Earlier this month, Eli Lilly and Company announced the topline results of its Anti-Amyloid Treatment in Asymptomatic Alzheimer’s disease (A4) Study. This study was conducted, in part, at the Memory and Aging Program (MAP) at Butler Hospital and the Alzheimer’s Disease and Memory Disorders Center at Rhode Island Hospital. It evaluated the efficacy of the investigative drug Solanezumab in slowing the onset and progression of memory loss in older adults who had evidence of amyloid plaques in the brain - believed to be related to the development of Alzheimer’s disease (AD).
A4 Study Results
The results showed the drug did not slow the progression of cognitive decline due to AD pathology when initiated in individuals with amyloid plaque but no clinical symptoms of the disease, known as the “preclinical stage” of AD1.
“Results of the A4 Study clearly showed that the primary and secondary endpoints were not met. Therefore, the A4 Study concludes our clinical development of Solanezumab and indicates that targeting soluble amyloid beta through this mechanism is not effective in this population,” said John Sims, head of medical, global brand development – Solanezumab, for Eli Lilly and Company.
Solanezumab only targets soluble amyloid beta. The treatment did not clear plaque or halt the accumulation of amyloid in participants treated with the drug in the A4 Study.
Useful Data from A4 Study
Although the results were negative for this particular trial, the data generated will provide valuable insights and potential advancements for the ongoing development of similar drugs, such as Donanemab, which are also being studied at MAP.
“Although it is undoubtedly disappointing when study results don’t come back as we’d hoped, it’s extremely important to remember that even negative results bring great value to our search for an effective treatment for Alzheimer’s disease, and the A4 Study is no exception to that,” said MAP Director Edward Huey, M.D.
Other Benefits of the A4 Study
MAP Founder and Principal Investigator of the A4 Study in Rhode Island Stephen Salloway, MD, MS said he is also heartened by the advances in knowledge, the enthusiasm for research, and the hope for an effective treatment for Alzheimer’s that the A4 trial achieved, even if the drug didn’t yield the results that many had hoped to see.
“We are so grateful to each and every study participant and study partner who gave of themselves and their time for this study, some for more than eight years,” Dr. Salloway said. “We had a great sense of excitement when we provided the first infusion to launch the A4 study at Butler Hospital in June of 2014 and this event was covered by media outlets around the world. We felt we were opening a new era in Alzheimer’s prevention. Though the results are disappointing, the A4 study demonstrated that it was possible to screen large numbers of cognitively unimpaired older individuals for AD risk, and in fact many were found to be at lower risk.”
“Today we have sensitive blood tests to make this screening process much more efficient and cost-effective, Dr. Salloway continued. “We need better prognostic markers like this to identify those most likely to progress and benefit from treatment during the study. We also need better measures of target engagement and treatment response to ensure we are on track to meet outcomes. And we need treatments, alone and in combination, with larger effects. There is a great deal to learn from the A4 data and that is thanks to the wonderful dedication of the study teams and the participants who made these advances possible.”
A4 Study Background
Launched in 2013, the A4 Study was a first-of-its-kind secondary prevention trial, enrolling more than 1,100 individuals between 65 and 85 years of age who had PET-imaging evidence of amyloid plaque accumulation in the brain and who did not have clinical impairment.
Solanezumab binds only to soluble amyloid-beta protein and was not expected to significantly remove deposited amyloid plaques. Donanemab and Remternetug, other Lilly investigational antibodies currently being developed in Phase 3, are different from Solanezumab in that they specifically target deposited amyloid plaque and have been shown to lead to plaque clearance in treated patients.
“While this study was negative, the unique data generated have increased our understanding of preclinical Alzheimer’s disease and will advance the next generation of AD prevention studies,” Sims said. “Raw data and analyses will be made widely available to researchers through the public-private partnership with the NIH-funded Alzheimer’s Clinical Trial Consortium. These data will serve the scientific community and enable Lilly and other drug developers to enhance our clinical trial designs for other potential medicines targeting Alzheimer’s disease.”
Reisa Sperling, M.D., a neurologist at the Brigham and Women’s Hospital, Harvard Medical School, and the A4 Study project director also pointed to the valuable data that the A4 study uncovered.
“These findings indicate that amyloid is a key driver of cognitive decline at the preclinical stage of Alzheimer’s disease,” she said. “Solanezumab did not substantially impact amyloid plaque burden in the brain, and unfortunately did not slow cognitive decline. These data suggest that we may need to be more aggressive with amyloid removal even at this very early stage of disease.”
Study Participant’s Perspective
For Peter Bristol, who participated in the A4 Study at the Memory and Aging Program at Butler Hospital, the results were also disappointing, but the bigger picture remains a positive one.
“The announcement was unanticipated. After all, I seemed as cognitively healthy at the end as I was in the beginning. I was disappointed. However, I soon realized in spite of these results, I effectively accomplished my goals,” he said.
Bristol says that he set three goals for himself when he began participating in the A4 study. Those goals centered around hope, trust, and commitment.
“The hope was that I would be given a preventable treatment for AD. But instead, I successfully added to the vast reservoir of data that will be mined by research scientists to conquer the cause and find the solution to this disease,” he says. “With regard to trust – that I would be treated professionally and with the utmost safety and care. The staff in the Memory and Aging Program exceeded my expectations with kindness, support, and interest in my progress through the trial. This gave me the incentive to advocate for and encourage participation in future trials.”
And of the “commitment” goal, Bristol says it was his commitment to complete the trial for future generations.
“The information learned from the A4 study will lead to better treatments that will help my children and grandchildren prevent AD. My study partner and the rest of my family gave me encouragement and support throughout the trial. They are proud and accepting of the time and effort to complete the study regardless of the results,” he said. “This trial opened new opportunities to continue my education by learning and understanding the complexity of AD and its sequential prevention and cure. I became more mindful to improve my nutrition, exercise, and mental stimulation. Even with my amyloid plaques, I will continue to assist Alzheimer’s Disease research for future generations. I will continue my goals by finding another trial that fits my abilities and again add to the reservoir of data so prevention or cure will be reached.”
The A4 Study is a landmark public-private partnership, funded by the National Institute on Aging (part of National Institutes of Health), Eli Lilly and Company, Alzheimer’s Association, GHR Foundation, Foundation for the National Institutes of Health, and several other organizations and donors. The A4 Study is coordinated by the Alzheimer’s Therapeutic Research Institute (ATRI) at the Keck School of Medicine of University of Southern California and is a project of the Alzheimer’s Clinical Trials Consortium (ACTC).
Full disclosure of the study results will be shared later in the year at a scientific conference.
More than 6.5 million Americans are currently suffering dementia due to Alzheimer’s disease2, and scientists expect this number to nearly triple by 20503. It is estimated that more than 20 million Americans and approximately 315 million people globally have preclinical Alzheimer’s disease, the earliest stages of the disease4,5.
References:
1. Sperling, Aisen, et al Alzheimer & Dementia 2011.
2. Centers for Disease Control and Prevention. Alzheimer’s Disease. Available at:
https://www.cdc.gov/dotw/alzheimers/index.html#:~:text=Alzheimer%27s%20disease%20is%20the%20most,of%20
death%20for%20all%20adults. Accessed November 9, 2022.
3. Alzheimer’s Disease International. Dementia Statistics. https://www.alzint.org/about/dementia-facts-figures/dementia-statistics/. Accessed November 9, 2022.
4. Brookmeyer, R. et al. “Forecasting the prevalence of preclinical and clinical Alzheimer’s disease in the United States.” Alzheimer’s & Dementia 14 (2018) 121-129.
5. Gustavsson, A. et al. “Global estimates on the number of persons across the Alzheimer’s disease continuum.” Alzheimer’s & Dementia (2022) 1-13.
