Clinical Response Among Participants with Warts in the Phase 3 Trial, Mavorixafor, an Oral CXCR4 Antagonist, for Treatment of Patients with WHIM Syndrome

Background Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a rare, combined primary immunodeficiency disorder caused by hyperactive CXCR4 signaling, leads to impaired leukocyte egress from bone marrow into peripheral blood. Among the variable multisystem manifestations, individuals are highly susceptible to recalcitrant warts. Plerixafor, an injectable CXCR4 antagonist, has shown improvement in warts in WHIM syndrome; however, the question remains whether CXCR4 antagonism shows a wart benefit in this population. Mavorixafor, an orally available reversible CXCR4 antagonist, demonstrated clinical efficacy in participants with WHIM syndrome in the 4WHIM phase 3 trial (NCT03995108). Here, we report the positive wart effect from chronic oral mavorixafor treatment in this post hoc analysis of participants enrolled in the study. Methods 4WHIM included a 52-week randomized, double-blind, placebo-controlled period (RCP) with an ongoing open-label mavorixafor-only extension (OLE); participants were aged ≥12 years with WHIM syndrome ± history of baseline warts. Local dermatologists reviewed 23 wart regions, and adjudicators reviewed 3 target wart regions. Wart assessments included Clinical Global Impression of Severity (CGI-S; 1 = no warts to 5 = very severe warts) and Clinical Global Impression of Change (CGI-C; +1 = worsening to -2 = complete resolution) scores (Figure); only CGI-S was used for this analysis. Change from baseline to week 52 (end of RCP) and to the end of the OLE year 1 (week 104) were analyzed. Figure. Clinical assessment tools and response definitions. Results Fifteen participants completed 2 years of the trial and had 70 defined wart areas, which were followed for 2 years. Despite a history of warts, no participants in the mavorixafor group had worsening warts during the RCP compared with 2/9 (22.2%) participants in the placebo group. After 2 years of mavorixafor treatment, 4 (66.7%) participants showed improvement and 2 (33.3%) achieved complete remission. Of participants in the RCP placebo group who transitioned to mavorixafor in the OLE, 3 (33.3%) had improvement and 2 (22.2%) experienced complete remission during RCP, whereas 6 (75.0%) participants showed improvement and 4 (50.0%) experienced complete remission during OLE. Conclusions Two-year treatment with chronic oral mavorixafor was associated with marked clinical improvement in wart severity, providing further evidence that CXCR4 antagonism leads to wart improvement in patients with WHIM syndrome.