After a Difficult Summer, X4 Celebrates Phase III Victory in WHIM Syndrome (Update) |  BioSpace

After a Difficult Summer, X4 Celebrates Phase III Victory in WHIM Syndrome (Update) | BioSpace

X4_Paula Reagan

Paula Ragan, President and CEO of X4/Courtesy of the company

Four months after implementing a restructuring initiative aimed at expanding cash flow, X4 Pharmaceuticals celebrates the first positive results, published on Tuesday, of its pivotal phase III trial of mavorixafor in WHIM syndrome.

In July, the Boston-based biopharmaceutical company made the difficult decision to cut its workforce by 20% and discontinue its oncology programs, leaving them to only progress through partnership.

These changes were expected to save the company $5 million this year and $20 million in 2023. Coupled with a $55 million capital raise, X4 should be able to extend its cash trail to in Q3 2023 as it awaits a Phase III reading.

That moment came when X4 revealed the results of its lead experimental therapy, mavorixafor. The CXCR4 antagonist was tested against placebo in 31 patients aged 12 and over with WHIM syndrome.

WHIM is a rare congenital immune deficiency named for its four main characteristics – warts, hypogammaglobulinemia, infections, and myelokathexis. Patients are particularly susceptible to infection and to developing certain types of cancers due to low neutrophil and lymphocyte counts.

Currently, no ongoing treatment is available for WHIM patients. Some receive immunoglobulin replacement therapy to increase IgG antibody levels. If infections become severe, patients may be given G-CSF, a type of growth factor that stimulates the production of white blood cells.

“[These current] drugs require injections and needles,” said Dr. Teresa Tarrant, associate professor of medicine at Duke specializing in immunology and principal investigator of the 4WHIM trial. BioSpace.

“[Mavorixafor] is an oral medication. This makes it a very exciting therapy. This is molecular medicine at its finest. Patients have defects in the CXCR4 protein and this treatment addresses them directly. The personalized therapy moving forward for rare disease patients is something we are really excited about.

Mavorixafor was well tolerated in the trial and met primary and secondary endpoints for increasing patient neutrophil and lymphocyte counts above clinically meaningful thresholds.

After the trial ended, 90% of placebo recipients elected to receive the treatment in an open-label extension.

Mavorixafor works by blocking over-activated signaling by CXCR4, the cellular receptor for CXCL12, to regulate the release of immune cells from the bone marrow into the peripheral blood. X4 believes that inhibiting the CXCR4/CXCL12 axis could ameliorate immune deficiencies, whether caused by a CXCR4 mutation or not.

If approved, mavorixafor would be the first treatment to address the underlying cause of WHIM syndrome. X4 is preparing to meet with regulatory authorities in the first half of 2023 to put the drug on the path to approval and commercialization, acting chief medical officer Murray Stewart said in a press release.

Although WHIM is considered extremely rare, some of the low number of diagnoses could be due to a lack of universal genetic testing and limited knowledge of the disease.

To combat this, X4 has partnered with Invitae to launch free genetic testing for people who may carry genetic mutations associated with chronic neutropenia to aid in better diagnoses.

The therapy is also thought to be useful for a variety of chronic neutropenic disorders, as the CXCR4 pathway is a key regulator of neutrophil release from the bone marrow. Mavorixafor is currently being studied in a phase Ib trial for these patients, both as monotherapy and in combination with the standard treatment, G-CSF.

“These results that were published today are extremely promising and exciting for the potential to look at other diseases where low neutrophil counts cause problems for people,” Tarrant said.

“It’s very, very encouraging. I think we are all hoping for an even wider impact.

X4 has a second CXCR2 antagonist in preclinical development, but the program is currently on hold and dependent on mavorixafor’s approval to advance.

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