Collaborative Opportunities in Vascular Dementia

Collaborative opportunities in Vascular dementia

Introduction

Vascular disease is a major cause of dementia

Vascular dementia (VaD) is the second most common form of dementia after Alzheimer’s Disease [1] and its prevalence increases with age [2,3]. In addition, cardiovascular disease contributes as a comorbidity to all other forms of dementia, and greatly increases the probability that Alzheimer’s pathology will result in clinical dementia [4]. Vascular cognitive impairment (VCI) is a term encompassing vascular dementia as well as milder forms of pre-dementia cognitive impairment related to vascular damage that do not meet the criteria for a diagnosis of dementia. Hence, vascular causes of dementia (or “vascular cognitive impairment”) affect a broad spectrum of patients with various manifestations of cognitive decline [3,5]. Throughout the workshop we discuss both VaD and VCI.

A recent Lancet Commission identified 12 risk factors for dementia, many of which act via vascular disease (notably, high blood pressure, diabetes, obesity, and lack of physical exercise) [6]. In addition, recent clinical trials have shown that vascular interventions have substantial impact on cognitive decline [7] and druggable targets are beginning to emerge [8,9]

However, there remains a significant unmet need for effective and safe treatments for VaD and VCI to help patients and carers today and into the future. Investment in the research and development of disease-modifying treatments are essential, to ensure those living with VaD have access to treatments that will improve overall quality of life.

Research charities including Alzheimer’s Research UK (ARUK), Alzheimer’s Society, British Heart Foundation (BHF), Diabetes UK, and Stroke Association have all highlighted VaD as a priority area for research investment and several

initiatives have been instigated to progress the research landscape. VaD is represented in the UK-wide research networks: Dementias Platform UK (DPUK) and the UK Dementia Research Institute (DRI) who are involved in the establishment of a new Centre for Vascular Dementia Research in partnership with BHF.

To address the vascular causes of dementia, a workshop was recently convened to explore the scope for a targeted initiative to facilitate cross-sector collaboration.

The Syndicate team at Medicines Discovery Catapult, together with colleagues at DPUK; Professors Stuart Allan and Atticus Hainsworth, engaged a small group of key opinion leaders including UK-based charities, clinical specialists, academic experts, and SMEs to identify common challenge areas and scope out opportunities to advance research efforts in VaD.

The aims of the workshop were to:

Better understand the current and future research landscape and identify where existing initiatives are already working to achieve these goals.

Better understand the perspectives of different key stakeholder groups and provide opportunities for collaboration.

Identify a specific challenge(s) where a collaborative approach could provide added benefit and significant breakthrough.

Workshop discussions

The workshop began with an introduction to funders’ perspectives followed by three breakout discussion groups. The introductory session provided an overview of existing collaborative opportunities in VaD from researchintensive UK-based charities and a new government initiative:

• Alzheimer’s Research UK (ARUK) (www.alzheimersresearchuk.org)

• Alzheimer’s Society (www.alzheimers.org.uk)

• Diabetes UK (www.diabetes.org.uk)

• Stroke Association (www.stroke.org.uk)

• Office of Life Sciences on the Dementia Mission (Life Sciences Vision – GOV.UK (www.gov.uk))

Alzheimer’s Research UK described their mission as “A world free from the harm and heartbreak of dementia”. They further explained their funding strategy with the majority of funding being allocated into understanding, treating, diagnosing and reducing risks. Funding for VaD is significantly lower than other dementias, 2.6% for VaD relative to the 34% awarded to Alzheimer’s disease. Alzheimer’s Research UK concluded there was a clear unmet need in VaD and a collaborative platform would greatly benefit this disease area.

Diabetes UK further elaborated on the need for an analysis of the gaps in VaD research, in order to identify opportunities for collaboration and investment, so as to address areas of unmet need. They currently have a focus on healthy ageing but expressed an interest in understanding shared mechanisms and comorbidities that included diabetes and vascular cognitive impairment. They noted that many people with diabetes have expressed a fear of developing dementia.

The Stroke Association highlighted that post-stroke dementia is a key area of focus. Dementia is a common consequence of stroke, affecting about one in 5 people who have had a stroke. However, post-stroke dementia is often overlooked and under researched. Building partnerships to leverage funding and expertise, as well as putting lived experience at the centre of their work, are key aims of their research strategy. A James Lind Alliance Priority Setting Partnership identified cognitive problems caused by stroke as the 2nd highest priority. The charity is using this to guide its funding and partnership working.

The Alzheimer’s Society funds both biomedical and care research. Their 20222027 research strategy covers: i) funding research of high quality, ii) increasing the number of dementia researchers, iii) aligning their organisational strategy to make the biggest difference for patients and iv) ensuring people affected with dementia remained central to their decision making.

The Office for Life Sciences talked about the scope of the Dementia Mission – a national multi-million pound initiative taking a mechanistic approach to biomarker development. For example, mechanisms common across neurodegenerative diseases, e.g., neuronal damage reflected by neurofilament light chain (NF-L), amongst other promising markers, once validated, could be prioritised and could be used in VaD as well as in other neurodegenerative diseases.

Finally, each organisation agreed with the need for increased cross-sector collaboration across all aspects of VaD to accelerate breakthroughs in the field.

Workshop sessions

Introduction: Funders

Perspective

Breakout

Session 1: Characterising the “at risk” population to drive the discovery of biomarkers of disease and progression

Breakout

Session 2: Industry-Academic drug discovery opportunities

Breakout

Session 3: Clinical Trial Endpoints

Breakout session 1:

Characterising the “at risk” population to drive the discovery of biomarkers for disease and progression.

A better understanding of the risk factors for VaD could enable the discovery of new biomarkers of disease onset and progression, which in turn could be a valuable tool for patient stratification and drug discovery efforts.

The breakout session discussion areas:

• How can the ‘at risk’ population be better defined?

• Are there molecular biomarkers for VaD that are trial-ready, or in the pipeline?

• Are there digital, imaging, or cognitive biomarkers that are trial-ready, or in the pipeline?

It was agreed that a key population where intervention should be focused was early stage, pre-symptomatic mild cognitive impairment, prior to transition to subjective cognitive impairment. In addition, primary prevention, ensuring patient adherence in controlling hypertension, diabetes, and peripheral cholesterol levels and promoting a general healthier lifestyle, would contribute to overall outcome improvement in patients with vascular risk factors.

In discussing the available potential biomarkers, a number of challenges were highlighted. MRI imaging biomarkers are currently available however, the use of MRI as a screening tool, within the current NHS diagnosis and treatment pathways, was challenging due to cost and access. Blood-based biomarkers are not yet established although there are a number under experimental exploration. It was suggested that collection of material from across different studies, including that obtained from patients seen either in

Neurology or Cardiovascular clinics would be beneficial. Similarly, the investigation of VaD risk factors could be assessed from brain scans carried out for other causes, with analysis of these eventually performed routinely using AI-based approaches. The development of assessment methods based on through-the-eye-imaging (including OCTA, optical coherence tomography angiography), which could be performed during routine eye tests and which can directly assess a part of the CNS microvasculature, could be likely in the next 5-10 years.

Considerable work is needed to generate and optimise biomarkers, which ideally would combine imaging and bloodbased readouts and incorporate genetic risk factors. The development of computational methods, potentially with the use of AI, to combine these, would allow patient stratification with respect to recognised risk thresholds.

It was suggested that collection of material from across different studies, including that obtained from patients seen either in Neurology or Cardiovascular clinics would be beneficial.

Breakout session 2:

Industry-Academia drug discovery opportunities

Direct collaboration and investment from the pharmaceutical industry and biotech in both the cerebrovascular and VaD fields is currently limited despite the unmet need. This is a common situation in areas where investment carries significant risk. However, new models for conducting drug discovery are now more common [10]. In these models, outsourcing and pre-competitive consortia have been successfully implemented to overcome barriers and tackle key challenges [10]. Such consortium may provide a basis from which to design a focused intervention in VaD.

The breakout session aimed to address the following questions:

1 How can industry engage with existing and future academic, clinical, and charity initiatives in VaD?

2 What is the academic research community ‘offer’ to industry in VaD research?

3 Where can industry best interact with academic and clinical research efforts?

4 Drug repurposing:

• What options are there to collaborate to drive repurposing of marketed drugs for VaD?

• What options are there to collaborate and explore the potential of non-marketed clinical stage compounds developed for other indications, in VaD?

There was general consensus that it was difficult to define and compartmentalise targets and mechanisms of focus in VaD. Questions were raised as to which therapeutic area does VaD research fit within pharmaceutical companies e.g., neurology, vascular, inflammation, immunology? It was suggested that the disease and therapy area-focused research departments within bigger pharmaceutical companies were a potential barrier to collaboration and required engagement with industry leaders to signpost efforts to the most relevant team.

It was acknowledged that industry requires defined mechanistic and translational models, preferably validated in several research institutes. This may be considered burdensome for academic labs, to carry out the same validation of models across groups. There was consensus that collaborative funding to establish and validate animal and cell models across multiple groups would lower the barrier for engagement with industry.

Interaction between academia and industry for pre-clinical projects can be difficult as the timelines and, as noted above, the industrial rigour of data generated by academic institutions, may not be sufficient for industrial partners, who in addition may require that projects adhere to a critical path

There was consensus

to ensure a quicker route to a decision point. Moreover, it was suggested that these projects would be more successful if there was an intermediary coordinating interaction between academia and industry, acting as a trusted and neutral broker for future partnership.

Repurposing of clinically available, marketed, drugs is of value for understanding the role of mechanisms in disease and the potential to bring these into new clinical use. Repurposing would be unlikely to gain the interest of pharmaceutical companies, due to commercial considerations. However, industry is interested in new targets where value can be demonstrated, which could be a catalyst for research in VaD. The role of drug repurposing within the overall therapeutic portfolio of VaD to help identify and validate such targets and mechanisms could provide a route to new drug discovery.

Workshop participants suggested that improving and enabling mobility between academia and industry, including SMEs, would facilitate greater collaboration. It would also facilitate the discovery of new, defined, and tractable targets and mechanisms, and act as a catalyst for the interest of industry partners. As above, an intermediary organisation to help forge these academic and industry partnerships would greatly benefit all stakeholders.

that

collaborative funding to establish and validate animal and cell models across multiple groups would lower the barrier for engagement with industry.

Breakout session 3:

Clinical trial endpoints

Building the confidence to invest in larger, more costly phase III clinical trials will require an agreed view of the desired outcomes for phase II clinical trials in VaD. Defining translational, neurocognitive endpoints could help to provide a stronger foundation for faster progression of treatments to the clinic.

The breakout session aims were to discuss:

1 What is considered the current gold standard for clinical trial endpoints in VaD?

2 What are feasible options for future trial endpoints?

3 What success criteria would be needed at phase II to support a phase III trial?

4 Can the VaD field learn from the progress in trial design applied in other areas e.g., platform or basket trials?

In discussing the current approach in VaD clinical trials it was acknowledged that most trials rely on patient follow-up with a cognitive test, alongside patientreported symptoms and changes to their lived experience e.g., dependency for day-to-day living. These latter tests can be subjective and as a clinical trial endpoint, pose measurement and reliability challenges. A range of other strategies and potential endpoints were discussed. These included: continuation of cognitive measurement outcomes for the duration and after completion of the trial; determination of personality and behavioural changes e.g., changes in apathy, in addition to current patientreported outcome measures. In addition, there is a need for novel clinical methods. These include imaging end points to visualise blood brain barrier integrity and brain blood flow (alongside automated assessment of current markers, such as white matter hyperintensities). Biological measurements of novel blood-based

biomarkers (e.g., IL-6, MMP-9, CRP and lipoprotein A) were considered potentially relevant and, while these are currently experimental, there is an increasing body of evidence to support potential use in clinical trials. Finally, a need for additional non-invasive measurements was noted, such as speech and voice cadence, alongside the established breath holding index to measure cerebral haemodynamic changes.

It was recognised that patients often present via different routes, typically either through established cardiovascular or neurology clinics and therefore, may represent different subgroups of VaD. Ensuring the inclusion of these differently presenting patient groups in platform trials would be highly beneficial although it would require coordination with the standard-of-care therapies each individual was taking, alongside the need to centralise logistics for rapid evolution of the trial.

Workshop conclusions

There was a high level of agreement within the workshop regarding the need to work together, and of the opportunities for new, focused efforts on vascular causes of dementia. All participants were willing to further explore these opportunities.

There was considerable enthusiasm within the workshop to forge new interactions and partnerships with industry, but also a recognition that these can be challenging due to potential differing priorities between industry and academia. Identifying ways to bring industry and academia together to focus on common opportunities and areas of unmet need through the development of defined areas of collaboration and funding would help catalyse the interests of both partnerships.

Three broad areas of consensus were identified:

1 The need to focus on early stage, pre-symptomatic, mild cognitive impairment, to obtain a better understanding of the mechanisms and potential targets for intervention, alongside earlier diagnosis of people with a high risk of developing VaD.

2 Clearer messaging concerning primary prevention and adherence to modifiable lifestyle interventions was considered of great importance, when focused on at-risk, pre-symptomatic patients.

3 New biomarkers that cover all aspects of diagnosis, alongside the validation of currently identified biomarkers, was considered essential. Ideally these would be suitable for robust decision making as clinical trial endpoints too. Such biomarkers would ideally include a variety of endpoints, including digital, cognitive, biological, imaging, and genetic, with the potential for the use of AI-methods to interrogate and integrate these.

Take Home Messages

1 New therapeutic interventions for vascular causes of dementia are emerging, incorporating de novo drug discovery and drug repurposing. However, increased industry engagement is required to advance this area.

2 Druggable targets are emerging. Examples are components of the neuro-inflammatory response (e.g., the inflammasome), endothelial function including the endothelin system and nitric oxide-PDE5 pathway, and signalling pathways leading to pericyte-mediated capillary constriction or to pericyte loss and blood-brain barrier breakdown.

3 The UK has considerable strengths in basic and applied research. The Vascular Brain Health community is a research network with international expertise in the pre-clinical and clinical aspects of dementia that can be leveraged.

4 Biomarkers for the vascular causes of dementia are urgently needed, both to improve accuracy of diagnosis and as trial endpoints. There are promising markers emerging that require support for validation.

5 Non-standard clinical trial approaches are needed, including those that incorporate novel, flexible models such as platform (or basket) trials, fail-early, and n=1 design etc. Albeit collaborations of groups are developing such as the ACORD for running and reporting of Multi-Arm Multi-Stage (MAMS) platform trials in neurodegenerative diseases. However, to enable this there is a need for clear endpoints and markers.

Next steps

Following the workshop, additional activities related to vascular dementia took place, including the UKDRI Vascular Theme meeting, which ultimately led to a publication of its discussion [11]. This was followed by the establishment of a new Centre for Vascular Dementia Research in partnership with BHF. This development is highly encouraging, as it signifies that the field of vascular dementia is gaining recognition, prominence, and momentum.

In summary, workshop attendees were united in the need to accelerate progress and explore further opportunities in VaD.

Key among these were the needs to align charity, academic, SME and pharma stakeholders on common challenges, reach consensus and provide a public statement on the “state of play in developing effective and safe treatments in vascular dementia”, and to build and facilitate collaboration between industry and academia that is of mutual benefit.

Survey results

Following the workshop, we conducted a post-workshop survey to gather valuable information from attendees. The purpose was to enhance our logistics and content for future workshops or work in VaD. Participants were asked to share their insight on various aspects of the workshop experience including:

1

Overall experience: How satisfied they were with the overall experience of the workshop.

2 Program design: How informative and logical was the workshop and was it well communicated.

3 Cohort: What additional expertise could the workshop have benefitted from?

The delegates displayed their likelihood of follow up on connections made during the workshop, over 95% strongly agreed to follow up on connections made at the workshop.

5% Not likely

95% Likely

The survey displayed three key areas which the respondents agreed would benefit future workshops:

1 A higher attendance and engagement from Pharma Industry Representatives to establish feasibility and overcoming barriers to the development for existing therapeutics and new mechanisms in vascular dementia.

2 A broader panel of the delegates to include patients or carers with experience of vascular dementia.

3 Increased representation of clinical trial and biomarkers experts.

4 Suggestions: What went well and what could have been improved?

5 Networking experience: Did the workshop provide a platform to network with colleagues within the field.

6 Future involvement: Who should be involved and how you would be involved in future workshops?

They also responded on the overall experience of the workshop, how informative the sessions were, the level of interest and engagement in the breakout group discussions and the value of workshop delegates covering a broad range of expertise; data are displayed as Box plots with the mean indicated with a line within the box. Score range was 0-10.

Overall experience

Informative

Interesting/engaging Coverage

Quotes from delegates

Vascular dementia is a key area of focus for the UK DRI. We run a very successful Vascular Theme including external partners/ collaborators like DPUK and BHF (Theme activities include annual early career research symposia and group leader’s retreats, sandpit events, scientific webinars etc.)

Giovanna Lalli and Joanna Wardlaw

Let’s keep up the momentum

Atticus Hainsworth - DPUK

Thank you Catapult for an excellent workshop

Dr Tom Blackburn - TP-Ventures

Fig 1: Survey results from delegates attending the Collaborative Opportunities in Vascular Dementia workshop organised by MDC in Manchester, April 2023.

Appendix 2: Workshop Attendees

The following people attended and contributed to discussions at the in-person workshop on 19th April 2023. We would like to thank all the workshop attendees for sharing their time, insights, and feedback with us.

Name Institution

Position

Alastair Webb University of Oxford Consultant Neurologist

Anna Morris Diabetes UK Assistant Director of Research Strategy and Partnership

Atticus Hainsworth St George’s University of London; DPUK Reader in Cerebrovascular Disease, DPUK Vascular Health Theme Leader

Axel Montagne

Centre for Clinical Brain Sciences and UK Dementia Research Institute, University of Edinburgh Chancellor’s Fellow, UKDRI Group Leader

Damian Crowther Dementia Discovery Fund Venture Partner

David Attwell UCL Principal investigator

Ekta Patel Medicines Discovery Catapult Partnership manager, Neuroscience

Emma Jones Medicines Discovery Catapult Lead Scientist, in vitro Neurobiology

Fiona Ducotterd ARUK UCL Drug Discovery Institute Chief Scientific Officer

Giovanna Lalli UK Dementia Research Institute Director of Scientific affairs

Greg O’Sullivan Astex External Science and Innovation, CNS

Hugh Markus University of Cambridge, DPUK Neurologist, DPUK Project Lead-Vascular Health

James Leiper British Heart Foundation Associate Medical Director-Research

Joanna Wardlaw

Centre of Clinical Brain Sciences and UK Dementia Research Institute, University of Edinburgh, DPUK

Chair of Applied Neuroimaging, Head of Neuroimaging Sciences, UKDRI Group Leader, DPUK Project Lead-Vascular Health

John Skidmore ARUK ALBORADA Drug Discovery Institute Chief Scientific Officer

Kerry Shea Medicines Discovery Catapult Lead Scientist, Molecular Biomarkers

Laura Ajram Medicines Discovery Catapult Partnership lead, Neuroscience

Lauren Moore Office for Life Sciences Policy Advisor, Dementia Mission

Lucy Devendra Alzheimer's Society Head of research

Ludovica Griffanti University of Oxford, DPUK Alzheimer’s Association Research Fellow, DPUK Project Lead-Imaging processing

Margarida (Guida)

Ruas ARUK Oxford Drug Discovery Institute Organelle Biology team leader

Nadeem Sarwar Eisai EMEA Global Head, Genomic Strategies & Global Head, Digital Therapeutics (DTx) Strategies, Dementia Mission co-Chair

Richard Francis Stroke Association Head of research

Rob Pinnock Biogen

Ross Dunne University of Manchester

Director of External Innovation

Consultant Old Age Psychiatrist, Greater Manchester NIHR CRN Division 4 lead for dementia, Honorary Senior Lecturer

Sara Imarisio Alzheimer's Research UK Head of Strategic Initiatives

Sian Gregory Alzheimer's Society Research Information Manager

Stuart Allan University of Manchester, DPUK Professor of Neuroscience

Terry Quinn University of Glasgow, DPUK

Reader and Honorary Consultant Physician in Stroke and Geriatric Medicine, DPUK Project Lead-Vascular Health

Tom Blackburn TP Bioventures/DPUK Founder, Chief Executive

Una Clancy Centre for Clinical Brain Sciences and UK Dementia Research Institute, University of Edinburgh

SCREDS Clinical Lecturer, Specialty Trainee in Geriatric/ General Internal Medicine

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Acknowledgements

MDC would like to acknowledge Dr Kiren Yacqub-Usman for her leadership in all activities and the development of the collaborative opportunities in vascular dementia post workshop report. MDC would like to emphasise the valuable contributions from Prof Atticus Hainsworth, Prof Stuart Alan, and from Dr Graeme Wilkinson (Head of VR&D and Strategy Lead for Healthy Ageing at MDC), and Dr Sara Imarisio (now Strategy Lead for Neuroscience at MDC). MDC would also like to acknowledge the significant contribution of Dr Laura Ajram (now CEO at the British Neuroscience Association) and Dr Ekta Patel in organising and delivering the workshop. Finally, MDC would like to extend its appreciation to all participants for their active involvement in the workshop and for their invaluable feedback on the post workshop report, the participation has greatly enriched the discussions and outcomes of the workshop.