First Prospective Drug Trial for VEXAS Syndrome

Despite recent research suggesting that VEXAS syndrome may impact as many as 1 in 4,300 men over age 50, no FDA-approved treatments yet exist for the progressive and often fatal disease linked to mutations in the UBA1 gene within blood cells. Experts at NYU Langone Health’s nationally renowned VEXAS Syndrome Care Program are leading the way toward addressing that need by helping to design and coordinate the first prospective, randomized therapeutic trial for the disease.

Program co-directors David B. Beck, MD, PhD, an associate professor of medicine and biochemistry and molecular pharmacology, and Gary H. Ho, MD, a clinical assistant professor in the Division of Rheumatology, have partnered with colleagues at the Mayo Clinic to launch PAXIS, a randomized, double-blind, placebo-controlled trial of the drug pacritinib.

Lack of Effective Treatments

While severe cases of VEXAS have been cured with bone marrow transplants, Drs. Beck and Ho are seeking more accessible treatment options as part of their push for comprehensive care. “The disease was only first described in 2020, and that means there are no established guidelines on how to treat it and there’s a lack of familiarity with the condition,” Dr. Ho says.

Although VEXAS-associated inflammation often responds to high-dose steroids, chronic use can cause toxicity. Researchers have begun investigating a variety of inflammation-treating biologics and immunosuppressive medications as potential alternatives, as well as drugs that address the disease’s hematologic symptoms. “From our initial discovery and characterization of VEXAS, we had found that patients have a certain type of inflammation in their blood where they have elevated interferon signatures,” Dr. Beck says.

That observation fueled an interest in pursuing studies with Janus kinase (JAK) inhibitors, including pacritinib, since interferons largely rely on JAKs for intracellular signaling. Early efforts are focused on pacritinib because it can tamp down inflammation in the bone marrow of patients with myelodysplastic syndrome. It is also already approved to treat myelofibrosis, another rare blood cancer where scar tissue forms in the bone marrow. “We were excited to explore this in a more systematic way,” Dr. Beck says.

An Unprecedented Trial

The multicenter phase 2 PAXIS trial investigating the efficacy and safety of pacritinib recently met its recruitment goal of 78 patients, randomized to three arms. For 6 months, participants receive a placebo, a half dose of pacritinib, or a full dose of the drug. After that initial period, patients can choose to continue in the trial’s open-label portion; if they’re faring poorly on placebo, for example, they can elect to take full-dose pacritinib. Participants who respond well can continue treatment after the trial.

“The whole trial had to be designed from scratch because there have been no clinical trials in VEXAS,” Dr. Ho says. “Key opinion leaders from multiple countries provided input on how to measure effectiveness, how to safely taper the steroids to avoid flares, and more. Through the expert consensus group, we also created a VEXAS disease activity score because there has been no validated disease activity measure.”

An adjudication committee compares disease activity scores before and after treatment to assess whether trial participants can reduce their steroid doses without experiencing the consensus definition of a VEXAS flare. The trial is also gauging the drug’s effect on inflammation markers such as C-reactive protein. Secondary endpoints include quality of life, hematologic improvement such as a reduction in transfusion requirements, and drug pharmacokinetics and pharmacodynamics.

A New Clinical Template

“During the process of setting up this trial, we’ve established a lot of the necessary tools to run trials in VEXAS,” Dr. Beck says. “It was a journey going from a disease that wasn’t well-characterized to a disease that we now have endpoints for characterizing the efficacy of therapies.”

The result is a template that can be applied to speed future VEXAS trials, Dr. Ho adds. “Many other VEXAS trials are going to come within the next year, and a lot of them are based on this initial trial’s design,” he says.

One such trial is a randomized phase 2/3, double-blind, placebo-controlled adaptive study evaluating another JAK inhibitor, momelotinib, which is also approved to treat myelofibrosis. NYU Langone will again serve as a site for the multicenter trial. As with PAXIS, the trial can cover travel and related costs to help reduce the burden on participants, Dr. Beck notes.

“We now have an international network of investigators who are studying VEXAS and, together, we can pursue more studies in the future,” he says. “It’s taken a great collaborative network to get to this point. Before we know whether these treatments are as potent as we hope, one of the most exciting developments is that we now have the tools and connections to move us closer to finding better therapies for patients.”