A Data-Driven Approach to Clinical Development in Alzheimer’s

Contributed Commentary by Dr. Gen Li, Phesi 

February 3, 2023 | Every three seconds, a patient develops Alzheimer’s. In 2020, more than 55 million people were living with the disease. This number is predicted to more than double every twenty years. Yet, despite extensive efforts and investments from the pharmaceutical industry over recent decades—with an estimated annual spend of $3.5 billion on Alzheimer’s and dementia research by the US government—progress has been slow. 

The recently announced phase III trial results from Biogen and Eisai for a monoclonal antibody Alzheimer’s treatment—called lecanemab—are encouraging. However, lecanemab has only been shown to slow cognitive decline in patients with early-stage Alzheimer’s, so it is by no means a cure. Moreover, the industry still lacks a comprehensive understanding of Alzheimer’s disease at a molecular level, and more needs to be done to focus our efforts on cohorts before the onset of the disease. 

At the same time, improvements in healthcare and medical treatments—including for many serious diseases like cancer—have extended human life expectancy. Unfortunately, increased longevity has yielded more Alzheimer’s patients, resulting in reduced quality of life for patients and their families and increased healthcare costs. The Lancet estimates that global healthcare spending on dementia patients has reached $594 billion and is set to reach $1.6 trillion by 2050. 

Recent research has linked Alzheimer’s to a microprotein called SCHMOOSE, which is associated with a 20-50% higher risk for the disease. A number of other findings have begun to illuminate some aspects of the disease. The industry has not been deterred by the slow strides we’ve made in Alzheimer’s research nor by numerous costly setbacks. According to ClinicalTrials.gov, there are more than 500 clinical trials in active recruitment for Alzheimer’s. 

Such continued efforts have helped to gain a vast data resource that will undoubtedly aid the clinical development industry’s goal of developing an effective treatment. However, the industry can only progress if it can make intelligent use of the data available. 

Piecing Together the Data Jigsaw 

To understand Alzheimer’s and increase the return on investment made in clinical development, biopharmaceutical companies must examine the considerable body of data that has been acquired to date. Even “failed” trials hold potentially significant information. With the right technology and data science approach, companies can piece together disparate datasets and uncover new insights. Generating a patient’s digital twin is one way of achieving this. 

Using the vast pool of data generated from historical and current trial records, as well as patient data, a digital twin can help study planners to gain a clearer picture of the at-risk population, accelerating research and allowing experimentation and modeling. The “typical” Alzheimer’s patient is a female aged 73 years old. She is 162.3 cm tall and weighs around 68 kg, with a BMI of 25.9, which is considered overweight. 

Examining trial and patient records in depth also allows researchers to gain insights into the relationship between a patient’s age and a particular measure of Alzheimer’s deterioration: the Mini-Mental State Examination (MMSE) (Journal of Psychiatric Research, DOI: 10.1016/0022-3956(75)90026-6). MMSE is a simple pen-and-paper test of cognitive function based on a possible score of 30 points. When we examine the data, a striking pattern emerges. In just twelve months, MMSE drops from 27.2 to 21.8 (an 18% loss of cognitive function). In 24 months, MMSE drops to 18.4. The takeaway is clear: after the initial onset of Alzheimer’s disease, deterioration is rapid and not always linear. 

The Implications for Clinical Development 

This analysis demonstrates the need for clinical development to focus on younger patients in the earlier stages of the disease or even before the onset of the disease. By targeting high-risk, non-symptomatic populations, we can uncover treatments with the potential to slow or prevent the onset of Alzheimer’s before rapid cognitive decline begins. 

There will be barriers to this approach. For example, clinical trial sponsors might struggle to recruit a large population of younger patients. Moreover, these trials likely have a more extended treatment duration and require more resources. However, these efforts will be worth it if we can slow the avalanche of Alzheimer’s disease progression. What’s more, there are ways to mitigate these challenges, using digital twins and adopting a “digital trial arm” where data is collated from similar or identical trials using the same agent—with real-world patient data—to model comparator outcomes while accelerating development accurately. 

The Future of Alzheimer’s Research 

Despite the many years and billions of dollars invested, progress in therapeutics for Alzheimer’s disease has not yet yielded a critical breakthrough. It remains a complex and steep hill for pharmaceutical companies to climb. The priority for clinical development should be revisiting historical data to identify hidden insights. Such insights will reveal new leads and enable the design of patient-centric trials that include younger participants and patients from pre-symptomatic high-risk groups. Alzheimer’s and other neurodegenerative conditions are a massive burden on society and significantly impact the quality of life of our aging global population. Preventative treatment is desperately needed. 

With an intelligent approach to data, the industry can begin to leverage digital twins for Alzheimer’s clinical trials, creating a digital arm, and reducing or eliminating the need for placebo treatments. In this way, we could more easily include younger and larger populations in clinical trials for Alzheimer’s treatments, beginning to develop therapies to slow the disease or prevent its onset. 

Dr. Gen Li is co-founder and president of Phesi. He can be reached at gen.li@phesi.com