A phase 3 randomized trial of mavorixafor, a CXCR4 antagonist, for WHIM syndrome
Por:
Badolato R, Alsina L, Azar A, Bertrand Y, Bolyard AA, Dale DC, Deyà-Martinez A, Dickerson KE, Ezra N, Hasle H, Kang HJ, Kiani-Alikhan S, Kuijpers TW, Kulagin A, Langguth D, Levin C, Neth O, Olbrich P, Peake J, Rodina Y, Rutten CE, Shcherbina A, Tarrant TK, Vossen MG, Wysocki CA, Belschner A, Bridger GJ, Chen K, Dubuc S, Hu Y, Jiang H, Li S, MacLeod R, Stewart M, Taveras AG, Yan T and Donadieu J
Publicada:
4 jul 2024
Ahead of Print:
1 jul 2024
Resumen:
We investigated efficacy and safety of mavorixafor, an oral CXCR4 antagonist, in 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) <= 0.4 x 10(3)/mu L. Participants received once-daily mavorixafor or placebo for 52 weeks. The primary end point was time (hours) above ANC threshold >= 0.5 x 10(3)/mu L (TAT(ANC); over 24 hours). Secondary end points included TAT absolute lymphocyte count >= 1.0 x 10(3)/mu L (TAT(ALC); over 24 hours); absolute changes in white blood cell (WBC), ANC, and absolute lymphocyte count (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 TAT(ANC) was 15.0 hours and 2.8 hours for placebo (P < .001). Mavorixafor LS mean TAT(ALC) was 15.8 hours and 4.6 hours for placebo (P < .001). Annualized infection rates were 60% lower with mavorixafor vs placebo (LS mean 1.7 vs 4.2; nominal P = .007), and total infection scores were 40% lower (7.4 [95% confidence interval [CI], 1.6-13.2] vs 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 treatment demonstrated significant increases in LS mean TAT(ANC) and TAT(ALC), reduced infection frequency, severity/duration, and was well tolerated. The trial was registered at www.clinicaltrials.gov as #NCT03995108.
Filiaciones:
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 A:
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
Univ Brescia, Dept Clin & Expt Sci, Brescia, Italy
ASST Spedali Civili, Brescia, Italy
Hosp St Joan de Deu, Pediat Allergy & Clin Immunol Dept, Clin Immunol &
Primary Immunodeficiencies Unit, Barcelona, Spain
Univ Barcelona, Dept Surg & Surg Specializat, Fac Med Ciencies & Salut,
Barcelona, Spain
Inst Recerca St Joan de Deu, Barcelona, Spain
Johns Hopkins Univ, Div Allergy & Clin Immunol, Baltimore, MD USA
Hosp Civils Lyon, Pediat Hematol & Oncol Inst, Lyon, France
Claude Bernard Univ, Lyon, France
Univ Washington, Med Ctr, Seattle, WA USA
Univ Texas Southwestern Med Ctr, Dallas, TX USA
Calif Dermatol Inst, Thousand Oaks, CA USA
Aarhus Univ Hosp, Dept Paediat, Aarhus, Denmark
Seoul Natl Univ, Canc Res Inst, Childrens Hosp, Dept Pediat,Coll Med,
Seoul, South Korea
Royal Free London NHS Fdn Trust, Dept Immunol, London, England
Univ Amsterdam, Emma Childrens Hosp, Dept Pediat Immunol Rheumatol &
Infect Dis, Med Ctr, Amsterdam, Netherlands
Pavlov Univ, RM Gorbacheva Res Inst, St Petersburg, Russia
Wesley Med Ctr, Immunol Dept, Sullivan Nicolaides Pathol Auchenflower,
Auchenflower, Qld, Australia
Emek Med Ctr, Pediat Hematol Unit, Afula, Israel
Israel Inst Technol, Ruth & Bruce Rappaport Fac Med, Technion, Haifa,
Israel
IBiS Univ Sevilla CSIC, Hosp Univ Virgen del Rocio, Paediat Infect Dis
Rheumatol & Immunol Unit, Inst Biomed Sevilla,Red Invest Translac
Infectol P, Seville, Spain
Univ Seville, Fac Med, Departmento Pediat, Seville, Spain
Queensland Childrens Hosp, South Brisbane, Qld, Australia
Dmitry Rogachev Natl Med Res Ctr Pediat Hematol On, Moscow, Russia
Univ Amsterdam, Med Ctr, Dept Hematol, Amsterdam, Netherlands
Duke Univ, Dept Med, Div Rheumatol & Immunol, Durham, NC USA
Med Univ Vienna, Dept Internal Med 1, Div Infect Dis & Trop Med, Vienna,
Austria
X4 Pharmaceut, Boston, MA USA
Sorbonne Univ, Hop Enfants Armand Trousseau, Assistance Publ Hop Paris,
Ctr Reference Neutropenies Chron, Paris, France
Green Submitted, hybrid
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