With the state of Parkinson’s research both experiencing change and cultivating much change, Simon R W Stott, Deputy Director of Research at The Cure Parkinson’s Trust, and Richard K Wyse, Director of Research and Development at The Cure Parkinson’s Trust, highlight a few of the clinical trial programmes seeking to achieve disease modification, and outline some of the issues that those efforts face.
These are the facts about Parkinson’s that most readers will be familiar with: it is the second most common neurodegenerative condition after Alzheimer’s. In the brain, it is characterised by the aggregation of certain proteins (such as alpha synuclein), and the degeneration of specific populations of neurons – most classically, the dopamine neurons in the substantia nigra. The loss of those particular cells is associated with the appearance of two or three motor features (bradykinesia, rigidity, and a resting tremor), but there are additional debilitating non-motor features that many sufferers also have to live with, including gastrointestinal issues, sleep disruption, and cognitive complaints. Currently there is no cure, and the primary treatments provide only short-term symptomatic relief.
What readers may not be aware of, however, is that Parkinson’s is ‘the only neurological disorder with increasing age-standardised rates of deaths, prevalence, and disability-adjusted life-years’ (www.ncbi.nlm.nih.gov/pubmed/30287051 ). As the average age of on-set for the condition is over 65 years of age, Parkinson’s represents a real public health burden for society at large as the overall population in Western societies continues to age. It will carry significant economic costs for society going forward unless better treatments are discovered.
Tremendous efforts are being made to find disease-modifying therapies for Parkinson’s, by groups like The Cure Parkinson’s Trust, the Michael J Fox Foundation, and the Silverstein Foundation. These efforts, however, are hampered by several rate limiting steps, such as the need for biomarkers and better methods of assessing / monitoring the condition.
Given the characteristic feature of protein aggregation in Parkinson’s, many of the ongoing clinical trials are focussed on removing aggregated proteins like alpha synuclein from the brain. One method currently being clinically tested is ‘immunotherapy’ – boosting the body’s immune system via the passive delivery of antibodies designed to target the aggregated form of the protein, or by active inoculation in the form of a vaccine.
The two leading immunotherapy clinical programmes are both conducting Phases II study at present – the Pasadena study being co-ordinated by Roche and the Spark study conducted by Biogen – both of which will be reporting results in the next few years. One issue with these approaches, however, is the limited amount of antibodies actually accessing the brain (less than two per cent of the injected total), and this has led to a number of biotech firms developing small molecule inhibitors of protein aggregation (such as NPT 088 from Proclara
Biosciences), and these too are currently being clinically tested.
Another method of clearing aggregated protein from neurons involves increasing autophagy. One such clinical trial programme, being conducted here in the UK (and supported by The Cure Parkinson’s Trust), is repurposing the expectorant Ambroxol for Parkinson’s. Pre-clinical research has suggested that this respiratory drug can not only raise levels of a lysosomal enzyme called glucocerebrosidase, but also increase exocytosis. These properties help with the breakdown and disposal of aggregated proteins and accumulated waste. A Phase II clinical trial has recently been conducted, the results of which are shortly to be announced.
A second drug that has evidence of increasing autophagy is the cancer drug Nilotinib which is also being repurposed for Parkinson’s in a Phase II clinical trial (also supported by The Cure Parkinson’s Trust). Numerous research groups have demonstrated that this c-ABL inhibitor has beneficial effects in models of Parkinson’s, and a small Phase I pilot clinical study provided supportive data justifying the larger, ongoing evaluation of this drug.
Mitochondrial dysfunction is a recognised feature of Parkinson’s and enhancing the performance of these ‘cellular power stations’ has been a continuous theme in research into the condition. A number of clinical trials are now evaluating the utility of various compounds for their ability to support and enhance mitochondrial function. One of these trials, being conducted in Sheffield, is the UP study – ‘UDCA in Parkinson’s’. Ursodeoxycholic acid (or UDCA) is a bile acid that is used in the treatment of gallstones. Previous pre-clinical research has demonstrated that UDCA also improves mitochondrial function in various models of Parkinson’s, and this has led to the initiation of the study in Sheffield.
One of the most exciting areas of clinical research for Parkinson’s at present, however, is the Exenatide / Bydureon clinical trial programme. This is a frontline treatment for diabetes that is being repurposed for Parkinson’s based on evidence that GLP-1 agonists exhibit neuroprotective properties in multiple neurodegenerative models. The Cure Parkinson’s Trust has supported this research effort since the pre-clinical stage, and in 2017 the results of a Phase II study indicated a stabilisation of motor features over a 40-week period in 20 people receiving the treatment (compared to the control group who continued to worsen). A major Phase III clinical trial will be initiated in September this year with the goal of testing efficacy of this weekly treatment in a cohort of 200 individuals with Parkinson’s.
One final aspect of Parkinson’s research that is experiencing significant progress is cell replacement therapy. When a person is diagnosed with Parkinson’s, they have lost approximately 60 per cent of their dopamine neurons in the substantia nigra. Replacement of these lost cells is an obvious potential remedy. The Cure Parkinson’s Trust has supported a clinical trial of foetal cell transplantation in Cambridge (UK) called Transeuro. It is apparent from that study, however, that cells multiplied and grown in culture have an advantage to the limited supply (and ethical dilemma) of foetal-derived cells. In addition, significant progress has been made in the development of protocols which allow researchers to differentiate bonafide dopamine neurons from embryonic stem cells.
This important progress has given rise to five ongoing clinical trial programmes for stem cell-derived cell transplantation in Parkinson’s, with additional interested parties preparing to initiate their own trials.
All of this clinical activity may sound exciting and raises hopes for disease-modifying therapies in the near future, but these clinical trial programmes face some significant challenges. One of the main issues plaguing clinical trial efforts has been the lack of biomarkers for
Parkinson’s. Currently, clinical rating scales and brain imaging methods are utilised in efforts to determine disease modification. Inter-rater variability and discrepancies between clinical results and image analysis render these methods rather blunt instruments, and treatment effects need to be large for positive results to be determined, while more subtle effects may be missed completely.
Alternative methods of assessment are being tested though. For example, technology is gradually being utilised in order to provide more objective measures. Tech firms are using artificial intelligence to assess video recordings of clinical assessments, providing more quantitative scores compared to the clinician estimations. In the forthcoming
Bydureon Phase III trial, a smart phone app will be used by a large portion of the participants to collect data and monitor their Parkinson’s features over the length of the trial, and similar technology is being utilised in the Pasadena immunotherapy trial being conducted by Roche in America.
In addition, novel techniques are being employed to evaluate the biological effect of treatments in trial participants. For example, analysis of brain-derive exosomes provided post hoc evidence of target engagement in the Phase II Bydureon trial, demonstrating that the drug was having a biological effect in the individuals in the treatment group. These exosomes can be collected from a blood sample, providing a simple, not-so invasive measure of biological activity in the brain.
Clinical trial design is also being reconsidered. The Cure Parkinson’s Trust is currently supporting the Australian Parkinson’s Mission, which involves four drugs being tested in a large five-arm clinical trial. This study design allows multiple treatments to be tested and compared against each other and a single placebo arm, offering a more efficient use of resources. And many new clinical trials are targeting specific subtypes of Parkinson’s. For example, the Phase II Ambroxol study mentioned included participants with a specific genetic form of the condition.
Any important feature of all of these clinical trials is the acknowledged requirement for added value in each study. Gone are the days when a clinical trial tested a drug and reported solely on the success or failure of the outcome. Each new trial now collects additional data – from blood samples and DNA, to the testing of new rating scales or assessment tools. And all of this information is feeding back into our understanding of Parkinson’s, and improving our ability to conduct these studies.
While all of these developments provide reasons for optimism for the Parkinson’s community – both patients and researchers – it is important to manage expectations. Neurodegenerative conditions have had a long and disappointing history of efforts to get new disease- modifying therapies approved for clinical use. And while there has never been so much research activity, the prudent course forward is to focus on what can be learned from each study and how it can be applied to improving our knowledge of Parkinson’s and the lives of those living with the condition.