Alzheimer’s Disease Clinical Trials: Where Do We Go Now?


  • Despite the high burden from Alzheimer’s disease, current therapies are only capable of managing the symptoms and experimental compounds designed to modify disease progression have failed clinical trials at an extremely high rate.
  • The technologies available and capable of visualizing early AD signs are extremely expensive and there is a lack of clear potential or reimbursement roadmap for their use. Learning from the past failures, current clinical trials in Alzheimer’s disease are focused on new therapeutic targets, segmented patient population based on markers or phenotypes indicating an expected benefit, and novel endpoint.
  • An awareness campaign will be required in order to educate stakeholders regarding biomarker use, particularly as primary endpoints shift from cognitive and functional measures. With this potential new treatment paradigm, pharmaceutical manufacturers will face several hurdles, such as communicating the value of treating preclinical Alzheimer’s disease patients with biologics over long durations, determining how to identify the right patient population, and building awareness of the novel endpoint.


This blog post is PART II of CBPartners’ 3-part series: 2019 Key Considerations for CNS Investment – read PART I: Central Nervous System (CNS) Drug Development Strategy: What is the Role of External Investment in this High-Risk Disease Space?  and PART III: Parkinson’s Disease Clinical Trials: How Close Are We to Disease-Modifying Therapies?

The slow clinical progress of Alzheimer’s disease treatments

Alzheimer’s is a central nervous system (CNS) disease and is the most common cause of dementia. Despite the high disease burden in Alzheimer’s disease (AD) patients, there is still no single test to provide a reliable or early diagnosis. Existing treatments are only aimed at managing disease symptoms. While many drug compounds have been developed and tested in clinical trials, virtually all of them have emerged as failures, and there has been a lot of discussion about what contributed to such high failure rate.

Why do trials for Alzheimer’s disease drugs keep failing?

The first commonly cited reason is the possibility that our perception of amyloid beta as the root cause of AD is not necessarily correct. This explanation is supported by a number of factors, including the string of failures among drugs targeting amyloid beta. $MRK’s EPOCH trial of the BACE-inhibitor verubecestat was not capable of reducing cognitive or functional decline, despite the demonstrated brain amyloid load reduction. Since the drug worked mechanistically and yet did not produce any clinical benefit, questions have been raised regarding the underlying hypothesis. The second reason is whether these AD drugs are administered too late, particularly as many of these failed treatments were studied in patients with mild-to-moderate AD – should they have been provided earlier?

Beyond these two reasons, there are additional variables that have been discussed as potential weaknesses in AD trials. For example, the FDA previously required cognitive and functional benefits as co-primary endpoints, but the draft guidance now suggests that the requirement should vary across disease stages. Additionally, much like most other drugs, AD clinical trials are typically divided into three main stages, and several drugs may have progressed into Phase III despite earlier studies that were considered to have inconclusive results or only positive post-hoc assessments. There have also been studies that include patients with clinical symptoms that are indicative of AD, but not necessarily confirmed with the key biomarkers. Some patients who have been enrolled in AD clinical trials may not have AD to begin with, and instead suffer from other diseases.

Four forward-looking clinical developments for Alzheimer’s disease

With insights from past failures, we believe that several factors will characterize future AD trials. First of all, the introduction of therapies with targets beyond amyloid beta. While amyloid beta peptide and tau protein are the hallmarks of AD, the failure of amyloid-targeting drugs has resulted in tau receiving more attention. Recent studies have also suggested that inflammation and infections may contribute to AD pathogenesis. It will be promising to target inflammatory mediators like RIPK1 or treat viruses like human herpesvirus (HHV) or herpes simplex virus (HSV). Secondly, the selection of patients with preclinical AD that also have the relevant biomarkers. With the idea that AD progression starts with biomarker changes before cognitive and functional declines, targeting patients without any cognitive issues may provide the opportunity to prevent or slow AD clinical manifestations. The use of biomarkers for patient selection will ensure that clinical trial patients are likely to have the disease based on ApoE4 genetic variant detection, amyloid imaging in the brain, and / or amyloid measurement in the cerebrospinal fluid (CSF). These trends suggest that AD is evolving into a phenotype-driven disease space where the patient population is divided into several segments depending on the likelihood of responding to treatments. Thirdly, the use of novel endpoints to assess treatment efficacy. Although the Food and Drug Administration (FDA) requires AD therapies to exhibit clinically meaningful cognitive and functional benefits, the agency has recently stated the plan to provide an accelerated approval based on biomarker response. Upcoming clinical trials may be designed with amyloid or tau measurement as the primary endpoint. Finally, the increasing level of evidence needed to support product development. Given the failure of AD clinical trials that have been initiated based on positive post-hoc data, manufacturers are likely to realize the greater importance of statistical rigor and become less willing to initiate expensive phase three trials without the sufficient evidence.

CBP Takeaways

1) With AD clinical trials targeting earlier disease stages, the number of potential patients will dramatically increase and the treatment process will start far earlier of the disease onset time and go for longer. While greater patient population and longer treatment duration are attractive from the commercial standpoint, payers will be concerned about the value of such strategy and may adopt a restrictive stance toward coverage, pricing, and reimbursement. Pharmaceutical manufacturers need to raise awareness around the clinical and economic value of treating many asymptomatic patients for years or even decades to prevent AD manifestation and / or slow disease progression.

2) AD is moving into a phenotype-driven disease space with patients getting segmented by specific markers (e.g., ApoE4 genetic variant) and the primary endpoints shifting from cognitive and functional measures to biomarker levels. Understanding which patients have AD and are likely to respond to treatments represents a positive trend in the field by potentially improving the success rate and reduce payer concerns associated with the large patient population and / or prolonged treatment approach. But the technologies available for visualizing early AD signs (e.g., PET imaging of brain amyloid) can be expensive given the costly procedure and the large patient population. While many AD biomarkers have been studied, they have yet to be clinically validated. Such diagnostic procedure can also result in administrative burden and long turnaround time. As a result, pharmaceutical manufacturers need to launch a disease state awareness campaign to educate stakeholders regarding biomarker use, its ability to predict treatment efficacy, and its correlation with validated clinical endpoints

3) With virtually all experimental AD therapies that target amyloid beta fail in clinical trials, there is a growing recognition about the need to use a more innovative or targeted treatment approach beyond just incremental changes in patient segmentation, treatment dose, and pharmacokinetic. Since large pharmaceutical manufacturers are experienced with late-stage clinical trials and commercial product launches, they should focus on partnering with early-stage high-risk ventures through collaborations or investments to gain access into novel treatment modalities.