Mavorixafor approved for treating WHIM syndrome

On April 29, 2024, the U.S. Food and Drug Administration (FDA) approved mavorixafor (trademarked as Xolremdi by X4 Pharmaceuticals) for the treatment of warts, hypogammaglobulinemia, immunodeficiency, myelokathexis (WHIM) syndrome. Mavorixafor is approved as a once-daily oral capsule for those 12 years old and older who have WHIM syndrome. The medication is the first drug approved for the treatment of WHIM, an ultrarare primary immunodeficiency (PI) with only 105 cases documented as of 2019. The approval of mavorixafor, which targets the protein that malfunctions in WHIM syndrome, is a milestone not only for those affected but also for precision medicine.

Individuals with WHIM syndrome have a range of symptoms that include recurrent respiratory, ear, and skin infections and extensive warts from human papillomavirus (HPV). The syndrome causes neutropenia and lymphopenia, or low numbers of white blood cells called neutrophils and lymphocytes, respectively. Since B cells, a type of lymphocyte, make antibodies, those with WHIM syndrome often have low antibody levels too. Over time, HPV and Epstein-Barr virus infections can lead to cancers like lymphoma. People with WHIM syndrome are typically treated with immunoglobulin (Ig) replacement therapy to provide them with antibodies, granulocyte colony-stimulating factor (G-CSF) to boost their production of neutrophils, and/or prophylactic antimicrobials to prevent infections. 

“Effective and innovative treatments are critical for those diagnosed with a primary immunodeficiency. The approval of Xolremdi marks an important advancement for people living with WHIM syndrome, who are susceptible to serious and frequent infections,” said Jorey Berry, president and chief executive officer of the Immune Deficiency Foundation (IDF). “We are very pleased to have been a partner to X4 in their journey to bring this much-needed treatment to this underserved rare disease community.”

As with leniolisib, approved last year to treat activated PI3K delta syndrome (ADPS), mavorixafor’s success rests on understanding the biology of WHIM syndrome. Most cases are caused by dominant variants in the CXCR4 gene, which means an individual only has to inherit one copy of the variant to have WHIM syndrome. The CXCR4 gene codes for a receptor protein that sits on the surface of many different kinds of cells, including neutrophils and B cells. When the receptor detects a chemical signal called CXCL12, the receptor tells the cell to mature and go to a particular place. If the neutrophil or B cell is circulating in the bloodstream, it will move to the bone marrow or to a lymph node or the spleen, respectively. To keep neutrophils and B cells from all moving to these locations, cells regularly recycle the receptor from their surface once it’s been activated by CXCL12. 

This is where the variants that cause WHIM syndrome come in. They are gain-of-function variants because they keep the receptor from being recycled as it should be. As a result, neutrophils build up in the bone marrow (which is called myelokathexis) and B cells build up in lymph nodes and the spleen, causing neutropenia and lymphopenia, respectively. Because these important immune cells aren’t distributed where they should be, bacteria and certain viruses like HPV have a much easier time establishing infections.

The CXCR4 receptor protein is also overly active in certain cancers, so researchers have been developing compounds that target it, called CXCR4 antagonists, for some time. These compounds dampen CXCR4 signaling and result in neutrophils and lymphocytes being released into the bloodstream. 

Mavorixafor is a CXCR4 antagonist. In a phase III trial where 14 patients with CXCR4 variants causing WHIM syndrome were given mavorixafor and 17 patients were given a placebo over 52 weeks, mavorixafor significantly increased neutrophil and lymphocyte counts and significantly decreased infection rates. Participants in the trial were allowed to continue on Ig therapy but were not allowed to be on G-CSF, other CXCR4 antagonists, or granulocyte-macrophage colony-stimulating factor (GM-CSF). Reported side effects in the trial included low platelet counts, rashes, inflammation of the inside of the nose, nosebleeds, vomiting, and dizziness.

Asked if mavorixafor is ultimately meant to replace or augment the standard treatment regimen for WHIM syndrome, an X4 representative noted, “The treatment regimen of a patient taking Xolremdi should be determined by the treating physician.” Also of note, all trial participants had confirmed variants in the CXCR4 gene, but Xolremdi has been approved for all individuals with WHIM syndrome, independent of their underlying genetic diagnosis.

“Until now, supportive care for people with WHIM syndrome has focused on symptom management and not the underlying cause of disease—the dysfunction of the CXCR4 pathway. I am thrilled that with the approval of Xolremdi, a therapy designed to address dysregulated CXCR4 pathway signaling, we now have a targeted treatment that has demonstrated the ability to elevate absolute neutrophil and lymphocyte counts, increasing WHIM patients’ ability to fight infections,” said Teresa K. Tarrant, M.D., associate professor of medicine, rheumatology, and immunology at Duke University School of Medicine and a principal investigator in the trial.

X4 Pharmaceuticals has contracted with PANTHERx, a specialty pharmacy, to distribute Xolremdi and is offering a patient support program called X4Connect. The company is also testing mavorixafor to treat severe, congenital neutropenia and Waldenstrom's macroglobulinemia, a type of cancer.