Alzheimer’s Disease - Why We May Be Entering a New Era of Drug Development
Alzheimer’s disease is a massively impactful condition. As the world grows older and lives longer, the impact may be more acute with each passing day. Recently, a US Congressional committee estimated the cost of Alzheimer’s disease to Americans will reach $1 trillion per year by 2050[i]. Today, over 6 million Americans are living with the disease, a number which is expected to double over the same time period[ii]. While new drugs have been approved that target the amyloid beta protein and associated plaques in the brain, the results have been mixed. Data shows a delay in cognitive decline by only ~35%, and these drugs are only FDA approved for patients with mild cognitive disease or the mild dementia stage of the disease. And an astounding 98% of clinical trails for Alzheimer’s disease have failed since ‘03[iii]. More solutions are desperately needed.
Fortunately, it is increasingly understood that many trails failed because of poor study design, incorrect disease stage testing, and limited statistical significance of eligible patients. High screen failure rates[iv] and late intervention hindered progress, meanwhile the focus on amyloid reduction has not consistently led to improvements[v]. Advances in understanding mean that hopefully this disease category has now entered a new phase - new treatment modalities have significantly expanded in clinical development recently, including targeting novel mechanisms such as senolytics, synaptic activity/ neurotransmitters, mitochondrial dysfunction and genetics, in addition to well studied approaches such as inflammation, oxidation, misfolded proteins, and vascular disease. New uses and/ or combinations of previously approved drugs in other indications can be a viable strategy, depending on intellectual property protection and the strength of data exclusivity post approval. Neuroprotective devices also present compelling opportunities. From a regulatory standpoint, we have heard from the CEO of a first in class Phase 2 ready Alzheimer’s drug that the FDA is starting to show a willingness to accelerate approval paths, with fewer patients needed in pivotal trials - as long as there is enough safety and the efficacy shown with validated markers of disease progression.
One interesting opportunity includes GLP1 receptor agonists, which have shown efficacy in an ever-increasing number of indications. While they were originally approved by the FDA for obesity and type 2 diabetes, they are now showing early signals that they can help delay the onset of Alzheimer’s disease in a retrospective study[vi]. Prospective double-blind placebo-controlled study results with Novo’s semaglutide are expected in 2026[vii]. While promising, the unmet medical need will continue, especially for patients with Familial Alzheimer’s disease (those who have a high genetic risk) and for whom treatment options are limited - notably, ApoE ε4 allele carriers have had brain bleeds or swelling in clinical trials with amyloid beta antibodies.
In addition to therapeutics, new diagnostic tools are becoming available that increase our confidence that Alzheimer’s disease can be better treated in the future. This includes amyloid beta and tau PET imaging tracers (radioactive markers), blood tests which can help neurologists diagnose the disease without the need for a spinal tap to obtain cerebrospinal fluid[viii], and cognition assessments which can increase the ability for patients and their caregivers to recognize disease progression and track treatment progress. In addition, we are seeing new innovative approaches that incorporate AI and machine learning, such as through voice recognition, movement, and hearing loss associated with Alzheimer’s. The potential for a less expensive monitoring technology than Positron Emission Tomography (PET), an expensive nuclear imaging machine that is generally only available in large medical centers, also increases the potential for significnatly less expensive clinical trials in the future.
Taken together, these advancements provide us with confidence to evaluate new treatments that will more significantly impact the progression of Alzheimer’s than the previous generation’s therapeutics. This gives up hope that in the next 10-15 years, the life sciences industry will have changed the nature of the fight against this terrible disease.
[i] United States Representative Don Beyer, Chairman, Joint Economic Committee, “The Economic Costs of Alzheimer’s Disease,” July 6, 2022.
[ii] Alzheimer’s Association 2024 Facts and Figures
[iii] Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 83-100, 2022
[iv] Key Barriers for Clinical Trials for Alzheimer’s Disease, USC Health Policy, August 2020.
[v] https://www.clinicalleader.com/doc/why-do-so-many-alzheimer-s-clinical-trials-fail-0001.
[vi] “Associations of semaglutide with first-time diagnosis of Alzheimer's disease in patients with type 2 diabetes: Target trial emulation using nationwide real-world data in the US”, Alzheimer’s and Dementia, 24 October 2024.
[vii] Clinicaltrials.gov ID NCT04777396, “A Research Study Investigating Semaglutide in People With Early Alzheimer's Disease (EVOKE)”, 10 January 2025.
[viii] “Highly accurate blood test for Alzheimer’s disease is similar or superior to clinical cerebrospinal fluid tests”, Nature Medicine, 21 February 2024.
