Trial in progress: A pivotal Phase 3 study to investigate efficacy, safety, and tolerability of mavorixafor in participants with primary chronic neutropenia – trial update

Abstract Background Primary chronic neutropenia (CN) is a rare immunodeficiency disorder characterized by absolute neutrophil count (ANC) <1500 cells/µL in peripheral blood persisting for ≥3 months and associated with increased susceptibility to severe infections that can be life threatening. The current standard of care for severe CN (ANC <500 cells/µL), injectable granulocyte colony-stimulating factor (G-CSF), is associated with side effects including bone pain, splenomegaly, thrombocytopenia, glomerulonephritis, vasculitis, and osteoporosis.1-3Long-term treatment with G-CSF, especially at high doses, is correlated with increased risks of myelodysplastic syndromes and leukemia in congenital neutropenia patients.3,4 Treatment options for primary CN that provide the opportunity to limit or eliminate G-CSF use is a critical unmet medical need. Mavorixafor, an oral CXC chemokine receptor 4 (CXCR4) antagonist that can increase circulating ANC levels and has the potential to reduce infection frequency, severity, and duration in patients with CN, has received FDA Fast Track designation (May 2025) for primary CN. Mavorixafor is approved for the treatment of WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome. The successful Phase 3 study in WHIM syndrome and Phase 2 study in primary CN informed the development of the current study. This pivotal study aims to evaluate the efficacy, safety, and tolerability of mavorixafor in participants with primary CN experiencing recurrent and/or serious infections. Study Design and Methods The 52-week, Phase 3, randomized, double-blind, placebo-controlled, multicenter, global study will enroll up to 150 participants aged ≥12 years with congenital or acquired primary autoimmune or idiopathic CN and ANC <1000 cells/μL at screening and baseline. Participants must have had ≥2 recurrent and/or serious infections in the last 12 months requiring antibiotics and/or a health-care facility visit. Participants are eligible for study inclusion regardless of current background CN therapy regimen. Participants on current CN therapy (e.g., G-CSF, immunoglobulin replacement therapy, prophylactic antibiotics) must be willing to maintain stable therapy regimens throughout the study. Approximately 40% of participants are expected to be receiving chronic G-CSF. Exclusion criteria include (1) diagnosis of secondary neutropenia; aplastic anemia; WHIM syndrome; CN associated with immune dysregulation, bone marrow failure, or isolated with cyclic presentation; or neutropenia associated with Duffy-null phenotype, except with autosomal dominant CN pathogenic variant; (2) received >1 dose of mavorixafor ever or another CXCR4 antagonist in the past 6 months; (3) using pegylated G-CSF, except for congenital neutropenia. Participants will be randomized 1:1 to placebo or mavorixafor, stratified by CN type (congenital or acquired primary autoimmune and idiopathic) and use of G-CSF as background therapy. Participants will receive mavorixafor (400 mg if body weight is >50 kg or 300 mg if ≤50 kg) or placebo orally once daily for 52 weeks. The co-primary endpoints are annualized infection rate and the proportion of ANC responders (ANC increase >500 cells/µL from baseline). Key secondary endpoints include severity and duration of infections, incidence of antibiotic use, incidence of oral ulcers, and evaluation of quality of life using the PROMIS SF Fatigue Questionnaire. Participants will be offered the option of home health or telemedicine visits, as deemed medically appropriate by the investigator. This pivotal study, evaluating the efficacy, safety, and tolerability of mavorixafor in participants with CN experiencing recurrent and/or serious infections, is expected to support the registration of mavorixafor, alone or in combination with G-CSF, for the treatment of primary chronic neutropenia.This trial (NCT06056297), initiated in 2024, has close to 100 study centers activated and continues to enroll participants with 1 of 3 primary CN types (congenital, acquired idiopathic, and acquired autoimmune), including those who have been inadequately controlled (ANC <1000 cells/µL) while on a stable G-CSF regimen from baseline. Multiple sites are recruiting; many are accepting patient referrals. References Dale, et al. Curr Opin Hematol. Jan 2019;26(1):16-21. Donadieu, et al. Orphanet J Rare Dis. May 19 2011;6:26. Fioredda, et al. Hemasphere. Apr 2025;9(4):e70113. Parisi, et al. J Clin Pathol. Aug 16 2024;77(9):586-604.