Keeping abreast of global progress

October 2, 2024

Living where we do, at the bottom of the world, can sometimes make it challenging to stay abreast of global developments, initiatives, and priorities in Parkinson’s research. Yes, research is published online, updates are frequently shared via social media, and Teams or Zoom calls are useful for semi-regular catch ups with our partner non-profit organisations in the UK, US and Australia. But there is no substitute for face-to-face catch ups and the intensity of a congress for really getting up to speed with the incredible volume of work and progress happening worldwide, and hearing updates prior to publication. Thus, it was a privilege for CEO Daniel to be invited to attend the international linked clinical trials (iLCT) meeting again this year, which was well planned to occur during the days immediately prior to the annual congress of the International Parkinson and Movement Disorders Society.

The iLCT programme was established in 2012 by our partner organisation Cure Parkinson’s (UK) to speed up the search for much-needed disease-modifying treatments (that can stop or slow progression) for Parkinson’s disease. It is a global programme centred around an annual two-day meeting at which a committee of >20 world-leading Parkinson’s experts evaluates, ranks, and prioritises a variety of drugs and compounds (normally 15–20 candidates, for which detailed dossiers are produced) with the potential to modify the progression of Parkinson’s. Drugs that are ranked highly enough are prioritised to move into clinical trials. There are several examples of iLCT committee-prioritized drugs that are now well into phase 2 or 3 clinical trials in people with Parkinson’s, such as the diabetes drug exenatide (one of a number of GLP-1 receptor agonists being assessed) and the cough suppressant ambroxol. The meeting this year was hosted by the impressive-looking Van Andel Institute in Grand Rapids, Michigan, and once again, there were some promising candidates reviewed and discussed, several of which will be prioritized for further investigation.

The meeting is also a great opportunity to learn about progress on existing trials and some of the initiatives aimed up speeding up the delivery of outcomes. The phase 3 trial of ambroxol is expected to commence very soon under the leadership of Tony Schapira in London, while the phase 3 exenatide trial led by Tom Foltynie (also based in London) has recently been completed, with results expected to be released later this month. Another trial of considerable interest is the NO-PARK study in Norway of the nutraceutical nicotinamide riboside (NR) being led by Charalampous ‘Haris’ Tzoulis, with the results of this trial expected in May 2025. If positive, it would be great to initiate a similar study in NZ. Haris is a rising star in the field of Parkinson’s research, and what he has been able to achieve in a country that is very similar in size to NZ is quite incredible.

It was fabulous to see representatives of Alzheimer’s Research UK present this year as well as the various Parkinson’s research-funding charities, with the learnings and sharing of knowledge being bi-directional. Charities in our space certainly know how to collaborate and share information for better efficiency and faster progress—always great to see! ARUK is one organisation that has grown impressively fast, leading to a significant investment (>£220M since 1998) in Alzheimer’s and dementia research, and some impressive outcomes.

With a shared goal of speeding up research and clinical trials to bring potential disease-modifying therapies to patients sooner, researchers in a number of countries are developing so-called multi-arm, multi-stage (MAMS) platform trials for the simultaneous testing of different interventions and more rapid progression from phase 2 into phase 3 clinical trials. The analogy that is often used is that of a football stadium: the way trials are traditionally conducted in most places is analogous to building a stadium for one match, then disassembling the stadium following the game, and doing this for every match! Ludicrous of course, but it is how the process has evolved (largely with patient safety in mind, but with obvious implications for costs and speed to generate outcomes). MAMS platform trials, which build the stadium once for multiple matches (ongoing clinical trials), are now established the UK (EJS-ACT-MAMS) and US (P2P), with similar platform trials being established in France and Norway. Australia also has a multi-arm trial platform (although it is not multi-stage, so is technically not a MAMS trial platform) called the Australian Parkinson’s Mission (APM), with results from the first set of trials expected in early 2025. Approaches and data are being harmonized across platforms, with learnings shared between countries. An impressive example of global collaboration among researchers and our non-profit partners, and one we would love to emulate in Aotearoa.

The International Parkinson and Movement Disorder Society meeting was a fabulous update on the latest in clinical practice and research with some excellent sessions and valuable discussions. Progress is being made in many different areas of research relating to Parkinson’s, but some of the highlights (for Daniel) were:

  • A presentation from Eng-King Tan from Singapore in which he showed results with a PET (a form of imaging) tracer ‘C05-05’ that binds alpha-synuclein fibrils (basically, early-stage aggregation of a key implicated protein) to detect aggregates in the brains of people with Parkinson’s (also multiple system atrophy and Alzheimer’s). This finding paves the way for effective live imaging of alpha-synuclein deposits in living patients (as opposed to having to wait to examine brains for these aggregates post-mortem). This is not just academic: as new therapies with the potential to stop or slow the disease are developed, such imaging can help match the therapy to the patient.

 

  • A fabulous talk from Jeff Kordower, Arizona State University, on co-pathologies in people with Parkinson’s (in addition to alpha-synuclein pathology, with is typical of Parkinson’s but not universal, a very high proportion of people with Parkinson’s also show brain pathology that is reminiscent of Alzheimer’s disease, and this may be a driver of dementia in the subset of Parkies who develop this). Of interest, Jeff also shared some exciting results in mouse and monkey models using intravenous delivery of the gene for a myokine (a small protein released into the circulation by skeletal muscle cells in response to muscular contractions) called irisin. Irisin crosses the blood–brain barrier (a challenge for many drugs) to get into the brain where it is neuroprotective through induction of the clearance of misfolded proteins (with no effect on normally folded alpha-synuclein), increased brain-derived neurotrophic protein (a growth factor that supports neuronal survival), and decreased neuroinflammation. This protein could explain why exercise is so protective in Parkinson’s, and the fact that the viral vector used to deliver the irisin gene can be injected intravenously (it is taken up by the liver and expressed there, with irisin protein being secreted into the circulation) is an added bonus, avoiding highly invasive neurosurgical approaches used to deliver the genes into the brain. We look forward to further updates on Jeff’s work and potential human trials.

 

  • Progress in biomarker research with skin immunostaining for a modified version of alpha-synuclein) now showing some validity and utility. Adding this to ongoing efforts with blood, nasal swabs, and new work with tear samples performed by the Centre for Brain Research’s Dr Victor Dieriks, and the invasive and painful lumbar puncture will hopefully not be required in future iterations of biofluid assessment for diagnosis and potential progression tracking.

 

  • A thought-provoking talk from Richard Smeyne, USA, on infections as a trigger predisposing to PD. Dr Smeyne showed evidence that viruses can act as a ‘hit’ in the multiple hit hypothesis of Parkinson’s—basically, the concept that development of Parkinson’s results from multiple triggers including genetic risk, lifestyle factors, and various types of environmental exposure (pollution, herbicides, pesticides, chemicals, and infections)—regardless of whether the virus can enter the brain (cross the previously mentioned blood—brain barrier; some do, many don’t). In a range of elegant animal studies Dr Smeyne showed that several viruses, including common influenza variants and SARS CoV-2 (which causes Covid), can induce an increase in misfolded alpha-synuclein protein, neuronal loss, and increased neuroinflammation. Moreover, on a background of a genetic risk factor or chemical exposure known to induce parkinsonism, the effects of viral infections were even more toxic, supporting the multiple hit hypothesis. Interestingly, vaccines protected against this hit to some extent. Provocatively, Dr Smeyne predicted a 150% increase in the risk of developing Parkinson’s among those who have recovered from a severe Covid infection. We knew there was a tidal wave of Parkinson’s coming—perhaps Covid has made it even larger! This certainly lends more urgency to the work on the olfactory bulb in Professor Curtis’s lab that we already support.

 

  • Dina Katabi from MIT gave a great talk on the Emerald remote health monitoring system for wireless (via radio waves—think sonar and radar) and sensor-free detection of gait, sleep, night-time breathing and posture (among other things) as a tool for early diagnosis of Parkinson’s. The system was highly sensitive and accurate compared with clinical assessments and could potentially be used as a measure of disease progression. Watch this space!

 

  • Finally (among the highlights—there was so much more!), the talented young neurologist Kumar Narayanan (University of Iowa) presented some promising results in animal models using the repurposed drug terazosin. This drug has been widely used to treat the symptoms of an enlarged prostate (among older men), but it was found to also increase the production of ATP (an energy source used by cells that is negatively affected in Parkinson’s), through an unexpected action on a key enzyme in the glycolysis pathway (essentially, the pathway by which glucose is broken down in cells to produce energy for important cellular processes). The dopaminergic neurons that die in Parkinson’s have very high energetic requirements owing to their massive size and complexity, and energy deficits are one of the mechanisms that lead to cell death. Following on from promising results in animal models, clinical trials of terazosin are due to start soon.

 

All in all, a couple of great meetings with some fabulous opportunities to catch up with leading international researchers and our non-profit partners. Perhaps next year we can bring a New Zealand-developed compound to the iLCT meeting or commit to a clinical trial of a promising new drug. We are only limited by the funding we can raise.

 

 

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