Results of a phase 2 trial of an oral CXCR4 antagonist, mavorixafor, for treatment of WHIM syndrome

Abstract

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 once daily. 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 in absolute neutrophil count (ANC) and absolute lymphocyte count (ALC). At doses ≥300 mg/d, ANC was maintained at >500 cells per microliter for a median of 12.6 hours, and ALC was maintained at >1000 cells per microliter for up to 16.9 hours. Continued follow-up on the extension study resulted in a yearly infection rate that decreased from 4.63 events (95% confidence interval, 3.3-6.3) in the 12 months prior to the trial to 2.27 events (95% confidence interval, 1.4-3.5) 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 www.clinicaltrials.gov as #NCT03005327.

Conflict of interest statement

Conflict-of-interest disclosure: D.C.D. and F.F. received research funding for the trial from X4 Pharmaceuticals, Inc. D.C.D. serves on the advisory board for X4 Pharmaceuticals, Inc. T.E., V.G., W.T., H.J., R.S., and S.B.C. are employees in X4 Pharmaceuticals, Inc and may own equity in the company. K.J.G. is a consultant for X4 Pharmaceuticals, Inc and is affiliated with Zymo Consulting Group LLC. The remaining authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Schematic overview of mavorixafor in WHIM syndrome. (A) Gain of function mutations in the CXCR4 receptor. Heterozygous autosomal dominant gain-of-function CXCR4 mutations cause WHIM syndrome. Schematic diagram of the human CXCR4 receptor showing extracellular, transmembrane, and intracellular domains and known mutated C-terminal (COOH) residues reported to cause WHIM syndrome. CXCR4 mutations truncate the C terminus by premature termination (red) or frameshift (gray). A stop mutation and a single amino acid substitution that causes WHIM syndrome are reported in position 343 (red and blue). (B) Chemical structure of mavorixafor (X4P-001). (S)-N1-((1H-benzo[d]imidazol-2-yl)methyl)-N1-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine. (C) Study flowchart. Patient P5 discontinued early because of a psoriasiform rash. Patients P3 and P4 did not continue on the extension phase because of personal preference and trial fatigue. (D) Mean (+ standard error) plasma concentration vs time profile of mavorixafor by dose presented on a semilog scale. The horizontal dotted line represents the IC50 of mavorixafor for CXCR4 inhibition, corrected for total (bound and unbound) drug levels.

Figure 2.

Global hematological response to mavorixafor. (A) Mean dose response ANC-time profile. The ANC threshold (500 neutrophils per microliter) is indicated by the dashed line. (B) Mean dose response ALC-time profile. The ALC threshold (1000 cells per microliter) is indicated by the dashed line. (C) Increasing concentrations of mavorixafor result in an increase in the total WBC counts in patients with WHIM syndrome. Box plots show WBC change from baseline ratio at 4 hours for 300-mg and 400-mg once-daily mavorixafor. For box plots, the dashed line is the median; the solid line is the arithmetic mean; the lower and upper ends of the boxes are the 25th and 75th percentiles, respectively; the lower whiskers show the lowest data value still within 1.5 interquartile range (IQR) of the lower quartile, and the upper whiskers show the highest value still within 1.5 IQR of the upper quartile. (D) Box plots of AUCANC for mavorixafor doses up to 400 mg, once daily. Box plots show AUCANC >600 cells per microliter threshold over 24 hours. The dotted line represents a null net AUC relative to the ANC theshold of 600 neutrophils/μL. The values above the dotted line represents the net AUC result above this threshold of 600 neutrophils/μL. N, number of patients; QD, once daily.

Figure 4.

Dose-dependent hematologic improvement. Mavorixafor produces an initial peak elevation in WBC count, ALC, ANC, and AMC at ∼4 hours postdose. The ALC threshold of 1000 cells per microliter and the ANC threshold of 500 neutrophils per microliter are indicated by dashed lines.

Figure 3.

Correlation between the hematologic response and mavorixafor concentration. The correlation coefficient is represented by r. Subjects may contribute to 1 or more time points because of dose escalation and/or repeated sampling over time. (A) Correlation between TATANC and mavorixafor concentration. (B) Correlation between TATALC and mavorixafor concentration.

Figure 5.

Clinical response to treatment. (A) Reduction in the annualized infection rate upon treatment with mavorixafor, 300 mg and 400 mg once daily. Reduction in the annualized infection rate upon treatment with mavorixafor, 300 mg and 400 mg once daily, compared with the 12 months prior and to lower doses of mavorixafor (50 to 150 mg once daily). The retrospective yearly infection rate in the 12 months prior to the trial was calculated based on the safety population (n = 8). The yearly infection rate is derived from the sum of the number of infection events for each patient divided by the total exposure time (in years). (B) Reduction in the annualized infection rate over time upon treatment with mavorixafor in patients treated at 300 mg and/or 400 mg once daily. Yearly infection rates compared with the 12 months prior to the study. The retrospective yearly infection rate in the 12 months prior to the trial was calculated based on the patients treated up to ≥300 mg (n = 7). The yearly infection rate at each treatment period is derived from the sum of the number of infection events for each patient divided by the exposure time (in years) at each time period. (C-D) Significant reduction in the number of cutaneous warts during long-term once-daily mavorixafor treatment. Patient P6 was treated with increasing doses of mavorixafor alone for a total of 18 months (including 14 months at 400 mg once daily). The patient was not given imiquimod or other treatments for HPV. (C) Warts at baseline. (D) Warts 18 months later, after 14 months at 400 mg. A significant decrease in wart burden could be seen after 6 months on treatment.