Cancer Institute, Boston, MA, United StatesDana-Farber Cancer Institute, Boston, MA, United StatesDana-Farber Cancer Institute, Boston, MA, United StatesDana-Farber Cancer Institute, Boston, MA, United StatesDana-Farber Cancer Institute, Boston, MA, United States2BeiGene USA, Inc., San Mateo, CA, United States2BeiGene USA, Inc., San Mateo, CA, United States2BeiGene USA, Inc., San Mateo, CA, United States2BeiGene USA, Inc., San Mateo, CA, United States2BeiGene USA, Inc., San Mateo, CA, United States2BeiGene USA, Inc., San Mateo, CA, United States2BeiGene USA, Inc., San Mateo, CA, United StatesDepartment of Health Technology, Technical University of Denmark, Kongens Lyngby, DenmarkDana-Farber Cancer Institute, Boston, MA, United States3Harvard Medical School, Boston, MA, United StatesDana-Farber Cancer Institute, Boston, MA, United States2BeiGene USA, Inc., San Mateo, CA, United States2BeiGene USA, Inc., San Mateo, CA, United States4Medical College of Wisconsin, Wauwatosa, WI, United StatesBackgroundCytokine release triggered by a hyperactive immune response is thought to contribute to severe acute respiratory syndrome coronavirus 2019 (SARS-CoV-2)–related respiratory failure. Bruton tyrosine kinase (BTK) is involved in innate immunity, and BTK inhibitors block cytokine release. We assessed the next-generation BTK inhibitor zanubrutinib in SARS-CoV-2–infected patients with respiratory distress.MethodCohort 1 had a prospective, randomized, double-blind, placebo-controlled design; cohort 2 had a single-arm design. Adults with SARS-CoV-2 requiring hospitalization (without mechanical ventilation) were randomized in cohort 1. Those on mechanical ventilation ≤24 hours were enrolled in cohort 2. Patients were randomized 1:1 to zanubrutinib 320 mg once daily or placebo (cohort 1), or received zanubrutinib 320 mg once daily (cohort 2). Co-primary endpoints were respiratory failure-free survival rate and time to return to breathing room air at 28 days. Corollary studies to assess zanubrutinib’s impact on immune response were performed.ResultsSixty-three patients in cohort 1 received zanubrutinib (n=30) or placebo (n=33), with median treatment duration of 8.5 and 7.0 days, respectively. The median treatment duration in cohort 2 (n=4) was 13 days; all discontinued treatment early. In cohort 1, respiratory failure-free survival and the estimated rates of not returning to breathing room air by day 28 were not significantly different between treatments. Importantly, serological response to coronavirus disease 2019 (COVID-19) was not impacted by zanubrutinib. Lower levels of granulocyte colony-stimulating factor, interleukin (IL)-10, monocyte chemoattractant protein-1, IL-4, and IL-13 were observed in zanubrutinib-treated patients. Moreover, single-cell transcriptome analysis showed significant downregulation of inflammatory mediators (IL-6, IL-8, macrophage colony-stimulating factor, macrophage inflammatory protein-1α, IL-1β) and signaling pathways (JAK1, STAT3, TYK2), and activation of gamma-delta T cells in zanubrutinib-treated patients.ConclusionsMarked reduction in inflammatory signaling with preserved SARS-CoV-2 serological response was observed in hospitalized patients with COVID-19 respiratory distress receiving zanubrutinib. Despite these immunological findings, zanubrutinib did not show improvement over placebo in clinical recovery from respiratory distress. Concurrent administration of steroids and antiviral therapy to most patients may have contributed to these results. Investigation of zanubrutinib may be warranted in other settings where cytokine release and immune cell exhaustion are important.Clinical Trial Registrationhttps://www.clinicaltrials.gov/study/NCT04382586, identifier NCT04382586.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1369619/fullSARS-CoV-2BTKzanubrutinibinflammatory mediatorsserological responsesingle cell RNA analysis |
| spellingShingle | Steven P. Treon Camille N. Kotton David J. Park Giorgia Moranzoni Camilla K. Lemvigh Joseph C. Gathe Tilly A. Varughese Christopher F. Barnett Johnny M. Belenchia Nina M. Clark Charles M. Farber Muhammad Bilal Abid Gulrayz Ahmed Christopher J. Patterson Maria L. Guerrera Jacob D. Soumerai Vipheaviny A. Chea Isabel P. Carulli Jackson Southard Shuqiang Li Catherine J. Wu Kenneth J. Livak Eric Holmgren Pil Kim Carrie Shi Holly Lin Vanitha Ramakrishnan Ying Ou Scott Olszewski Lars Rønn Olsen Derin B. Keskin Derin B. Keskin Zachary R. Hunter Christopher Tankersley Todd Zimmerman Binod Dhakal A randomized, placebo-controlled trial of the BTK inhibitor zanubrutinib in hospitalized patients with COVID-19 respiratory distress: immune biomarker and clinical findings Frontiers in Immunology SARS-CoV-2 BTK zanubrutinib inflammatory mediators serological response single cell RNA analysis |
| title | A randomized, placebo-controlled trial of the BTK inhibitor zanubrutinib in hospitalized patients with COVID-19 respiratory distress: immune biomarker and clinical findings |
| title_full | A randomized, placebo-controlled trial of the BTK inhibitor zanubrutinib in hospitalized patients with COVID-19 respiratory distress: immune biomarker and clinical findings |
| title_fullStr | A randomized, placebo-controlled trial of the BTK inhibitor zanubrutinib in hospitalized patients with COVID-19 respiratory distress: immune biomarker and clinical findings |
| title_full_unstemmed | A randomized, placebo-controlled trial of the BTK inhibitor zanubrutinib in hospitalized patients with COVID-19 respiratory distress: immune biomarker and clinical findings |
| title_short | A randomized, placebo-controlled trial of the BTK inhibitor zanubrutinib in hospitalized patients with COVID-19 respiratory distress: immune biomarker and clinical findings |
| title_sort | randomized placebo controlled trial of the btk inhibitor zanubrutinib in hospitalized patients with covid 19 respiratory distress immune biomarker and clinical findings |
| topic | SARS-CoV-2 BTK zanubrutinib inflammatory mediators serological response single cell RNA analysis |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1369619/full |
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