Results of a Phase 3 Trial of an Oral CXCR4 Antagonist, Mavorixafor, for Treatment of Patients With WHIM Syndrome

Abstract

BackgroundWarts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome is a rare, combined immunodeficiency presenting with leukopenia and infections, predominately caused by gain-of-function variants in CXCR4. Mavorixafor, an investigational oral CXCR4 antagonist, demonstrated promising efficacy and safety profiles in a phase 2 trial for participants with WHIM syndrome. ObjectiveTo report results of the randomized, double-blind, multicenter, placebo-controlled period of a phase 3 study evaluating the efficacy and safety of mavorixafor in participants with WHIM syndrome (NCT03995108). MethodsParticipants aged ≥12 years with clinical diagnosis of WHIM syndrome, confirmed CXCR4 variant, and absolute neutrophil count (ANC) or total white blood cell (WBC) count ≤400 cells/µL at screening were eligible. Participants were randomized 1:1 to receive mavorixafor (>50 kg, 400 mg once daily [QD]; ≤50 kg, 200 mg QD) or placebo for 52 weeks. The primary endpoint was time above threshold ANC (TAT-ANC). Figure 1 shows study design and select secondary endpoints. ResultsOverall, 31 participants were randomized (mavorixafor, n = 14; placebo, n = 17) and received ≥1 dose of treatment (intent-to-treat population). The primary endpoint, mean TAT-ANC, was 15.04 (mavorixafor-group) vs 2.75 hours (placebo-group; P <.0001). Additionally, mean TAT absolute lymphocyte count (TAT-ALC) was 15.80 (mavorixafor-group) vs 4.55 hours (placebo-group; P < .0001). Mean absolute WBC count, ANC, and ALC increased from baseline into normal range and sustained at each timepoint assessed over 52 weeks with mavorixafor versus placebo. Compared with placebo-group, mavorixafor-group showed 60% lower annualized infection rate (least squares [LS] mean: mavorixafor, 1.7; placebo, 4.2; nominal P = .0072), and 40% lower total infection score, a combination of infection number and severity (LS mean [95% CI]: mavorixafor, 7.41 [1.64–13.19]; placebo, 12.27 [7.24–17.30]). Greater reduction in infection duration and type and antibiotic use was observed with mavorixafor versus placebo.No discontinuations occurred due to adverse events (AEs). No treatment-related serious AEs or treatment-limiting toxicities were observed (Table 1). [Display omitted] Table 1Overall summary of AEs from the randomized, placebo-controlled periodParticipants, n (%)abcdMavorixafor (n = 14)Placebo (n = 17)Total (n = 31)Any TEAEe14 (100.0)17 (100.0)31 (100.0)Treatment-related TEAEe7 (50.0)3 (17.6)10 (32.3)Any SAE5 (35.7)2 (11.8)7 (22.6)Treatment-related SAE0 (0)0 (0)0 (0)TEAE leading to treatment discontinuatione,f0 (0)0 (0)0 (0)Treatment-limiting toxicity0 (0)0 (0)0 (0)AE, adverse event; SAE, serious adverse event; TEAE, treatment-emergent adverse event.Data cutoff November 11, 2022.aSafety was evaluated in the safety population, defined as all participants who received ≥1 dose of study medication (either mavorixafor or placebo). Participants were analyzed according to the treatment they actually received.bPercentages were based on the number of participants in each analysis group.cAll AEs were coded using Medical Dictionary for Regulatory Activities Version 25.0.dIf a participant had ≥2 AEs, the participant is counted only once in a category for the n. The same participant may appear in different categories.eTEAEs were defined as any AEs that begin or worsen on or after the start of study drug through 10 days after the last dose of study drug.fOne participant had a TEAE that emerged during the randomized, placebo-controlled period but leading to treatment discontinuation after entering the open-label period. ConclusionsPrimary and first key secondary endpoints were met. Mavorixafor-group showed significantly higher mean TAT-ANC and TATALC and greater reduction in infection frequency, severity, and duration versus placebo-group. Mavorixafor was generally well tolerated over the 52-week treatment period. About 87% of eligible participants enrolled in the open-label extension.