An artistic impression of amyloid plaques in Alzheimer’s disease [Adobe Stock]
Alzheimer’s disease is reaching epidemic proportions with an estimated 6.9 million Americans age 65 and older are living with the condition, according to the Alzheimer’s Association. Researchers have worked for decades to develop disease-modifying therapies for the condition and the period from the early 2000s to mid-2010s was characterized by intense research interest in AD, especially focusing on amyloid-targeting therapies, as the graph below demonstrates.
In a pivotal trial, Kisunla reduced decline by up to 35% compared to a placebo and lowered the risk of disease progression by up to 39%. Similar to lecanemab (received traditional FDA approval on July 6, 2023) and aducanumab (withdrawn earlier this year), Kisluna targets amyloid plaques, addressing a key pathological feature, albeit a controversial one, of Alzheimer’s disease.
The early 2000s to mid-2010s saw a gold rush of research, but much of that would evaporate as the failure rate of those trials emerged as one of the highest across drug development. When FDA granted accelerated approval to aducanumab, the first monoclonal antibody for Alzheimer’s, it was the first new treatment to win that status for Alzheimer’s since 2003, as FDA noted.
Alzheimer trials over time based on data from clinicaltrials.gov
The amyloid hypothesis has been a tough nut to crack
The amyloid hypothesis has remained controversial in the scientific community. In 2018, Sumner et al. in Frontiers in Neuroscience discuss in their review, the “amyloid cascade hypothesis” has been a dominant theory in Alzheimer’s research for decades, but its validity subject to intense debate. The authors note that “Despite substantial research and numerous trials, the success rate for the condition was meager. The article observed that “The success rate of approving novel drugs is very low; with only 9.6% of candidates that enter clinical trials gaining FDA approval… the outlook for Alzheimer’s drugs is even bleaker, with an approval rate of only 0.4% between 2002 and 2012; one of the poorest success rates of any disease.”
Below is a network graph delineating Alzheimer’s clinical trials based on data from clinicaltrials.gov.
| Medication | Brand Name(s) | Approval Year | Indications | Manufacturers | Class/Mechanism |
|---|---|---|---|---|---|
| Donepezil | Aricept, Eranz, E2020 | 1996 | All stages of Alzheimer’s Disease | Pfizer, Eisai | Cholinesterase inhibitor |
| Rivastigmine | Exelon, Prometax, SDZ ENA 713 | 2000 | Mild to moderate Alzheimer’s Disease and mild to moderate dementia in Parkinson’s Disease | Novartis Pharmaceuticals | Cholinesterase inhibitor |
| Memantine | Namenda, Ebixa, Axura, Akatinol, Memary | 2003 | Moderate to severe Alzheimer’s Disease | Forest Laboratories, Lundbeck, Merz Pharma | NMDA receptor antagonist |
| Galantamine | Razadyne, Reminyl, Nivalin | 2004 | Mild to moderate Alzheimer’s Disease | Janssen, Ortho-McNeil, Sanochemia, Shire, Takeda | Cholinesterase inhibitor |
| Combination | Namzaric (Donepezil + Memantine) | 2014 | Moderate to severe Alzheimer’s Disease | Allergan | Cholinesterase inhibitor + NMDA receptor antagonist |
| Suvorexant | Belsomra, MK-4305 | 2014 (Insomnia), 2020 (Alzheimer’s) | Insomnia, including in mild to moderate Alzheimer’s Disease | Merck | Orexin receptor antagonist |
| Brexpiprazole | Rexulti, OPC 34712 | 2015 (Schizophrenia), 2023 (Alzheimer’s) | Schizophrenia, Agitation in Alzheimer’s | Lundbeck, Otsuka | Serotonin-dopamine activity modulator |
| Aducanumab | Aduhelm, BIIB037 | 2021 (discontinued in early 2024) | Alzheimer’s Disease (early stages) | Biogen, Eisai | Anti-amyloid immunotherapy |
| Lecanemab | Leqembi, BAN2401, mAb158 | 2023 | Early Alzheimer’s Disease | BioArctic AB, Biogen, Eisai | Anti-amyloid immunotherapy |
| Donanemab | Kisunla | 2024 | Early symptomatic Alzheimer’s Disease | Eli Lilly | Anti-amyloid immunotherapy |
The Frontiers review also discusses several high-profile clinical trial failures, including those of bapineuzumab, solanezumab, and santenerumab, which all targeted different epitopes of the Aβ peptide. These failures led to a loss of confidence and investment in amyloid-targeting therapies, contributing to a steep decline in Alzheimer’s clinical trials circa 2017.
FDA-approved medications for Alzheimer’s disease
The FDA has approved several medications for Alzheimer’s disease over the years, with recent approvals focusing on disease-modifying therapies. The above table provides an overview of FDA-approved medications for Alzheimer’s disease, including their approval years, indications, and mechanisms of action.
Filed Under: Neurological Disease
