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 positive results from the Phase 2 clinical trial, we initiated a global Phase 3 pivotal trial of mavorixafor in adults and pediatric patients (ages 12 and above) with WHIM.
  • The 4WHIM Phase 3 clinical trial (NCT03995108 is a global, randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of mavorixafor in WHIM patients with mutations in the CXCR4 gene.
    • The primary endpoint of the 4WHIM trial is a clinically relevant reduction of severe neutropenia as measured by the increase in time above threshold (500 cells per microliter) for the absolute neutrophil count (or “TAT-ANC”) in peripheral blood.
    • Additional endpoints include assessments of other cell types in the blood, including absolute lymphocyte count, absolute monocyte count, and total white blood cells, and assessments of infection burden (severity, rate), as well as changes in cutaneous wart burden at 52 weeks. A number of quality-of-life measurements, health economic metrics, and other exploratory endpoints are also being assessed.
    • The trial is fully enrolled with patients aged 12 and older receiving mavorixafor or placebo orally once daily for 52 weeks; all patients then become eligible to receive treatment with mavorixafor in an open-label trial extension.
  • Results from the 4WHIM trial are expected in the fourth quarter of 2022.
  • 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 designed to assess the safety and tolerability of daily, oral mavorixafor with or without G-CSF, in participants with chronic neutropenic disorders including severe congenital (of genetic causation), idiopathic (of unknown cause), or cyclic. Participants are being dosed with a single dose of oral Mavorixafor (400 mg QD) to assess for magnitude of treatment response.
  • This trial is fully enrolled; results are anticipated in the third quarter of 2022.

 

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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