Alzheimer’s Disease (AD) is a progressive, irreversible brain disorder that affects memory, thinking, and language skills. Age is the best-known risk factor for AD, with symptoms usually appearing after 60 years of age. According to the Alzheimer’s Association and the Center for Diseases Control and Prevention, the number of people living with AD in the United States (US) is projected to double from 6.9 million in 2020 to nearly 14 million in 2060. AD is a top 10 leading cause of death in the US, and despite substantial efforts, there is still no cure for AD at any stage. 

The FDA’s draft guidance, “Early Alzheimer’s Disease: Developing Drugs for Treatment,” released in March 2024, aims to help sponsors by providing a clear framework for developing and evaluating new treatments, particularly in the early stages of the disease that occur before the onset of overt dementia (i.e., stages 1 through 3, referred to as “early AD”).  

This blog outlines FDA’s current thinking on diagnostic criteria and clinical staging of AD and provides perspectives around outcome measures and the use of biomarkers to refine AD clinical trial designs. 

The critical need: Earlier intervention 

Delaying, halting, or reversing the pathophysiological process that leads to overt dementia is the leading target of presymptomatic or very early symptomatic interventions. Yet, clinical trials have historically enrolled patients who exhibit both the cognitive changes typical of clinically evident AD, and a degree of functional impairment associated with overt dementia. Several of these studies utilized the Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog) to assess the level of cognitive disfunction in patients; however, there is a concern on whether this scale is able detect important changes at earlier stages of disease.  

Patients with mild cognitive impairment or early stages of AD may have minimal or no signs of cognitive and/or functional deficits. For these patients, drug developers may consider the use of early surrogate endpoints which are reasonably likely to predict clinical benefit. In recent years, efforts have been made to identify and incorporate biomarkers which may be used as surrogate endpoints reflecting earlier AD into clinical trials. FDA also emphasizes the use of biomarkers in AD to establish reliable diagnosis for adequate stage categorization of the disease.  

Defining the stages  

Although AD progresses continuously through the years from onset, FDA recommends its categorization into clinical stages, which are conceptually useful to inform patient diagnosis, enrollment, and the selection of appropriate endpoints in clinical trials. Important findings applicable to the categorization of AD in different stages include, 1) changes as measured by biomarkers, 2) detectable abnormalities on sensitive neuropsychological measures, and 3) cognitive symptoms reported by patients or observers with the presence or absence of functional impairment.  

The AD stages are: 

• Stage 1 (early AD): Patients with characteristic pathophysiological changes of AD but no evidence of clinical impact. 

• Stage 2 (early AD): Patients with characteristic pathophysiological changes of AD and subtle detectable abnormalities on sensitive neuropsychological measures or subjective complaints of mild cognitive symptoms but no functional impairment. 

• Stage 3 (early AD): Patients with characteristic pathophysiological changes of AD, generally more apparent detectable abnormalities on sensitive neuropsychological measures, and mild but detectable functional impairment. 

• Stages 4, 5, and 6 (mid/late AD): Patients with overt dementia, progressing through mild, moderate, and severe stages. 

It is important to define an AD patient population using these conceptual stages to allow and inform appropriate outcome measure (endpoint) selection. In descriptions/designs of clinical studies, FDA recommends that sponsors identify both the stage of AD defined for study eligibility and enrollment, and the stage of AD anticipated for most of the enrolled study population at the time of primary outcome assessment.  

The table below summarizes FDA’s considerations for the development of pharmacotherapies specifically targeting early AD stages: 

Stage 1	Stage 2	Stage 3
It can be challenging in trials of typical duration (≤ 2 years) to demonstrate clinically meaningful benefit because there is no clinical impairment to assess at baseline, and patients may have variable latency to symptom onset.  Effect on pathophysiological changes, as demonstrated by an effect on various biomarkers, may be appropriate.  Acceptable to conduct a study of sufficient duration for evaluation of clinical outcomes. As subjects transition to Stage 2 during the trial, the principles applicable to Stage 2 would apply.  A time-to-event analysis approach could also be considered.	It may be difficult to establish a clinically meaningful benefit on subtle cognitive deficits unless the trial has a long duration.  Acceptable to conduct a study of sufficient duration for evaluation of clinical measures for Stage 3 patients. As patients transition to Stage 3 during the trial, the principles applicable to Stage 3 would apply.  FDA will consider strong justifications that a persuasive effect on cognition as measured by sensitive neuropsychological tests may provide adequate support for a marketing approval.  A time-to-event analysis approach could also be considered.	Many of the tools typically used to measure functional impairment in later dementia stages of AD (Stages 4-6) may not be suitable.   An integrated scale that assesses independent effects on both daily function and cognition is acceptable as a single primary efficacy outcome measure.   In early Stage 3 AD, FDA will consider strong justifications that a persuasive effect on cognition as measured by sensitive neuropsychological tests may provide adequate support for a marketing approval.  A time-to-event analysis approach could also be considered.

Key components of an early AD trial  

Both clinical outcome assessments and biomarkers should be included in early AD clinical trials. It is expected that biomarker evidence of disease will establish a reliable diagnosis of subjects in clinical trials of early AD. Direct measures of clinical benefit or validated endpoints may support a traditional approval, while surrogate or intermediate clinical endpoints may support an accelerated approval.  

Features of outcome measures for early AD include: 

• Clinical endpoints: FDA recognizes that it may take some time to establish clinically meaningful endpoints in early AD due to the minimal/absent cognitive and functional deficits. Many tools typically used to measure functional impairment in patients with later dementia stages of AD would not be sensitive enough to detect changes in early AD. FDA may consider other approaches, including endpoints based on cognitive assessments or surrogate endpoints as a basis for approval in early AD (noting that new approaches must be supported by strong scientific justifications). 

• Time-to-event analysis: Represents the time to the occurrence of a clinically meaningful event during the progressive course of AD, and is generally an acceptable primary efficacy measure in early AD clinical trials.  

• Surrogate endpoints: Acceptability may depend on the stage of disease, patient population enrolled, therapeutic mechanism of action, and availability of current treatments. Clinical outcome assessments should be included in clinical trials for early AD to assess early clinical changes that may potentially provide support for (or confirm) any changes observed in biomarkers.  

A powerful tool for early AD: Biomarkers  

According to the Alzheimer’s Association, several potential biomarkers are being studied for their ability to indicate early stages of AD. For example, two hallmark brain changes in AD, – the accumulation of protein fragments known as beta-amyloid and tau – are biomarkers that can be detected using imaging technologies or assessed through a cerebrospinal fluid (CSF) test. However, the presence of these biomarkers alone is not sufficient to determine an AD diagnosis.  

Molecular imaging, which uses positron emission tomography scans, is among the most active areas of research aimed at finding new approaches to diagnose early AD. Four injectable radioactive diagnostic agents have been approved by the FDA for clinical use. Florbetaben F-18 (Neuraceq®), florbetapir F-18 (Amyvid®), and flutemetamol F-18 (Vizamyl®) are approved for detection of beta-amyloid in the brain, and flortaucipir F-18 (Tauvid®) is approved for detection of tau in the brain. There are also new FDA-approved CSF tests such as Lumipulse® and Elecsys®. These new diagnostic agents can be used by clinicians to detect amyloid and tau markers in CSF.  

FDA’s new draft guidance strongly supports and encourages continued research in understanding the role of biomarkers in AD, and stresses the potential importance of biomarkers in the successful development of effective treatments for use in the earliest stages of AD. 

Offering hope to AD patients 

Overall, this guidance enhances the potential for developing effective AD treatments by supporting early-stage interventions and improving the regulatory framework for drug approval. Notably, FDA highlights the importance of developing and validating new biomarkers for early AD that may detect the disease in initial days before symptom manifestation. Regardless of the selected regulatory pathway, diagnostic approach, and outcome measure for development in early AD, sponsors are urged by FDA and regulatory professionals to discuss their plans with the appropriate division early in development.  

Premier has extensive experience in supporting development programs in the neuroscience realm. For support with your AD program, contact us.   

 

REFERENCES: 

[1] About Alzheimer’s. CDC (2024). https://www.cdc.gov/alzheimers-dementia/about/alzheimers.html

[2] Alzheimer’s Disease. FDA Fact Sheet (2024). https://www.fda.gov/consumers/minority-health-and-health-equity-resources/alzheimers-disease

[3] Biomarkers and Alzheimer’s disease. Alzheimer’s Association (2023). https://www.alz.org/media/Documents/alzheimers-dementia-biomarkers-and-alzheimers-disease-ts.pdf

[4] FDA position statement “Early Alzheimer’s disease: Developing drugs for treatment, Guidance for Industry (2019). Marwan N. Sabbagh, Suzanne Hendrix, John E. Harrison. https://www.sciencedirect.com/science/article/pii/S2352873718300799