Long-term treatment with once-daily oral mavorixafor, an inhibitor of CXCR4, reduced the number of cutaneous warts and infections and effectively increased neutrophil and lymphocyte levels in patients with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, according to results of a small phase II study published in Blood.
WHIM syndrome is a rare, severely debilitating primary immunodeficiency caused by C-terminal autosomal dominant gain-of-function mutations in the CXCR4 gene, which encodes a factor regulating trafficking of white blood cells between bone marrow and blood compartments. In addition to the clinical manifestations mentioned in the disease name acronym, WHIM syndrome is associated with severe neutropenia, profound lymphopenia, and monocytopenia. Mavorixafor is an small-molecule, selective antagonist of the CXCR4 receptor designed to increase the mobilization and trafficking of white blood cells in patients with WHIM syndrome.
In this phase II study, researchers led by David Dale, MD, of the University of Washington, evaluated the safety and preliminary efficacy of mavorixafor in 8 adult patients with WHIM syndrome with an absolute neutrophil count (ANC) ≤400/μL, absolute lymphocyte count (ALC) ≤650/μL, or both.
Mavorixafor was administered in escalating doses from 50 mg to 400 mg once daily. Doses were escalated if participants’ area under the curve (AUC) over 24 hours for absolute neutrophil count (ANC) was <2,000 or AUC for absolute lymphocyte count (ALC) was <5,000 cell/hour/μL. Five patients who completed ≥25 weeks of the initial escalation period continued on to the extension study for up to 28.6 months.
Participants’ mean age was 33 years. All patients had cytopenias as well as at least two characteristic manifestations of WHIM syndrome (including warts, hypogammaglobulinemia, or infections that required antibiotic therapy) within the past year.
Treatment with mavorixafor lasted for a median of 16.5 months (mean = 15.4 months; range = 6 days to 28.6 months). The long-term extension study lasted for a median of 19.6 months (mean = 21.2 months; range = 16.3-28.6 months).
At 16.5 months, the investigators observed dose-dependent increases of ANC and ALC. Mavorixafor doses ≥300 mg per day maintained ANC levels >500 cells/μL for a median of 12.6 hours and ALC levels >1,000 cells/μL for up to 16.9 hours.
All but 1 patient experienced a treatment-emergent adverse event (TEAE). Most TEAEs were grade 1 in severity, and included nausea, nasal dryness, dry mouth, and dyspepsia. Infections were the most common TEAEs but were considered unrelated to the study drug and reported as outcomes as part of an exploratory endpoint. The authors added that the frequency of TEAEs did not increase stepwise with increasing doses and no serious AEs were reported.
Treatment duration at effective doses correlated with reduction in yearly infection rate, the investigators noted. In the extension study, the yearly infection rate prior to study start was 4.63 events, which was comparable to the number of annual events in the 7 patients treated at doses up to 300 mg (n=5 events) and the 4 patients treated with subtherapeutic doses (n=4.53 events). However, the yearly infection rates in patients who received mavorixafor at daily doses of 300 mg and 400 mg were considerably lower, at 2.41 and 2.14 events per year, respectively.
Longer time on treatment also was associated with a lower rate of infections. In the first 6 months, the rate was 3.14, but dropped to 2.0 at 6 months, and to 0.8 for patients treated longer than 12 months, “providing preliminary evidence of the importance of long-term treatment to prevent infections and their related morbidity in WHIM syndrome,” the researchers wrote.
The 4 patients who had warts at study start experienced a “gradual but marked disappearance” of lesions, with an average 75% reduction after 5 to 18 months without adjunctive treatment.
“These data highlight that mavorixafor provides improved and durable clinical efficacy compared with current therapeutic options for WHIM syndrome,” the researchers concluded. “The favorable tolerability profile is highlighted by the high compliance to treatment and by the fact that 5 of the 8 patients enrolled remain on the long-term extension.”
Limitations of this study included the small sample size (although WHIM syndrome is very rare), as well as the lack of a comparator control or placebo group.
Study authors report relationships with X4 Pharmaceuticals, which sponsored this trial.
Dale DC, Firkin FC, Bolyard AA, et al. Results of a phase 2 trial of an oral CXCR4 antagonist mavorixafor for treatment of WHIM syndrome. Blood. 2020 August 31. [Epub ahead of print]