학술논문
Phase 3 randomized trial of mavorixafor, CXCR4 antagonist, in WHIM syndrome.
Document Type
Academic Journal
Author
Badolato R; University of Brescia & ASST Spedali Civili, Brescia, Italy.; Alsina L; Universitat de Barcelona, Spain.; Azar A; Johns Hopkins University, Baltimore, Maryland, United States.; Bertrand Y; Institute of Pediatric Hematology and Oncology, LYON, France.; Bolyard AA; University of Washington, Seattle, Washington, United States.; Dale DC; University of Washington School of Medicine, Seattle, Washington, United States.; Deyà-Martinez À; Hospital Sant Joan de Déu, Barcelona, Spain.; Dickerson KE; UT Southwestern Medical Center, Dallas, Texas, United States.; Ezra N; California Dermatology Institute, Thousand Oaks, California, United States.; Hasle H; Aarhus University Hospital, Aarhus, Denmark.; Kang HJ; Seoul National University College of Medicine, Seoul, Korea, Republic of.; Kiani-Alikhan S; Royal Free London NHS Foundation Trust, London, United Kingdom.; Kuijpers TW; Academic Medical Center (AMC), Amsterdam, Netherlands.; Kulagin A; Pavlov University, St. Petersburg, Russian Federation.; Langguth D; Sullivan Nicolaides Pathology Auchenflower, Wesley Medical Center, Queensland, Australia.; Levin C; Israel Institute of Technology, Israel.; Neth O; Ped Infectious Diseases and Immunodeficiency, Sevilla, Spain.; Olbrich P; Universidad de Sevilla, Spain.; Peake J; Queensland Children's Hospital, Queensland, Australia.; Rodina Y; Dmitry Rogachev National Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation.; Rutten CE; Amsterdam UMC, Amsterdam, Netherlands.; Shcherbina A; Dmitry Rogachev National Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation.; Tarrant TK; Division of Rheumatology and Immunology, Department of Medicine,, Durham, North Carolina, United States.; Vossen MG; Medical University of Vienna, Vienna, Austria.; Wysocki CA; UT Southwestern Medical Center, Dallas, Texas, United States.; Belschner A; X4 Pharmaceuticals, Inc., Boston, Massachusetts, United States.; Bridger GJ; X4 Pharmaceuticals, Inc., Boston, Massachusetts, United States.; Chen K; X4 Pharmaceuticals, Inc., Boston, Massachusetts, United States.; Dubuc S; X4 Pharmaceuticals, Inc., Boston, Massachusetts, United States.; Hu Y; X4 Pharmaceuticals, Inc., Boston, Massachusetts, United States.; Jiang H; X4 Pharmaceuticals, Inc., Boston, Massachusetts, United States.; Li S; X4 Pharmaceuticals, Inc., Boston, Massachusetts, United States.; MacLeod R; X4 Pharmaceuticals, Inc., Boston, Massachusetts, United States.; Stewart M; X4 Pharmaceuticals, Inc., Boston, Massachusetts, United States.; Taveras AG; X4 Pharmaceuticals, Inc., Boston, Massachusetts, United States.; Yan T; X4 Pharmaceuticals, Inc., Boston, Massachusetts, United States.; Donadieu J; Hopital Trousseau, Paris, France.
Source
Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE
Subject
Language
English
Abstract
We investigated efficacy and safety of mavorixafor, an oral CXCR4 antagonist for participants with Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome, a rare immunodeficiency caused by CXCR4 gain-of-function variants. This randomized (1:1), double-blind, placebo-controlled, phase 3 trial enrolled participants aged ≥12 years with WHIM syndrome and absolute neutrophil count (ANC) ≤400/μL. Participants received once-daily mavorixafor or placebo for 52 weeks. Primary endpoint was time (hours) above ANC threshold ≥500/μL (TATANC; over 24 hours). Secondary endpoints included TAT absolute lymphocyte count ≥1000/μL (TATALC; defined similar to TATANC); absolute changes in white blood cell (WBC), ANC, and ALC from baseline; annualized infection rate; infection duration and total infection score (combined infection number/severity). In 31 participants (mavorixafor, n=14; placebo, n=17), mavorixafor least squares (LS) mean TATANC was 15.0 hours, placebo 2.8 hours (P<0.001). Mavorixafor LS mean TATALC was 15.8 hours, placebo 4.6 hours (P<0.001). Higher absolute WBC, ANC, and ALC levels were seen with mavorixafor than placebo at each timepoint assessed. Annualized infection rates were 60% lower with mavorixafor versus placebo (LS mean 1.7 versus 4.2; nominal P=0.007) and total infection scores were 40% lower (7.4 [95% CI, 1.6-13.2] versus 12.3 [95% CI, 7.2-17.3]). Treatment with mavorixafor reduced infection frequency, severity, duration, and antibiotic use. No discontinuations occurred due to treatment-emergent adverse events (TEAEs); no related serious TEAEs were observed. Overall, mavorixafor-treated participants showed significant increases in LS mean TATANC and TATALC, reduced infection frequency, severity/duration. Mavorixafor was well tolerated in participants with WHIM syndrome. Trial was registered at ClinicalTrials.gov NCT03995108.
(Copyright © 2024 American Society of Hematology.)
(Copyright © 2024 American Society of Hematology.)