Trials - Repurposed drugs Donate The journey to discovering new treatments for Parkinson's (PD) is a lengthy and expensive one. The Cure Parkinson's Trust(CPT) is determined to identify potential new treatments to slow, stop, or reverse PD. Our Linked Clinical Trials initiative (LCT) 'repurposes' already approved and available drugs and therapies for other conditions, for the potential treatment of Parkinson's. A major part of our fundraising is directed towards funding these extremely important trials. Annually in September, through the pioneering Linked Clinical Trials (LCT) initiative, the Linked Clinical Trials committee meets in person to examine dozens of potential therapeutics; those that have the highest likelihood of successfully treating Parkinson’s are selected for advancement to clinical trials. Listed below are the drugs chosen by the committee to date, based on: drug safety, the drug’s ability to pass the blood-brain barrier, mode of action relevant to putative disease mechanisms in Parkinson’s, ability to measure the drug’s effectiveness, and demonstrated success in several preclinical Parkinson’s models (Brundin et al 2013). Note: Please click in to the drug name (highlighted) for further explanation. GLP-1 Agonists Liraglutide, Lixisenatide, Exenatide and Bydureon belong to a group of safe and well-tolerated drugs called GLP-1 agonists. They are used to treat insulin resistance in type 2 diabetes and in recent years there has been research based evidence to suggest that they show great promise as a new treatment for Parkinson's. A recent meeting conducted by CPT, discussed the further development of trials for these important drugs to ensure that we can find the right routes forward in bringing viable treatments to people with Parkinson’s as quickly as possible. Exenatide is a type 2 diabetes drug that has shown potential neuro-protection in laboratory experiments (*1). Parkinson’s patients given Exenatide for one year continued to show improvements compared to the control group a year after discontinuing treatment. The next phase of these trials, using a weekly dose of the drug Bydureon (AstraZeneca) led by Prof. Tom Foltynie at University College London (UCLH) and funded by the Michael J. Fox Foundation for Parkinson’s Research, have recently finished. Find out more here... Lixisenatide and Liraglutide are two injectable Diabetes treatments which have been moved into Parkinson’s clinical trials. CPT and Van Andel Research Institute(VARI) are collaborating with the lead investigators in France and the U.S. as well as the pharmaceutical companies Sanofi and NovoNordisk. Two distinct trials have been designed with targeted populations of people with Parkinson’s to investigate this potentially important new approach to treatment. Nilotinib For the last few years the LCT committee has explored whether 'inhibition of c-Abl' would offer a disease-modifying approach for PD. In 2010 a group of researchers published a paper demonstrating that there is increased levels of abl in the Parkinsonian brain, and by blocking the abl protein, c-Abl inhibition could effectively protect models of Parkinson’s disease. Read the paper here: 'Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin's ubiquitination and protective function' - Dawson et al. C-Abl is a protein that also recently emerged as a therapeutic target showing early promise as a potential disease-modifying therapy when preliminary results were released from a small study at Georgetown University on 'c-Abl inhibition' by Nilotinib in 6 ‘late stage PD patients’ and 6 patients with ‘dementia with Lewy bodies’. While more research must be done to understand its role in PD progression, a lot of activity in the 'c-Abl' field is being carried out to help answer some key questions about its potential. “Based on compelling biochemical evidence and considerable discussion, this expert committee concluded that the use of Nilotinib had significant potential to slow neurodegeneration in PD.” - The Cure Parkinson's Trust Linked Clinical Trials Committee (LCT). The Cure Parkinson's Trust LCT Committee built a working party comprising the company who own the drug, certain members of the LCT committee and potential funding partners, to design a robust trial to understand the effects of 'c-Abl inhibition' by Nilotinib in people with Parkinson’s. Recently, Dr Richard Wyse (CPT), Prof. Patrik Brundin (Van Andel Institute - VARI) and Todd Sherer (Michael J Fox Foundation) - published their article 'Nilotinib – Differentiating the Hope from the Hype' in the Journal of Parkinson's Disease July 2016 discussing the Georgetown safety trial. At the same time, Michael J Fox Foundation, VARI and CPT announced their collaborative partnership to assess the clinical use and development of Nilotinib in Parkinson's. In November 2017 The Michael J Fox Foundation (MJFF) and the Van Andel Research Institute (VARI) announced their recruitment for the Phase 11a trial across various centres in the States to test the safety and tolerability of repurposing Nilotinib in Parkinson's disease. On 25th October 2017 SEONGNAM, a private Korean biotech company, and Neuraly Inc., a startup from Johns Hopkins School of Medicine, announced a collaboration to co-develop novel c-Abl inhibitors for Parkinson's. On 9th March 2017, US biotech Inhibikase announced an MJFF-funded trial to explore the safety profile and brain penetrance of advanced c-Abl inhibitors in pre-clinical models versus other drugs in their class. In addition, Inhibikase is planning another Nilotinib trial, along with another medicine Dasatinib, to investigate its potential in Parkinson's. Also, Georgetown University is moving forward with their further clinical assessments of Nilotinib in PD. These trials are happening simultaneously across different sites with diverse study designs. The benefit of multiple trials is that researchers will be armed with more data to assess this treatment and help build new pathways faster. Further reading: Uncovering the Promise of c-Abl as a Therapeutic Target: Testing Available Treatments and Supporting New Therapies - Posted by Todd Sherer, PhD, March 09, 2017 EPI-589 EPI-589 is owned by Edison Pharmaceuticals who are running a 'proof of concept' in Parkinson's trial. EPI-589 was designed to treat rare mitochondrial diseases in children. We now know that mitochondrial dysfunction is a hallmark of genetic types of Parkinson’s(*2) and is also thought to be a feature in Parkinson’s where the cause is not known. This trial will help us understand whether this drug can improve mitochondrial function in neurons and, what benefit this has for people with Parkinson’s. UCL is now seeking people with Parkinson's to take part in a new Phase 2A study of EPI-589 in Parkinson’s. For this trial UCL are recruiting those at the very earliest stages of Parkinson's who have not taken any Parkinson's medication or those with genetic forms of Parkinson's (specifically parkin, PINK1, LRRKE) who are currently taking Parkinson's medication. The trial will last 5 months in total and all participants will take the drug EPI-589. It is hoped, that this will be the first step in the development of a new Parkinson’s treatment. The study is being led by Professor Huw Morris and Dr Vincenzo Libri at the Leonard Wolfson Experimental Neurology Centre at UCLH in London. ** This trial is now recruiting in London, Tuebingen, Los Angeles and Boston. If you believe you are a suitable candidate and are interested in being involved, please contact the study team on (+44) 203 448 4531 or contact [email protected] OR [email protected] For further detailed information about the trial click here. Simvastatin Simvastatin already treats high cholesterol but could have neuroprotective qualities in Parkinson’s due to its anti-inflammatory properties. Simvastatin’s effects in Parkinson’s are the subject of a clinical trial that is now underway in 23 centres across the UK led and supported by the University of Plymouth, with funding from CPT and JP Moulton Trust. This trial is currently still recruiting. Ambroxol Ambroxol was prioritised by the LCT committee in 2014. This anti-mucolytic drug has now moved into a small proof of concept study at the Royal Free Hospital in London involving a small cross section of people with Parkinson’s, including those with genetic forms of the disease who carry a single copy of the glucocerebrosidase enzyme gene mutation (GBA), that is the most common genetic risk factor for PD. It is believed that Ambroxol may help cells to counter the effect of the GBA mutation by increasing levels of glucocerebrosidase in neurons which is understood to enable cells to better dispose of unwanted toxic proteins such as alpha-synuclein. This trial is supported by the John Black Charitable Foundation and VARI. ** Feb 2016: Professor Anthony Schapira and Sanofi have recently announced their work into further therapies targeted to the GBA gene mutation to understand more about the pathways of glucocerebrosidase (GCase) and its connection to the toxic protein alpha-synuclein. CPT continues to support and follow Professor Schapira's work in this exciting research area - please see 'Glucocerebrosidase Mutations in Parkinson Disease'. Deferiprone Deferiprone was prioritised in 2012 and a pan-European study is going ahead thanks to funding by the European Commission’s Horizon 2020. Recruitment for the trial is underway. CPT is fully supporting this trial in terms of recruitment and providing information. The Sky study (Study of Parkinson’s Early Stage - the Jersey Shore Medical Center) is also evaluating Deferiprone in early stage Parkinson's patients and to determine the optimal dose based on motor symptom improvement and safety. SKY is looking to enrol people who were diagnosed with Parkinson’s within the last three years. Existing treatments for Parkinson’s involve giving drugs that increase dopamine in the brain or copy its action. SKY is taking a different approach by looking at the build-up of iron observed in certain regions of the brain among people with Parkinson’s. It is not known whether this build-up of iron is causing harm to the brain cells, or whether removing it may improve the motor symptoms of the disease or slow its progression. The SKY clinical study aims to address these questions. To find participating centres please visit: FoxTrialFinder (study ID #4412) or clinicaltrials.gov (study ID #NCT02728843) N-Acetyl Cysteine (NAC) NAC was prioritised by the LCT committee in 2014. We are working with an expert team in the US led by Dr Carlie Tanner to develop a trial evaluating NAC as a possible treatment for Parkinson’s. NAC is currently used to treat paracetamol (acetaminophen) overdose and to loosen mucous in cystic fibrosis sufferers or chronic obstructive pulmonary disease. Note: Funding is still required for this important trial. Publications for further information: *1. Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Kahan J, Ell P, Whitton P, Wyse R, Isaacs T, Lees A, Limousin P, Foltynie T. 2014. Motor and cognitive advantages persist 12 months after exendatide exposure in Parkinson’s disease. J Parkinson’s Dis 4(3):337–344 *2. Pink1, Parkin, DJ-1 and mitochondrial dysfunction in Parkinson's disease - Mark W Dodson, Ming Guo Repurposing Drugs: 'Can You Teach Old Drugs New Tricks?' This informative article appears in Nature 14 June 2016 by Nicola Nosengo May the Next PD Treatment Already Be Here? This article originally appeared in the Parkinson's Disease Foundation newsletter autumn 2013 by Dr.James Beck, Vice President, Scientific Affairs, Parkinson's Disease Foundation. Dr. Beck attended the first three of CPT's Linked Clinical Trials prioritisation meetings.