There are presently over 140 drugs being explored as possible treatments for Alzheimer’s Disease (AD) in clinical trials. Of these, nearly 80% are intended to slow the progression of AD. Historically, cholinesterase inhibitor drugs such as galantamine, rivastigmine and donepezil have been approved for treatment of AD. These drugs have been shown to mitigate symptoms of AD, such as memory loss, however they are unable to treat the underlying neurobiological cause of the condition. As such, these drugs do not slow AD progression and are not considered a long-term solution in the battle to end the most common form of neurodegenerative disease. 

Within the past year, two new AD treatment drugs were submitted to the US Food and Drug Administration for possible approval: donanemab and lecanemab (Leqembi®). In addition to aducanumab (Adulhelm®), which was granted accelerated approval in 2021, these drugs represent the first AD treatments in decades and bring renewed hope to AD patients, their families, and healthcare providers. Donanemab and lecanemab differ from most past treatments in that they have demonstrated the ability to clear amyloid plaques, an indicator of AD progression, from the brain. The two drugs are administered to patients via intravenous drip and have been primarily explored as treatments for patients at early stages in the disease process (e.g., mild cognitive impairment (MCI), mild AD dementia). 

Donanemab 

Eli Lilly and Company released the full results of the large, final-stage TRAILBLAZER-ALZ2 trial at the Alzheimer’s Association International Conference 2023 in Amsterdam. This study recruited over 1,100 older adults with amyloid plaques and symptoms of cognitive impairment based on objective testing and standardized self-report measures. Relative to placebo, participants taking donanemab showed approximately 20% slowing in the rate of cognitive decline over 18 months (using the ADAS-cog measure), with benefits particularly pronounced for participants who were at an early stage in the disease process (the primary analysis population, ~35% slowing). Nearly half of participants taking donanemab (47%) showed no progression in their cognitive decline one year later, as compared to less than a third of participants (29%) taking the placebo drug. Importantly, participants taking donanemab also showed 40% slowing in the rate of decline of their ability to perform everyday activities, such as managing finances and safe driving. A decision regarding traditional FDA approval for donanemab is expected later this year.  

The question remains as to whether the apparent cognitive and functional benefits of donanemab treatment and similar anti-amyloid therapies will continue to slow disease progression over the long-term and if the size of the effect will grow over time.  A long-term slowing of disease progression would represent a significant breakthrough in the treatment of AD.  

Other studies using donanemab are also underway, including examining whether the drug can delay or prevent development of AD (TRAILBLAZER-ALZ3) and comparing the effectiveness of donanemab to aducanumab, another anti-amyloid drug (TRAILBLAZER-ALZ4). Additionally, Eli Lilly and Company are currently conducting a large phase-3 study (TRAILBLAZER-ALZ1) for another drug, remternetug. Preliminary results have shown that remternetug may be better able to clear amyloid plaques from the brain than donanemab. 

Lecanemab 

In November 2022, results of the Eisai and Biogen-sponsored Clarity-AD trial were released at the Clinical Trials on Alzheimer’s Disease conference. This study enrolled nearly 1,800 older adults who were at an early stage in the Alzheimer’s Disease process. Relative to placebo, participants taking lecanemab showed a 27% slowing in the rate of cognitive decline after 18 months (using the CDR sum of boxes measure). Like the donanemab study, participants taking lecanemab showed a 37% slowing of decline in their ability to perform everyday activities relative to placebo. Lecanemab received traditional approval by the FDA in 2023, and a decision by the Medicine and Healthcare Products Regulatory Agency (MHRA) in the United Kingdom is expected in 2024. 

How can Cambridge Cognition help with Alzheimer’s Disease Clinical Trials? 

While donanemab and lecanemab represent significant advances in the treatment of AD, there is a lot of work left to do. Through the design and implementation of empirically validated and clinically-relevant cognitive tasks, the Cambridge Cognition team is committed to helping develop the next generation of AD treatments. Biologic and digital biomarkers will be crucial to help identify and follow the patient populations that are most likely to benefit from the current and next generation treatments being developed.  

Six ways we can help with AD trials: 

1. Increased Sensitivity to Disease and Strong Psychometric Properties. Tasks designed by Cambridge Cognition have been employed in over 200 AD-related academic publications. Our tasks have been utilized as cognitive endpoints by leading pharmaceutical companies from small phase 1 AD safety and efficacy studies to large-scale phase 3 trials, as well as in trials for other neurodegenerative diseases. 
2. Cognitive Screening. Several of our tasks, such as the Paired Associates Learning (PAL), have been used to efficiently screen for patients at heightened risk of developing AD. This in turn allows for higher confidence of enrolling individuals at the target stage of the disease process and reduced recruitment costs.  
3. Sample Enrichment. Relative to traditional cognitive assessments, tasks designed by Cambridge Cognition tap a wider array of cognitive domains and in greater depth. Between the large suite of visually-based tasks available via our CANTAB platform and our cutting-edge speech-based assessments available via our recent merge with Winterlight Labs, we provide a comprehensive and sensitive means of assessing AD throughout the disease process.  
4. Decentralized Trial Capabilities. Clinical trials have historically been limited in their ability to recruit participants of varying socioeconomic backgrounds, with individuals located in rural areas and/or without reliable transportation particularly neglected. This is concerning should AD treatments be marketed to these individuals as the generalizability of trial results are unclear. We have developed and validated several cognitive tasks capable of being administered repeatedly in a participant’s home without an administrator present. This translates to lower study costs, lower participant burden and more fine-grained longitudinal assessments of cognitive functioning in an ecologically valid manner. Furthermore, we have the capability of consenting participants remotely through our eConsent tool, ClinPal. 
5. Options for Remote Tracking of Side Effects. Side effects are a common concern in any clinical trial, including AD studies. Some participants in the AD trials previously described experienced brain swelling, headache, fall risk and confusion/altered mental status while taking the experimental medication. Our eCOA solution allows for remote monitoring of these symptoms. 
6. Sensitivity to Other Dementias. Researchers have discussed the likelihood that recent advances in AD treatments will carry over to other forms of dementia, such as Vascular Disease, Parkinson’s Disease or Lewy Body Disease. Cambridge Cognition has extensive experience in countless neurodegenerative indications and prepares batteries tailored to the disease of interest and goals of the sponsor.