A new Alzheimer's prevention study has been awarded a $74.5 million five-year grant from the National Institute on Aging (NIA), part of the National Institutes of Health (NIH). The study will focus on members of the world's largest autosomal dominant Alzheimer's disease (ADAD) kindred in Colombia, who carry a genetic mutation that leads to early-onset Alzheimer's.
The study, led by the Banner Alzheimer's Institute in Phoenix and the Neurosciences Group at the University of Antioquia (GNA) in Medellin, Colombia, will initially focus on removing amyloid plaques using Eli Lilly and Company's donanemab. Subsequently, the trial will evaluate different strategies to prevent the recurrence of plaque deposits and other disease elements. Enrollment is anticipated to commence in the fall of 2025.
Study Design and Interventions
The first phase of the study will utilize donanemab, an antibody therapy developed by Eli Lilly and Company, to reduce existing amyloid plaques to levels consistent with a negative amyloid PET scan. Donanemab has demonstrated efficacy in clearing amyloid plaques and slowing cognitive decline and has recently received FDA approval for patients with mild cognitive impairment and dementia due to Alzheimer's disease. This study aims to provide further insights into the drug's safety, tolerability, and biological efficacy in both unimpaired and impaired stages of ADAD.
The second phase will compare the following approaches for safety, tolerability, and ability to prevent amyloid plaque accumulation and other biological and clinical features of the disease:
- Participants continuing to receive donanemab infusions.
- Participants receiving RG6289, Roche's investigational gamma secretase modulator, an orally administered drug designed to limit amyloid protein production.
- Participants receiving a combination of donanemab and RG6289.
- A control group receiving a placebo.
Building on Previous Research
This study leverages the foundation, partnership, infrastructure, and knowledge gained from the original API ADAD Colombia Trial, which was initiated by the NIH in 2012. While the investigational drug crenezumab in the original trial did not demonstrate plaque clearance or clinical benefit, it established paradigms for accelerating the evaluation of potential prevention therapies. It also developed methods for conducting trials in vulnerable populations in developing countries, leading to a growing number of prevention trials. Both the original and the new trial utilize GNA's identification of approximately 6,000 distant relatives from the Colombian PSEN1 E280A kindred, including about 1,200 who carry the ADAD-causing genetic mutation.
Expert Perspectives
"We are excited about the chance to advance the fight against Alzheimer's disease in partnership with our outstanding colleagues and these unique families in Colombia," said Robert Alexander, MD, the API's chief scientific officer and one of the prevention trial leaders. "This study will clarify the extent to which the antibody treatment reduces amyloid plaques in the unimpaired and impaired stages of ADAD and test different approaches to maintain low amyloid levels following plaque removal."
The new study will enroll 200 cognitively unimpaired and mildly impaired mutation carriers and 40 non-carriers (who will receive placebo) from the Colombian kindred.
Collaborative Effort
The research is supported by grant R01AG086363 from the NIH National Institute on Aging. Lilly and Roche are donating the drug supplies for the study. The study is led by Drs. Robert Alexander, Eric Reiman and Jessica Langbaum from BAI and its API; David Aguillón from the University of Antioquia; and Yakeel Quiroz from the University of Antioquia and Massachusetts General Hospital. API also received a $3 million grant from the Zurich-based NOMIS Foundation to continue assessing mutation carriers and non-carriers, provide longitudinal data and blood samples, accelerate enrollment, and provide education and social support.
