Mavorixafor in Waldenstrom Macroglobulinemia
X4 is developing mavorixafor as an oral, once-daily treatment for patients with Waldenstrom macroglobulinemia (WM). WM is a rare blood cancer and a type of B-cell non-Hodgkin’s lymphoma characterized by the accumulation of malignant B-cells in the bone marrow, leading to the overproduction of immunoglobulin (Ig) M. Typical WM symptoms include increased blood viscosity due to high IgM levels, brushing or skin lesions, anemia and enlarged lymph nodes and spleen. WM has approximately an 8-year survival rate post-diagnosis.
About 90% of WM patients present with mutations in the MYD88 gene, while 30-40% of patients present with additional mutations in the CXCR4 gene, leading to overstimulation of the CXCR4 pathway. Aberrant CXCR4 expression on cancerous B-cells contributes to sequestration of malignant B-cells in the bone marrow as well as an increased survival, proliferation, and migration of cancer cells to lymph nodes and metastatic sites. WM patients with CXCR4 mutations tend to have increased bone marrow disease burden, higher serum IgM levels, and a higher risk of developing symptomatic blood hyperviscosity.
No current treatments show a complete response for WM patients. The oral BTK inhibitor ibrutinib, which inhibits the MYD88-Bruton tyrosine kinase (BTK) mediated pathway, has shown major response (MR) rates (decrease in serum IgM levels from baseline of more than 50%) of up to 80%. Yet, MR rates in WM patients with both MYD88 and CXCR4 mutations are only as high as 60%, and these patients have a four-fold likelihood of ibrutinib discontinuation.
We are currently testing mavorixafor in combination with ibrutinib in a Phase 1b trial in patients with MYD88 and CXCR4 mutations. Since mavorixafor targets the CXCR4 pathway directly, we are evaluating mavorixafor’s ability to mobilize white blood cells out of the bone marrow and improve treatment response.