There is now its first drug for a primary immune defect, the rarity of which means that it can remain undetected in a patient for years or be misdiagnosed. The FDA has approved a once-daily therapy that addresses the underlying genetic problem that causes the inherited disorder, called WHIM syndrome.
The regulatory decision announced Monday for X4 Pharmaceuticals’ drug applies to WHIM patients ages 12 and older. The daily capsule, known in development as Mavorixafor, is marketed under the brand name Xolremdi (pronounced “zohl-REM-dee”).
The name WHIM is an acronym for warts, hypogammaglobulinemia, infections, and myelocathexis, the four most common clinical manifestations of the disease. However, the disease is not limited to these symptoms and progresses differently from patient to patient. There is no standard of care for WHIM, which is treated with various therapies that address the symptoms and common infections.
“The exciting thing about this approval is that for the first time WHIM patients and their physicians will receive treatment that targets the underlying cause of the disease,” Paula Ragan, CEO of Boston-based X4, said during a conference call Monday .
According to the Centers for Disease Control and Prevention, there are more than 400 types of primary immune deficiency. WHIM can confuse patients and doctors, who either confuse the disease with one of these immune deficiencies or attribute the symptoms to children who simply get a lot of infections – which many children do, Dr. Teresa Tarrant, professor of rheumatology and immunology at Duke University School of Medicine and lead researcher in the pivotal study of the X4 drug. WHIM is suspected when the severity and frequency of infections exceeds what is typical in most children, she said in an interview.
You can think of WHIM as a traffic problem for immune cells. In some immune defects, the body does not produce enough immune cells or the immune cells it does produce do not function properly. In WHIM, functional immune cells are produced by the bone marrow, but they cannot enter the bloodstream to fight pathogens. Myelocathexis, the “M” in WHIM, is the retention of immune cells in the bone marrow. WHIM is based on a rare mutation in the CXCR4 gene, which encodes a chemokine receptor, a protein involved in regulating the movement of immune cells in the body.
The first genetic mutation leading to WHIM was identified in 2003. Scientific research, including work on X4, has since identified other mutations that lead to the disease. Defective CXCR4 protein keeps CXCR4 pathway signaling in a hyperactive state, which in turn causes immune cells to remain trapped in the bone marrow, Tarrant said. She compares this pathway to an on-off switch to remove cells from the bone marrow. X4’s drug is a small molecule that selectively targets and blocks the CXCR4 cell receptor.
“With WHIM, many patients have a problem with switching off (turning off), so the signaling is constantly on,” Tarrant said. “It’s hyperactive. This drug dampens hyperactive signaling.”
X4 studied mavorixafor in a placebo-controlled Phase 3 clinical trial involving 31 patients with WHIM syndrome. The main goal of the 52-week study was to show a statistically significant increase in the time, measured in hours, that neutrophil counts were above a certain threshold. The results showed that the study met this goal as well as an important secondary endpoint, namely measuring lymphocyte counts. Additional results showed that the X4 drug resulted in a statistically significant reduction in annual infection rates and a clinically meaningful reduction in the severity and duration of infections. The drug was well tolerated by the study participants.
A rare disease is typically defined as a disease that affects 200,000 or fewer patients in the United States. According to X4 market research, WHIM is extremely rare, affecting approximately 1,000 people in the United States. The mean age of diagnosis is 5.5 years. However, for some patients it may take much longer to figure out what’s going on. Tarrant said her first clinical encounter with WHIM was with someone whose disease was not diagnosed until the patient was in their late 30s. While some primary immunodeficiencies can be detected through newborn screening, WHIM is not one of them. These tests only catch children with extremely low immune cell levels, Tarrant explained. The low WHIM values can be seen in the blood work. But children don’t typically get many blood draws, she said.
While WHIM can be diagnosed with a genetic test that confirms the CXCR4 mutation, Chief Commercial Officer Mark Baldry noted the FDA’s decision does not require this. Xolremdi’s label covers patients with a clinical diagnosis of WHIM. Xolremdi is available in 100 mg capsules and is dosed according to the patient’s weight. Patients weighing 50 kg (approximately 110 pounds) or more are instructed to take 400 mg once daily. For these patients, the annual wholesale price of the drug is $496,400. People weighing less than 50 kg take a 300 mg dose of Xolremdi once daily, which costs $372,300 annually. Based on clinical trial experience and company research, X4 estimates that 90% of WHIM patients require the higher dose. Baldry said Xolremdi is available now, but added that it could take six months to a year for payers to begin covering it.
Mavorixafor was licensed from Genzyme, a Sanofi subsidiary. With the approval of the molecule, X4 now owes a milestone payment of $7 million as well as royalties from product sales, said Chief Financial Officer Adam Mostafa. The company is not currently providing a sales forecast for the drug. The approval comes with a priority review voucher, which X4 can use in the future for faster regulatory review of various drugs for rare diseases. But companies typically monetize these vouchers and sell them at prices in excess of $100 million. Mostafa said X4 plans to sell its voucher and Sanofi-Genzyme is not entitled to the proceeds from that sale.
X4 is also evaluating mavorixafor for the treatment of chronic neutropenia. According to an investor presentation, the company expects to begin a Phase 3 trial in this indication by the end of June. The pipeline includes two additional CXCR4-targeting drugs. X4P-003 is a next-generation drug that X4 says has improved properties and potential applications in other diseases linked to the CXCR4 receptor. Meanwhile, X4P-002 offers the possibility of crossing the blood-brain barrier to achieve this goal. Both molecules are in preclinical development.
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