Iron Chelation Clinical Trials
All NBIA disorders share iron accumulation in the globus pallidus structure of the brain. It remains unclear, however, whether excess iron causes NBIA or is brought on by some other problem. Iron chelating drugs were thought to be a potential NBIA therapy by removing excess iron from the brain.
Iron chelating agents have been tried without clear benefit. Initially, trials were limited by the development of systemic iron deficiency before any clinical neurologic benefits were evident.
A long-term deferiprone (iron chelator) study with 88 participants with Pantothenate Kinase-Associated Neurodegeneration (PKAN) was done from December 2012 to April 2015 through an international trial conducted at clinical centers in the US, Germany, Italy and the United States under a 5.2 million euros (approximately 7 million USD) EU grant called Treat Iron-Related Childhood-Onset Neurodegeneration, or TIRCON. Unlike earlier drugs, deferiprone crosses the blood-brain barrier and removes intracellular iron. There was also an open label extension study for an additional 18 months which completed in 2018 where the drug was made available to everyone who took part in the trial.
The study was a gold standard study: randomized, double-blind and placebo-controlled. “Placebo-controlled” means that in the context of the study, deferiprone was compared with a placebo. A placebo looks identical to the deferiprone but does not contain any active ingredient.
This study showed that while the drug successfully reduced the amount of accumulated iron in the brain for PKAN individuals regardless of onset age, the treatment was not effective for PKAN patients in a statistically significant way. The study found a slight indication that deferiprone may slow the progression of the disorder in older patients with later-onset, or atypical PKAN.
The lead investigator of the trial in the United States, Dr. Elliot Vichinsky of the University of California, San Francisco Benioff Children’s Hospital in Oakland, said that older and younger PKAN individuals showed improvement with deferiprone in dystonia of the lower face and lower legs, as well as in cognitive functioning, especially memory. But the benefit in younger children, who tend to have a faster-moving, more severe form of PKAN was less than that of older adults with a later onset of disease, and neither was statistically significant.
Vichinsky said, "The drug was well-tolerated, and the safety profile was very good."
But because the study did not meet a key goal - showing a statistically important improvement from deferiprone in all age groups – the U.S. Food and Drug Administration has not approved it for use in PKAN.
Published papers on this work:
2019 - Safety and efficacy of deferiprone for pantothenate kinase-associated neurodegeneration: a randomised, double-blind, controlled trial and an open-label extension study