From left, James Jackson, PsyD, Jillian Rhoads, PhD, and Narender Annapureddy, MD, MSCI, were co-investigators of a study conducted in the Vanderbilt Clinical Research Center that identified a potential treatment for the "brain fog" associated with lupus, an autoimmune disease.
(photo by Susan Urmy)
Nicole Keepers is an expert on systemic lupus erythematosus (“lupus”). For years she has endured debilitating consequences of this autoimmune disease, which attacks tissues throughout the body, including the brain.
While immunosuppressive and anti-inflammatory drugs lessen some of her symptoms, including fatigue, vasculitis (inflammation of the blood vessels), and abnormal heart rhythms, they do not relieve the difficulty she has with memory and concentration.
An estimated 200,000 people in the United States have lupus. About 80% of them experience “brain fog,” cognitive problems that impair learning, memory and attention.
But there is hope. On April 20, researchers at Vanderbilt Health and Evergreen Therapeutics Inc., a biopharmaceutical company based in Bethesda, Maryland, reported that EG501, a small-molecule oral tablet developed by the company, improved objectively measured cognitive function in a small group of people with lupus.
Keepers was one of 56 lupus patients randomly assigned to receive EG501 or an inactive placebo during a 12-week Phase 2 clinical trial called ClearMEMory that was conducted at the Vanderbilt Health Main Campus and two other centers. Within the first month, she guessed she was in the treatment group.
“I felt sharper,” said the 47-year-old former paramedic, who moved to Tennessee from Wisconsin with her husband, Jay, four years ago. “I could pay better attention … I could concentrate on what I was doing without losing track, without getting lost.”
“I am very optimistic about these results and hope that additional testing will bring a new therapeutic option to market for this population,” Leslie Crofford, MD, the study’s principal investigator and former director of the Division of Rheumatology and Immunology at Vanderbilt Health, said in a news release.
“ClearMEMory reinforces our conviction that cognitive dysfunction in lupus is a treatable, objective clinical problem,” added Charles Lee, MD, DrPH, co-founder and Chief Medical Officer of Evergreen Therapeutics, which sponsored the study.
Evergreen Therapeutics is now preparing for a larger, Phase 3 clinical trial to validate these results.
Lupus patients “often identify cognitive problems as among the most disabling (symptoms) they have,” said study co-investigator James Jackson, PsyD, research professor of Medicine at Vanderbilt Health. “We’ve got a lot more work to do, but I think (ClearMEMory) is really welcome news for people who need good news.”
‘Put it in patients’
The EG501 study was the inaugural project of Vanderbilt Health’s Drug Repurposing program, which was established in 2016 as part of the Vanderbilt Institute for Clinical and Translational Research (VICTR) to investigate new uses for drugs already on the market.
In October 2025, the drug repurposing team reported the results of another successful clinical trial. Adding guanfacine, a drug used to treat high blood pressure, to routine trigeminal nerve block injections enhanced pain relief in patients with trigeminal neuralgia — intense, sudden facial pain that can feel like an electric shock.
A phenome-wide association study (PheWAS) identified a link between genetic variants of a membrane receptor found in certain nerves and increased risk for trigeminal nerve disorders. Based on this finding, the researchers tested whether guanfacine, an “agonist” that activates adrenergic receptors at nerve terminals, might help relieve the pain.
Currently 11 therapeutic candidates are making their way through Vanderbilt Health’s development pipeline in autoimmune diseases, oncology, neuropathology and neuroscience, and skin and tissue repair.
Identifying new therapeutic uses for known compounds is a major emphasis area for the National Institutes of Health, which funds much of the nation’s basic biomedical research. Vanderbilt Health, a leader in genomic medicine and clinical trials, is uniquely positioned to meet the challenge.
Hundreds of computational models hinting at the potential therapeutic activity of various drugs have been published, but unless those models are studied in humans, “nobody knows if they work,” said Jillian Rhoads, PhD, a clinical scientist on VICTR’s drug repurposing team. “You’ve got to put it in patients.”
The EG501 project began with another PheWAS, a research innovation developed at Vanderbilt Health more than a decade ago that scours the de-identified electronic health records of patients whose DNA is stored in its biobank, BioVU, for symptoms or disease traits associated with specific genetic variations.
What “popped out” was a polymorphism, or genetic variation, expressed in lupus patients who also had cognitive symptoms. The variation increases the activity of an NMDA receptor in nerve cells in the brain that plays an important role in learning and memory.
Targeting the receptor
The finding raised an intriguing possibility: Perhaps drugs that “antagonize,” or turn down, the activity of the NMDA receptor could relieve the brain fog associated with lupus.
In 2022, the researchers partnered with Evergreen Therapeutics to explore NMDA receptor antagonists, including EG501, which in preliminary studies reduced neuroinflammation and provided neuroprotection in the brain.
Adults with lupus and cognitive dysfunction determined by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scoring system were recruited for ClearMEMory, a controlled, double-blinded, Phase 2 safety and efficacy trial of EG501 also conducted at the Cleveland Clinic and the University of Texas Health Science Center at Houston.
At 12 weeks, subjects in the EG501 group showed significantly greater improvement in objective cognitive performance as measured by a change in the RBANS Total Scale Index score, compared to those in the control group.
One of them was Keepers, who lives in Iron City, a tiny community in Lawrence County, just north of the Tennessee-Alabama state line.
Keepers is grateful for the “phenomenal” care she has received at Vanderbilt Health, and from the Drug Repurposing team, which she said is working “to make this disease better,” easier to bear.
She eagerly awaits the completion of the validation studies and market approval so she can begin taking EG501 again — and feel like herself once more.
Others who contributed to the EG501 project are Lillian Ahmad, MS; John Williams, PhD; Liping Du, PhD; Jana Shirey-Rice, PhD; VICTR Executive Director Jill Pulley, MBA; VICTR Director Wesley Self, MD, MPH; Erin Collar, MPH; Elizabeth Johnson; Sharon Phillips, MSPH; and Narender Annapureddy, MD.
In addition to Evergreen Therapeutics, support for the Drug Repurposing program was provided by the Kleberg Foundation and by a National Institutes of Health Clinical and Translational Science Award, UL1TR002243.
