Mavorixafor (Xolremdi®): A Comprehensive Monograph on a First-in-Class CXCR4 Antagonist for WHIM Syndrome and Beyond

1.0 Executive Summary

Mavorixafor, marketed as Xolremdi®, represents a landmark achievement in the field of precision medicine for rare immunological disorders. It is a first-in-class, orally administered, selective antagonist of the C-X-C chemokine receptor 4 (CXCR4). The drug's development and approval are founded on a sophisticated understanding of the pathophysiology of WHIM (Warts, Hypogammoglobulinemia, Infections, and Myelokathexis) syndrome, a rare primary immunodeficiency caused by gain-of-function mutations in the CXCR4 gene. By directly targeting the underlying genetic defect, Mavorixafor corrects the pathological retention of neutrophils and lymphocytes in the bone marrow, a mechanism that distinguishes it from previous supportive therapies.

The United States Food and Drug Administration (FDA) granted approval for Mavorixafor in April 2024 for the treatment of WHIM syndrome in patients aged 12 years and older. This decision was based on the robust and clinically meaningful results of the pivotal 4WHIM Phase 3 trial. The study unequivocally met its primary and key secondary endpoints, demonstrating a highly statistically significant increase in the time that absolute neutrophil counts (TATANC) and absolute lymphocyte counts (TATALC) were maintained above clinically relevant thresholds. More importantly, this hematologic correction translated into tangible clinical benefits, including a 60% reduction in the annualized infection rate and a 40% reduction in a composite score of infection severity and frequency compared to placebo.