Deferiprone Found to Worsen, Not Ease Symptoms in Phase 2 Trial
Iron-binding therapy failed to slow Parkinson's in new patients
Deferiprone, an iron chelator (binder) therapy, does not slow the progression of Parkinson’s disease in newly diagnosed patients who have never received treatment, according to data from a Phase 2 clinical trial.
Instead, after about nine months of treatment in these patients, deferiprone was associated with a worsening of motor and nonmotor symptoms compared with a placebo.
These findings support the non-involvement of brain iron buildup in Parkinson’s progression, as suggested by a study published earlier this year that found no signs of such association.
“In participants with early Parkinson’s disease who had never received [standard treatment] and in whom [such] treatment … was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks,” the researchers wrote.
The trial findings were published in the New England Journal of Medicine, in a study titled “Trial of Deferiprone in Parkinson’s Disease.”
Investigating brain iron buildup
In Parkinson’s disease, nerve cells that produce the brain-signaling molecule dopamine are progressively lost in certain parts of the brain, particularly the substantia nigra. Because dopamine helps control body movement and coordination, the loss of these cells leads to abnormally low dopamine levels and the onset of Parkinson’s symptoms.
Analyses of brain tissue from deceased Parkinson’s patients showed elevated iron levels in the substantia nigra, and excess iron in the brain has been linked to neuronal death in animal studies. Together, these findings suggest iron buildup may play a role in Parkinson’s development and/or progression.
However, a previous MRI imaging study reported that iron buildup in the substantia nigra did not contribute to disease development or progression but appeared to be related to disease duration and the use of levodopa, a dopamine precursor that’s used as a standard Parkinson’s treatment.
Deferiprone, sold by Chiesi Global Rare Diseases under the brand name Ferriprox, is a lab-made, orally-available, iron-chelating agent designed to reduce iron levels. It works by entering cells and removing toxic iron from organ tissues and fluids. It is approved to remove excess iron after blood transfusions in people with blood conditions such as sickle cell disease.
Small placebo-controlled trials investigating deferiprone in Parkinson’s have produced mixed results, with some indicating improvements in motor function and others reporting no motor effects.
The Phase 2 FAIRPARK-II clinical trial (NCT02655315) sought to shed light on the treatment’s effects by evaluating the impact of deferiprone in 372 adults. These patients were newly diagnosed with Parkinson’s but had yet to be treated with levodopa or other dopamine-related, or dopaminergic, therapies.
Participants were randomly assigned to receive either 15 mg per kilogram of deferiprone (186 patients) or a placebo (186 patients) twice daily for 36 weeks, or nearly nine months. Dopaminergic therapies were withheld unless patients needed them to control symptoms.
The study’s main goal was assessing changes in the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) total score at week 36. MDS-UPDRS is a measure of Parkinson’s severity covering motor and mental function, as well as activities of daily living, in which higher scores indicate worse disability.
Overall, 118 patients (63.4%) in the deferiprone group and 165 (88.7%) in the placebo group completed the trial. A greater proportion of individuals in the deferiprone group withdrew from the trial due to disease progression that warranted dopaminergic therapy compared with those on a placebo (22% vs. 2.7%).
Results showed that after 36 weeks, the mean MDS-UPDRS total score increased (worsened) by 15.6 points in deferiprone-treated patients versus 6.3 points among those on a placebo — a difference of 9.3 points in favor of the placebo.
These findings were not influenced by trial site, patients’ age, sex, total disability, or iron levels in the substantia nigra before treatment.
Deferiprone found to make disease worse
Data on secondary measures showed that all MDS-UPDRS subscores were higher in the deferiprone group than in the placebo group, indicating worse motor function, mood/behavior, and ability to perform activities of daily living.
Deferiprone treatment also was associated with worse quality of life, as assessed with the 39-item Parkinson’s Disease Questionnaire.
In participants with early Parkinson’s disease … deferiprone was associated with worse scores in measures of parkinsonism
MRI imaging analyses of a subgroup of patients found that the binder treatment led to a greater reduction in substantia nigra’s iron content than did the placebo, which demonstrated “target engagement of deferiprone,” the researchers wrote.
Levels of ferritin, a blood protein that stores iron, were reduced more with deferiprone than with a placebo, while the levels of prolactin, a hormone whose production is suppressed by dopamine, were more increased.
The team speculated that the iron-chelating effects of deferiprone may have reduced the activity of iron-dependent tyrosine hydroxylase, an enzyme critical for dopamine production.
As such, a deferiprone-induced drop in dopamine may have triggered symptoms instead of slowing disease progression. The higher prolactin levels detected in deferiprone-treated patients were consistent with this interpretation, they added.
Regarding safety, 87.1% of patients on deferiprone and 80.1% of those in the placebo group reported one or more adverse events or side effects. Serious adverse events were reported in 4.8% of patients in the placebo group and 9.7% of those receiving the treatment — and included a drop in white blood cell counts in some individuals.
“A total of 13 participants in the deferiprone group and 6 in the placebo group withdrew because of adverse events,” the researchers wrote.
Although side effects unrelated to Parkinson’s disease were similar between the two groups, a greater proportion of deferiprone-treated participants reported fatigue and psychiatric problems than those on a placebo.
“Despite evidence of target engagement of iron reduction in the substantia nigra of participants with Parkinson’s disease who had never received levodopa … 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,” the researchers wrote.
“Whether participants receiving dopaminergic therapy would have a different outcome remains unclear, but in trials of deferiprone involving a total of approximately 240 participants who were receiving dopaminergic therapy, no worsening in scores of Parkinson’s disease activity was observed with this agent, and some participants even had improvement in such scores,” they added.
Simply put, the researchers concluded that “deferiprone was associated with adverse events.”
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