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
Authors: Dale David C. , Alsina Laia , Azar Antoine , Badolato Raffaele , Bhandari Ashish , Belschner Andrea , Bertrand Yves , Cadavid Diego , Dickerson Kathryn E. , Ezra Navid , Hasle Henrik , Hoffman Harold , Jiang Honghua , Kang Hyoung Jin , Kiani-Alikhan Sorena , Kuijpers Taco W. , Kulagin Aleksandr D. , Langguth Daman , Levin Carina , MacLeod Richard , Neth Olaf , Peake Jane , Rodina Yulia , Sharathkumar Anjali , Shcherbina Anna , Tang Weihua , Vossen Matthias G. , Donadieu Jean 
Published: November 2021

Abstract
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.
Methods: This phase 3 trial (4WHIM; NCT03995108) is a randomized, double-blind, placebo-controlled study with open-label extension (OLE) and planned enrollment of 18 to 28 patients from sites in Asia, Australia, Europe, Israel, and the United States. Patients aged ≥12 years with a confirmed CXCR4 mutation consistent with WHIM syndrome phenotype and a screening absolute neutrophil count (ANC) ≤400 cells/µL without clinical evidence of active systemic infection are eligible for enrollment. Patients are randomized 1:1 to receive mavorixafor (400 mg in adults, and adolescents weighing &gt;50 kg; 200 mg in adolescents weighing ≤50 kg) or matching placebo once daily for a total of 52 weeks (≥9 patients per group). Patients who complete the randomized period or are granted early release due to recurrent infections requiring treatment (≤2 requiring hospitalization or 4 requiring intravenous antibiotic or granulocyte colony-stimulating factor) are eligible to enroll in the OLE and receive mavorixafor until commercial availability or study termination. The primary end point is the number of hours above ANC threshold of 500 cells/µL over a 24-hour period, assessed prior to treatment, and 4 times (every 3 months) over the 52-week randomized period. Secondary end points include infection rates adjudicated by a blinded, independent committee, change from baseline in cutaneous warts also with blinded assessment, number of hours above absolute lymphocyte count (ALC) of 1000 cells/µL over a 24-hour period, and patient-reported outcomes such as work/school absence and quality of life assessment using age-appropriate questionnaires.
Patient Demographics and Characteristics: As of July 15 2021, the first 18 patients have enrolled from 10 countries and 15 sites. Of these, 56% are pediatric patients, 56% are males, 56% of the patients have warts, 94% have nonsense and 6% have frameshift CXCR4 mutations. All patients had severe neutropenia (ANC ≤400 cells/μL) and majority had significant lymphopenia (ALC ≤1000 cells/μL).
Conclusions: Evidence supporting efficacy of current therapies in WHIM syndrome is lacking, and approved therapies targeting the underlying molecular mechanisms and hence, able to address the full clinical spectrum of this condition, are needed. The 4WHIM study is the first double-blind, placebo-controlled, randomized trial in patients with this syndrome and is an important next step in the clinical development of a novel, orally bioavailable targeted therapy for WHIM syndrome and potentially for other individuals with related cellular immunodeficiencies. This robust study will build on the findings of the phase 2 trial that suggested a clinical benefit of mavorixafor for WHIM syndrome by incorporating a broader, global population of patients observed for a longer period of time. Full phase 3 trial results are anticipated in late 2022.

Disclosures
Dale: X4 Pharmaceuticals: Consultancy, Honoraria, Research Funding. Azar: X4 Pharmaceuticals: Research Funding. Badolato: Angelini: Consultancy; X4 Pharmaceuticals: Consultancy; Janssen: Consultancy; SOBI (IDMC): Other. Bhandari: X4 Pharmaceuticals: Current Employment. Belschner: X4 Pharmaceuticals: Current Employment. Cadavid: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Dickerson: Bluebird Bio: Membership on an entity's Board of Directors or advisory committees. Hoffman: Zomagen: Research Funding; Novartis: Consultancy, Speakers Bureau; Takeda: Research Funding; Jecure: Research Funding. Jiang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Kang: Cartexell: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kulagin: Roche: Speakers Bureau; Sanofi: Speakers Bureau; Generium: Speakers Bureau; Biocad: Research Funding; Apellis: Research Funding; Alexion: Research Funding; X4 Pharmaceuticals: Research Funding; Novartis: Speakers Bureau; Johnson & Johnson: Speakers Bureau; Pfizer: Speakers Bureau. Langguth: RCPA: Membership on an entity's Board of Directors or advisory committees. MacLeod: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Sharathkumar: Amgen: Research Funding; BMS: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; X4 Pharmaceuticals: Research Funding; NIH Trials of Pediatric VTE: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Shcherbina: X4 Pharmaceuticals: Speakers Bureau. Tang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Vossen: X4 Pharmaceuticals: Other: PI in WHIM Trial; Brothers of St. John: Consultancy; Austrian National Bank: Research Funding; Menarini: Honoraria; Gilead: Honoraria; Astro Pharma: Honoraria.