We have developed a pipeline of small-molecule, oral antagonists of the chemokine receptor CXCR4. We believe that inhibition of the CXCR4 receptor creates the potential to provide therapeutic benefit across a wide variety of diseases, including chronic neutropenic disorders and certain types of cancer, where there remain significant unmet needs. We are currently focused on advancing our lead candidate, mavorixafor, for the treatment of a number of chronic neutropenia indications, while also pursuing partnership opportunities to further advance our oncology programs.
*Programs only being advanced through partnership
*Programs only being advanced through partnership
Mavorixafor is an investigational, orally available CXCR4 antagonist designed to facilitate the mobilization of white blood cells from the bone marrow into the blood, to increase levels of circulating neutrophils, lymphocytes, and monocytes, and to improve immune system function.
- WHIM syndrome is both a rare combined immunodeficiency and a congenital neutropenic disorder in which the body’s immune system does not function properly and has trouble fighting infections. In many patients, it is caused by genetic variations in the CXCR4 gene that result in white blood cells getting trapped in the bone marrow, frequently causing both neutropenia (low levels of circulating neutrophils) and lymphopenia (low levels of circulating lymphocytes).
- WHIM syndrome is named for its four common clinical findings, although not all patients experience all symptoms, and not all symptoms are required for a diagnosis:
- Warts (related to infection with the Human Papilloma Virus (HPV)),
- Hypogammaglobulinemia (low immunoglobulin, or IG, levels),
- Infections (both bacterial and fungal), and
- Myelokathexis (a hyper-dense population of immune cells in the bone marrow).
- Approximately 30-40% of people with WHIM syndrome develop HPV-associated cancers as they age.
- The incidence and prevalence of WHIM syndrome are not well established. Through market research, we estimate that there are more than 1,000 individuals with WHIM syndrome in the U.S.
- Following positive Phase 2 clinical results, we initiated a pivotal Phase 3 trial of mavorixafor in people with WHIM syndrome. The 4WHIM Phase 3 clinical trial was a 52-week, global, randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of oral, once-daily mavorixafor in people aged 12 and older.
- In November 2022 and May 2023, we reported positive results from the 4WHIM trial:
- 4WHIM met its primary endpoint, with mavorixafor achieving clinical and statistical superiority over placebo (P<0.0001) when measuring the length of time that participants’ absolute neutrophil counts (ANC) remained above a clinically meaningful threshold of 500 cells per microliter (severe neutropenia), over 24-hour periods at 4 time points throughout the 52-week trial.
- 4WHIM also met a key secondary endpoint, with mavorixafor achieving clinical and statistical superiority over placebo (P<0.0001) when measuring the length of time that participants’ absolute lymphocyte counts (ALC) remained above a clinically meaningful threshold of 1,000 cells per microliter (lymphopenia), over 24-hour periods at 4 time points throughout the 52-week trial.
- In the trial, mavorixafor also demonstrated clinically meaningful improvements versus placebo across a number of key infection metrics, including reductions in the rate, severity, and duration of infections and in the use of antibiotics.
- Mavorixafor was generally well tolerated in the trial, with no treatment-related serious adverse events reported and no discontinuations for safety events.
- In late October 2023, our New Drug Application (NDA) submitted to the United States Food and Drug Administration (FDA) for the approval of once-daily, oral mavorixafor to treat individuals aged 12 and older with WHIM syndrome was accepted for Priority Review, establishing a goal of six months review from the date of acceptance and assigning a Prescription Drug User Fee Act (PDUFA) target action date of April 30, 2024.
- Mavorixafor has received multiple special designations from global regulatory authorities in WHIM syndrome, including Breakthrough Therapy Designation, Fast Track Designation, and Rare Pediatric Designation in the U.S., and Orphan Drug Status in both the U.S. and European Union. In addition, X4 is eligible to receive a Priority Review Voucher (PRV) as a result of mavorixafor’s Rare Pediatric Designation in the U.S.
- There are currently no approved treatments for WHIM syndrome.
- Due to its demonstrated ability to durably elevate levels of circulating white blood cells across multiple clinical trials, we believe that mavorixafor may be useful in the treatment of people with a variety of chronic neutropenic disorders.
- Chronic neutropenic disorders are rare blood conditions lasting more than three months, persistently or intermittently; people with chronic neutropenia are at higher risk of developing infections and certain cancers and having a reduced quality of life due to low levels of neutrophils circulating in the blood.
- People living with neutropenia have few treatment options; patients are commonly treated with granulocyte colony-stimulating factor (G-CSF), an injectable therapy that has been associated with burdensome side effects, including severe bone pain and myalgia.
- In September 2022, we announced the successful completion of a proof-of-concept, Phase 1b clinical trial, designed to assess the safety and tolerability of a single daily dose of oral mavorixafor, with or without G-CSF, in participants with chronic neutropenic disorders including idiopathic, cyclic, and congenital neutropenia. Results showed that 100% of study participants (n=25) achieved robust responses to mavorixafor and that 100% of neutropenic participants (n=14) achieved normalized neutrophil counts.
- We are currently conducting a Phase 2 clinical trial (NCT04154488) that aims to evaluate the safety and efficacy of chronic daily oral mavorixafor with or without G-CSF in people with chronic neutropenic disorders.
- Waldenström’s macroglobulinemia (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.
- About 90% of WM patients present with genetic variations in the MYD88 gene, while 30-40% of patients present with variations in the CXCR4 gene as well. Patients with the double variants tend to progress more quickly, even while on treatment, and have poorer outcomes.
- We have evaluated the safety and efficacy of oral, once-daily mavorixafor in combination with the oral BTK inhibitor ibrutinib in a Phase 1b trial in WM patients with MYD88 and CXCR4 variations. Since mavorixafor has been shown to target the CXCR4 pathway directly, we evaluated mavorixafor’s ability to mobilize white blood cells out of the bone marrow and improve treatment response.
- Results from the trial showed that:
- 91% (10/11) of evaluable participants achieved a major response to therapy (≥ 50% reduction in serum IgM from baseline), with 100% (7/7) of relapsed/refractory participants achieved a major response.
- Trial participants achieved elevations in absolute neutrophil count (ANC), with no neutropenic events reported; participants also experienced a reduction in infections over time with chronic dosing.
- Mavorixafor in combination with ibrutinib showed a safety profile similar to ibrutinib monotherapy.
- Mavorixafor has been granted Orphan Drug Status in the U.S. in WM, regardless of patients’ CXCR4 variant status.
- Further clinical development of mavorixafor in WM will now be subject to completing a strategic partnership.