Therapeutics

Deferiprone

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Overview

Name: Deferiprone
Synonyms: Ferriprox
Chemical Name: 3-hydroxy-1,2-dimethylpyridin-4(1H)-one
Therapy Type: Small Molecule (timeline)
Target Type: Metals
Condition(s): Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis
U.S. FDA Status: Alzheimer's Disease (Phase 2), Parkinson's Disease (Phase 2/3), Amyotrophic Lateral Sclerosis (Phase 2/3)
Company: Apotex Inc., Chiesi Pharmaceuticals Inc.
Approved for: Iron overload due to thalassemia syndromes

Background

Deferiprone is an orally available, brain-penetrant iron chelator that removes iron from the brain and other tissues. It is a second-line treatment for iron overload due to repeated blood transfusions in people with thalassemia who do not respond to or cannot take other chelators. It was approved in the European Union in 1999, and in the U.S. in 2011. Generic versions are available. The most common side effects include red-brown urine from iron secretion, nausea, abdominal pain, and vomiting. Deferiprone can cause low granulocyte or neutrophil counts.

Perturbed iron homeostasis is associated with neurodegeneration in Alzheimer’s, Parkinson’s, and other diseases. People with AD and PD show elevated iron in specific brain regions (for review, see Belaidi and Bush, 2015). Excess brain iron has been reported to correlate with accelerated cognitive decline in people with AD, whether measured in postmortem tissue (Ayton et al., 2019), by MRI (Ayton et al., 2017), or by using CSF ferritin as a biomarker (Ayton et al., 2015). Studies variously suggest excess iron may harm neurons by promoting Aβ production, Aβ and tau toxicity, oxidative cell death, and/or microglia-driven inflammation.

No preclinical data are published for deferiprone in transgenic mouse models of Alzheimer’s amyloidosis. The iron chelator clioquinol and its derivative PBT2 both have been reported to lessen amyloid deposition and improve cognition in such models. In rats treated with the anti-cholinergic compound scopolamine, deferiprone lessened Aβ deposition and mitigated memory impairment (Fawzi et al., 2020). In mice expressing P301L human mutant tau, deferiprone was reported to have reduced iron and aggregated tau in brain, as well as anxiety-like behavior, but in 2023 this paper was retracted (Rao et al., 2020, retraction notice). Deferiprone improved motor function in a mouse model of Huntington’s disease and behavioral deficits in a mouse model of α-synuclein aggregation (Agarwal et al., 2018; Carboni et al., 2017).

Findings

Following some case reports and open-label pilot studies in neurodegenerative conditions with iron accumulation (Kwiatkowski et al., 2012; Abbruzzese et al., 2011), clinical trials started up. Between 2013 and 2016, an open-label Phase 2 trial in Lille, France, tested deferiprone in 23 people with ALS, subsequently reporting that a 12-month course was safe (Moreau et al., 2018). A Phase 2/3 placebo-controlled trial involving 372 patients started in January 2019, and was to finish in November 2023.

In January 2018, a Phase 2 trial began in people with Alzheimer’s disease. At nine sites across Australia, the Deferiprone to Delay Dementia (3D) study was to recruit 171 people with mild cognitive impairment or mild dementia and evidence of Aβ deposition, randomizing them two to one to 15 mg/kg deferiprone delayed-release tablets twice daily, or placebo, for one year. Cognitive performance on the Neuropsychological Test Battery was the primary outcome; secondary outcomes included safety and brain volume changes. Brain iron was measured by MRI. At the July 2020 Alzheimer’s Association International Conference, the investigators reported that, as of June, 50 participants had been randomized and 20 had completed treatmen (Ayton et al., 2020). The trial was expected to finish in 2023. According to results presented at the August 2024 AAIC, deferiprone treatment caused significant acceleration of cognitive decline, compared to placebo. Patients on placebo declined by an average of 0.295 points, while those who got deferiprone declined 0.863 points. The biggest changes occurred in domains related to executive function. MRI confirmed significant lowering of brain iron in the hippocampus in people taking deferiprone. The trial enrolled 81 patients, and 54 completed treatment. Most of the withdrawals (20 out of 27) were in the deferiprone group.

Several trials have been completed in Parkinson’s disease. Data for two placebo-controlled studies are published. In a 40-patient Phase 2/3 trial completed in October 2011, a six-month course of 30 mg/kg daily deferiprone reduced substantia nigra iron levels and slowed decline on the Unified Parkinson’s Disease Rating Scale (Devos et al., 2014). A Phase 2 trial in 22 participants, conducted in London, reported a reduction in brain iron and a trend toward improvement in motor scores and quality of life (Martin-Bastida et al., 2017). A dose-ranging Phase 2 trial evaluating a delayed-release formulation in 140 people with PD, conducted at 20 sites in Canada and European countries, finished in September 2019. Results posted on clinicaltrials.gov show no significant differences in outcomes compared to placebo.

In February 2016, a larger trial began recruiting 372 Parkinson’s patients at 25 sites in eight European countries, to evaluate a nine-month regimen of 30 mg/kg per day of the same formulation.The trial was completed in September 2020. According to published results, deferiprone treatment was associated with worsening of motor and nonmotor symptoms compared to placebo, despite evidence of greater reduction of iron in the brain (Devos et al., 2022).

Trials in neurodegeneration with brain iron accumulation, Friedreich’s ataxia, and ruptured brain aneurism and stroke are ongoing or completed. Compassionate use is available for the genetic disorder pantothenate kinase-associated neurodegeneration, where iron buildup in the brain leads to loss of motor function.

For details on deferiprone trials, see clinicaltrials.gov.

Last Updated: 15 Aug 2024

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References

Therapeutics Citations

  1. Clioquinol
  2. PBT2

Paper Citations

  1. Kwiatkowski A, Ryckewaert G, Jissendi Tchofo P, Moreau C, Vuillaume I, Chinnery PF, Destée A, Defebvre L, Devos D. Long-term improvement under deferiprone in a case of neurodegeneration with brain iron accumulation. Parkinsonism Relat Disord. 2012 Jan;18(1):110-2. PubMed.
  2. Abbruzzese G, Cossu G, Balocco M, Marchese R, Murgia D, Melis M, Galanello R, Barella S, Matta G, Ruffinengo U, Bonuccelli U, Forni GL. A pilot trial of deferiprone for neurodegeneration with brain iron accumulation. Haematologica. 2011 Nov;96(11):1708-11. PubMed.
  3. Moreau C, Danel V, Devedjian JC, Grolez G, Timmerman K, Laloux C, Petrault M, Gouel F, Jonneaux A, Dutheil M, Lachaud C, Lopes R, Kuchcinski G, Auger F, Kyheng M, Duhamel A, Pérez T, Pradat PF, Blasco H, Veyrat-Durebex C, Corcia P, Oeckl P, Otto M, Dupuis L, Garçon G, Defebvre L, Cabantchik ZI, Duce J, Bordet R, Devos D. Could Conservative Iron Chelation Lead to Neuroprotection in Amyotrophic Lateral Sclerosis?. Antioxid Redox Signal. 2018 Feb 8; PubMed.
  4. Devos D, Moreau C, Devedjian JC, Kluza J, Petrault M, Laloux C, Jonneaux A, Ryckewaert G, Garçon G, Rouaix N, Duhamel A, Jissendi P, Dujardin K, Auger F, Ravasi L, Hopes L, Grolez G, Firdaus W, Sablonnière B, Strubi-Vuillaume I, Zahr N, Destée A, Corvol JC, Pöltl D, Leist M, Rose C, Defebvre L, Marchetti P, Cabantchik ZI, Bordet R. Targeting chelatable iron as a therapeutic modality in Parkinson's disease. Antioxid Redox Signal. 2014 Jul 10;21(2):195-210. Epub 2014 Feb 6 PubMed.
  5. Martin-Bastida A, Ward RJ, Newbould R, Piccini P, Sharp D, Kabba C, Patel MC, Spino M, Connelly J, Tricta F, Crichton RR, Dexter DT. Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson's disease. Sci Rep. 2017 May 3;7(1):1398. PubMed.
  6. Devos D, Labreuche J, Rascol O, Corvol JC, Duhamel A, Guyon Delannoy P, Poewe W, Compta Y, Pavese N, Růžička E, Dušek P, Post B, Bloem BR, Berg D, Maetzler W, Otto M, Habert MO, Lehericy S, Ferreira J, Dodel R, Tranchant C, Eusebio A, Thobois S, Marques AR, Meissner WG, Ory-Magne F, Walter U, de Bie RM, Gago M, Vilas D, Kulisevsky J, Januario C, Coelho MV, Behnke S, Worth P, Seppi K, Ouk T, Potey C, Leclercq C, Viard R, Kuchcinski G, Lopes R, Pruvo JP, Pigny P, Garçon G, Simonin O, Carpentier J, Rolland AS, Nyholm D, Scherfler C, Mangin JF, Chupin M, Bordet R, Dexter DT, Fradette C, Spino M, Tricta F, Ayton S, Bush AI, Devedjian JC, Duce JA, Cabantchik I, Defebvre L, Deplanque D, Moreau C, FAIRPARK-II Study Group. Trial of Deferiprone in Parkinson's Disease. N Engl J Med. 2022 Dec 1;387(22):2045-2055. PubMed.
  7. Belaidi AA, Bush AI. Iron neurochemistry in Alzheimer's disease and Parkinson's disease: targets for therapeutics. J Neurochem. 2015 Nov 6; PubMed.
  8. Ayton S, Wang Y, Diouf I, Schneider JA, Brockman J, Morris MC, Bush AI. Brain iron is associated with accelerated cognitive decline in people with Alzheimer pathology. Mol Psychiatry. 2019 Feb 18; PubMed.
  9. Ayton S, Fazlollahi A, Bourgeat P, Raniga P, Ng A, Lim YY, Diouf I, Farquharson S, Fripp J, Ames D, Doecke J, Desmond P, Ordidge R, Masters CL, Rowe CC, Maruff P, Villemagne VL, Australian Imaging Biomarkers and Lifestyle (AIBL) Research Group, Salvado O, Bush AI. Cerebral quantitative susceptibility mapping predicts amyloid-β-related cognitive decline. Brain. 2017 Aug 1;140(8):2112-2119. PubMed.
  10. Ayton S, Faux NG, Bush AI, Alzheimer's Disease Neuroimaging Initiative. Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE. Nat Commun. 2015 May 19;6:6760. PubMed.
  11. Fawzi SF, Menze ET, Tadros MG. Deferiprone ameliorates memory impairment in Scopolamine-treated rats: The impact of its iron-chelating effect on β-amyloid disposition. Behav Brain Res. 2020 Jan 27;378:112314. Epub 2019 Oct 20 PubMed.
  12. Rao SS, Portbury SD, Lago L, Bush AI, Adlard PA. The Iron Chelator Deferiprone Improves the Phenotype in a Mouse Model of Tauopathy. J Alzheimers Dis. 2020;77(2):753-771. PubMed. RETRACTED
  13. Agrawal S, Fox J, Thyagarajan B, Fox JH. Brain mitochondrial iron accumulates in Huntington's disease, mediates mitochondrial dysfunction, and can be removed pharmacologically. Free Radic Biol Med. 2018 May 20;120:317-329. Epub 2018 Apr 4 PubMed.
  14. Carboni E, Tatenhorst L, Tönges L, Barski E, Dambeck V, Bähr M, Lingor P. Deferiprone Rescues Behavioral Deficits Induced by Mild Iron Exposure in a Mouse Model of Alpha-Synuclein Aggregation. Neuromolecular Med. 2017 Sep;19(2-3):309-321. Epub 2017 Jun 16 PubMed.

External Citations

  1. Ayton et al., 2020
  2. clinicaltrials.gov
  3. clinicaltrials.gov
  4. retraction notice

Further Reading

Papers

  1. Bortolami M, Pandolfi F, De Vita D, Carafa C, Messore A, Di Santo R, Feroci M, Costi R, Chiarotto I, Bagetta D, Alcaro S, Colone M, Stringaro A, Scipione L. New deferiprone derivatives as multi-functional cholinesterase inhibitors: design, synthesis and in vitro evaluation. Eur J Med Chem. 2020 Jul 15;198:112350. Epub 2020 Apr 25 PubMed.
  2. Sripetchwandee J, Wongjaikam S, Krintratun W, Chattipakorn N, Chattipakorn SC. A combination of an iron chelator with an antioxidant effectively diminishes the dendritic loss, tau-hyperphosphorylation, amyloids-β accumulation and brain mitochondrial dynamic disruption in rats with chronic iron-overload. Neuroscience. 2016 Sep 22;332:191-202. Epub 2016 Jul 9 PubMed.
  3. Dekens DW, De Deyn PP, Sap F, Eisel UL, Naudé PJ. Iron chelators inhibit amyloid-β-induced production of lipocalin 2 in cultured astrocytes. Neurochem Int. 2020 Jan;132:104607. Epub 2019 Nov 21 PubMed.
  4. Devos D, Cabantchik ZI, Moreau C, Danel V, Mahoney-Sanchez L, Bouchaoui H, Gouel F, Rolland AS, Duce JA, Devedjian JC, FAIRPARK-II and FAIRALS-II studygroups. Conservative iron chelation for neurodegenerative diseases such as Parkinson's disease and amyotrophic lateral sclerosis. J Neural Transm (Vienna). 2020 Feb;127(2):189-203. Epub 2020 Jan 7 PubMed.
  5. Liu JL, Fan YG, Yang ZS, Wang ZY, Guo C. Iron and Alzheimer's Disease: From Pathogenesis to Therapeutic Implications. Front Neurosci. 2018;12:632. Epub 2018 Sep 10 PubMed.
  6. Prasanthi JR, Schrag M, Dasari B, Marwarha G, Dickson A, Kirsch WM, Ghribi O. Deferiprone Reduces Amyloid-β and Tau Phosphorylation Levels but not Reactive Oxygen Species Generation in Hippocampus of Rabbits Fed a Cholesterol-Enriched Diet. J Alzheimers Dis. 2012 Jan 1;30(1):167-82. PubMed.
  7. Mahoney-Sánchez L, Bouchaoui H, Ayton S, Devos D, Duce JA, Devedjian JC. Ferroptosis and its potential role in the physiopathology of Parkinson's Disease. Prog Neurobiol. 2021 Jan;196:101890. Epub 2020 Jul 26 PubMed.
  8. Chand K, Rajeshwari, Candeias E, Cardoso SM, Chaves S, Santos MA. Tacrine-deferiprone hybrids as multi-target-directed metal chelators against Alzheimer's disease: a two-in-one drug. Metallomics. 2018 Oct 17;10(10):1460-1475. Epub 2018 Sep 5 PubMed.
  9. Rao SS, Adlard PA. Untangling Tau and Iron: Exploring the Interaction Between Iron and Tau in Neurodegeneration. Front Mol Neurosci. 2018;11:276. Epub 2018 Aug 17 PubMed.
  10. Kontoghiorghes GJ, Kolnagou A, Peng CT, Shah SV, Aessopos A. Safety issues of iron chelation therapy in patients with normal range iron stores including thalassaemia, neurodegenerative, renal and infectious diseases. Expert Opin Drug Saf. 2010 Mar;9(2):201-6. PubMed.
  11. Boddaert N, Le Quan Sang KH, Rötig A, Leroy-Willig A, Gallet S, Brunelle F, Sidi D, Thalabard JC, Munnich A, Cabantchik ZI. Selective iron chelation in Friedreich ataxia: biologic and clinical implications. Blood. 2007 Jul 1;110(1):401-8. PubMed.