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Clinical Trial
. 2024 Jul 4;144(1):35-45.
doi: 10.1182/blood.2023022658.

A phase 3 randomized trial of mavorixafor, a CXCR4 antagonist, for WHIM syndrome

Raffaele Badolato  1 , Laia Alsina  2   3   4 , Antoine Azar  5 , Yves Bertrand  6 , Audrey A Bolyard  7 , David Dale  7 , Àngela Deyà-Martínez  2   3   4 , Kathryn E Dickerson  8 , Navid Ezra  9 , Henrik Hasle  10 , Hyoung Jin Kang  11 , Sorena Kiani-Alikhan  12 , Taco W Kuijpers  13 , Alexander Kulagin  14 , Daman Langguth  15 , Carina Levin  16   17 , Olaf Neth  18 , Peter Olbrich  18   19 , Jane Peake  20 , Yulia Rodina  21 , Caroline E Rutten  22 , Anna Shcherbina  21 , Teresa K Tarrant  23 , Matthias G Vossen  24 , Christian A Wysocki  8 , Andrea Belschner  25 , Gary J Bridger  25 , Kelly Chen  25 , Susan Dubuc  25 , Yanping Hu  25 , Honghua Jiang  25 , Sunny Li  25 , Rick MacLeod  25 , Murray Stewart  25 , Arthur G Taveras  25 , Tina Yan  25 , Jean Donadieu  26
Affiliations
Clinical Trial

A phase 3 randomized trial of mavorixafor, a CXCR4 antagonist, for WHIM syndrome

Raffaele Badolato et al. Blood. .

Abstract

We investigated efficacy and safety of mavorixafor, an oral CXCR4 antagonist, in participants with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a rare immunodeficiency caused by CXCR4 gain-of-function variants. This randomized (1:1), double-blind, placebo-controlled, phase 3 trial enrolled participants aged ≥12 years with WHIM syndrome and absolute neutrophil count (ANC) ≤0.4 × 103/μL. Participants received once-daily mavorixafor or placebo for 52 weeks. The primary end point was time (hours) above ANC threshold ≥0.5 × 103/μL (TATANC; over 24 hours). Secondary end points included TAT absolute lymphocyte count ≥1.0 × 103/μL (TATALC; over 24 hours); absolute changes in white blood cell (WBC), ANC, and absolute lymphocyte count (ALC) from baseline; annualized infection rate; infection duration; and total infection score (combined infection number/severity). In 31 participants (mavorixafor, n = 14; placebo, n = 17), mavorixafor least squares (LS) mean TATANC was 15.0 hours and 2.8 hours for placebo (P < .001). Mavorixafor LS mean TATALC was 15.8 hours and 4.6 hours for placebo (P < .001). Annualized infection rates were 60% lower with mavorixafor vs placebo (LS mean 1.7 vs 4.2; nominal P = .007), and total infection scores were 40% lower (7.4 [95% confidence interval [CI], 1.6-13.2] vs 12.3 [95% CI, 7.2-17.3]). Treatment with mavorixafor reduced infection frequency, severity, duration, and antibiotic use. No discontinuations occurred due to treatment-emergent adverse events (TEAEs); no related serious TEAEs were observed. Overall, mavorixafor treatment demonstrated significant increases in LS mean TATANC and TATALC, reduced infection frequency, severity/duration, and was well tolerated. The trial was registered at www.clinicaltrials.gov as #NCT03995108.

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Conflict of interest statement

Conflict-of-interest disclosure: R.B. is a consultant for X4 Pharmaceuticals, Inc, Angelini Pharma, and Janssen. L.A. has received research funding (to Institu de Recerca Sant Joan de Déu) from CSL Behring, Pharming, and Grifols and is a speaker for Novartis, Sanofi, Roche, and UCB Pharmaceuticals. A.A. has received research funding/grants from X4 Pharmaceuticals, Inc, Grifols, and Argenx; and is a consultant for Grifols, Argenx, Takeda Pharmaceuticals, Adma Biologics, Inc, and Octapharma. A.A.B. has received research funding from X4 Pharmaceuticals, Inc, and the National Institutes of Health. D.D. has consulted, received research funding from, and received honoraria from X4 Pharmaceuticals, Inc. K.E.D. is on the advisory board of Agios. H.J.K. receives research funding from Amgen and is a member on the board of directors or advisory committees for Amgen, Novartis, GPCR Therapeutics, and Cartexell. A.K. has received research funding (to Pavlov University) from X4 Pharmaceuticals, Inc, Alexion, and Apellis and is a speaker for Novartis, Generium, Sobi, AstraZeneca, and Johnson & Johnson. D.L. is a board member for RCPA. C.L. receives research grants from Emek Center Pediatric Hematology University Hospital. J.P. is on the advisory board of Allergy & Anaphylaxis Australia, Food and Allergy Standards Australia and New Zealand, and National Blood Authority and is the director of the Australasian Society of Clinical Immunology and Allergy (QPIAS). A.S. is a speaker for Sobi, Novartis, and Octapharma. T.K.T. is a consultant for X4 Pharmaceuticals, Inc and also receives research funding from X4 Pharmaceuticals, Inc, AbbVie, Inc, Viela Bio, Horizon, and Chiesi. M.G.V. has received research funding outside the current work from Austrian National Bank, a grant from Pfizer, and honoraria from Gilead, Astro Pharma, and Menarini. J.D. is a consultant for X4 Pharmaceuticals, Inc. A.B., K.C., S.D., Y.H., H.J., S.L., R.M., T.Y., and A.G.T. are current employees and/or have equity ownership in X4 Pharmaceuticals, Inc. M.S. was employed by X4 Pharmaceuticals, Inc, at the time of this work, has equity ownership in X4 Pharmaceuticals, Inc, and is a member of the board of directors of X4 Pharmaceuticals, Inc. G.J.B. is a member of the board of directors of X4 Pharmaceuticals, Inc, and has stock options in the company. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
LS mean TATANC and TATALC. TATANC (A) and TATALC (B) vs time on treatment with mavorixafor vs placebo over 52 weeks (intent-to-treat [ITT] population). TATANC LS mean (95% CI) for mavorixafor vs placebo at weeks 13, 26, 39, and 52 were 18.6 hours (14.5-22.7) vs 2.8 (0-6.4), P < .001; 14.4 (9.7-19.0) vs 1.8 (0.0-5.5), P < .001; 14.2 (9.9-18.5) vs 0.8 (0.0-4.0), P < .001; and 13.0 (6.0-20.0) vs 5.6 (0.2-11.1), P = .10, respectively. TATALC LS mean (95% CI) for mavorixafor vs placebo at weeks 13, 26, 39, and 52 were 17.5 (14.1-20.8) vs 4.9 (1.9-7.8), P < .001; 14.9 (12.1-17.6) vs 3.4 (1.2-5.7), P < .001; 16.8 (13.2-20.4) vs 4.8 (2.1-7.5), P < .001; and 14.0 (8.9-19.2) vs 5.1 (1.1-9.2), P = .01, respectively. At week 52, 3 of 17 participants receiving placebo were given mavorixafor in advance of their week 52 assessments. One participant receiving mavorixafor did not take mavorixafor at week 52. Some samples collected were not measurable; 3 participants in the mavorixafor group discontinued mavorixafor treatment.
Figure 2.
Figure 2.
LS Mean ANC, ALC, AMC, and WBC counts from baseline (week 0) to 52 weeks (ITT population). (A) LS Mean ANC over post–dose dense sampling period. (B) LS Mean ALC over post–dose dense sampling period. (C) LS Mean AMC over post–dose dense sampling period. (D) LS Mean WBC counts over post–dose dense sampling period. All P values are nominal. At week 52, 3 of 17 participants receiving placebo were given mavorixafor in advance of their week 52 assessments as they entered the open-label portion of the trial. One participant receiving mavorixafor did not take mavorixafor at week 52. Some samples collected were not measurable; 3 participants in the mavorixafor group discontinued mavorixafor treatment.
Figure 3.
Figure 3.
Infection parameters (ITT population). (A) Total infection score (mean, 95% CI) by 3-month interval with mavorixafor vs placebo. (B) Annualized infection rate (mean, 95% CI) by 3-month interval with mavorixafor vs placebo. (C) Annualized infection rate (mean, 95% CI) with CTCAE grade ≥3 by 3-month interval with mavorixafor vs placebo. (D) Proportion of participants experiencing infection events. CTCAE, Common Terminology Criteria for Adverse Events.
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