Mavorixafor reduces infection rates among patients with WHIM syndrome
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Key takeaways:
- Patients with WHIM syndrome have frequent recurrent infections.
- Patients on mavorixafor saw an approximately 60% reduction in annualized infection rates.
- Only 7% of patients had a grade 3 or higher infection.
Daily treatment with mavorixafor improved outcomes among patients with warts, hypogammaglobulinemia, infections and myelokathexis, or WHIM syndrome, in the 4WHIM phase 3 clinical trial, according to the drug’s developer, X4 Pharmaceuticals.
WHIM syndrome is a rare, combined immunodeficiency disease caused by reduced mobilization and trafficking of white blood cells from the bone marrow due to over-signaling of the CXRC4/CXCL12 pathway.
Patients with WHIM syndrome typically have neutropenia and lymphopenia. As a result, they experience frequent recurrent infections. Increased risks include lung disease, refractory warts from underlying human papillomavirus infection, limited antibody levels and certain types of cancer.
Treatment options
Current treatment for WHIM syndrome primarily focuses on managing and addressing the symptoms associated with the condition.
“For some severely neutropenic patients, this includes weekly granulocyte-colony stimulating factor (G-CSF) injections, which may be painful and can be burdensome,” Teresa Kathleen Tarrant, MD, associate professor in rheumatology and immunology at Duke University School of Medicine, told Healio.
Also, Tarrant said, not everyone responds to G-CSF or can tolerate it.
“Antibiotics and antiviral medications are often used to treat infections, and immunoglobulin replacement therapy may be used to boost the immune system,” she continued. “Methods like cryotherapy or surgical excision can be used for wart removal.”
As a small-molecule, oral CXCR4 receptor antagonist mavorixafor has shown potential in improving the treatment of WHIM syndrome by targeting the underlying biology of the condition, Tarrant said.
“Unlike the current treatment options that primarily focus on managing symptoms, mavorixafor directly addresses the dysregulation of the CXCR4 receptor, which is a key driver in WHIM syndrome,” she said.
“By blocking CXCR4, mavorixafor helps reverse abnormal retention of neutrophils and other white blood cells in the bone marrow, releasing them into the bloodstream so they can better fight infections,” she continued.
If approved, Tarrant said, mavorixafor would represent a convenient, daily oral treatment in the management of this rare immune disorder.
Study design, results
The trial involved 31 patients aged 12 years and older with WHIM. Fourteen patients received oral doses of mavorixafor determined by weight ( 50 kg, 400 mg ; < 50 kg, 200 mg) and 17 received placebo, both administered once a day for 52 weeks.
“This age group is in line with the average age at which patients experience symptoms of WHIM syndrome,” Tarrant said. “WHIM is a genetic disease that individuals are born with, and onset of symptoms is variable, which the trial patient population (48% of participants were aged 12 to 18 years) reflected.”
The treatment group experienced an approximately 60% reduction in annualized infection rate compared with the placebo group (P < .01). Also, the treatment group experienced less than one infection per year, compared with 4.5 for the placebo group, achieving statistical significance during the second half of the trial (P < .005).
One of the patients in the treatment group and five of the patients in the placebo group experienced an infection that was grade 3 or higher, which the researchers called a 75% reduction in the number of patients experiencing severe infections.
The patient in the treatment group with the severe infection had it during the first 3 months of the trial. After the first 3 months, there were no more serious infections in the treatment group. The frequency of severe infections in the placebo group, however, was unchanged throughout the 52-week trial.
The researchers additionally said that treatment with mavorixafor reduced the total duration of infections by more than 70% compared with placebo, as the mean was 14.1 days for the treatment group and 49.1 days for the placebo group.
Total infection scores, which combine infection number and severity, included 7.41 (95% CI, 1.64-13.19) for the treatment group and 12.27 (95% CI, 7.24-17.3) for the placebo group, for a 40% difference.
Further, the placebo group experienced more upper and lower respiratory tract infections and skin infections than the treatment group. Also, 10 of the placebo patients and three of the treatment patients required antibiotic treatment during the study. Both groups saw slight improvements in warts, with no differences between them.
There were no drug-related serious adverse events, treatment-limiting toxicities or discontinuations due to safety, the researchers said, and the treatment was generally well tolerated.
“Mavorixafor demonstrated clinically meaningful improvements across a number of key infection metrics in the trial,” Tarrant said. “If approved, this could translate into patients avoiding fatal infections and costly emergency room visits and hospitalizations, improving their overall quality of life.”
Approximately 90% of the patients continued with the ongoing open-label extension study for further treatment. X4 Pharmaceuticals said that it recently completed its pre-NDA meeting with the FDA and remains on track to submit for approval of mavorixafor for WHIM syndrome early in the second half of 2023.
“I believe that the data support regulatory submission for approval of mavorixafor in WHIM syndrome,” Tarrant said.
For more information:
Teresa Kathleen Tarrant, MD, can be reached at teresa.tarrant@duke.edu.