This article was originally published by Lundbeck on July 17, 2019.

By Mark Terry

Leigh Callahan, PhD, is a respected epidemiologist and outcomes researcher who focuses on rheumatic disease. Her husband, John Winfield, MD, now retired, had a distinguished career as a researcher and rheumatologist. While their professional lives have focused principally on joints, they now find themselves at the leading edge of brain research. This is because John has Alzheimer’s, Leigh is his care partner, and together they are participating in a groundbreaking research project that seeks to generate patient/care partner insights and develop new meaningful, measurable outcomes that can help guide future Alzheimer’s drug development.  

The Alzheimer’s Disease Patient and Caregiver Engagement (AD PACE) initiative is a public-private collaboration led by UsAgainstAlzheimer’s (a nonprofit organization that advocates for funding and innovative approaches to Alzheimer’s treatment). AD PACE is unique in both its scope and focus:  Through AD PACE, patients and care partners, leading pharmaceutical companies (including Lundbeck), academics and government agencies are joining forces to identify and prioritize the real-world treatment needs and preferences of people affected by Alzheimer’s. The goal of this first-of-its-kind collaboration is to develop a scientifically reliable understanding of outcomes that are most meaningful to patients and care partners so that they can be incorporated into clinical trial design, regulatory approval and, eventually, clinical care.

Lundbeck is an AD PACE founding sponsor and member of the Executive Steering Committee; Leigh and John, also Executive Steering Committee members, are participating in the design and review of the initiative’s “What Matters Most” (WMM) study, an 18-month, two-part research initiative. The WMM Phase 1 findings were presented today at the Alzheimer’s Association International Conference (AAIC), the world’s largest gathering of Alzheimer’s and dementia researchers. The study marks the first time that Alzheimer’s patient/care partner preferences have been examined in a pre-competitive setting with this level of scientific rigor, explains Ann Hartry, PhD, Lundbeck’s vice president of Health Economics and Outcomes Research and the AD PACE Executive Steering Committee representative. According to Hartry, AD PACE could broaden the scope of outcomes that define success today, so that new outcomes – ones more meaningful to patients and care partners than the standardized memory and cognition measurement tools in place today – can be evaluated as elements of clinical trial success. 

“These findings will influence the research landscape by enabling those of us working to improve the lives of people affected by Alzheimer’s to better define the goals of our interventions. Having scientifically confirmed knowledge of what matters most to patients and caregivers will help us to design our trials with these endpoints in mind,” Hartry says.

The WMM study also validates and seeks to harness the day-to-day struggles and treatment needs of people like Leigh and John – needs that, to date, have been assumed, but never confirmed through a scientific process. “It’s so valuable to get information on what actually matters most to the person with the disease and the care partner, rather than just treating the checkboxes,” Leigh says.

What Matters to Leigh and John

John was diagnosed with Alzheimer’s seven years ago, at age 70. The disease has progressed, but slowly – more of a “creeping,” Leigh says. The couple still enjoy the opera and regularly socialize with friends, but John’s memory loss and confusion are an ever-present aspect of their lives. Leigh hung clocks and signs throughout their home to help John keep track of his routine and the activities that go along with each part of the day. While he still reads the newspaper daily, he sometimes must read an article several times because he has forgotten the beginning by the time he reaches the end. And that’s what matters to John, Leigh says. “He wants to read a New York Times article and remember how it started.”    

Leigh, meanwhile, has slightly different treatment priorities, and she appreciates that AD PACE is incorporating the preferences of care partners. “The lens of the patient and the lens of the caregiver are very different,” she says. “The things that matter to me are the losses of executive function and being able to give him instruction and have him follow through. So, it’s always going to be important to look at both sides of this.” 

Of high priority to both Leigh and John is managing the frustration and fear that John sometimes experiences. “Some days he’ll stand in front of the coffee pot, unsure of how to use it. That’s when his frustration kicks in and those are the times that are the most stressful,” Leigh says. “Right now, his biggest outcome of importance would be a treatment that alleviates the fear and anxiety he feels in those moments. But these types of activities of daily living outcomes – fear caused by not knowing how to use the coffee pot – aren’t being measured, and we don’t yet have the scientific rigor to measure those sorts of ‘downstream’ symptoms.”

What Matters Most Findings

The first phase of the What Matters Most study was a qualitative survey of 60 patients and caregivers. Among the survey results presented at AAIC:

• Nearly all patient participants, including those with no clinical diagnosis of Alzheimer’s and unimpaired cognition, experienced symptoms related to communication and language.
• “Improving and restoring memory” and “stopping disease progression” were the most important treatment outcomes across all participant groups (patients and caregivers) – underscoring the need to better understand how these two very different patient outcomes are weighted by individuals across the multiple stages of the disease. 

The results may not seem radical – people with memory loss are concerned about memory loss; but they are still significant, Leigh says. “Even if the results show what we expected, it’s still important to reaffirm what is important,” she explains. “Yes, memory ranked up at the top, but digging into how and why memory loss is important helps us get closer to outcomes that matter most, like knowing how to make a cup of coffee. This sort of real-world outcome that matters prompts us to look for signals of other things that may not be being measured today.”

Also noteworthy was the researchers’ conclusion that while traditional neuropsychological assessments measure various aspects of cognitive functioning often impaired by the disease, it is unclear whether they can measure the often-subtle changes that are important to individuals with Alzheimer's and care partners, such as decreased socialization due to concerns about forgetting names or losing track when speaking to others; depressed or anxious thoughts due to changes in memory; and increased dependence on others for even basic chores. 

According to Lundbeck’s Hartry, these research results are important because they lay the foundation for the WMM second phase: a quantitative study that will gather more explicit information about treatment preferences and help researchers develop a mechanism for measuring them in the clinical setting so that these patient-driven preferences can be recognized as a valid and clinically meaningful clinical trial endpoint. The Phase 2 quantitative stage is already underway, with results anticipated later this year.

“As the only global pharmaceutical company solely focused on the brain, we are deeply committed to advancing therapies that make a meaningful difference in the lives of people impacted by Alzheimer’s - and restore brain health,” Hartry says. “But we know we can’t do it alone, and we understand that patients and caregivers play a critical role in advancing treatments that have most meaningful impact. If the measures we use in our clinical trials assess items of little importance to our patients, then we risk developing a drug that misses the mark.”

"Now and in the future, information ascertained from AD PACE research will ultimately help to inform trial design, endpoints and outcomes measures, validate the latest science, and prepare us for a cure,” says George Vradenburg, chairman and co-founder of UsAgainstAlzheimer’s. “Further, we intend for this research to inform payers’ coverage and reimbursement decisions, so our system is ready when an effective treatment and cure finally does arrive.”

For the Future

Leigh recognizes that a breakthrough Alzheimer’s treatment may not come in time to stop John’s disease, but they both think it’s important to participate in the research. “John and I are scientists and we understand the power of what AD PACE is going to do,” she says. “We’re participating for the future. If we can make a difference in any way toward moving the needle forward in this disease, we want to do that. We’re not going to hide with this disease, we’ve got to do this.”