By Alexander Shtilbans, MD, PhD
Assistant Professor of Neurology, Weill Cornell Medical College
SYNOPSIS: In a randomized, placebo-controlled treatment trial, deferiprone administered to early, levodopa-naive Parkinson’s disease patients over 36 weeks was associated with worsening of their symptoms, in spite of imaging evidence for reduction of iron in the substantia nigra.
SOURCE: Devos D, Labreuche J, Rascol O, et al. Trial of deferiprone in Parkinson’s disease. N Engl J Med 2022;387:2045-2055.
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. Despite global research efforts, there still are no proven neuroprotective or disease-modifying drugs. Overaccumulation of intracellular iron in the substantia nigra of patients with PD has been observed and thought to be associated with activation of microglia and neuroinflammation, causing oxidative stress, formation of reactive oxygen species (ROS), and, ultimately, neurodegeneration. Preliminary small clinical trials using an oral iron chelator, deferiprone, which crosses the blood-brain barrier, have shown that treatment decreased iron in the substantia nigra and produced transient improvements in the motor scores of PD patients, but its effect on disease progression was unclear.
The FAIRPARK-II study investigators conducted a Phase II, multicenter, randomized, double-blind, placebo-controlled treatment trial of deferiprone in patients with early PD who were never treated with levodopa. From 2016 to 2019, the study randomized 186 subjects to each arm, and they were included in the intention-to-treat analysis. Demographic characteristics of the patients within the two groups were comparable except for slightly longer disease duration in the deferiprone group.
Participants received oral deferiprone at a dose of 15 mg per kilogram twice daily or matching placebo for 36 weeks, followed by a four-week washout period. They were evaluated every 12 weeks and at the end of the 40-week period.
One hundred seventeen participants from the active arm and 165 from the placebo group completed the study. The primary endpoint was the change from baseline to week 36 in the Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) total score (parts I-IV). The secondary outcomes were changes in activities of daily living and motor function and the sum of scores in these two parts between baseline and week 36.
To confirm target engagement, brain iron levels were measured with magnetic resonance imaging (MRI) T2* sequence in some of the patients. Dopaminergic function was measured in all participants by DaTscans at baseline and at week 40. Twenty-two percent of the patients in the deferiprone arm and 2.7% from the placebo arm required levodopa therapy and withdrew from the study. Thirteen participants in the active group and six in the placebo group withdrew because of adverse events, including agranulocytosis and neutropenia. The most common adverse event was fatigue (24.7% in deferiprone group and 11.3% in placebo group).
At the end of the trial, mean MDS-UPDRS total score increased (worsened) by 15.5 points with deferiprone and by 6.3 points with placebo. MDS-UPDRS scores for activities of daily living and motor function also were higher (worse) in deferiprone-treated patients compared to placebo. Brain MRI showed a greater decrease in iron accumulation in deferiprone group compared with placebo. DaT binding was similar in both groups at week 40. Plasma ferritin levels decreased more with deferiprone than with placebo.
The authors concluded that while deferiprone reduced brain iron accumulation in the substantia nigra, putamen, and caudate nuclei, it did not confer neuroprotection, but was associated with symptomatic worsening over a 36-week period.
COMMENTARY
The observed worsening of patients taking deferiprone in this study was a surprise, since previous small studies in patients on concurrent dopaminergic medications showed mild symptomatic improvement in those taking deferiprone.
Although overaccumulation of iron in the substantia nigra may be toxic to dopaminergic neurons and result in neurodegeneration, iron also is a cofactor of tyrosine hydroxylase, which is responsible for conversion of tyrosine to dopamine. Therefore, removal of iron may have reduced formation of dopamine, which in turn caused symptomatic worsening but did not accelerate the progression of the disease. For example, some mutations in tyrosine hydroxylase are known to cause dopamine responsive dystonia (DRD), which can mimic parkinsonism. Very small doses of levodopa significantly improve the symptoms in DRD, and this may explain why the results of earlier clinical studies of deferiprone in PD patients taking dopaminergic medications were somewhat positive. To overcome this confounding factor, an iron chelator should be tested on patients taking levodopa, and a trial could employ a delayed start design, which can differentiate a symptomatic effect from a disease-modifying one.
The duration of the study (36 weeks) may have been too short to see a disease-modifying effect of deferiprone. Moreover, the sensitivity of a DaTscan might not be high enough to discern changes over a 40-week period. MRI imaging measured iron content and not neuromelanin, which is a natural chelator of brain iron, and usually decreases with progression of PD.
However, over-accumulation of iron in the substantia nigra in PD patients is real and pathogenic, thus representing a legitimate target for potential disease-modifying therapy. We know that multiple pathways are involved in the complex neurodegenerative process of PD. Therefore, a combination of several medications targeting additional disease mechanisms, such as misfolded alpha-synuclein, neuroinflammation, and mitochondrial dysfunction, might show additive or synergistic efficacy to slow PD progression.
