Chronic Neutropenic Disorder Programs (In-House)

Mavorixafor in WHIM Syndrome

  • WHIM syndrome is a rare and often difficult-to-diagnose primary immunodeficiency in which the body’s immune system does not function properly and has trouble fighting infections. In most patients, it is caused by mutations in the CXCR4 gene that result in white blood cells getting trapped in the bone marrow.
  • WHIM syndrome was named for its four main symptoms: 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% to 40% of WHIM patients 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. However, the diagnosis of WHIM is not well defined due to the emerging understanding of the genetics underlying WHIM syndrome, lack of universal or accessible genetic testing, and limited medical education and awareness of the disease, which is in part driven by the lack of available disease-modifying treatments.
  • To date, 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 has been generally well tolerated. The FDA granted Breakthrough Therapy Designation (BTD) for mavorixafor in WHIM Syndrome based on the Phase 2 trial results.
  • Following these positive clinical results, we initiated a pivotal Phase 3 trial of mavorixafor in people with WHIM syndrome. The 4WHIM Phase 3 clinical trial was a global, randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of oral, once-daily mavorixafor in people with genetically confirmed WHIM syndrome. Originally designed to enroll 18-28 patients, the trial enrolled 31 patients aged 12 and older who received either 400 mg mavorixafor (n=14) or placebo (n=17) orally once daily for 52 weeks.
  • In November 2022, we reported positive top-line results from the 4WHIM trial:
    • 4WHIM met its primary endpoint, with mavorixafor achieving clinical and statistical superiority over placebo when measuring TAT-ANC, or 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 when measuring TAT-ALC, or 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.
    • Mavorixafor was generally well tolerated in the trial, with no treatment-related serious adverse events reported and no discontinuations for safety events.
  • Additional data review and analysis of the secondary and exploratory endpoints of the 4WHIM trial are ongoing, with plans to present detailed results at a future medical meeting.
  • There are no existing treatments that specifically target the underlying causes of WHIM syndrome; if approved, mavorixafor would be the first therapy available specifically to treat those diagnosed with WHIM syndrome.

 

Mavorixafor in Chronic Neutropenia

  • Due to its demonstrated ability to broadly and durably elevate blood levels of white blood cells including neutrophils, we believe that mavorixafor may be useful in the treatment of patients with a variety of chronic neutropenic disorders.
  • Chronic neutropenia is defined as periods lasting more than three months persistently or intermittently where there are abnormally low levels of neutrophils circulating in the blood.
  • Most chronic neutropenic disorders are rare blood conditions characterized by increased risks of infections and cancer due to abnormally low levels of neutrophils in the body. In all cases, the CXCL12/CXCR4 pathway is the key regulator of neutrophil release from the bone marrow.
  • People living with neutropenia have few treatment options; patients are most commonly treated with granulocyte-colony stimulating factor (G-CSF), an injectable therapy associated with significant side effects, including severe bone pain and myalgia and increased risk of cancer in some patients.
  • We are conducting a proof-of-concept, Phase 1b clinical trial, (NCT04154488) designed to assess the safety and tolerability of daily, oral mavorixafor with or without G-CSF, in participants with chronic neutropenic disorders including idiopathic, cyclic, or congenital neutropenia.
  • In the first part of the trial, participants were dosed with a single dose of oral mavorixafor to assess for magnitude of treatment response. Results from the first part of this trial demonstrated good tolerability and mavorixafor’s ability to raise neutrophil counts in 100% of patients dosed (n=25) and across all patient populations studied, both as monotherapy and in combination with standard of care, injectable granulocyte colony-stimulating factor (G-CSF).
  • An amendment to the Phase 1b clinical trial is currently being initiated and aims to evaluate the use of daily oral mavorixafor with or without G-CSF for 6 months in up to 50 participants with chronic neutropenic disorders. The study extension is also expected to assess the durability of ANC responses, the potential of mavorixafor to enable patients to taper down dosing with G-CSF, and to evaluate the tolerability of mavorixafor in combination with G-CSF in chronic use.

 

X4P-003

  • This candidate, a novel, small-molecule CXCR4 antagonist, has progressed to pre-clinical development and patent applications have been filed
  • Further advancement of X4P-003 will be dependent on the potential first approval of mavorixafor and lifecycle management of the company’s product portfolio.
 

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