Trial of Cholesterol Medication in Barth Syndrome Patients Opens in UK

The Barth Syndrome Foundation (BSF) and the Barth Syndrome UK announced the start of the CARDIOMAN clinical trial evaluating whether bezafibrate, a cholesterol medicine, can treat boys and men with a rare mitochondrial disease called Barth syndrome.

The trial is running in Bristol, England, and was made possible by a joint effort of academic centers and organizations in the U.K. and abroad. It expects to conclude in December, and is recruiting patients ages 6 and older.

Barth syndrome, caused by mutations in the tafazzin (TAZ) gene, is a rare and life-threatening disease of males with no approved therapies.

Tafazzin, the protein this gene produces, is needed for cells to make a mature, functional version of cardiolipin, a type of lipid (fatty compound) found at the inner membrane of mitochondria — the ‘powerhouses’ of cells. Cardiolipin is crucial for maintaining mitochondrial shape, energy production, and protein transport within cells.

Many Barth syndrome patients have problems metabolizing fats, leading to a buildup of monolysocardiolipins (MLCL) and fewer mature cardiolipins (specifically tetralinoleylcardiolipin, L4-CL) in various tissues. This impairs mitochondrial activity, potentially driving the disease.

Among Barth’s defining characteristics is an enlarged and weakened heart (dilated cardiomyopathy), and a risk of heart failure.

Bezafibrate works to lower the levels of lipids, such as cholesterol and triglycerides. Approved since 1978 (and sold under brand names that include Bezalip, Cedur, Eulitop, and Befizal), bezafibrate is available in Canada and the European Union but not in the U.S.

CARDIOMAN (2015-001382-10) is a randomized, double-blind, placebo-controlled trial to investigate the safety and efficacy of bezafibrate on lipid metabolism and heart function in up to 18 boys and young men with Barth syndrome. The trial is primarily taking place at the University Hospitals Bristol NHS Foundation Trust (UHB).

Researchers believe the compound will promote mitochondrial growth and bring MLCL to L4-CL ratios closer to normal.

Bezafibrate or an inactive placebo will be given patients for four months, followed by a one month break. Then these patients will switch treatment for another four months, meaning that those initially given bezafibrate will move to placebo and vice versa.

Participants will be assessed at the study’s start and at the end of each four-month treatment period for changes in blood cells, exercise capacity, quality of life, and other variables. Heart function will be evaluated during exercise stress by ultrasound imaging.

Laboratory work at University of Bristol (UoB) and Great Ormond St Hospital will try to identify markers for future use based on bezafibrate’s effects on enrolled patients’ cells and mitochondria. A natural substance called resveratrol, which has shown cardiovascular promise in the lab, will also be tested.  

“Bezafibrate offers hope that we may discover a safe and effective therapy to fight this debilitating disease in children and adults,” Colin Steward, the trial’s principal investigator and founder of the Barth Syndrome Service at the UHB, in a press release.

CARDIOMAN is the second trial in Barth syndrome. TAZPOWER (NCT03098797) underway in Baltimore, is evaluating the efficacy of under-the-skin injections of elamipretide, a potential mitochondrial treatment being developed by Stealth BioTherapeutics.

“Five years ago, a clinical trial in Barth syndrome seemed elusive. We are now on the advent of multiple trials that have built on the innovation and scientific network that BSF has seeded over the years across the globe,” said Emily Milligan, the foundation’s executive director.

Funding from the U.K.’s Medical Research Council (MRC) and National Institute for Health Research (NIHR) are supporting the study.

More information about CARDIOMAN is available on its official BSF site here.