Periodic Reporting for period 5 - FAIR-PARK-II (Conservative iron chelation as a disease-modifying strategy in Parkinson’s disease: a multicentric, parallel-group, placebo-controlled, randomized clinical trial of deferiprone) Reporting period: 2021-05-01 to 2021-10-31 Summary of the context and overall objectives of the project In Parkinson’s disease (PD), excess iron is detected in the substantia nigra pars compacta, where dopaminergic neurons are exposed to high levels of oxidative stress. Pilot clinical studies demonstrated that iron chelation therapy with the deferiprone (DFP): induces neuroprotection in cell models of PD, reduces regional siderosis of the brain, reduces motor handicap and slows the progression of motor handicap. Project’s objective is to demonstrate DFP slows the progression of handicap in de novo PD patients while not affecting systemic parameters. We observed a reduction of the abnormal iron accumulation in the nigro-striatal pathway that degenerates in PD under DFP as compared with controls. No significant reduction of iron was observed in the brain areas which did not abnormally accumulate iron and did not degenerate. It demonstrates the concept of conservative iron chelation (objectives 1&2). A large data base of images and biological samples has been built to allow the analysis of biomarkers (objective 4). Requests for ancillary studies have been received (objectives 3&4). Biomarker data seemed to provide encouraging evidence of neuroprotection (objectives 4&5). We discussed with Chiesi to pursue the development of DFP in PD The development in PD will be successful if DFP is co-prescribed with dopaminergic therapy and evaluated over a longer term to demonstrate clinical impact. We hope to convince also other laboratories (Abferro/Pharmacosmos and Alterity therapeutics) to carry out this development in PD and other neurodegenerative diseases (Objective 6). Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far The results are not available before for the end of February 2022, thus it is not possible to include an overview of them. As soon as they will be available, meetings with the consortium will be scheduled to discuss the exploitation and dissemination. In WP1 the management and coordination framework was implemented to ensure their fulfilment within time plan and budget with an 18 month extension at no cost due to slow recruitment and to the Covid-19 pandemic In WP, submissions to competent Authorities and Ethical committees have been done. Drug was managed by ApoPharma. The study has been monitored. During the 5th period, the database has been cleaned, and locked on 17/09/21. The statistical analysis of the project is still under progress. In WP3, the sponsor selected 24 European expert centres, to perform patients’ recruitment. On December 2019, 372 patients were included.In WP4. The MRI and Dat scan protocols were successfully implemented. The protocol of Transcranial Ultrasound was active. A secure digital tool for data sharing and imaging services was finalized. In the sub-task 4.3 data analysis is ongoing. Biologic samples of the subtasks 4.4 4.5 and 4.6 were delivered to responsible working groups, underwent quality control and are awaiting analysis for pre-defined parameters. WP5 provided a health economic evaluation to evaluate the resource use, costs and health status in order to calculate the cost-effectiveness of the treatment. The SENSE-PARK wearable device system measured in daily life over the entire day. Raw data were then extracted and transferred in a data format ready to run analysis and algorithm applications WP6, FPII logo, graphic standard, brochures, flyers and public website were created. The protocol was registered on the ClinicalTrials.gov and Fox Trial Finder Publication Policy and dissemination strategy were made and the exploitation plan updated in 2017. The consortium participated in major events to present the project and disseminate results. In WP7, the setup of the study was compliant with all ethical aspects. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) A- Evaluation of the disease-modifying effect by investigating whether DFP reduces disease progression in de novo patients without dopaminergic treatment. In an intention-to-treat analysis, the mean change in the total MDS-UPDRS score was 16.7 points with DFP and 6.3 points with placebo. The iron content was reduced under DFP in the nigro-striatal pathway. A change in the volume of the putamen and caudate nucleus was observed between both groups with a smaller volume in the placebo group. DFP without dopaminergic treatment worsened the motor and non-motor handicap of persons at the time of PD diagnosis as compared with placebo. The wet and dry markers suggested a reduction of iron related oxidative stress and cell death. This provides evidence that the iron accumulation in the nigro-striatal pathway is a compensatory mechanism for increasing dopamine synthesis but at the expense of iron-related cell death. Longer trials in PD persons under dopaminergic treatments are necessary to evaluate the efficacy and safety of DFP to reduce disease progression.B- Impact of DFP treatment on the autonomy, quality of life and health economics: We were not able to demonstrate an improvement for these aspects. To hope for a therapeutic effect on quality of life and autonomy, it will be necessary to conduct a therapeutic trial in patients receiving a dopaminergic treatment and to carry out a therapeutic trial of more than one year.C- To make iron chelators available to PD patients more rapidly: Development in PD will be successful if DFP is co-prescribed with dopaminergic therapy and evaluated over a longer term to demonstrate clinical impact. We hope to convince Chiesi and other laboratories to carry out this development.D- Surrogate biomarkers and theranostic biomarkers: We want to develop surrogate biomarkers by analysing a large range of biological, radiological and genetic biomarkers. An analysis of theranostic biomarkers could help the choice of treatment after only few months. Several biomarkers could change the clinical management of PD and facilitate assessment of the risk/benefit balance for treatment decisions. E- European clinical networks for ND: We obtained another European grant (Center of Excellence in ND: COEN “Iron-Syn”) to better decipher the regulated cell death associated with iron accumulation and the alpha synucleinopathy. We develop a new iron chelator (SP420 from Abfero pharmaceuticals/Pharmacosmos) for conservative iron chelation as a disease modifying modality in PD, thanks to another European funds (EUROSTAR: PD-IRON SYN)The expected impacts:- Iron chelation is the leading treatment for ferroptosis, a new form of regulated iron-related death. However, many other anti-ferroptosis treatments are in development, such as the one with our partner PTC therapeutics.- FPII study has been a catalyst for preclinical research, particularly in demonstrating the importance of iron-related regulated death: ferroptosis. It has also been a catalyst for pharmaceutical development of new iron chelators and new anti-ferroptotics. The study also catalyzed the search for combination biomarkers to demonstrate neuroprotection that look promising to support future therapeutic trials. Finally, FP II provided clinical evidence that dynamic iron accumulation in the nigro-striatal pathway is a mechanism for compensating for dopamine depletion by increasing endogenous dopamine synthesis. However, we suspect that this accumulation is to the detriment of neuronal survival by promoting ferroptosis and precipitating the aggravation of the disease. Therefore, the strategic hypothesis is to treat patients with a moderate dose of iron chelator combined with dopaminergic therapy to avoid symptomatic worsening and allow neuroprotection. logo-fair-park-vd-72.jpg
