Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson's disease

Abstract

Parkinson's disease (PD) is associated with increased iron levels in the substantia nigra (SNc). This study evaluated whether the iron chelator, deferiprone, is well tolerated, able to chelate iron from various brain regions and improve PD symptomology. In a randomised double-blind, placebo controlled trial, 22 early onset PD patients, were administered deferiprone, 10 or 15 mg/kg BID or placebo, for 6 months. Patients were evaluated for PD severity, cognitive function, depression rating and quality of life. Iron concentrations were assessed in the substantia nigra (SNc), dentate and caudate nucleus, red nucleus, putamen and globus pallidus by T2* MRI at baseline and after 3 and 6 months of treatment. Deferiprone therapy was well tolerated and was associated with a reduced dentate and caudate nucleus iron content compared to placebo. Reductions in iron content of the SNc occurred in only 3 patients, with no changes being detected in the putamen or globus pallidus. Although 30 mg/kg deferiprone treated patients showed a trend for improvement in motor-UPDRS scores and quality of life, this did not reach significance. Cognitive function and mood were not adversely affected by deferiprone therapy. Such data supports more extensive clinical trials into the potential benefits of iron chelation in PD.

Conflict of interest statement

Whilst Michael Spino, John Connelly and Fernando Tricta are employees of ApoPharma Inc., the drug company did not financially sponsor the clinical trial; however they did generously donate free of charge deferiprone and matched placebo and helped with the critique of the manuscript.

Figures

Figure 1

Flow diagram showing the random assignments of the two doses of deferiprone, 20 or 30 mg/kg and placebo to the 22 Parkinson’s disease patients.

Figure 2

Percentage change in the median UPRDS III motor scale of PD patients receiving placebo (A, n = 8), 20 (B, n = 6) or 30 (C, n = 5) mg/kg/deferiprone for 2, 4 and 6 mg of treatment. Values are presented in box plots with whiskers representing the minimum and maximum values.

Figure 3

Mean T2* MRI values in the dentate nucleus (A) and caudate nucleus (B) of Parkinson’s disease subjects receiving 20 mg/kg/day, (grey bars, n = 6) or 30 mg/kg/day (black bars n = 5) mg/kg/day deferiprone or placebo (open bars, n = 8) at 3 months and 6 months. Values are represented as mean ± SEM. T2* value is prior to the commencement of treatment, and then after 3 and 6 months of drug treatment. **p < 0.01 as assessed by Pairwise comparison.

Figure 4

Percentage change in the median plasma ferritin values of PD patients receiving placebo (A, n = 8), 20 (B, n = 6) or 30 (C, n = 5) mg/kg/deferiprone for 2, 4 and 6 mg of treatment. Values are presented in box plots with whiskers representing the minimum and maximum values.

Figure 5

Examples of changes in ferritin levels and T2* values in two PD patients receiving chelation therapy for 6 months. (A) Plasma ferritin level <100 ng/ml at the beginning of the study (B) plasma ferritin level >300 ng/ml. Ferritin values are denoted by circles, caudate nucleus T2* values by upright triangles, dentate nucleus values by downward triangles and substantia nigra by squares.

Figure 6

Correlation between IL-6 (pg/ml) and ferritin (ng/ml) baseline values from all clinical trial PD subjects. Statistical evaluation is by non-parametric correlation of Spearman (r = 0.5751, p = 0.005).