Trials in Progress: A Phase 3 Study to Investigate Efficacy, Safety, and Tolerability of Mavorixafor in Participants with Congenital and Acquired Primary Autoimmune and Idiopathic Chronic Neutropenic Disorders

Background and Significance

Chronic neutropenia (CN) is a rare primary immunodeficiency disorder characterized by an absolute neutrophil count (ANC) of <1500 cells/µL in peripheral blood that persists for at least 3 months and is related to idiopathic or congenital causes.^1,4 Infections are typical consequences of CN, most frequently impacting the oral cavity, nose, throat, lungs, ears, and skin.^{3, 5} These can progress to include premature tooth loss as a result of periodontitis, and recurrent and/or severe infections that may lead to hospitalizations related to pneumonia, cellulitis, abscesses, and sepsis.^3,5 Injectable granulocyte colony-stimulating factor (G-CSF) is currently standard of care for patients with severe CN (ANC <500 cells/µL ).^2,3 Mavorixafor is an oral therapy that can increase circulating ANC levels and has the potential to reduce the frequency, severity, and duration of infections in patients with CN. This pivotal study aims to evaluate the efficacy, safety, and tolerability of mavorixafor in participants with 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, acquired primary autoimmune, or idiopathic CN disorders, and trough ANC of <1500 cells/μL at screening and baseline. Participants are eligible for study inclusion regardless of their current background therapy regimen. All participants must be experiencing CN sequelae, specifically ≥2 recurrent and/or serious infections in the last 12 months requiring use of antibiotics and/or a visit to a healthcare facility. That is, participants entering the study are inadequately controlled and experiencing recurrent and/or serious infections despite use of their current treatment regimens. Participants on current CN therapy (e.g., G-CSF, immunoglobulin replacement therapy, prophylactic antibiotics, or “watchful waiting”) during the previous 12 months must be willing to maintain stable CN therapy regimens throughout the study. Approximately 40% of enrolled participants will continue to receive a stable dose of chronic G-CSF during the entire duration of the study. Exclusion criteria include 1) diagnosis of secondary neutropenia, aplastic anemia, WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome, CN associated with immune dysregulation, bone marrow failure, or isolated with cyclic presentation; 2) having ever received >1 dose of mavorixafor or another CXC chemokine receptor 4 antagonist in past 6 months; 3) using pegylated-G-CSF, except in congenital neutropenia.

Participants will be randomized 1:1 to placebo or mavorixafor, stratified by type of CN (congenital, acquired primary autoimmune, or idiopathic) and presence of background G-CSF 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 two-component primary endpoint comprises annualized infection rate and the proportion of ANC responders (≥ 1500 cells/μL or ≥2-fold increase from baseline if baseline < 500 cells/μL) in the mavorixafor group compared to placebo group. 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, a patient-reported outcome. Participants who, in the opinion of the investigator, do not require in-clinic assessment for a scheduled study visit will be offered the option of home health or telemedicine visits. All efforts will be made to ensure home health visits are conducted to the same standard as in-person study visits.

In conclusion, this randomized, double-blind, pivotal study aims to evaluate the efficacy, safety, and tolerability of mavorixafor in participants with CN experiencing recurrent and/or serious infections and will support the registration of mavorixafor for the treatment of congenital, acquired primary autoimmune, or idiopathic as a monotherapy and in combination with G-CSF.

EU CT: 2023-508482-32-00

1. Badolato R, et al. Blood. 2024;144(1):35-45.
2. Dale DC et al. Curr Opin Hematol. 2017;24(1):46-53.
3. Dale DC et al. Blood Adv. 2022:6(13):3861-3869.
4. Newburger PE et al. Semin Hematol. 2013;50(3):198-206.
5. Skokowa J et al. Nat Rev Dis Primers. 2018;3(1):17032.