Deferiprone effectively reduced iron deposition in the substantia nigra, but it did not beneficially reduce symptom progression, and, instead, was associated with clinically worse symptoms and adverse events in patients newly diagnosed with Parkinson disease (PD). These are the findings of a study published in The New England Journal of Medicine.
Individuals with PD present with higher iron content in the substantia nigra, a feature that may promote symptom progression and contribute to the pathophysiology of the disorder. Deferiprone is an iron chelator, which may effectively reduce iron deposition in the nigrostriatal pathways of patients with PD; however, no study to date has provided evidence of the effects of deferiprone on PD progression.
Researchers conducted a multicenter, international, randomized, double-blind, placebo-controlled, phase 2 trial (FAIRPARK-II; ClinicalTrials.gov Identifier: NCT02655315) across 23 sites from February 2016 to December 2019 to assess the impact of deferiprone on disease progression in 372 adults newly diagnosed with PD (mean age, 62 years; participants, two-thirds men). These individuals had never taken levodopa.
The researchers randomly assigned 186 patients to the intervention group and 186 to the placebo group. Patients in the intervention group received 15 mg per kilogram of body weight of oral deferiprone twice daily while those in the comparator group received a matched placebo for a total of 36 weeks followed by a 4-week wash-out period.
They assessed the patients at baseline and weeks 12, 24, 36, and 40. Comprehensive outcome assessments occurred at baseline and weeks 36 and 40 after a wash-out period, while safety checks and disease progression occurred at weeks 12 and 24.
After 36 weeks of treatment, the effect of deferiprone on PD symptom progression was measured against placebo using the change in total score on the Movement Disorder Society’s revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) from baseline.
Average MDS-UPDRS scores for the deferiprone group increased from 34.3 at baseline by 15.6 points, while average scores in the placebo group increased from 33.2 at baseline by 6.3 points (mean difference between groups: 9.3 points; 95% CI, 6.3-12.2; P <.001).
A small subgroup of patients from 10 of the 23 sites underwent magnetic resonance imaging (MRI) scans to allow for visualization of the effect of deferiprone on iron deposition throughout the nigrostriatal pathway. These MRI scans indicated that deferiprone effectively reduced iron deposition, which decreased more in the intervention group than the placebo group.
PD symptom progression necessitated initiation of dopaminergic therapy in 22% of patients (n=41) in the deferiprone group compared with only 2.7% in the placebo group (n=5), resulting in withdrawal from the study.
During the study period, the most serious adverse events that occurred in the deferiprone group included agranulocystosis (n=2) and neutropenia (n=3). In total, 13 patients in the intervention group and 6 in the placebo group withdrew due to adverse events.
“Despite evidence of target engagement of iron reduction in the substantia nigra of participants with Parkinson’s disease who had never received levodopa and in whom treatment with a dopamine agonist was not planned, deferiprone was not associated with benefit as compared with placebo in measures of the progression of Parkinson’s disease, and there was evidence of clinical worsening.”
Study limitations included lack of racial diversity, high participant dropout rates (particularly in the deferiprone group) requiring imputation, and results which opposed the initial hypothesis that deferiprone would slow PD symptom progression and improve functional outcomes compared with placebo.
The trial was funded by the European Union Horizon 2020 funding program through the FAIR PARK II network.
Devos D, Labreuche J, Rascol O, et al. Trial of deferiprone in Parkinson’s disease. N Engl J Med. Published online December 1, 2022. doi:10.1056/NEJMoa2209254