Alzheimer’s research: Cutting through the noise to find the signal
This year, 21st September marked World Alzheimer’s Day, with 1st to 29th September World Alzheimer’s Month.
Alzheimer’s disease (AD) is not a normal part of ageing, but the risk of developing it increases as we get older, with ‘late onset’ Alzheimer’s describing the disease for those who develop it over the age of 65. Unfortunately, AD can affect younger people, too, with at least three in every 100 people with Alzheimer’s in the UK under the age of 65, according to Alzheimer’s Research UK.
In basic terms, what causes AD is a build-up of two proteins: amyloid and tau. Whereas amyloid build up occurs in the space between different cells in the brain, tau builds up in the brain’s nerve cells themselves. Research is ongoing to understand the detailed cause and innovate an effective treatment – from Eisai’s Leqembi to Roche’s trontinemab, now testing in preclinical-stage patients at elevated risk of cognitive decline, and – of course – Eli Lilly's Kisunla, which recently went to appeal against a decision by the EMA's human medicines committee not to approve it.
Additionally, Lilly launched a new awareness campaign in the US this month, focussing on dementia, and named A-list actress Julianne Moore to front it. Brain Health Matters is a global campaign encouraging people to take charge of their brain health and lower their risk of dementia from conditions like Alzheimer's disease, running on US television, digital, and audio platforms, backed up by a supporting website.
Our brain health, then, is very much front of mind, so to speak. And amongst all these developments, Paul O’Donohoe, senior director, eCOA product and science at Medidata, and Kaycee Sink, chief medical officer at Cogstate, spoke with pharmaphorum about how clinical trials for Alzheimer’s have evolved and what this means for patients and sites.
Q: Historically, what challenges have been associated with conducting clinical trials in Alzheimer’s disease?
Sink: A key challenge in the early days of Alzheimer’s disease research was confirming that patients actually had the disease. Previously, you could only be certain by carrying out a brain biopsy. Consequently, many trials included patients who did not have Alzheimer’s, which made it difficult to detect the benefits of the treatments.
Endpoints have also been a challenge. Early research used patients with moderate to severe disease to develop endpoints. However, as our understanding of Alzheimer’s has grown, we’ve had to discover more sensitive endpoints that can be used for milder and earlier stages of the disease.
O’Donohoe: From a technology perspective, complex assessments of Alzheimer’s disease were originally developed using pen and paper. In the past, patients may have been asked to draw shapes or conduct physical tasks in the real world. Advancements in electronic data capture have improved data quality and reduced the workload for site and patients, as they increasingly conduct assessments digitally.
Digital techniques have not completely replaced the physical: there is still a need to complete some tasks with physical props, but these can be planned for as part of a broader eCOA (electronic Clinical Outcome Assessments) workflow to limit patient burden while maintaining the data quality benefits of electronic capture.
Q: What are some impacts of the clinical trials on patients and sites?
Sink: Clinical trials can be demanding for patients. Days on site can be long and cognitively taxing. Alzheimer’s trials often also involve a study partner to report on some outcomes, as the nature of this disease means patients cannot remember what they may have forgotten.
Though there are burdens, on-site clinical trials do have some advantages. When I was a site principal investigator, I often saw patients create a community with study staff, and study partners felt they were receiving extra support, as they could ask staff questions and get feedback.
O’Donohoe: What Kaycee points out is an essential consideration when developing technologies for Alzheimer’s trials. We often have a desire to turn everything digital in trials and complete tasks remotely, especially since the COVID-19 pandemic, but physical appointments can have real benefits for patients and caregivers. This is why thoughtful implementation of technology is great because it offers flexibility, and patients can choose what is best for them.
Sink: Yes, where appropriate, decentralised trials and home assessments are incredibly valuable, particularly as the industry is focussing more on the earlier stages of Alzheimer’s. In these earlier disease stages, patients or study partners may still be working and can’t take full days off work to take part in the trial. Decentralised options can open up broader participation.
Q: Do Alzheimer’s trials require different approaches and what are the benefits of this?
O’Donohoe: Technology-driven solutions such as eCOA are now well-established in clinical trials, but the complex nature of CNS trials means you need a unique blend of expertise to create effective solutions. The complexity and subjective nature of many traditional Alzheimer's assessments highlights the need to have robust quality checks built into the trial, such as carrying out third-party review of completed patient assessments. Ideally, the data capture and third party checks should all be embedded in your trial technology to make it as streamlined as possible.
Q: How do you ensure new technologies don’t create extra burdens for patients, caregivers, or sites?
O’Donohoe: This is a concern across all disease and therapeutic areas. While it’s important to prioritise the patient experience, this can mean an increased strain on the site, as without the right support they can become the troubleshooters for the new technology. We must make sure there are also technological innovations that help sites, even if that’s something as simple as providing a single sign-on for a platform, so sites can manage all aspects of their trial from one location.
Q: What is the role and future potential of sensors and wearables in Alzheimer’s studies?
Sink: Historically, sensors and wearables have been a niche add-on to clinical trials and have not been used to test drugs for efficacy. However, wearables can offer rich data. For example, people’s gait changes early in the disease and, while gait mats are impractical, wearables provide non-invasive, real-world, insight into movement.
O’Donohoe: We are still in the early days of figuring out what wearables actually tell us in the context of clinical research. To date, the focus has largely been on activity levels and sleep, as these are readily understood. Wearables have been used in trials on the benefit of exercise on Alzheimer’s, as they provide information on how much activity a patient did outside their exercise session, but it is important for the industry to spend time understanding what meaningful endpoints are for patients.
Sink: From a patient perspective, wearables need to be discreet and comfortable. I remember cases where patients have refused to wear technology due to its aesthetics, so I hope wearables will continue to become less obtrusive.
Q: When designing a trial for Alzheimer’s, what should sponsors focus on?
Sink: Data quality is critical. You don’t want to spend millions of dollars on a clinical trial and realise that the data is too noisy to find the signal. Making sure the data you collect is as clean as possible is always worthwhile.
O’Donohoe: I hope clinical trial sponsors can be braver in including sensors and wearables as an exploratory endpoint. Sponsors often don’t include them in early studies, as they want to keep the budget lean. However, to advance endpoints in the field we need to test more novel things in the early stages, so they are ready for Phase 3.
There should also be a focus on feeding data back to patients and caregivers. Patients have dedicated huge amounts of time and effort to the trials, and I believe there is a moral imperative to give patients access to their data in some form. The infrastructure to provide the data to patients exists, but this can only happen in collaboration with sponsors.
Sink: You just need to be careful with what information you share back with patients and when you share it. The worry is that the information will change their behaviour and introduce unwanted noise into the trial!
Q: How do you expect the Alzheimer’s clinical trial landscape to evolve over the next five to ten years?
Sink: As research is increasing its focus on prevention and moving upstream in the disease, I think decentralised trials and home-based assessments are going to increase. This is going to create new challenges, but as an industry we continue to find innovative ways to address obstacles.
I also expect a wider variety of drugs, mechanisms of action, and targets to be studied. And we will see a larger breadth of patient populations regarding disease severity and potentially comorbidities with Alzheimer’s disease.
O’Donohoe: It’s likely that we will see clinical trials engaging with patients far earlier in the disease lifecycle using sensitive screen tools, and subsequently monitoring patients over a longer period of time in their own homes before seeing these transition into a more “traditional” Alzheimer’s study when their disease progresses beyond a certain point.
About the interviewees
Paul O’Donohoe is senior director, eCOA product and science, at Medidata Solutions, a clinical software platform provider. He is responsible for developing the company's scientific expertise for electronic clinical outcome assessments and mobile health in clinical trials and supports internal teams and sponsors around the implementation of industry and regulatory best practices in studies using eCOA. He is passionate about developing the field of eCOA and mobile health through research and active involvement in industry consortia, and is currently the industry vice-director of the C-Path ePRO Consortium.
Dr Kaycee Sink is the chief medical officer at Cogstate, where she leads the support of clinical trials in Alzheimer’s disease and other neurodegenerative disorders, including the advancement of new innovations to improve data quality and trial efficiency for more accurate conclusive studies. Dr Sink is board certified in internal medicine and geriatric medicine, with over 20 years of experience in clinical care and research in neurodegenerative disorders. Prior to joining Cogstate, she worked at Genentech where she was principal medical director in neurodegeneration. Dr Sink joined Genentech in 2017 after 13 years on faculty at Wake Forest School of Medicine, where she rose to tenured Full Professor of Medicine, Neurology, and Public Health Sciences. Dr Sink obtained her medical degree at the University of CA, San Francisco, and subsequently trained in internal medicine followed by clinical and research fellowships in geriatrics, also at UCSF. She continues to see patients and teach in the Memory Assessment Clinic as adjunct faculty at Wake Forest School of Medicine in Winston Salem, NC.
