X4P-001: A Novel Molecularly-Targeted Oral Therapy for Whim Syndrome
Authors: Dale David , Bolyard Audrey Anna , Dick Emily , Kelley Merideth L. , Makaryan Vahagn , Johnson Ramsey , Gan Lu , Parasuraman Sudha 
Published: April 2021

Abstract
Background: WHIM syndrome (WHIMs; Warts, Hypogammaglobulinemia, Infections, Myelokathexis) is a rare autosomal dominant immunodeficiency disease attributable to mutations in CXCR4 . Most patients have severe neutropenia and lymphocytopenia with total white blood cell counts (WBC) &lt;1.0 x 109/L. In general, children have more frequent and more severe infections than adults. Adults are at risk of human papilloma virus (HPV)-associated malignancies. There are no treatments approved for WHIMs although immunoglobulin and G-CSF are used to treat clinical symptoms of the disease. CXCR4 antagonists are being evaluated as a treatment for patients with WHIMs.
Methods: We have begun the phase 2, dose-titration portion of a phase 2/3 study of a novel, orally bioavailable, selective, CXCR4 antagonist, X4P-001, in adult patients with genetically confirmed WHIMs to evaluate safety and tolerability of X4P-001 and determine the dose for a phase 3 study. All patients were required to be off chronic immunoglobulin and/or G-CSF treatment while on study. Patients receive increasing doses of X4P-001 ranging from 50 mg to 300 mg orally once daily with periodic monitoring of serial blood counts and intra-patient dose escalation is based on 24-hour serial area-under-the-curve (AUC) measurements of absolute neutrophil counts (ANC) and absolute lymphocyte counts (ALC) with prespecified thresholds.
Results: As of July 10, 2017, 4 patients (2 females, 2 males; age range 19 to 57 years; 3 with R334X and 1 with E343X mutation) have been enrolled. The study entry screening WBC was 0.775 x 109/L +/-0.16 (mean +/- SEM); ANC was 0.125 x 109/L +/- 0.027; and ALC was 0.588 x 109/L +/- 0.155. All patients had mild hypogammaglobulinemia; the mean levels were: Immunoglobulin G 766 +/- 130 (SEM), IgA 50 +/- 17, IgM 74 +/- 13. In the 6 months prior to study entry, these adult patients had up to 6 episodes of infections, primarily upper respiratory and skin infections.
Patients 1 and 2 have escalated through 50 mg/day and 100 mg/day to 150 mg/day over a total exposure period of 169 days. Patients 3 and 4 have escalated from 100 mg/day to 200 mg/day with an exposure period of 62 and 54 days, respectively. All patients have demonstrated a dose-dependent increase in ANC and ALC from screening values, with ALC increasing in greater proportion than ANC. At the 100 mg dose level, the pre-dose WBC was 1.24 x 109/L +/- 0.469 (mean +/- SEM) with peak levels of 2.8 x 109/L +/- 0.721 (increase=2.3 fold), the pre-dose ANC was 0.385 x 109/L +/- 0.178) with peak levels of 0.58 x 109/L +/- 0.202 (increase=1.5 fold) and pre-dose ALC was 0.728 x 109/L +/- 0.276 with peak levels of 2.143 x 109/L +/-0.513 (increase=2.9 fold). The increases in the pre-dose levels of both neutrophils and lymphocytes above the study entry screening values after 1-3 months on treatment suggest a continuing effect of daily exposure to this drug. However, the ANC and ALC responses thus far are below the targeted AUC for ANC and ALC, so dose escalation continues.
Thus far, X4P-001 has been well tolerated and the most common treatment-related adverse events are mild dyspepsia and dry eyes. Patients have not required antibiotic treatment for infections during the cumulative 15 months on X4P-001, except for Patient 1 who had an infection at the start of the study.
Conclusion: Preliminary data suggests X4P-001 is a promising oral agent for treating WHIM syndrome.

Disclosures
Dale: Sanofi Aventis: Consultancy, Editor, Current Opinions in Hematology, Honoraria; Cellerant: Membership on an entity's Board of Directors or advisory committees; Genzyme (now owned by Sanofi-Aventis): Consultancy, Patents & Royalties, Research Funding; Genkyotex: Other: DSMB (work completed 6/2015); Hospira: Consultancy; Prolong: Consultancy; Boheringer-Ingelheim: Consultancy; Coherus: Consultancy; Omeros: Other: DSMB; Shire: Other: Independent Review Board; X4Pharma: Research Funding; Philips: Research Funding; Wolter Kluwer: Other: Editor, Current Opinions in Hematology; WedMD/Medscape: Membership on an entity's Board of Directors or advisory committees; National Institutes of Health: Research Funding; University of Washington: Employment, Research Funding; American College of Physicians: Other: Editor and author; GlaxoSmithKline: Equity Ownership; Johnson&Johnson: Equity Ownership; Amgen: Consultancy, Research Funding. Johnson: X4 Pharmaceuticals: Employment. Gan: X4 Pharmaceuticals: Employment, Equity Ownership. Parasuraman: X4 Pharmaceuticals: Employment, Equity Ownership.