Introduction
Dementia clearly represents a global and growing health challenge, estimated to affect over 100 million people worldwide by 2050. Lewy body dementia (LBD), the second commonest cause of degenerative dementia after Alzheimer’s disease (AD), accounts for around 10% of all clinically diagnosed cases [
1,
2] and Lewy body pathology is present in up to 25% of dementia cases at autopsy. LBD includes two closely related conditions, dementia with Lewy bodies (DLB) when dementia develops before or within a year of onset of motor symptoms, and Parkinson’s disease dementia (PDD) when dementia occurs during the course of established Parkinson’s disease (PD) [
3]. Both DLB and PDD are associated with very poor outcomes in terms of diminished quality of life [
4], more rapid functional decline, and increased mortality compared to other dementias [
5]. Limited symptomatic treatments exist, primarily cholinesterase inhibitors and memantine, but there are no disease-modifying treatments for LBD. Better treatments to improve these poor clinical outcomes are urgently needed.
The pathophysiology of LBD is complex. Alpha-synuclein deposition occurs intra-neuronally in the form of Lewy bodies and Lewy neurites, as in PD, and there are variable amounts of Alzheimer's type pathology, particularly non-neuritic amyloid plaques with a variable extent of tau tangle pathology. Other changes, such as neuroinflammation, are increasingly recognised to occur early in the disease [
6,
7] and may impact the outcome, as has been shown for other dementias [
8]. As such, potential strategies targeting disease modification may be directed at influencing α-synuclein deposition (either decreasing deposition, decreasing phosphorylation, or accelerating clearance), Alzheimer’s type amyloid and tau changes, or affecting the neuroinflammatory cascade.
DLB and PDD potentially represent a spectrum of disease, rather than discreet conditions, and treatment approaches for these integrated disorders for pharmacological and non-pharmacological management share much in common [
9]. With the identification of several new potential treatment targets for LBD, there has been renewed interest from the biopharmaceutical industry in LBD clinical trials with several ongoing and some promising early results reported. For example, a Phase 2 study of neflamapimod, a mitogen-activated protein kinase (MAPK) inhibitor, which may regulate the endosomal protein Rab5 and modulate neuroinflammation by shifting microglial activation from a proinflammatory to a phagocytic state, has been shown to improve cognition in early reports [
10,
11]. Despite this increased interest, there are only 14 ongoing Phase 2 or Phase 3 clinical trials of pharmaceutical interventions registered for DLB and PDD on the clinicaltrials.gov trial registry (compared to 158 studies for AD and >1800 for cancer), emphasising the urgent need to enhance the emerging treatment pipeline (
https://clinicaltrials.gov/ct2/home, accessed 01/09/2022, search terms: Recruiting, Active, not recruiting, Enrolling by invitation Studies | Parkinson’s disease dementia OR Lewy body dementia OR Lewy OR Parkinson’s disease with dementia OR Parkinson-Dementia syndrome OR Lewy Body Parkinson dementia | Phase 2, 3).
An alternative to developing pharmacological agents de novo, at substantial cost and long lead-in time before clinical use, is to consider repositioning or repurposing of existing clinically available agents for new indications. This has been advocated for several conditions including cancer and other types of dementia [
12,
13]. Many drugs, though developed for one target mechanism, have multiple pharmacological actions that may offer benefit in other conditions. Drugs that have already been approved by regulatory authorities or whose development was discontinued prior to approval have established dosing, tolerability, safety and side effect and well as manufacturing challenges, offering a significant reduction in development time for clinical trials. Many are off or nearing end of patent, thus offering the prospect of a widely available low-cost agent [
12]. Drug repurposing has been defined as the application of established drug compounds to new therapeutic indications and offers a route to drug development that is accessible to academic institutions, government and research council programmes, charities and not-for-profit organisations thus complementing the work of pharmaceutical and biotechnology companies. Drug repositioning occurs within the biopharma industry during drug development and refers to the development of an agent for an indication other than the indication it was originally intended for. This new indication is prioritised during the development process and before approval [
14]. Our study focused on drug repurposing.
With many potential candidates for repurposing, a key question is how to choose a compound or compounds with sufficient evidence to move forwards to clinical trials guiding both the scientific community and funders. A prioritisation process is important to achieve this and to gain both consensus and scientific credibility; such a process has been used in Alzheimer’s disease as previously prioritised compounds have been taken forward to clinical trials [
15].
The aim of this study was, therefore, to undertake a robust prioritisation exercise to identify potential agents that might be suitable for repurposing for LBD (either DLB or PDD or both) and to assemble an international expert panel to provide a view on (a) whether there was sufficient evidence for a compound(s) to be taken forward into clinical trials and (b) if so, the compound’s priority order for further study. The intention was to develop an international consensus on the pathway forwards for clinical studies of repositioned and repurposed agents for LBD.
Conclusions
We provide a comprehensive review of recently published and ongoing trials of agents potentially suitable for repurposing for LBD. Our initial prioritisation exercise identified nine candidate compounds or classes of compounds. In Table
2, we summarise the agents prioritised through our Delphi process, their proposed mechanisms of action, available evidence and future work required. As part of the methodology we followed for the Delphi consensus recommendations, we did not exclude compounds that are already in trials; therefore, ambroxol and nilotinib were highly prioritised in the process. While these trials are still ongoing, our Delphi consensus reviews show clear support for continuing research on the role of these compounds as disease-modifying treatments in DLB and PDD.
Table 2
Summary of agents prioritised for repurposing for LBD by the international Delphi panel
Ambroxol | -Neuroprotective effects through upregulating GCase | -Reduction of α-synuclein pathology and improved mitochondrial function -Penetrates the CSF and engages the treatment target in humans | -Pharmacokinetics -Better understanding of mechanisms -Phase 2 work needed with CNS or CSF biomarkers to support target engagement |
Nilotinib/bosutinib | -Increases the clearance of α-synuclein, amyloid, hyperphosphorylated tau -Stimulates autophagy -Anti-inflammatory effect -Rescues synaptic dysfunction | -Safe, well tolerated -Increase in dopamine metabolites in the CSF -Reduction of CSF α-synuclein oligomers and hyperphosphorylated tau -Worsening of motor scores | -Await results of ongoing trials -Safety work, especially in older adults and QTc prolongation |
Liraglutide/exenatide | -Decreases astrocyte and microglial activation -Decreases chronic inflammation and lipid peroxidation -Suppresses the apoptosis pathway -Increases autophagy-related protein expression -Reduces free oxygen species | -Improvements in off-medication scores on part 3 of the MDS-UPDRS -Lower rate of PD compared to the use of other antidiabetic drugs | -Phase 2 work needed with CNS or CSF biomarkers to support target engagement in LBD |
Candesartan/telmisartan | -Inhibits the expression of TLR2 and TLR4 -Reverses the activated proinflammatory phenotype of primary microglia -Reduces TNF-α levels | -Improvement of motor deficits in animal models -Reduction in levels of α-synuclein and attenuation of ER stress-triggered neuronal apoptosis -Improvement of cognitive performance in various cohorts | -More preclinical evidence and studies on whether they cross the BBB -Additional epidemiological evidence -Phase 2 trials in LBD |
Metformin | -Prevents α-synuclein phosphorylation and aggregation -Prevents astroglia and microglia activation -Improves cell survival and promotes autophagy | -Reduction of amyloid beta secretion and tau phosphorylation -Improves cognitive performance in animal models. -Improves motor impairments in PD animal models -Improves verbal learning and memory in amnestic MCI. | -Phase 2 research needed with CNS or CSF biomarkers to support target engagement in LBD -Prodromal studies in enriched RBD may have a direct relevance for LBD |
Fasudil | -Promotes the degradation of α-synuclein via autophagy through the JNK 1/Bcl-2/beclin 1 pathway -Dilates cerebral vessels -Inhibits the release of intracellular calcium | -Reduction of phosphorylated α-synuclein -Improves motor deficits in various animal models of PD -Rescues cognitive deficits, reduced acetylcholinesterase activity and oxidative stress in AD animal models | -Need clinical/pharmacokinetic studies to CNS penetration -Phase 1 clinical studies |
Following detailed evidence-based review, over two thirds of the panel identified ambroxol as the top priority compound for both DLB and PDD, though even more (79%) thought there was evidence for PDD. Ambroxol, initially developed as a mucolytic agent, has activity as a molecular chaperone for the lysosomal enzyme GCase. Loss of function mutations in the
GBA1 gene that encodes GCase are one of the leading genetic risk factors for the synucleinopathies of PD and DLB [
30]. This appears to be a highly promising compound for repurposing, and the largest planned trial is a Phase 2 Norwegian study of people with dementia or MCI with Lewy bodies that will enroll 172 participants [
36]. Further trials are warranted.
Nilotinib and bosutinib are tyrosine kinase inhibitors and have shown promising preclinical evidence of effects both on α-synuclein and hyperphosphorylated tau as well as evidence of tolerability. However, during the course of this Delphi panel study, a double-blind placebo control Phase 2 study over 6 months in people with PD suggested that those on nilotinib had worse motor scores than placebo and, importantly, there was no evidence of central CNS penetration as dopamine metabolites in CSF did not change [
50]. This suggests that, of the two compounds, bosutinib may be more worthy of further investigation than nilotinib.
There was support for the GLP-1 receptor agonists liraglutide and exenatide, and both are being assessed in AD trials, while exenatide is undergoing a Phase 3 trial in PD. Subcutaneous administration is required which is clearly less convenient than oral therapy, but trials of other agents administered subcutaneously or even by intravenous infusion have proved acceptable in AD. While not the focus of this repurposing study, oral GLP-1 receptor agonists are becoming available (e.g. semaglutide) which would be an easier dosing route for future studies [
213], while alogliptin, an oral compound inhibiting DPP-4, the enzyme that inactivates GLP-1, thus boosting GLP-1 indirectly, is also trialled in PD [
214].
Candesartan and telmisartan are ARBs, in wide clinical use as antihypertensives and for heart failure. They have a number of potential actions of relevance in LBD including actions on microglia and the endoplasmic reticulum. No trials are ongoing or planned in LBD, though there are ongoing trials in MCI and AD. There is good rationale for examining these compounds in LBD.
Metformin is a widely used anti-hyperglycaemic drug which has been shown to prevent α-synuclein phosphorylation and aggregation in animal models and prevent astroglial and microglial activation. There are ongoing studies in MCI and AD, but no identified studies in LBD. The panel concluded that studies of metformin in LBD are therefore warranted.
Fasudil is a selective rhoA/kinase (ROCK) inhibitor used for the treatment of subarachnoid haemorrhage in China and Japan. There are ongoing studies in progressive supranuclear palsy and ALS, but no studies in AD or LBD. Notably fasudil was prioritised in a recent Delphi consensus study of repurposing in AD [
13].
In summary, through an international Delphi study, we have identified several promising compounds that have sufficient evidence to be taken forward into Phase 2 and Phase 3 studies for LBD. Given the current lack of any disease-modifying therapies and the huge burden of disease globally, both in terms of numbers affected and adverse impact on quality of life and mortality, there is a clear and urgent need to undertake clinical trials of these compounds in LBD.
Acknowledgements
RENEWAL Study Group (group authorship members):
Dag Aarsland, Centre for Age-Related Medicine (SESAM), Stavanger University Hospital, Stavanger, Norway; Department of Old Age Psychiatry, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, UK
Frederic Blanc, ICube Laboratory UMR 7357 and FMTS (Fédération de Médecine Translationnelle de Strasbourg), IMIS team, University of Strasbourg and CNRS, Strasbourg, France. CM2R (Research and Resources Memory Centre), Geriatric Day Hospital and Cognitive-behavioural Unit, Geriatrics Department, University Hospitals of Strasbourg, Strasbourg, France.
Bradley Boeve, Department of Neurology Mayo Clinic Rochester Minnesota USA.
David J Brooks, Positron Emission Tomography Centre Newcastle University, Newcastle upon Tyne United Kingdom; Department of Nuclear Medicine and PET Centre Aarhus University Hospital Aarhus Denmark.
K. Ray Chaudhuri, King’s College London, Department of Neurosciences, Institute of Psychiatry, Psychology & Neuroscience and Parkinson’s Foundation Centre of Excellence, King’s College Hospital, London, UK
Jeffrey Cummings, Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas, Las Vegas, NV, USA.
Howard H. Feldman, Dept. of Neurosciences, University of California San Diego (UCSD), San Diego, CA, USA, Alzheimer Disease Cooperative Study, UCSD, San Diego, CA, USA,
Leon Flicker, Geriatric Medicine, Western Australian Centre for Health & Ageing, University of Western Australia, Royal Perth Hospital, Perth, Western Australia, Australia.
James E Galvin, Comprehensive Center for Brain Health, Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA.
Donald G Grosset, Institute of Neuroscience and Psychology, University of Glasgow, United Kingdom
Manabu Ikeda, Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Japan.
Susan Kohlhaas, Alzheimer’s Research UK, Cambridge, UK
Brian Lawlor, The Global Brain Health Institute, Trinity College Dublin, D02 PN40 Dublin, Ireland.
Afina W Lemstra, Department of Neurology, Alzheimer Center Amsterdam, Amsterdam University Medical Center, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
Iracema Leroi, Department of Psychiatry and The Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland.
Elisabet Londos, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden; Memory Clinic, Skåne University Hospital, Malmö, Sweden.
James B. Leverenz, Lou Ruvo Center for Brain Health Neurological Institute Cleveland Clinic Cleveland Ohio USA
Simon Lewis, Parkinson's Disease Research Clinic, Brain and Mind Centre, University of Sydney, New South Wales, Australia.
Ian McKeith, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
Roger Mills, Institute of Psychiatry Psychology and Neuroscience, King's College London, London, UK; Vincere Consulting, LLC, San Diego, CA, USA.
Richard Oakley, Alzheimer's Society UK, London, UK
Jill Richardson, Neuroscience, Discovery Research, MSD, London, UK
Marwan Sabbagh, Barrow Neurological Institute Phoenix, AZ, USA
John Skidmore, ALBORADA Drug Discovery Institute, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, UK
Per Svennigsson, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, King’s College Hospital, London, UK
Pietro Tiraboschi, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133, Milan, Italy.
Daniel Weintraub, Department of Psychiatry University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Zuzana Walker, Division of Psychiatry, University College London, London, UK; Essex Partnership University NHS Foundation Trust, Essex, UK
Rosie Watson, Department of Medicine - The Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, 3050, Australia; Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
Rimona S. Weil, Dementia Research Centre, University College London, London, UK; Wellcome Centre for Human Neuroimaging, University College London, London, UK; Movement Disorders Consortium, National Hospital for Neurology and Neurosurgery, London, UK
Caroline H. Williams-Gray, John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Cambridge, UK; Cambridge University Hospitals NHS Trust, Cambridge, UK.
Alison Yarnall, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK; NIHR Newcastle Biomedical Research Centre, Faculty of Medical Sciences, Newcastle University, UK; Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK.