X4 joins hands with Yale on rare disease program

Yale University campus - red building and a quadrangle with trees
The biotech will collaborate with the lab of Yale immunobiologist João Pedro Pereira, Ph.D.

Yale University has teamed up with cancer biotech X4 Pharmaceuticals to work on its therapy for WHIM syndrome, a rare genetic disorder that plays havoc with the immune system but has no approved treatment.

The Cambridge, Massachusetts, biotech—which specializes in drugs targeting the CXCR4 receptor—says it will help Yale investigate the molecular mechanisms behind WHIM syndrome, specifically the role that CXCR4 mutations may play in the disease. CXCR4 is the receptor for the chemokine CXCL12, and research has suggested that the interplay of the receptor and its ligand can downplay immune responses.  

In patients with WHIM syndrome, reduced immunity makes them vulnerable to a range of symptoms, notably—as the acronym indicates—warts, hypogammaglobulinemia (low antibody levels), infections, and myelokathexis (a severe deficiency in white blood cells).

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Some patients are treated off-label with GCSF drugs such as filgrastim to improve white blood cell counts, while antibiotics and infusions of immune globulin are used to try to reduce infections. Still, there are no drugs available to treat the underlying disease mechanism.

X4 was launched with financial backing from Genzyme founder Henri Termeer before his death earlier this year, and came out of stealth mode in 2015 around lead drug X4P-001, a CXCR4 inhibitor that is being tested in phase 1/2 trials in clear cell renal cell carcinoma (ccRCC), melanoma and other solid tumors.

The biotech has always had ambitions outside of cancer, however, and started a phase 2/3 trial of a low-dose formulation of X4P-001 in WHIM syndrome January, with the aim of enrolling 33 patients ages 13 or older with the disorder. It is hoping to complete the trial in August 2019.

Linking with Yale gives X4 the opportunity to collaborate with João Pedro Pereira, Ph.D., an associate professor of immunobiology who is involved with Yale's stem cell and cancer centers. His research focuses on the process that generates many different cell types including all immune cells, and its role in conferring immunity.

"The incorrect positioning of immune cells in primary and secondary immune organs due to CXCR4 mutations has been well documented," said Pereira.

"This research will elucidate the fundamental mechanisms that lead to chronic impairment of the immune system, particularly of long-term immunity, as a result of aberrant immune cell positioning and trafficking."

The number of patients with WHIM is hard to estimate, but X4 reckons that there could be several thousand people worldwide affected with the disorder.

Another group with WHIM syndrome in its sights is the National Institute of Allergy and Infectious Diseases (NIAID), which is running a study comparing Sanofi Genzyme's Mozobil (plerixafor) with filgrastim that is due to generate results in 2021.