GHR partners Eli Lilly and Brigham and Women's Hospital announced results from the A4 Study, a landmark in Alzheimer’s Disease research as the first large-scale clinical trial testing an Alzheimer’s prevention strategy in the general population. Unfortunately, A4 was not successful in preventing cognitive decline due to Alzheimer’s Disease. 

Funded by a public-private-philanthropic partnership involving the National Institutes of 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, A4 was a massive ten-year undertaking. It involved dozens of research sites, hundreds of investigators, and thousands of patient volunteers. The study screened healthy adults aged 65-85 for the presence of amyloid plaques. Those with accumulated plaques were treated with Lilly’s anti-amyloid drug solanezumab. 

Although the study did not achieve its goal, A4 is providing key learnings for future prevention trials about how to identify patients at risk, when to intervene, and what level of treatment may be needed.

Read the full press release here.

From Eli Lilly and Company:

INDIANAPOLIS, March 8, 2023 /PRNewswire/ -- Eli Lilly and Company announced today that solanezumab did not slow the progression of cognitive decline due to Alzheimer's disease (AD) pathology when initiated in individuals with amyloid plaque but no clinical symptoms of the disease, known as the preclinical stage of AD1. Solanezumab only targets soluble amyloid beta. The treatment did not clear plaque or halt accumulation of amyloid in participants treated with the drug in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's disease (A4) Study.

"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. "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. 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."

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. Participants were randomized to either solanezumab or placebo and then treated for approximately 4.5 years.

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.

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 disease 4, 5.

During the double-blind portion of the study, results showed:

• Solanezumab did not slow cognitive decline on the primary outcome measure, the Preclinical Alzheimer Cognitive Composite (PACC) [mean change (95% CI): placebo -1.4 (‑1.76, ‑1.04); solanezumab -1.69 (-2.13, -1.26); p-value 0.26)]. The PACC was developed to measure the aspects of cognitive decline relevant in preclinical AD and is an equally weighted composite that tests episodic memory, timed executive function, and global cognition.
• Secondary clinical outcome results were consistent with the primary outcome, numerically favoring placebo compared with solanezumab.
• 36.1% of participants starting at the stage of preclinical AD progressed on the Clinical Dementia Rating-Global Scale (defined as CDR-global score greater than 0 at two consecutive visits or final visit). CDR-GS is a clinician-rated scale that provides an overall assessment of the participant's clinical stage of AD. Similar rates of progression were seen with both the solanezumab and placebo groups.
• On amyloid PET imaging, amyloid continued to accumulate over time in both the placebo (65.9 Centiloid baseline, 17.5 Centiloid increase) and solanezumab (66.2 Centiloid baseline, 12.1 Centiloid increase) groups.
• Higher baseline amyloid levels were strongly associated with a greater risk of progression to symptomatic Alzheimer's disease (p-value<0.001). 
• The solanezumab and placebo groups were well-balanced at baseline, and results were consistent across multiple analysis methods and models.
• Safety results in the A4 Study were consistent with the safety profile observed in previous solanezumab Phase 3 studies. Amyloid-Related Imaging Abnormalities with edema/effusion (ARIA-E) were uncommon and similar between treatment and placebo groups.

"These findings indicate that amyloid is a key driver of cognitive decline at the preclinical stage of Alzheimer's disease. 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," said Reisa Sperling, M.D., a neurologist at the Brigham and Women's Hospital, Harvard Medical School and the A4 Study project director. "We are so very grateful to the participants, their study partners, the clinical trial site investigators and staff, and the entire study team for their longstanding dedication to this important study. It is imperative that we learn everything we can to inform ongoing and future trials in our quest to prevent memory loss due to Alzheimer's disease."

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.

About the A4 Study 
The Anti-Amyloid Treatment in Asymptomatic Alzheimer's disease (A4) Study is a Phase 3, double-blind, placebo-controlled study in males and females ages 65 to 85 years with preclinical AD (that is, in individuals with evidence of brain amyloid pathology on PET amyloid imaging who are clinically unimpaired but at high risk for cognitive decline). 

The A4 Study tested whether solanezumab could slow the progression of Alzheimer's disease-related cognitive decline, brain imaging, and other biomarkers over the course of approximately 4.5 years. The study included more than 1,100 participants at 67 sites throughout the United States, Japan, Canada and Australia.

GHR’s Health Initiative has committed more than $17 million over 5 years to scaling up important Alzheimer’s disease prevention research already underway. The Foundation is targeting funding to improve some of the largest research efforts in the field, including Washington University's DIAN-TU Study, which is quickly evaluating potential prevention treatments among those who are most likely to develop the disease, and Harvard University's A4 Study, which is working toward FDA approval for prevention therapy in the general population.

A recent Nature article highlights the importance of preclinical treatments, like DIAN-TU, which are initiated in cognitively unimpaired at-risk people, and are intended to postpone, reduce the risk of or completely prevent the clinical onset of Alzheimer’s. The authors argue that we need faster ways to evaluate these treatments, new ways to collaborate towards common goals and determination to expedite preclinical trials.

One useful tool for accelerating the initiation and performance of these trials is Collaboration for Alzheimer’s Prevention (CAP), a convening and consensus-building initiative co-founded by DIAN-TU and A4, among others. Important strides made by CAP include:

• Development of trial outcomes, including cognitive and clinical endpoints and biomarkers
• Standardization of sample and data collection, such as the use of tau imaging in all CAP trials
• Participant recruitment and retention through the development of a registry
• Data and sample sharing mechanisms

​These developments help carry out Alzheimer’s prevention trials with care, thoroughness and maximum impact. ​While all research is uncertain, the potential to turn the tide and provide hope for all families that face Alzheimer’s has never been more promising.  To learn more about GHR’s Alzheimer’s prevention funding efforts, contact us.

Recently more than 700 Alzheimer’s disease researchers attended the seventh annual Clinical Trials in Alzheimer’s Disease (CTAD) Conference in Philadelphia to discuss new developments in the field. In a press release describing the conference, CTAD described two highlights: new investigational compounds and collaborations for Alzheimer’s prevention.

The latter described the progress made by the Collaboration for Alzheimer’s Prevention (CAP), an umbrella group including two studies funded, in part, by GHR—the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) Study and the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU).

At the conference, director of DIAN-TU Randall Bateman spoke on the progress of the CAP partnership. Despite differences in populations, the four studies have found common ground on a clear set of cognitive domains to test and compare results. All CAP trials now also plan to use tau imaging, thanks to a partnership between the NIH and 10 industry partners.

CAP’s updates, while notable, are only a portion of the rapidly changing landscape of Alzheimer’s research. Other notable progressions presented at CTAD, such as the new compounds being developed and the creation of the Alzheimer’s Prevention Registry to accelerate enrollment in trials, will intersect with GHR’s Health Initiative’s involvement as organizations and researchers work together to find effective treatment.

GHR Foundation’s Health Program funds research to support the prevention of Alzheimer’s disease. The FoundationFuondation             has committed more than $10 million over the next 5 years to scale up important research already underway, including some of the largest research efforts in the field.

One such research program is the A4 Study. This study, led by Harvard researcher Dr. Reisa Sperling and coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego, is a clinical trial focused on determining the effectiveness of prevention therapy before Alzheimer's disease impacts the brain.

Enrollment for the study is underway and researchers are currently looking for volunteers aged 65+ with normal memory function to be screened for an Alzheimer’s amyloid plaques. Those found eligible for the study will receive prevention treatment at locations across North America and Australia.

While all research is uncertain, the potential to turn the tide and provide hope for all families that face Alzheimer’s has never been more promising. If you know someone who might be qualified and interested in participating in the study, have them examine the eligibility requirements and learn more here. To learn more about partnering with GHR Foundation to fund innovative Alzheimer’s research, contact us.

With a focus on Alzheimer’s disease prevention research, GHR Foundation funded a groundbreaking Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study which may help identify people who are highest risk to develop the disease. This research will also identify treatments – and when to best administer them – to slow or prevent Alzheimer’s. Long-term, the Foundation hopes the A4 study and complementary research will result in FDA approval for Alzheimer’s prevention therapies.

The A4 study team is continuing to develop the clinical partnerships necessary to study 1,000 patients and has created tools to share background with potential participants. GHR Alzheimer’s advisory board member and lead A4 researcher Dr. Reisa Sperling explains the research and how people can get involved in the research in a recent YouTube video. 

GHR looks forward to learning more about the impact of A4 on early detection and treatment of Alzheimer’s disease.