FAIRPARK II
Research type
Research Study
Full title
Conservative iron chelation as a disease-modifying strategy in Parkinson's disease.
IRAS ID
196056
Contact name
David Burn
Contact email
Sponsor organisation
Centre Hospitalier Regional et Universitaire de Lille
Eudract number
2015-003679-31
Duration of Study in the UK
2 years, 10 months, 14 days
Research summary
Research Summary:
Parkinson’s disease (PD) is a common, chronic, fast-progressing disease. None of the currently available drugs can slow down the dramatic progression of the motor handicap (e.g. falls) and non-motor handicap (dementia), which generally lead to institutionalisation and death. At present, only symptomatic treatments are available (i.e., drugs that partially and transiently reduce the patient’s level of handicap). None of the treatments have demonstrated the ability to decrease the long-term progression of handicap. For many years, the excess oxidative stress related to mitochondriopathy (a disease caused by a mutation part of the DNA) has been considered as one of the main mechanisms involved in cell death. Oxidative stress is made worse by free iron. Chelation (binding) of this free iron is known to dramatically increase cell survival. However, to develop this therapeutic approach in humans, binding strategies that target local and regional iron overload in the brain will need to avoid general iron depletion via the redistribution of iron to endogenous acceptors (i.e. in order to prevent harmful systemic metal loss): this is the new concept of “conservative iron chelation”. We recently demonstrated the feasibility, efficacy and acceptability of the conservative iron chelation approach in pilot translational studies in PD with a prototype drug: deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one, DFP) (in the FAIR-PARK-I project led by the applicant and funded by French Ministry of Health). The only available blood-brain-barrier-permeable iron chelator DFP is approved for treating systemic iron overload in transfused patients with thalassemia. DFP has been on the EU market since 1999, with a favourable risk/benefit balance at dose of 75 to 100 mg/kg/day. We shall adopt a repositioning strategy by using DFP at a lower dose of 30 mg/kg/day in this new indication for local iron overload in PD. DFP will be the first-in-class drug for this novel therapeutic strategy.Summary of Research:
Parkinson's disease (PD) affects millions of people worldwide and is characterized by the loss of brain cells (neurons) that produce dopamine – a molecule which is essential for the control of normal movement. Drug treatments that replace missing dopamine can markedly improve the symptoms of PD but cannot slow or stop the further loss of nerve cells and the disease from getting worse over time.Iron is involved in the production and breakdown of dopamine. It has been shown that reducing iron levels can limit nerve cell death. Deferiprone is a drug that can reduce iron levels.
Earlier studies in small groups of patients with PD have suggested that treatment with Deferiprone, as well as the use of dopamine-replacing drugs, not only reduces brain iron accumulation but also improves normal movement.
The FAIRPARK-II study enrolled 372 people with PD in centres across Europe to test whether Deferiprone could slow disease progression when given soon after diagnosis. Patients consenting to participate were randomly assigned to receive either oral deferiprone (186 participants) or identical appearing placebo (186 participants) for 9 months. The treatment was ‘double-blind’ i.e. patients and treating physicians were unaware of which treatment they were receiving.
Analysis of the FAIRPARK-II study results indeed showed that deferiprone reduced iron in the brain areas important for the control of movement. However, surprisingly, treatment with Deferiprone did not improve movement control over the 9 months of the study. In fact, Deferiprone treated patients had worse symptoms.
This finding is unexpected and requires re-thinking of current concepts of the role of brain iron in PD.
Although the results of FAIRPARK-II unfortunately do not allow us to propose a new treatment to slow down PD in the short term, they are important in understanding the role of iron in the brain in PD patients. Further investigation of the role that iron might play in PD is needed.
REC name
North East - Tyne & Wear South Research Ethics Committee
REC reference
16/NE/0200
Date of REC Opinion
19 Jul 2016
REC opinion
Further Information Favourable Opinion