The promise of targeting iron in the brain for Parkinson’s

Iron is often discussed in connection to red blood cells where too little of it can cause anaemia. However, too much iron can also cause damage, since balanced iron levels are essential for chemical reactions that keep all cells alive, including neurons. One of the hallmarks of Parkinson’s is excessive iron build up in the key brain area connected to movement, the substantia nigra. This can be observed by MRI or ultrasound, and is linked to the characteristic “hyperechogenicity” of this region in Parkinson’s.

This excess iron hampers neuronal survival directly, and increases the build up of a-synuclein which damages neurons as it forms clumps inside them. So reducing this excess iron using “iron chelator” drugs should be beneficial. One of these is Deferiprone, often used in blood disorders where regular blood transfusions can unintentionally cause iron overload. Since it crosses the blood-brain barrier, an important hurdle when targeting the brain, it mops up excess iron and counteracts its toxic effect on neurons. Based on this and strong evidence from animal studies, Deferiprone was prioritised by the LCT committee in 2012 as a potential disease modifying therapy.

Two phase II trials addressing the safety and tolerability of Deferiprone in people with Parkinson’s showed promising in terms of movement scores and overall good tolerability, with the exception of three cases of immune cell reduction which resolved rapidly. These relatively small, placebo controlled studies showed that Deferiprone reduced iron in brain regions controlling movement, and patients also showed indications of symptom improvement.

FAIRPARK II (link below), a larger European multicenter, parallel-group, placebo-controlled, randomized clinical trial, is recruiting newly diagnosed patients to assess whether Deferiprone can slow down Parkinson’s. 388 people will take Deferiprone orally twice daily or placebo for 9 months, and will be monitored over the course of a month after the end of the treatment period. Their movement scores as well as aspects of quality of life and cognition will be assessed.

If Deferiprone has a disease modifying effect in these phase II studies, then a Phase III trial is the next step to further assess its efficacy in a larger group of people with Parkinson’s.

FAIRPARK II Trial

https://clinicaltrials.gov/ct2/show/NCT02655315

http://fairpark2.eu/

SKY Trial

https://clinicaltrials.gov/ct2/show/NCT02728843

https://foxtrialfinder.michaeljfox.org/trial/4412/

Martin-Bastida, A., Ward, R. J., Newbould, R., Piccini, P., Sharp, D., Kabba, C., . . . Dexter, D. T. (2017). Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson’s disease. Sci Rep, 7(1), 1398. doi:10.1038/s41598-017-01402-2

https://www.nature.com/articles/s41598-017-01402-2.pdf

Devos, D., Moreau, C., Devedjian, J.C., et al. (2014). Targeting chelatable iron as a therapeutic modality in Parkinson’s disease. Antioxid Redox Signal, 21, 195-210.

http://online.liebertpub.com/doi/pdfplus/10.1089/ars.2013.5593