Brain Iron Chelation Linked With Worse Outcomes in Early Parkinson's

 Brain iron chelation with deferiprone was associated with worse parkinsonism symptoms and adverse events in early Parkinson's disease, the FAIRPARK-II trial showed.

From baseline to week 36, mean total scores on the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) worsened more with deferiprone than placebo, reported David Devos, MD, PhD, of Université Lille in France, and co-authors in the New England Journal of Medicine.

Mean MDS-UPDRS scores were 34.3 in the deferiprone group and 33.2 in the placebo group at baseline. At 36 months, scores worsened by 15.6 points with deferiprone and 6.3 points with placebo (difference 9.3 points, 95% CI 6.3-12.2, P<0.001).

Symptom progression led to dopaminergic therapy in 22.0% of the deferiprone group and 2.7% of the placebo group. Nigrostriatal iron content decreased more in the deferiprone group, indicating target engagement. A total of 9.7% of people in the deferiprone group and 4.8% in the placebo group had serious adverse events.

The findings preclude testing higher doses of deferiprone and argue against further exploring the drug in Parkinson's disease, noted Douglas Galasko, MBBCh, of the University of California, San Diego, and Tanya Simuni, MD, of Northwestern University in Chicago, in an accompanying editorial.

"The FAIRPARK-II trial provides evidence that deferiprone does not slow progression in Parkinson's disease, but the data from this trial could nevertheless stimulate studies to clarify the role of iron in the pathogenesis of Parkinson's disease," Galasko and Simuni wrote. "However, the findings raise cautions about iron chelation as a therapeutic intervention in neurodegenerative disorders."

Iron deposition in the brain occurs with aging and has been implicated in Parkinson's and other neurodegenerative disorders. Brain iron may be a plausible therapeutic target, but it also has a biological role in Parkinson's as a cofactor for tyrosine hydroxylase activity.

FAIRPARK-II was a phase II study of 372 people with newly diagnosed Parkinson's disease who had never received levodopa. Participants were screened from February 2016 through December 2019; they had a mean age of about 62 at baseline, and nearly two-thirds were men.

For 36 weeks, 186 people received oral deferiprone at 15 mg per kilogram of body weight twice a day and 186 people received placebo. The primary outcome was the change from baseline in MDS-UPDRS total scores, which range from 0 to 260 with higher scores representing worse impairment. The MDS-UPDRS assesses mental function, activities of daily living, and motor function.

A total of 118 participants (63.4%) in the deferiprone group and 165 (88.7%) in the placebo group completed the trial at week 36.

The primary outcome was imputed for 54 people in the deferiprone group and 11 people in the placebo group. Forty-one participants (22.0%) on deferiprone and five (2.7%) on placebo withdrew from the trial because their disease progression warranted dopaminergic therapy. Another 13 deferiprone participants and six placebo participants withdrew due to adverse events.

Brain MRI in a subgroup of participants showed that deferiprone was associated with a greater reduction of iron content in nigrostriatal pathways, particularly in the substantia nigra. Dopamine transporter imaging showed no differences between deferiprone and placebo.

Parkinson's disease progression was reported as an adverse event in 24.2% of the deferiprone group and 7.0% of the placebo group. Serious adverse events included agranulocytosis in two participants in the deferiprone group and neutropenia in three.

Deferiprone's detrimental effects became evident as more people left the trial to start dopaminergic therapy and by visual inspection of MDS-UPDRS graphs at month 3, Devos and co-authors noted.

"We speculate that the early separation of curves in favor of the placebo group may be consistent with a negative symptomatic effect of deferiprone rather than an accelerating effect on underlying disease progression," the researchers wrote.

"This conjecture is based on chelation of brain iron by deferiprone that presumably reduced activity of tyrosine hydroxylase, the rate-limiting enzyme for dopamine production, which is consistent with the increased levels of plasma prolactin, an inhibitor of which is dopamine," the team added.

Results should be viewed in the context of a hypothesis that deferiprone would have superior clinical outcomes, Devos and colleagues noted. "There was also a need for imputation of a large amount of clinical outcome data owing to participant dropout, particularly in the deferiprone group, and a lack of racial diversity."

Disclosures

The trial was supported by the European Union Horizon 2020 funding program. ApoPharma and Chiesi provided deferiprone and placebo for the study.

Devos reported no disclosures.

Galasko reported personal fees from Biogen, GE Healthcare, Springer, Eisai, Generian, and Cognition Therapeutics.

Simuni reported grants or personal fees from 4D Pharma, Acadia, AcureX, AskBio, Amneal, Blue Rock Therapeutics, Caraway, Critical Path for Parkinson's Consortium, Denali, Michael J. Fox Foundation, NeuroDerm, Roche, Sanofi, Sinopia, Sunovion, Takeda, UCB, Vanqua Bio, Voyager, Biogen, NINDS, Parkinson's Foundation, and Prevail.

Primary Source

New England Journal of Medicine

Source Reference: Devos D, et al "Trial of deferiprone in Parkinson's disease" N Engl J Med 2022; DOI: 10.1056/NEJMoa2209254.

Secondary Source

New England Journal of Medicine

Source Reference: Galasko D, Simuni T "Lack of benefit of iron chelation in early Parkinson's disease" N Engl J Med 2022; DOI: 10.1056/NEJMe2213120.

https://www.medpagetoday.com/neurology/parkinsonsdisease/102035