Binding to, or chelating, toxic levels of iron in the brain can slow the progression of a neurodegenerative disorder known as pantothenate kinase-associated neurodegeneration (PKAN), results from a Phase 3 trial show.
These findings may be relevant for other neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s and multiple sclerosis, which are also associated with high levels of iron in the brain, its researchers say.
The results, ”Safety and efficacy of deferiprone for pantothenate kinase-associated neurodegeneration: a randomised, double-blind, controlled trial and an open-label extension study,” were published in the journal The Lancet Neurology.
Iron is required for normal physiological functions; however, excessive levels can be toxic and abnormal high levels of iron are seen in several neurodegenerative diseases, from PKAN to Parkinson’s, Alzheimer’s, and MS.
Researchers conducted a Phase 3 trial (NCT01741532), called TIRCON, to evaluate the safety and efficacy of deferiprone in treating PKAN, a form of neurodegeneration that results in severe, involuntary muscle contractions (dystonia).
Deferiprone is an oral iron chelator approved to treat conditions linked with iron overload after blood transfusions in people with thalassemia, an inherited blood disorder characterized by lower levels of hemoglobin and fewer red blood cells.
The trial enrolled 88 patients with pantothenate kinase-associated neurodegeneration from four hospitals in Germany, Italy, England and the US. The participants, ages 4 and older, were randomized to deferiprone at 30 mg/kg a day (divided into two equal doses) or a placebo. Treatment was maintained for 18 months followed by an 18-month open-label extension phase, the TIRCON-Extension trial (NCT02174848).
Using magnetic resonance imaging (MRI) scans of the brain, researchers observed that treatment with deferiprone significantly lowered concentrations of iron in a specific part of the brain, called the globus pallidus, after 18 months compared to levels in the placebo group.
The globus pallidus is a region that is connect to several brain regions, and supports functions that include motivation, cognition and action.
Treatment with deferiprone also decreased the number of PKAN patients who required other medications to control dystonia (11% compared to 21% in the placebo group). Slight, but not significant, improvements in disease progression with deferiprone treatment after 18 months were also seen compared to placebo. This was assessed using the Barry-Albright Dystonia (BAD) scale, which tests the severity of dystonia in eight different body regions.
This improvement appeared to be greater in a subset of later-onset patients with atypical pantothenate kinase-associated neurodegeneration, who had almost a 50% slower disease progression rate when treated with deferiprone compared to placebo. In placebo group patients who switched to deferiprone treatment in the TIRCON-extension trial, disease progression slowed by more than 60%.
Deferiprone appeared to be well-tolerated, with placebo and treatment groups reporting similar side effects. Anemia was the exception, as 21% of deferiprone treated patients reporting this side effect compared to no patients in the placebo group.
“The finding that brain iron can be markedly lowered by a chelator may have important implications also for age-associated neurodegenerative conditions such as Parkinson’s disease,” Thomas Klopstock, the Ludwig-Maximilians-University of Munich and the study’s first author, said in a news release.