2023 AAIC: Has the New Era of Alzheimer's Disease Treatment Truly Begun?

Just 10 days after Leqembi received full approval, the annual AAIC conference was held in Amsterdam, the Netherlands, on July 16, in a hybrid online and offline format.

As the world’s largest and most influential annual conference in the field of Alzheimer’s disease,This year’s AAIC saw record attendance, drawing more than 10,000 participants and featuring over 3,000 scientific presentations.A large number of researchers, scholars, and industry professionals flocked to the RAI Amsterdam Convention Centre, the largest exhibition center in the Netherlands, to embrace a new world in the transformed field of Alzheimer’s disease (AD).

This stands in stark contrast to the atmosphere of 2022.At last year’s AAIC conference in San Diego, the Alzheimer’s disease community appeared uncertain and fraught with concern, due to the controversial approval of the new AD drug Aduhelm and the inability to accurately predict whether lecanemab would emerge as a more efficacious new AD therapy in the coming months.

This year, with the FDA’s full approval of Leqembi and Medicare’s announcement that it would cover the drug, stakeholders appear to have gained clarity on the path forward, becoming more resolute and optimistic. Prior to the conference, Joanne Pike, President of the Alzheimer’s Association, stated, “Ushering in a new era of Alzheimer’s disease treatment is a vision we all share. For decades, we have worked tirelessly toward this goal, and now, reality appears far more promising.”

At this year’s Alzheimer’s Association International Conference (AAIC), scientific presentations covered a broad spectrum of research on Alzheimer’s disease (AD) and other dementias, primarily highlighting advances in novel pharmacotherapies, accurate early diagnosis, and scientific investigations into risk factors for AD and other dementias. Among these, Eli Lilly emerged as the most discussed entity at the conference due to its new AD drug, donanemab. The release of the revised NIA-AA clinical guidelines for Alzheimer’s disease has once again charted the course for future diagnostic pathways in the AD field. Meanwhile, the application of blood-based biomarkers and CRISPR technology is propelling AD treatment into the next frontier.

It is evident that the overarching theme of this year’s AAIC conference is ushering in transformation, a shift inextricably linked to a core issue—the approval of Leqembi.If, just over ten days ago, the significance of the FDA’s full approval of the first new Alzheimer’s disease (AD) drug in two decades remained somewhat unclear to us, then the AAIC conference held more than ten days later has demonstrated how a single new drug, as a starting point, can truly inspire and transform the entire academic, clinical, and industrial communities, thereby driving a paradigm shift across the entire AD field.

As Joanne Pike commented, “We all know this is just the beginning.”

The approval of Leqembi has validated the feasibility of treating Alzheimer’s disease (AD) by clearing cerebral β-amyloid, further igniting pharmaceutical industry efforts to develop new drugs based on this hypothesis. The era of amyloid-lowering therapies for Alzheimer’s disease appears to be just beginning.

At this year's AAIC conference, the atmosphere within the industry has remained at a high point.In particular, the more comprehensive clinical data on Eli Lilly’s new drug, donanemab, have provided compelling scientific evidence, while the application of CRISPR technology is building a platform for the development of next-generation Alzheimer’s disease therapies.

Following the approval of Leqembi, Eli Lilly’s Donanemab has surged ahead to become a highly anticipated star drug for Alzheimer’s disease.

On July 17, Eli Lilly presented the full results of the Phase III TRAILBLAZER-ALZ 2 clinical trial at the AAIC, demonstrating that donanemab significantly slowed cognitive and functional decline in patients with early symptomatic Alzheimer’s disease.

In subjects with low levels of tau protein (n=1,182), treatment with donanemab significantly slowed the decline in iADRS scores by 35% and in CDR-SB scores by 36%. Among all subjects with early symptomatic Alzheimer’s disease who were amyloid-positive (n=1,736), donanemab significantly slowed the decline in iADRS scores by 22% and in CDR-SB scores by 29%. The data presented at AAIC provide robust evidence that, regardless of the baseline clinical or pathological stage of the disease, treatment with donanemab yields cognitive and functional benefits compared with placebo.

Currently, Eli Lilly has submitted a New Drug Application (NDA) for Donanemab, and the FDA is expected to make an approval decision by the end of the year.

However, like Leqembi, Donanemab’s side effects have also raised concerns, with many industry insiders still worried that amyloid plaque-clearing drugs may cause brain swelling and bleeding in patients.

To address these side effects, more novel therapies are emerging. Among the companies that presented updates on new drug treatments at the AAIC conference, two saw their stock prices surge due to positive clinical trial results.

Acumen Pharmaceuticals Announced Phase I Clinical Data for Its New Alzheimer’s Disease Drug ACU193 at AAIC, Sending Its Stock Price Soaring by 55%.According to reports, ACU193 represents an attempt to improve upon existing antibodies by targeting and binding to amyloid-beta oligomers (AβO), rather than amyloid plaques or fibrils. Acumen believes that this approach may reduce the incidence of imaging abnormalities known as ARIA-E associated with drugs such as Leqembi and Donanemab; however, this effect requires further confirmation through future clinical trial data.

ProMIS Neurosciences also saw its stock price rise, as the company presented preclinical data on PMN310, an AβO antibody for the treatment of AD, in a poster session at the AAIC conference.As a result, the company’s stock price surged by 120.28% on the day. Like Acumen, ProMIS has chosen to target amyloid-beta oligomers (AβO). Preclinical data indicate that PMN310 can selectively bind to toxic AβO in brain extracts from Alzheimer’s disease (AD) patients, exhibiting lower binding affinity for Aβ monomers compared with other anti-Aβ antibodies such as Leqembi and Donanemab. Furthermore, PMN310 demonstrated the ability to fully preserve memory function in two rodent models of AD.

Beyond therapies targeting Aβ antibodies, the application of CRISPR technology in the field of Alzheimer’s disease (AD) is particularly promising.

AAIC Reports Two Novel CRISPR-Based Gene-Editing Therapies for Alzheimer’s Disease. One therapy aims to mitigate the effects of APOE-e4, the strongest known genetic risk factor for Alzheimer’s disease, while the other focuses on reducing the production of beta-amyloid, a toxic protein in the brain. Just ten years after its debut, CRISPR is being applied to treat Alzheimer’s disease, a condition with complex underlying causes.

Although related research is still in its early stages, the application of CRISPR has propelled Alzheimer’s disease (AD) treatment into the realm of precision medicine. Maria Carrillo, Chief Science Officer of the Alzheimer’s Association, stated that innovative concepts such as CRISPR will be welcomed in the field of AD therapeutics.

John Dwyer, Chairman of the Global Alzheimer’s Platform Foundation, stated while attending this year’s AAIC conference:“The approval of Leqembi will bring a large number of patients, but the public health system is not yet prepared for assessment, diagnosis, prescription, and comprehensive treatment.”

Joanne Pike also shared this view, stating, “Science is providing patients with new treatment options, but now our policymakers and health systems must also deliver on their promises.”

For many people, diagnosing Alzheimer’s disease has long been fraught with barriers, errors, and frustrations. It is reported that in the next two years, 750,000 to 2 million people in the United States will seek Alzheimer’s assessments, but the wait time for a diagnosis after scheduling an appointment with a neurologist could be as long as five years.

To enable early diagnosis and maximize patients’ chances of benefiting from pharmacotherapy, primary care physicians must closely monitor patients’ clinical conditions and refer them to specialists. Meanwhile, patients need to undergo diagnostic tests, such as PET scans or lumbar punctures, to confirm the presence of amyloid protein in their brains.

A report released by the European Brain Council in March shows that,To improve the early detection and diagnosis of Alzheimer’s disease (AD), the most urgent task is to raise public awareness of AD and enhance professional education.Meanwhile, this must be accompanied by a transformation of the healthcare system, with more personnel and services deployed to enhance diagnostic capabilities.

Diagnosis is not the only challenge facing the public health system. Both Leqembi and Donanemab, which is expected to be approved this year, must be administered via injection at medical centers. Due to safety concerns and potential side effects, some patients may require close monitoring during treatment, including MRI scans.

Upon approving Leqembi, the FDA issued a boxed warning, recommending that physicians test patients for genetic mutations associated with an increased risk of ARIA and advising caution when prescribing Leqembi to patients taking blood thinners. This underscores the need to improve the quality of care provided by healthcare professionals and to accelerate the development of supporting infrastructure.

These issues are not limited to the United States; as Leqembi has already submitted marketing authorization applications in Europe, China, and other regions, its eventual approval will pose a series of challenges for healthcare systems worldwide.

At the conference, Kristian Steen Frederiksen, a neurologist at the Danish Dementia Research Centre, noted that even in relatively advanced healthcare systems, the adoption of new drugs can be slow and limited to medical centers with the necessary infrastructure.

As John Dwyer stated, “Once the substantial investments in new drug development for Alzheimer’s disease (AD) begin to yield returns, the major limitations and challenges in patient access to AD treatments will shift to public health systems.”

In anticipation of emerging issues and challenges, the AAIC conference has taken the lead in updating a proposed clinical guideline for Alzheimer’s disease, focusing on how to achieve early and accurate diagnosis of AD.

The original guidelines were first published in 2011 and first revised in 2018.The proposed guidelines released at this conference represent the second revision, primarily focusing on two aspects: first, modifying the staging system for Alzheimer’s disease (AD) progression; and second, changing the diagnostic approach for AD, with biomarker-based testing becoming the mainstream standard.

Regarding the AD diagnostic staging system, this guideline adopts a numeric staging system to assess disease progression, similar to the systems used in cancer diagnosis. The National Institute on Aging and the Alzheimer’s Association (NIA-AA), which led the publication and revision of this guideline, have eliminated the use of terms such as “mild,” “moderate,” and “severe.” Instead, they have designed a seven-point rating scale based on patients’ cognitive and biological changes. Patients are assigned a score from 1 to 7 according to the presence of abnormal disease biomarkers and the extent of cognitive changes. This system also includes four biological stages ranked as a, b, c, and d.

Regarding AD diagnostic methods, traditional diagnosis primarily relies on memory tests to assess patient symptoms; however, this approach increases the risk of misdiagnosis and is considered one of the reasons for the failure of early amyloid-clearing drug therapies in treating AD.Biomarker-based testing methods will significantly improve diagnostic accuracy.

In 2018, brain PET scans and cerebrospinal fluid (CSF) testing were incorporated into the guidelines as primary methods for detecting cerebral amyloid in the diagnosis of Alzheimer’s disease (AD). However, these techniques require lumbar puncture, have limited accessibility, and are costly; therefore, they are not routinely used in standard clinical practice. Consequently, the 2018 guideline revisions were intended primarily for research purposes.

The approval and market launch of Leqembi has driven changes in Alzheimer’s disease (AD) diagnostic approaches, necessitating that research-oriented diagnostic methods align more closely with large-scale clinical practice. As Leqembi requires evidence of amyloid accumulation in the brain, Medicare will expand coverage for brain PET scans. However, “this simply does not address the large-scale public health challenge,” noted Clifford Jack, the neuroradiologist who led the revision of these guidelines.

Current research indicates that blood tests can work synergistically with new Alzheimer’s disease (AD) therapies and are poised to become the gold standard for measuring amyloid. The newly released guidelines will, for the first time, provide physicians with guidance on using blood tests to assess signs of Alzheimer’s disease in the brain.

Clifford Jack stated that blood tests will reduce diagnostic costs for patients. Furthermore, since Alzheimer’s disease biomarkers appear in the blood before evidence of the disease is visible on brain scans, this testing will also help physicians better stage the disease and determine the patient’s disease stage.

Blood testing methodologies have further evolved at this year's AAIC conference.

According to a study presented at the conference, researchers from the University of Gothenburg in Sweden have developed a finger-prick blood test designed to measure key biomarkers for Alzheimer’s disease. The published results indicate that the test successfully detected AD biomarkers in patient blood samples applied to dried blood spot cards and shipped overnight to Sweden without any special temperature control.

Hanna Huber, the author of this study, stated that blood tests typically require professional administration at a clinic, along with strict delivery and storage conditions. However, fingerstick blood sampling is a simple and convenient testing method that can be performed at home, facilitating improved early diagnosis and monitoring of patients considered at risk or those undergoing treatment with new medications.

The emergence and widespread adoption of new diagnostic methods will feed back into the industry.Previously, due to the uncertainty surrounding diagnostic methods for Alzheimer’s disease (AD), patient enrollment in clinical trials of AD therapies often faced significant challenges, making it difficult to identify eligible participants under stringent criteria. With the incorporation of blood-based biomarker testing into clinical guidelines, conditions will be established for more precise identification of AD patients in future pharmaceutical clinical trials. It is conceivable that this advancement will remove one obstacle from the development of new AD drugs.

This will also mark a new starting point for the Alzheimer’s disease industry.

Reference Article:

Phil's Journal: Before AAIC in Amsterdam, Leading Alzheimer's Advocates Weigh in，BeingPatient

With momentum on Alzheimer’s therapies, Europe sees delivery challenges ahead, too，STAT

With New Therapies That Promise to Slow Alzheimer’s Disease, Researchers Race to Reform How Patients are Diagnosed，CNN

AAIC 2023 – Acumen’s new amyloid approach impresses，Evaluate Vantage

AAIC 2023 News Highlights，AAIC