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The journey to discovering new treatments for Parkinson's (PD) is lengthy and expensive. The Cure Parkinson's Trust (CPT) is determined to fast-track potential new treatments to slow, stop, or reverse PD. Our international Linked Clinical Trials initiative (LCT) 'repurposes' already approved and available drugs and therapies for other conditions, with the potential for treatment of Parkinson's, reducing the time to reach patients by a number of years.

Repurposing Drugs: (A major part of our fundraising is directed towards funding these extremely important trials.)

Annually in September, through our pioneering international Linked Clinical Trials (LCT) initiative, the Linked Clinical Trials committee evaluates multiple drugs currently used, or being developed, in other therapeutic areas, as well as considering natural, non-pharmaceutically based compounds. The committee prioritises drugs and compounds from a dossier of recommendations compiled by Drs. Richard Wyse and Simon Stott (CPT's Director and Deputy Director of Research and Development) and assesses which of these putative treatments would potentially be most suited to move immediately into pilot clinical trials. Aspects considered include known modes of action, safety, blood-brain-barrier penetration, preclinical data in models of PD and relevance to patients along with the possibility to monitor target engagement in the brain (Brundin et al 2013).

LCT is the legacy of Tom Isaacs, founder of The Cure Parkinson’s Trust, and now brings together charities, research organisations and experts from around the world. Since the first annual meeting in 2012, over 2000 drugs have been screened to be repurposed for Parkinson’s. These efforts have been instrumental in bringing directly to trial a number of important drugs with disease modifying potential.

A recent paper (not yet open access) published in the Journal of Parkinson's Disease 'The Linked Clinical Trials initiative (LCT) for Parkinson's disease' by Prof. Patrik Brundin and Dr Richard Wyse, presents the origins of this pioneering initiative:

'...By mid 2019, it is expected that at least 25 drugs prioritised by LCT will have gone to trial, or reached trial completion. It was originally envisaged that several drugs could be tested in parallel, hence “Linked” trials which might share a single control group or similar protocol, to allow for direct comparison. Now, using innovative trial designs this aspect of the programme is also possible.'

Other Recent Papers of Interest

A recent informative paper featuring a number of CPT’s Linked Clinical Trials candidate drugs provides context and an independent rationale for the importance of this programme: 'Drug Repurposing in Parkinson's Disease' ~ Dilan Athauda, Tom Foltynie.

'Can You Teach Old Drugs New Tricks?' This informative article appears in Nature 14 June 2016 by Nicola Nosengo

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 (exendin) led by Prof. Tom Foltynie at University College London (UCLH) and funded by the Michael J. Fox Foundation for Parkinson’s Research, has recently finished and a larger phase III trial is about to begin and will run to 2021. Find out more about Exenatide 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.

The Liraglutide trial is recruiting in the US - find out more here

Nilotinib: C-Abl Update

Background:

In 2010, Professor Ted Dawson (a member of CPT's international Linked Clinical Trials committee) and his research team at Johns Hopkins University School of Medicine reported that a protein called c-Abl is activated in the brains of people with Parkinson's. They also found that inhibiting this protein had a neuroprotective effect in models of Parkinson's. This original result has been independently replicated by multiple research groups, indicating that c-Abl is a bona fide and potentially important target for research into slowing the progression of Parkinson's. Read more here.

There is a strong scientific rationale to study c-Abl inhibitors in Parkinson’s disease, since multiple studies have shown the c-Abl inhibition is protective in multiple models of Parkinson’s disease.

Professor Ted Dawson

Clinical evaluation:

Subsequent to this preclinical research, a very small pilot clinical study was initiated in people with Parkinson's using a c-Abl inhibitor drug called Nilotinib - used in the treatment of leukaemia. The results of this pilot study indicated initial safety in people with Parkinson’s at two doses. Given the open label nature of the study, further evaluation into safety and tolerability in larger, placebo controlled clinical trials to replicate these initial findings was essential. Read more here. Two studies have now been conducted to assess Nilotinib in a blinded approach.

The need for novel c-Abl inhibitors:

Whilst those clinical trials were conducted, further novel c-Abl inhibitors have been generated for testing in Parkinson's, principally because Nilotinib has very limited penetrance through the blood to brain barrier - this blood brain barrier is so effective at protecting the brain against harmful substances that it often prevents access of many drugs. In fact, only 0.5‐1% of Nilotinib has been detected in the brains of people taking this drug. Read more here.

There are further novel c-Abl inhibitors now being clinically tested which demonstrate a more effective penetrance and target engagement. These trials include:

  • K0706, which is being clinically tested in the Sun Pharma SPARC large Phase II "PROSEEK" study, which involves 500+ participants. Find out more here
  • FB-101, which is being clinically tested by 1ST Biotherapeutics. Find out more here
  • IkT-148009, which is being developed by the biotech company Inhibikase
  • Radotinib, which is being developed by the biotech company Ilyang Pharmaceutical

These novel drugs have been designed to achieve better brain penetrance. The trials will include more appropriate measurement of target engagement, such as highly sensitive imaging tools, for testing whether c-Abl inhibitors do have a disease modifying effect in Parkinson’s and therefore potential to slow, stop or even reverse Parkinson’s.

Read the full Michael J Fox Foundation Press Release 5th December : Though Safe and Tolerable, Nilotinib Does Not Show Promise for Benefit in Phase II Nilotinib for Parkinson’s Disease (NILO-PD) Trial

Join NILO-PD Steering Committee members for a webinar on Tuesday, December 17 at 5pm GMT (12 p.m. ET) to hear more about the study’s design and top-line findings and to ask questions. Register at: www.michaeljfox.org/webinars.

UDCA - Ursodeoxycholic acid

This trial has begun and is joint funded by the JP Moulton Foundation and CPT. Find out more about the background to this trial - Professor Oliver Bandmann's presentation at the Parkinson's Academy

EPI-589

EPI-589 is owned by Bioelectron 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. 

The next phase of a 2A study has completed and results will be published soon: Phase 2A study of EPI-589 in Parkinson’s.

The study is led by Professor Huw Morris and Dr Vincenzo Libri at the Leonard Wolfson Experimental Neurology Centre at UCLH in London and it is hoped, that this will be the first step in the development of a new Parkinson’s treatment.

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 joint funding from CPT and the JP Moulton Trust.

Ambroxol

Ambroxol was prioritised by the LCT committee in 2014. This anti-mucolytic drug moved into a small proof of concept study at the Royal Free Hospital in London involving a 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.

Find out more about the online Rapsodi study which aims to provide a platform for identifying the early features of Parkinson's and the role of certain genetic mutations in order to develop new, neuroprotective treatments.

Read Professor Schapira's article: 'Glucocerebrosidase Mutations in Parkinson Disease'.

Deferiprone

Deferiprone - was prioritised  by the LCT committee 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 enroll 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)

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