Global Phase 3, Randomized, Placebo-Controlled Trial with Open-Label Extension Evaluating the Oral CXCR4 Antagonist Mavorixafor in Patients with WHIM Syndrome (4WHIM): Trial Design and Enrollment

Background: WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome is a rare primary immunodeficiency associated with broad cytopenia, including neutropenia. It is caused by gain-of-function mutations in C XCR4, leading to dysregulated immune cell trafficking with retention of neutrophils, lymphocytes, and monocytes in the bone marrow and in some cases, hypogammaglobulinemia. As a result, patients with WHIM syndrome have recurrent bacterial and viral infections, and unusual susceptibility to human papillomavirus infection predisposing individuals to recalcitrant warts and malignancy (McDermott D, et al. Immunol Rev. 2019;91-102). Therapeutic options are limited and do not address the underlying pathogenic mechanism of WHIM syndrome. The investigational oral CXCR4 antagonist mavorixafor directly targets the underlying cause of disease and has been shown to increase absolute neutrophil, lymphocyte, and monocyte counts, and to decrease annualized infection rate, and reduce cutaneous wart burden in a phase 2 trial of adults with WHIM syndrome (NCT03005327; Dale D, et al. Blood. 2020;136: 2994-3003). Findings from an ongoing long-term extension of this study support a sustained clinical benefit of long-term mavorixafor treatment in patients with WHIM syndrome. Here, we describe the design of a global phase 3 registrational trial evaluating the safety and efficacy of mavorixafor in WHIM syndrome in participants aged ≥12 years while reporting on preliminary baseline characteristics of the enrolled population.