Continued Research into Early-Stage Clinical Trial Drug Development for Alzheimer’s

Over the last few decades, researchers have gained a much deeper understanding of Alzheimer’s disease, its pathology, and the underlying mechanisms of the disease. The growing knowledge of Alzheimer’s disease has paved the way for many promising avenues for treatments and therapies, creating a more robust and diverse pipeline of drugs to target a breadth of identified mechanisms. We have moved beyond treating the symptoms of Alzheimer's disease and are on the path to treating the disease at its core.

An incredibly promising Alzheimer’s research pipeline is emerging. Currently, there are 208 active Alzheimer’s clinical trials, including a whopping 118 trials evaluating disease-modifying therapies. However, pharmaceutical companies face many challenges and barriers that contribute to failed clinical trials. As much as 94.1% of drug-based neurological disease clinical trials fail—however, this doesn’t necessarily mean all of the failed drugs were ineffective. Many believe that failed drug-based neurological disease trials stem largely from unreliable data.

Let’s take a deeper look into pivotal clinical trials for Alzheimer’s disease drugs, common challenges with early-stage clinical trial drug development for Alzheimer’s disease, and how these challenges may be solved through a precision approach.

Pivotal Clinical Trials for Alzheimer’s Disease Drugs

Aducanumab (Aduhelm) was the first FDA-approved treatment for Alzheimer’s disease to enter the market since 2003 and is the first in the monoclonal antibody therapy class. Following the approval of Aducanumab, several other emerging amyloid-related therapies are beginning to be pushed forward. Biogen and Eisai’s treatment, Lecanebab, and Eli Lilly and Company’s treatment, Donanemab, both received the FDA’s Breakthrough Therapy designation for the treatment of Alzheimer’s.

According to the Alzheimer’s Drug Discovery Foundation’s 2021 Alzheimer’s clinical trial report, a vast range of targets, as well as a growing list of therapy types, are currently in the pipeline, and 77% of the 118 disease-modifying trials have novel targets other than amyloid or tau. New targets in disease-modifying therapies include neuroprotection, inflammation, mitochondria and metabolic dysfunction, vascular disease, synaptic activity and neurotransmitters, and genetics and epigenetics. 

The wide range of targets opens the door to a more precise, personalized approach to treating Alzheimer’s disease. Every individual’s neurocognitive domain functions are affected uniquely in the presence of Alzheimer’s, meaning the treatment pathways will also likely be unique. Utilizing multiple effective treatments personalized to an individual’s unique impairments will allow for more individualized and more effective treatment and care.

Challenges in Early Stage Clinical Trial Drug Development for Alzheimer’s Disease

While the potential of emerging drugs and therapies for Alzheimer’s disease progresses rapidly, diagnostics tools and methods for robust monitoring of neurocognitive function for clinical trials remain rather outdated, driving subject recruitment costs through the roof, prolonging timelines for early-stage clinical trial drug development for Alzheimer’s, and contributing to clinical trial failures. Common challenges in early-stage clinical trial drug development for Alzheimer’s disease occur during subject selection and longitudinal monitoring of neurocognitive changes within subjects.

Screening and Subject Selection

Subject screening and recruitment for clinical trials for Alzheimer’s disease is currently very cost-inefficient due to a lack of precision diagnosis. To determine subject eligibility, many early-stage Alzheimer’s drug clinical trials require expensive positron emission (PET) scans or invasive cerebrospinal fluid analyses as a part of the key inclusion criteria to establish protein levels, such as beta-amyloid and tau. As there can be hundreds or even thousands of potential subjects, the screening and selection process can skyrocket clinical trial expenses. 

Unfortunately, costly imaging and diagnostic procedures have been the standard for this process, as there has been a lack of reliable measurement tools available to understand precisely where potential subjects lie on a disease continuum, meaning pharmaceutical companies lack tools to narrow the subject pool before completing hundreds or thousands of costly PET scans.

Longitudinal Monitoring of Neurocognitive Changes within Subjects

Expensive imaging techniques, such as PET scans and magnetic resonance imaging, used to visualize changes within the brain are also commonly utilized as a primary outcome to assess drug efficacy. However, protein levels in the brain, for example, may not be the best indicator of whether or not an Alzheimer’s subject has improved. Neither brain imaging nor traditional neurocognitive assessments have the data granularity or ecological validity to truly understand a drug’s impact on the subject’s true brain function and ability to complete Activities of Daily Living (ADLs).