By Ivo Carre, business analyst, Lifescience Dynamics
In the search for effective treatments for complex neurological diseases, such as Alzheimer's disease (AD), the development of novel biomarker assays and diversification in therapeutic approaches have driven continued progress across the disease’s therapeutic landscape. Recent developments promise hope for individuals grappling with AD, including the recent approval of the amyloid targeting therapeutic Leqembi and the expected approval of donanemab. In addition, therapeutic methods including correcting risk genes, transplanting stem cell-derived neurons, and focusing on other disease-associated targets, such as tau and TREM2, are providing additional cause for optimism.
While these approaches are at varying stages of development, they highlight that a growing wealth of advancements are happening in both drug delivery and therapeutic strategy. This article will look at the factors contributing to this "renaissance" in AD drug development.
Shifting Trends In Regulatory Approvals
Between 2000 and 2015, neurological drugs faced approval rates below the mean across all indications, with Alzheimer's drugs experiencing even lower success rates. Financial incentives have played a crucial role in the resurgence of AD drug development, which, in part, has been driven by the escalating financial burdens on governments and healthcare providers. The global economic burden of AD and related dementias cost an estimated $2.8 trillion in 2019, which is expected to rise to $4.7 trillion by 2030. This financial pressure has fueled a significant reinvigoration of the AD pipeline and academic level research, leading to drug development expanding beyond just amyloid-targeting therapies to those that also target tau, the innate immune system (including inflammatory pathways), and cellular replacement therapies.
Up until 2021, however, only a handful of drugs, including donepezil, galantamine, memantine, and rivastigmine, had been approved for treatment. But then there was an uptick in FDA approvals. In 2021, although cancer drugs accounted for 30% of all new FDA approvals, neurology saw the second most approvals for the third time in a row (10%).
Most notable for the AD field was the approval of Biogen’s Aduhelm (aducanumab). The drug was the first monoclonal antibody targeting beta-amyloid plaques – abnormal clumps of protein that accumulate in the brains of Alzheimer's patients. However, the drug faced controversy because of concerns about efficacy, the quality of the data from clinical trials, and the drug’s high cost. This led many to question whether amyloid was an appropriate target for the treatment of AD. However, the recent milestone from Eisai showed this not to be the case, as the FDA granted full approval of Leqembi — a promising drug designed for individuals in the early stages of AD that also targets amyloid. While not a cure, the drug has demonstrated efficacy in slowing down the progression of the disease.
Moreover, with the upcoming development of a subcutaneous reformulation anticipated in 2024, greater access to the treatment is expected, as the treatment will no longer require access to a transfusion center. Initial data shows comparable safety and efficacy to the current intravenous Leqembi.
However, the fact that disease progression still occurs following application of amyloid drugs does indicate other pathways aside from amyloid are involved in disease progression.
New Therapies In The Pipeline
Alternative therapeutic strategies for addressing the continued progression of disease aside from treatment with an amyloid targeted therapy may consist of modulating the inflammatory response and other immune-related processes. For example, the ability to correct risk genes such as TREM2 or APP offers a novel approach to the treatment of AD. Meanwhile, cellular therapies including ablation or transplantation of stem cell derived neurons and/or microglia offer potential ways of treating and even restoring lost functionality due to the disease. Such strategies, however, remain years away from clinical use, but with an estimated 141 candidate treatments in development, including antibodies and small molecules that target TREM2, inflammatory molecules, metabolic dysfunction, synaptic integrity, and tau, novel approaches to the treatment of Alzheimer’s are likely to see approval in the next few years.
Due to this expansion in AD research, more and more companies are looking to develop combination therapies to advance the efficacy of current treatments, with immune (TREM2) and tau targeting strategies seen as prime contenders for amyloid dual therapeutic strategies.
Evolution Of Diagnostic Tools And Biomarkers
Biomarkers are a defined biologic or objective measure that can be measured as an indicator of normal biological processes. They allow a researcher or clinician to understand the biologic process occurring in a patient at any given moment and are largely used to diagnose disease through detecting clinically significant changes in defined biomarkers
Currently, doctors use imaging of the brain, cognitive assessment examination such as the mini mental state examination (MMSE), or cerebrospinal fluid (CSF) to diagnose the disease through detection of disease-associated biomarkers. These methods largely require specialized equipment with CSF analysis requiring a spinal tap. These drawbacks can therefore limit patients’ access to a diagnosis due to the need for access to specialized clinics.
Now, researchers are looking at blood-based biomarkers (BBBMs) as a possible diagnostic tool to revolutionize Alzheimer’s diagnosis. Biomarkers, such as the Aβ40:42 ratio, p-Tau level, t-Tau level, and NfL level (currently assessed through CSF), are showing promise as possible ways to diagnose the disease in the future. BBBMs also allow for less invasive, decentralized testing, subsequently increasing patient access. These types of biomarkers are seeing greater use in clinical trials; however, no biomarker assays have been approved by the FDA for clinical use.
Market Dynamics At Play
The expansion of the pipeline beyond amyloid-targeting therapies has been a significant breakthrough. While increased funding and heightened public awareness have contributed to the AD drug development resurgence, the market trajectory may depend on the success of drugs like Leqembi, the first amyloid drug covered for insurance reimbursement. It has the potential to set the stage for subsequent developments, influencing the investment in developing new drugs.
The ongoing advancements in both drug delivery and therapeutic strategies underscore a growing wealth of progress in the battle against Alzheimer's disease. This is just the beginning of what’s to come in the treatment of this disease.
About The Author:
Ivo Carre is a business analyst with Lifescience Dynamics, a company dedicated to helping optimize clinical and commercial strategies in the biopharma industry. Before joining Lifescience Dynamics, Ivo completed a Ph.D. in Neuroscience at King’s College London where he investigated the neuro-innate immune system, focusing on microglia and the impact of the neuro-glycome in Alzheimer’s disease. He also obtained an MSc in neuroscience from University College London.