In a landmark development for patients with a rare genetic disorder, the U.S. Food and Drug Administration (FDA) has approved chenodeoxycholic acid, marketed as Ctexli, for the treatment of cerebrotendinous xanthomatosis (CTX). The approval in February 2025 marks the culmination of decades of research at Oregon Health & Science University (OHSU) and offers new hope to families affected by this devastating condition.
CTX is a rare recessive genetic disorder that impairs the body's ability to metabolize cholesterol, resulting in the accumulation of sterol molecules throughout the body. Patients typically experience chronic diarrhea from birth, juvenile cataracts, seizures, developmental delays, and intellectual disability. As the disease progresses, patients may develop tendon xanthomas—sterol deposits in tendons—and severe neurological issues including cognitive decline and dementia.
Decades of Research Lead to Breakthrough
The journey to FDA approval began with pioneering work by William E. Connor, M.D., and his wife, Sonja Connor, R.D., M.S., at OHSU. Their research on rare diseases linked to abnormalities in cholesterol and related sterol molecules laid the foundation for subsequent breakthroughs.
Andrea DeBarber, Ph.D., research associate professor in the OHSU School of Medicine, has continued this work for the past decade, developing improved biomarker tests for CTX and advocating for FDA approval of the treatment.
"This drug has been the standard of care for CTX for the last 40 years or so," DeBarber explained. "It replaces the missing bile acid in people with CTX, it normalizes their biomarker levels, and stabilizes or improves clinical manifestations, preventing further disease progression."
In 2019, the OHSU Sterol Analysis Laboratory became the first lab in the United States to offer sensitive testing to measure bile alcohol biomarkers in the urine of CTX patients, significantly improving diagnostic capabilities. This advancement was crucial, as researchers discovered that some patients with CTX may have normal plasma cholestanol levels but abnormal bile alcohol concentrations.
The RESTORE Clinical Trial
The pivotal moment came in 2020 when the OHSU Sterol Analysis Laboratory partnered with Mirum Pharma for the RESTORE clinical trial, designed to gather data for FDA approval of chenodeoxycholic acid for CTX. This was the first clinical trial of its kind for the condition.
"This achievement was made possible by the Sterol Analysis Laboratory's work over the last 10 years to develop sensitive tests for CTX biomarkers," said Igor Landais, Ph.D., a quality assurance expert at the OHSU Vaccine & Gene Therapy Institute. "OHSU's is the only lab in the world that could perform some of these tests to the exacting standards required by the FDA."
P. Barton Duell, M.D., professor of medicine in the OHSU School of Medicine and director of the Sterol Analysis Laboratory since 2005, collaborated to oversee the clinical trial. "The results of the RESTORE study provided critical data that convinced the FDA to approve chenodeoxycholic acid for treatment of CTX," he said.
A Mother's Advocacy Journey
The human impact of this approval is perhaps best illustrated by the story of Susan Stewart and her son, Eric. When Eric was 2 years old, Stewart noticed his speech wasn't developing normally. Despite consulting multiple specialists, Eric's condition remained undiagnosed as his health deteriorated.
"He was in a wheelchair by age 14," Stewart recalled. "I saw him dying before my eyes. We had to stop Special Olympics because he didn't have the energy anymore."
After years of searching for answers, Stewart found information about rare genetic disorders and eventually connected with Dr. Connor at OHSU. A series of tests measuring abnormal sterol biomarkers led to Eric's diagnosis at age 16: he had CTX.
Dr. Connor recommended treatment with chenodeoxycholic acid, which at the time was approved for gallstones but not for CTX.
"At the time, it wasn't even made in the U.S., so I had to pay for it out-of-pocket from England," Stewart said. "Eventually it became available in the U.S., but we had to fight to get it covered because it was off-label usage."
The treatment has dramatically improved Eric's quality of life. Now 34, he no longer uses a wheelchair and has regained some independence. While still nonverbal and living in a group home, his disease progression has stopped.
Push for Newborn Screening
Despite this significant advancement, advocates believe more work remains to be done. Stewart, DeBarber, and Duell are all members of the CTX Alliance, which is advocating for CTX to be added to the Recommended Uniform Screening Panel (RUSP) for newborn screening.
DeBarber has collaborated with researchers at the University of Washington and in the Netherlands to develop biomarker testing that can screen newborns for CTX. With a reliable test now available and an FDA-approved treatment, the team is preparing to present new data to support adding CTX to the RUSP.
"Some of the infants who have CTX die very early of liver disease, and others slowly progress until they are in their 30s or 40s," Stewart explained. "It's a horrible disease, but it's treatable now. No children should have to suffer the way Eric did."
Early diagnosis is critical because treatment can prevent disease progression but cannot reverse damage that has already occurred. DeBarber emphasized the urgency of newborn screening: "It's heartbreaking to see children and adults who had to wait too long for a diagnosis or who've been misdiagnosed and whose disease has progressed too far. We want to try and make sure every patient has access to early diagnosis and treatment."
Implications for Rare Disease Research
The approval of Ctexli represents a significant milestone in rare disease research and treatment. It demonstrates how dedicated research at academic institutions, partnerships with pharmaceutical companies, and patient advocacy can come together to address unmet medical needs.
Andrew Chitty, M.B.A., director of OHSU's University Shared Resources program, noted that supporting this clinical trial allowed the core laboratory to build critical infrastructure at OHSU, including obtaining analytical instruments required for human clinical trials.
For patients and families affected by CTX, the FDA approval means improved access to a life-changing treatment. For researchers and clinicians, it validates decades of work and provides a foundation for further advances in diagnosing and treating rare genetic disorders.
As the CTX Alliance continues to push for newborn screening, there is hope that future generations of patients will benefit from early diagnosis and treatment, potentially avoiding the devastating progression of this rare but treatable disease.
