Dr Warren on the Goal of the 4WARD Trial Evaluating Mavorixafor in Chronic Neutropenia

[The 4WARD trial aims] to really be able to answer the question about [the] efficacy of mavorixafor in [patients with] chronic neutropenia, especially the ability to positively impact infection rates.

Julia T. Warren, MD, PhD, an assistant professor of pediatrics (hematology) at the Perelman School of Medicine at the University of Pennsylvania, a hematologist in the Division of Hematology and member of the Comprehensive Bone Marrow Failure Center at Children’s Hospital of Philadelphia, and a faculty member of the Institute for Regenerative Medicine at the University of Pennsylvania, discussed the goals and eligibility criteria of the pivotal phase 3 4WARD trial (NCT06056297) evaluating the oral CXCR4 antagonist mavorixafor (Xolremdi) in patients with chronic neutropenia, and how the study is designed to assess the agent’s effect on infection rates and absolute neutrophil count (ANC).

Mavorixafor is currently FDA approved for the treatment of patients 12 years of age and older with WHIM syndrome (warts, hypogammaglobulinemia, infections and myelokathexis) to increase the number of circulating mature neutrophils and lymphocytes. The agent is also being evaluated in the management of chronic neutropenia, and data from an open-label phase 1b/2 trial (NCT04154488) showed that mavorixafor monotherapy (n = 10) produced durable mean increases in ANC, and all patients with congenital neutropenia in the granulocyte colony-stimulating factor (G-CSF) combination arm (n = 13) reduced their G-CSF dose while maintaining a normal mean ANC.

The randomized, double-blind, placebo-controlled 4WARD trial is designed to determine whether mavorixafor is efficacious in chronic neutropenia, particularly with respect to its ability to reduce infections, Warren explained. Eligible patients need to have a chronic neutropenia diagnosis, which includes germline genetic causes of congenital neutropenia as well as diagnoses such as chronic idiopathic neutropenia, Warren noted, adding that patients with cyclic neutropenia are excluded. Among the key inclusion criteria, patients must have had at least 2 infections attributable to their neutropenia within the prior 12 months, according to Warren. Enrolled patients are receiving once-daily oral mavorixafor or placebo, with or without stable doses of G-CSF, for 52 weeks. The primary end points are annualized infection rate and positive ANC response.

The trial also aims to characterize what happens to ANC over a longer period, Warren added. Earlier phase 1, phase 1b, and phase 2 studies began to address that question over shorter time frames, but 4WARD will evaluate ANC across a full 12 months of treatment, she said. Because that is one of the central questions being asked, patients must enter the study with an ANC below 1000 cells/μL to determine whether mavorixafor can have a significant impact over time, Warren concluded.