Results of a Phase 2 Trial of an Oral CXCR4 Antagonist Mavorixafor for Treatment of WHIM Syndrome.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare primary immunodeficiency caused by gain-of-function mutations in the CXCR4 gene. We report the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of mavorixafor from a phase 2, open-label, dose-escalation and extension study in 8 adult patients with genetically confirmed WHIM syndrome. Mavorixafor is an oral, small molecule, selective antagonist of the CXCR4 receptor, that increases mobilization and trafficking of white blood cells from the bone marrow. Patients received escalating doses of mavorixafor up to 400 mg QD. Five patients continued on the extension study for up to 28.6 months. Mavorixafor was well tolerated with no treatment-related serious adverse events. At a median follow up of 16.5 months, we observed dose-dependent increases of absolute neutrophil counts (ANC) and absolute lymphocyte counts (ALC). At doses at or above 300 mg per day, ANC was maintained above 500 cells/μL for a median of 12.6 hours, and ALC above 1000 cells/μL for up to 16.9 hours. Continued follow-up on the extension study demonstrated a decreased yearly infection rate from 4.63 [95%CI 3.3,6.3] events in the 12 months prior to the trial to 2.27 [95%CI 1.4, 3.5] events for patients on effective doses. We observed an average 75% reduction in the number of cutaneous warts. This study demonstrates that mavorixafor 400 mg once-daily mobilizes neutrophil and lymphocytes in adult patients with WHIM syndrome and provides preliminary evidence of clinical benefit for patients on long-term therapy. The trial was registered at as # NCT03005327.

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