X4 Pharmaceuticals Initiates Phase 1b Clinical Trial of Mavorixafor in Combination with Ibrutinib for the Treatment of Waldenström’s Macroglobulinemia (WM)
– Trial to assess safety and tolerability of mavorixafor in combination with ibrutinib in WM patients with MYD88/CXCR4 double mutation associated with treatment resistance –
“There is a significant unmet medical need for patients living with WM who have CXCR4 mutations. The development of a therapeutic CXCR4 antagonist such as mavorixafor represents a very important advance for targeted therapy of this disease,” said
“The CXCR4 mutation, which is present in approximately 30 to 40 percent of patients with WM, is known to play an important role in treatment resistance, and is associated with higher rates of disease burden, making the CXCR4 pathway a critical therapeutic target for patients with WM,” said
The Phase 1b multi-center, open-label, dose-escalation, clinical trial is designed to assess the safety and tolerability of mavorixafor in combination with ibrutinib in patients with WM who have acquired a “gain of function” mutation in CXCR4 in addition to the MYD88 mutation, which is a hallmark of WM diagnosis.1 In addition, the trial is designed to measure changes in serum immunoglobulin M (IgM) and hemoglobin (Hgb) from baseline, both biomarkers are key elements of clinical response in WM patients.2,3 The clinical trial is expected to enroll approximately 12-18 patients.
“Having established proof of concept for mavorixafor in WHIM patients, we believe that there is a compelling case to evaluate mavorixafor’s same mechanism of action in WM patients who have acquired gain-of-function mutations in the CXCR4 receptor, which is known to result in treatment-resistant cancer,” said
This trial is being conducted as part of a collaboration with
About Waldenström’s Macroglobulinemia (WM)
Waldenström’s macroglobulinemia is a rare form of non-Hodgkin’s lymphoma in which abnormal white blood cells produce an excess of monoclonal immunoglobulin M (IgM) which can result in symptoms of anemia, hyper viscosity, neuropathy or other complications. Recent advancements in whole-genome sequencing have enabled the characterization of genetic mutations in the disease. WM is the result of a somatic mutation in the MYD88 gene, which is present in 90% of patients, with a subset of these patients having an additional mutation in the CXCR4 gene.4,5 Mutations of the CXCR4 gene in WM patients are associated with active tumor cells and possible drug resistance to Burton tyrosine kinase (BTK) inhibitors, such as ibrutinib,6 significantly longer median time to major response and substantially shorter median progression free survival.7
X4 Pharmaceuticals’ lead product candidate, mavorixafor (X4P-001), is a potential first-in-class, once-daily, oral inhibitor of CXCR4, currently in a Phase 3 clinical trial for the treatment of WHIM syndrome, a rare, inherited, primary immunodeficiency disease caused by genetic mutations in the CXCR4 receptor gene. Mavorixafor has demonstrated proof-of-concept in WHIM syndrome in a Phase 2 clinical trial, including clinically meaningful increases in neutrophil and lymphocyte biomarker counts, as well as a trend of reduction in infection rates and wart burden, and a favorable safety profile. Mavorixafor was recently granted Breakthrough Therapy Designation by the
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. These statements may be identified by the words “may,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “estimate,” “predict,” “project,” “potential,” “continue,” “target” or other similar terms or expressions that concern X4's expectations, strategy, plans or intentions. Forward-looking statements include, without limitation, statements regarding the clinical development of mavorixafor, WM or X4's other product candidates or programs. These statements are subject to various risks and uncertainties including, without limitation, the risk that trials and studies may be delayed and may not have satisfactory outcomes, potential adverse effects arising from the testing or use of mavorixafor or other product candidates, and the risk that costs required to develop product candidates or to expand X4’s operations will be higher than anticipated. Any forward-looking statements in this press release are based on management's current expectations and beliefs. Actual events or results may differ materially from those expressed or implied by any forward-looking statements contained herein, including, without limitation, the risks and uncertainties described in the section entitled “Risk Factors” in X4’s most recent Annual Report on Form 10-K filed with the
1 Hunter ZR, Yang G, Xu L, et al. Genomics, Signaling, and Treatment of Waldenström Macroglobulinemia. J Clin Oncol. 2017;35(9):994-1001.
2 Response Assessment in Waldenström Macroglobulinemia: Update from the
3 Blood Cancer J. 2018 Apr; 8(4): 40. Published online 2018
5 Garlapow M. Hematology Advisor. Subtype of CXCR4 Mutation Correlated With Inferior Response to Ibrutinib in Waldenström Macroglobulinemia. 2019 July 30. https://www.hematologyadvisor.com/home/topics/lymphoma/cxcr4-nonsense-mutation-associated-with-decreased-progression-free-survival-after-ibrutinib-treatment/.
6 Cao Y, Hunter Z, Liu X, et al. The WHIM-like CXCR4(S338X) somatic mutation activates AKT and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom’s Macroglobulinemia. Leukemia. 2015;29(1):169-76.
7 Treon et al, EHA 2018.
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