FDA approves mavorixafor for WHIM syndrome

Key takeaways:

• Patients experience recurrent infections that may be life-threatening.
• Mavorixafor is a CXCR4 receptor antagonist.
• A phase 3 study found increased neutrophils and lymphocytes and fewer infections.

The FDA has approved mavorixafor for treating warts, hypogammaglobulinemia, infections and myelokathexis — or WHIM — syndrome, a rare and chronic primary immunodeficiency, according to a press release from X4 Pharmaceuticals.

“We’re really committed to this area of immune disorders. It has been ignored by industry, unfortunately, and that’s really hard for doctors in terms of diagnosis,” Paula Ragan, PhD, president and CEO of X4 Pharmaceuticals, told Healio.

The CXCR4 gene codes for a chemokine receptor that regulates the release of white blood cells from bone marrow to peripheral blood. Autosomal dominant pathogenic variants in this gene predominantly cause WHIM syndrome.

Reduced mobilization and trafficking of white blood cells from the bone marrow due to over-signaling of the CXCR4/CXCL12 pathway can lead to neutropenia and lymphopenia, followed by frequent recurrent bacterial and viral infections.

“Mavorixafor is an oral once-daily capsule form that is an antagonist of the receptor,” Ragan said. “It’s helping turn it off.”

The FDA approved mavorixafor, which will use the brand name Xolremdi, for patients aged 12 years and older.

Disease burden

X4 Pharmaceuticals reports that 92% of patients with WHIM syndrome, which can be seen in both children and adults, experience infections.

“In our recent phase 3 study, we’ve seen significant upper respiratory tract, lower respiratory tract, and also serious skin infections,” Ragan said.

Pneumonia and end-organ damage including bronchiectasis and hearing loss are possible, X4 Pharmaceuticals said, along with a 30% risk for cancer by age 40 years with malignancies associated with HPV and EBV.

“There have been reports of massive sepsis and even death,” Ragan said. “It’s a challenging disease, and we’re excited to hopefully get at the root cause of the problem with mavorixafor.”

Although patients are born with WHIM syndrome, they may experience symptoms for decades before they are diagnosed, even beginning in infancy, Ragan said.

“This high risk of serious infections presents early, but it takes a long time and journey for a clinician to diagnose this disease,” she said.

WHIM syndrome is heterogenous, X4 Pharmaceuticals said, with nonspecific symptoms that vary between patients and add to difficulties in diagnosis. Fewer than a quarter of patients with WHIM syndrome experience warts, hypogammaglobulinemia, infections and myelokathexis together, the company added.

Even when it has been diagnosed, Ragan said, patients live with uncertainty.

“They never know when that infection is going to pop up, and they’ve had to really limit their ability to travel, limit their ability to commit to certain life events, even including work,” Ragan said.

“This is a really significant problem. The severity and the lack of predictability of their own lives just creates a totally different trajectory for these folks,” she continued.

Current treatments manage symptoms without addressing genetic causes, Ragan said.

Since 98% of patients have neutropenia and 88% have lymphopenia, X4 Pharmaceuticals said, granulocyte colony-stimulating factor infusion and immunoglobulin replacement therapy are common.

“Neutrophils and lymphocytes are your soldiers that circulate in your blood to try to identify pathogens and fight those infections,” Ragan said, adding that patients “have profoundly low counts, almost an order of magnitude lower.”

Antibiotics are common as prophylactics or for treating acute infections as well, Ragan continued.

Study results, next steps

Prior to submitting its new drug application for mavorixafor to the FDA last October, X4 Pharmaceuticals conducted a randomized, placebo-controlled, double-blind phase 3 study of the drug among adolescents aged 12 to 18 years and adults with WHIM syndrome.

Participants used 200 mg or 400 mg mavorixafor (n = 14) or placebo (n = 17) based on weight once daily for 52 weeks.

“We saw resoundingly high or increased improvements in both neutrophil counts and lymphocyte counts,” Ragan said.

Mean times at or above a threshold of 500 cells/µL for absolute neutrophil count over a period of 24 hours assessed every 3 months for 52 weeks included 15.04 hours for the treatment group and 2.75 hours for the placebo group (P < .0001).

Similarly, mean times at or above a threshold of 1,000 cells/µL for absolute lymphocyte count included 15.8 hours for the treatment group and 4.55 hours for the placebo group (P < .0001).

The study also found a 60% reduction in annualized infection rates and a 40% lower total infection score in the treatment group, as days with an infection fell from about 49 days to 14 days as well. The treatment group additionally reported less antibiotic usage.

Also, there were no drug-related serious adverse events or withdrawals from the study due to the drug, and about 87% of participants rolled over from phase 3 into the open label extension study, which Ragan said indicated both strong tolerability and patient interest in the drug.

“It’s clear mavorixafor is providing that benefit,” Ragan said. “Based on our phase 3 data, we look like we can really have a huge impact on their overall infection risk and burden.”

With approval, X4 Pharmaceuticals’ field team will call on physician and patient advocacy groups to inform them about mavorixafor’s availability. The company also will continue its Path Forward free genetic testing program to foster diagnosis.

“It’s really about generating education and awareness in the physicians and then giving them the tools to actually help them through the diagnosis process,” Ragan said. “In the event that physicians have that curiosity and would like to explore genetic testing, it’s easily available for them.”

Ragan is optimistic about the drug’s success.

“This is all about seeing patients who have a very targeted root cause of their disease and bringing a very targeted option for them and hopefully changing their lives,” she said.

References:

• Badolato R, et al. Abstract 2. Presented at: CIS 2023 Annual Meeting; May 18-21, 2023; St. Louis, Missouri.
• X4 Pharmaceuticals WHIM syndrome fact sheet. Accessed April 23, 2024.