Deferiprone use to reduce substantia nigra iron accumulation in Parkinson’s disease failed to halt disease progression in a recent RCT
Deferiprone which acts as an iron chelating agent, failed to delay the progression of symptoms in patients diagnosed with early Parkinson’s disease prior to treatment with levodopa according to a recent randomised trial by French researchers.
Globally, Parkinson’s disease is estimated to affect around 10 million people. It is a neurodegenerative disorder that mostly presents in later life, with generalised slowing of movements (bradykinesia) and at least one other symptom of resting tremor or rigidity, due to the loss of dopaminergic activity in the substantia nigra. Within the central nervous system, iron is present in several proteins involved in important processes such as oxygen transportation, oxidative phosphorylation and the synthesis and metabolism of neurotransmitters. However, during ageing, different iron complexes accumulate in brain regions and changes in iron homoeostasis result in altered cellular iron distribution and accumulation in diseases such as Alzheimer’s and Parkinson’s disease. It has therefore been proposed that a moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality for Parkinson’s disease. Deferiprone is the only orally active iron-chelating drug to be used therapeutically in conditions of trans fusional iron overload. Moreover, early data suggests that deferiprone use in early Parkinson’s disease, did lead to a reduction in substantia nigra iron levels in a small number of patients. As a result, in the current trial, the French team undertook, a phase 2, randomised, double-blind trial involving participants with newly diagnosed Parkinson’s disease who had never received levodopa. Participant were randomised 1:1 to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. The team set the primary outcome as the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and which ranges from 0 to 260, with higher scores indicating more severe impairment, at 36 weeks.
Deferiprone and outcomes in early Parkinson’s disease
A total of 372 participants with a mean age of 62.5 years (37% female) were randomised to deferiprone (186) or placebo. The mean MDS-UPDRS baseline score was 34.3 and 33.2 in the deferiprone and placebo groups respectively.
At week 36, the MDS-UPDRS score increased by 15.6 points (i.e., worsened) in the deferiprone group and by 6.3 points with placebo. (mean difference = 9.3, 95% CI 6.3 – 12.2, p < 0.001).
When the researchers looked at iron levels in the brain among a subgroup of 148 patients (70 in the placebo arm), there was a greater decrease among those assigned to deferiprone (-0.65 vs -0.17).
Based on these findings, the authors concluded that despite reducing iron brain levels, deferiprone use was associated with worse scores in measures of Parkinsonism than in those with placebo over a period of 36 weeks.
Devos D et al. Trial of Deferiprone in Parkinson’s Disease. N Eng J Med 2022