X4 Pharmaceuticals has launched a Phase 1b trial to assess the safety and tolerability of mavorixafor (X4P-001), in combination with Imbruvica (ibrutinib), for the treatment of people with Waldenström’s macroglobulinemia (WM), a rare form of non-Hodgkin’s lymphoma (NHL).
The multi-center, dose-escalation Phase 1b trial will be conducted in collaboration with the Leukemia & Lymphoma Society (LLS), under the nonprofit’s Therapy Acceleration Program (TAP) — designed to advance treatments that have the potential to change the standard of care. The study is expected to enroll 12 to 18 people who carry mutations in the MYD88 and CXCR4 genes.
In addition to safety assessments, trial investigators also will evaluate changes in the levels of two biomarkers of clinical response in WM: immunoglobulin M and hemoglobin. Topline data from the trial is expected later this year.
“We are excited to initiate our first clinical trial in WM and look forward to providing initial results in the second half of 2020 as we continue to advance our pipeline as rapidly as possible for patients in need,” Lynne Kelley, MD, FACS, chief medical officer of X4 Pharmaceuticals, said in a press release.
Most people with WM carry mutations in the MYD88 gene. Those mutations lead to the overactivation of a protein that stimulates the expansion of a subset of immune cells, called lymphoplasmacytic cells, that cause the disease.
WM is also known as lymphoplasmacytic lymphoma. Its cells have characteristics of both lymphoma and myeloma cells and produce excessive amounts of immunoglobulin M, a type of antibody.
A subset of WM patients also carry “gain-of-function” mutations in the CXCR4 gene. These result in the overactivation of the CXCR4 receptor, a protein that promotes the growth, proliferation, and migration of malignant immune cells.
Poor treatment responses to Bruton’s tyrosine kinase (BTK) inhibitors, like Imbruvica, are associated with these CXCR4 mutations, as is shorter patient survival.
“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 Christian Buske, MD, director of the Institute of Experimental Cancer Research and a physician and professor of medicine at the University of Ulm.
“There is a significant unmet medical need for patients living with WM who have CXCR4 mutations,” said Steven Treon, MD, PhD, director of the Bing Center for Waldenström’s Macroglobulinemia and professor of medicine at Harvard Medical School.
“The development of a therapeutic CXCR4 antagonist such as mavorixafor represents a very important advance for targeted therapy of this disease,” Treon said.
Mavorixafor is a first-in-class, oral inhibitor of the CXCR4 receptor, which was proven in a previous Phase 2 trial (NCT03005327) to be safe and effective for the treatment of WHIM syndrome. WHIM — an acronym for some of the disorder’s characteristic symptoms, including warts, hypogammaglobulinemia, infections, and myelokathexis — is a rare, primary immunodeficiency disease caused by gain-of-function mutations in CXCR4.
The therapy’s efficacy against the disorder is currently being confirmed in a larger Phase 3 trial (NCT03995108), which is enrolling 28 patients, ages 12 and older.
“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,” Kelley said.
In addition to WM and WHIM syndrome, mavorixafor also is being developed to treat patients with severe congenital neutropenia and clear cell renal cell carcinoma.
