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.

C2N Diagnostics Announces Follow-on Investment from GHR Foundation as It Builds on Success in Novel Diagnostics to Aid in Alzheimer’s Disease Fight

ST. LOUIS — February 16, 2023 — C2N Diagnostics, LLC, a leader in advanced brain health diagnostics, today announced it has received a $15 million program-related investment from GHR Foundation. This financing, an expansion of GHR’s initial $20 million program-related investment to C2N in early 2020, signifies the foundation’s deep commitment to the company and to reducing the global burden of Alzheimer’s disease through early detection and prevention.
 
C2N will allocate the additional GHR funding to support its newest generation blood test, PrecivityAD2™, which is expected to perform with similar accuracy to PET imaging and cerebrospinal fluid analysis, but with considerably better accessibility, affordability, and logistical ease. The company also will conduct additional clinical studies to continue building real-world evidence around the use of the PrecivityAD® and PrecivityAD2™ blood tests in clinical care. The investment will enable broader market access, expanded medical education, biomarker pipeline development, and infrastructure growth to facilitate global expansion.
 
C2N also will invest capital to expand workflow efficiencies to prepare for higher testing volumes and substantial growth in the commercial demand for its family of Precivity™ blood tests.
 
C2N recently marked the two-year anniversary of the launch of the PrecivityAD® blood test. The PrecivityAD® blood test is the first to be a widely accessible blood test that assists healthcare providers with Alzheimer’s diagnosis. GHR’s support was an essential part of C2N’s success in positioning the PrecivityAD® blood test for entry into the clinic.
 
“As a hope-fueled global funder in service to people and their limitless potential for good, GHR Foundation is honored to partner with the C2N Diagnostics team and bolster the difference they’re making in the lives of patients and families dealing with the uncertainty of an Alzheimer’s diagnosis,” says Amy Rauenhorst Goldman, Chief Executive Officer and Chair of GHR Foundation.
 
As part of the financing, Fred Miller, GHR’s Chief Operating Officer and Managing Director of Biomedical Programs, will become a Board Observer to C2N. Mr. Miller says, “C2N has made great progress since our initial program-related investment in 2020. GHR continues to believe that C2N’s technology will play a critical role in the early and accurate diagnosis of Alzheimer’s disease. We look forward to deepening our partnership with the C2N team and supporting the next phase of their work.”       
 
Dr. Joel Braunstein, C2N president and CEO, says, “We thank Ms. Goldman, Mr. Miller and the entire GHR Foundation team for their tremendous support that will allow us to continue leading the way in biomarker innovation and quality. Our team is committed to helping patients with cognitive impairment receive a timely and accurate diagnosis so that they may begin a proper treatment plan. Having GHR Foundation by our side enables us to amplify our impact and global presence, thereby, bringing us one step closer to realizing our full ambitions.”

Excitement and anticipation are building for the use of blood tests to detect Alzheimer’s Disease. A recent article in the Washington Post detailed the work of GHR partner C2N Diagnostics and the groundbreaking research of its co-founder, Dr. Randall Bateman.

From The Washington Post:

“For C2N, the journey to this moment began years ago. It started, like many advances in science, with a few seemingly simple questions that Bateman, then a postdoctoral research fellow, asked Holtzman, his mentor. Why do people — but not other mammals — get amyloid plaques in their brains? Is the protein accumulating and not being cleared? In 2004, Bateman launched a groundbreaking experiment to measure how quickly amyloid is produced and cleared by the brain. For 36 hours, spinal catheters collected cerebrospinal fluid from several participants, some of whom had Alzheimer’s. Bateman served as his own first subject. The study showed that Alzheimer’s patients produced amyloid beta at the same rate as other people but cleared it more slowly. Bateman theorized that the clearance rates might form the basis for a diagnostic test, but ultimately went in a different direction. Brain abnormalities develop 10 to 20 years before symptoms emerge, suggesting people might be able to take steps to delay or prevent the disease. Blood tests could alert individuals to their risks, allowing them to receive a preventive therapy, if one is developed, or pursue better exercise and diet.”

Read more on the the Alzheimer's blood test research landscape.

GHR’s goal is to help patients and families live full lives in a world where Alzheimer’s Disease becomes a preventable condition. GHR aims to halt Alzheimer's disease prior to the onset of cognitive symptoms by supporting new diagnostic tools and prevention trials. Learn more about our work on Alzheimer’s prevention.

GHR partner C₂N Diagnostics, a leader in advanced brain health diagnostics, has entered several important partnerships in the last quarter that will advance access to its PrecivityAD blood test. The PrecivityAD test is an innovative new blood test intended for use in patients with cognitive impairment. The test aims to help healthcare providers determine the presence or absence of amyloid plaques in the brain, a hallmark sign of Alzheimer’s disease.

Two of these new partnerships expand access to the test in Brazil and Australia. In Brazil, C2N is partnering with Grupo Fleury, one of Brazil’s leading healthcare companies. The partnership will introduce the most advanced set of plasma biomarkers to detect changes that indicate the presence of Alzheimer’s disease pathology in patients experiencing memory difficulties. In Australia, a partnership with Healius Ltd, one of Australia's leading listed healthcare companies, will enable the use of C₂N’s PrecivityAD blood test and related brain health biomarkers in memory and dementia care.

In addition, C2N and Eisai, Inc. are partnering to build awareness about how blood-based assays for cognitive impairment, including Alzheimer’s disease (AD), may help patients receive a timely diagnosis and appropriate treatment, especially in traditionally underserved communities. The development and adoption of blood-based assays in everyday clinical practice is an important step in improving care for people in remote and underserved communities where access to the traditional diagnostic tools of positron emission tomography (PET) and lumbar punctures are not viable options. 

C₂N Diagnostics’ Alzheimer's blood test was introduced into the clinic in October of 2020, a breakthrough healthcare innovation for patients, advocates, and physicians who have long awaited an easy to administer test that can help them better understand Alzheimer’s disease. 

Learn more about C₂N Diagnostics’ partnerships.

An air of optimism marked the Alzheimer’s Association International Conference (AAIC) in San Diego last week, as over 9,000 scientists joined in-person and virtually to share research discoveries, connect with their peers and learn from others. Several presenters highlighted the exciting potential of recent scientific developments, considered almost impossible to conceive of five or ten years ago. Today, the scientific community can completely remove amyloid plaque in the brain as measured by PET scans – the buildup of which is considered a precursor to Alzheimer’s Disease. New blood biomarkers offer greater understanding and ability to detect disease, without the cost and invasiveness of alternative testing procedures. Finally, prevention therapy offers the potential to treat Alzheimer’s patients ten to twenty years before the onset of symptoms.

The Alzheimer’s Association is a valued partner in our shared journey to find a way to prevent Alzheimer’s Disease and related dementias. Together, we have provided key philanthropic support to prevention trials in early onset families and in the general population. 
​
You can review the news highlights from AAIC and press releases to learn more about the exciting discoveries shared at AAIC 2022.

From Nature:

"Aisen foresees a future — maybe just a decade or so down the line — in which much of the burden of Alzheimer’s disease might actually be prevented. “We’re heading towards screening people from middle age on with blood tests, and treating those who show amyloid abnormalities with drugs that reduce the generation of amyloid plaques,” he says. “I am optimistic.”

A lot needs to go right for this hopeful view to become reality. Large clinical trials will have to show that these therapies work, and amyloid-clearing drugs will have to be proven to be safe and affordable. After decades of setbacks and failed clinical trials, some dementia researchers prefer to express caution. “The field is taking tremendous risks by engaging in studies that can cost billions of dollars,” says neurologist David Knopman at the Mayo Clinic in Rochester, Minnesota.

It will take a while for answers to emerge. Some trials of Alzheimer’s disease prevention are just getting started, and some ongoing ones could stretch into the next decade."

Read more. 

C2N Diagnostics’ Alzheimer's blood test was introduced into the clinic in October of 2020, a breakthrough healthcare innovation for patients, advocates, and physicians who have long awaited an easy to administer test that can help them better understand Alzheimer’s disease. C2N developed this groundbreaking test based upon longtime GHR partner Dr. Randall Bateman’s initial discovery of how to measure amyloid proteins in blood, validating its results in a clinical trial of 686 patients. 

From C2N Diagnostics: 

"C2N Diagnostics today announced its latest innovative offering for enhancing care in brain health: a high-resolution mass spectrometry-based plasma tau multi-analyte assay (p-tau MAA) for Research Use Only (RUO). 

This assay uses a small sample of blood to precisely and simultaneously measure different phosphorylated and nonphosphorylated forms of the tau protein, including forms with phosphorylation at the tau217 and tau181 sites. The assay draws upon prior discoveries by medical researchers that complex interactions among abnormal tau and beta-amyloid proteins and several other factors play a vital role in Alzheimer’s-related brain changes."

​Read more. 

From the NIH National Institute on Aging:

"As we mark the 10-year anniversary of the National Plan to Address Alzheimer’s Disease, which arose from the National Alzheimer's Project Act (NAPA), it’s striking to pause for a moment and consider how far we have come. Thanks to increased congressional funding, NIH spending on Alzheimer’s and related dementias research advanced nearly 4.5-fold between fiscal years 2015 and 2020, reaching $2.87 billion. This momentum has enabled NIA-funded science to take significant strides forward.

NIA small business innovation research funding helped validate and commercialize the PrecivityAD™ test, a more affordable and less invasive alternative to traditional Alzheimer’s tests like spinal taps or brain scans. This blood biomarker-based test is now widely available to doctors and researchers across the United States."

​Read more.

From the National Institute on Aging at NIH:
​
Scientists have demonstrated that a new blood test can accurately predict the presence of beta-amyloid plaques in the brain, according to a new study funded in part by NIA. Published in Neurology, the study analyzed the ability of a blood test to predict the presence of Alzheimer’s disease-associated protein beta-amyloid in the brain. The new blood test, which performs comparably to existing brain scan- or spinal tap-based tests, could lower costs and expand the availability of diagnostic studies for Alzheimer’s disease.

Read more.