Advancements in Late-Stage Alzheimer's Treatments Extend Beyond Amyloid and Tau

The future of Alzheimer’s treatment is shifting away from traditional targets of amyloid plaques and tau tangles, opening doors to varied therapeutic approaches aimed at decelerating cognitive decline.

In the last two years, anti-amyloid antibodies such as Eisai and Biogen’s Leqembi and Eli Lilly’s Kisunla have emerged, making history as the first effective treatments for slowing Alzheimer’s disease. Despite these advances, the disease continues to progress. Today, new therapeutics targeting different biological mechanisms are in Phase III trials, suggesting a future where Alzheimer’s can be managed through multiple pathways.

According to neuroscientist Jeffrey Cummings from the University of Nevada, there are currently 32 Alzheimer’s therapeutics undergoing 48 Phase III trials. Six target amyloid-β and one targets tau; others focus on neuroprotection, growth factors, neurotransmitters, neurogenesis, inflammation, and proteinopathies. Notably, 21 of these are aimed at modifying the disease itself.

Rebecca Edelmayer of the Alzheimer’s Association notes that the increasing understanding of Alzheimer’s biology is paving the way for new treatment targets, which may not replace current drugs like Leqembi and Kisunla but could provide additional options for managing the disease.

Leqembi was approved by the FDA in January 2023 as the second disease-modifying treatment for Alzheimer’s, with Kisunla following in July 2024. These drugs showed moderate efficacy in reducing clinical decline, with Leqembi achieving a 27% reduction and Kisunla a 29% reduction. Both drugs, however, come with significant side effects such as amyloid-related imaging abnormalities (ARIA), which indicates possible brain swelling or bleeding. The debate continues among experts regarding their overall clinical benefits.

Leqembi requires bi-monthly intravenous infusions, while Kisunla needs a monthly infusion, posing challenges for patients and healthcare systems alike. Future Alzheimer’s treatments aim for easier administration.

Athira Pharma’s fosgonimeton, a small-molecule therapeutic, is in Phase II/III trials and can be injected daily at home. While the drug didn’t meet primary endpoints in trials, it stabilized or improved cognition and function in specific patient subgroups, showing promise in reducing inflammation and amyloid toxicity.

Anavex Life Sciences Corp. is testing blarcamesine (ANAVEX 2-73), an oral therapy targeting neuronal homeostasis. In its Phase IIb/III study, blarcamesine slowed Alzheimer’s progression by 38.5% at 48 weeks, showing no adverse neuroimaging effects, unlike Leqembi and Kisunla.

Novo Nordisk’s semaglutide, a GLP-1 receptor agonist known for weight loss, is also being tested for Alzheimer’s, with a Phase III study expected to conclude in 2026. Early studies suggest semaglutide may reduce neuroinflammation and improve vascularization.

Neurim Pharmaceuticals is investigating piromelatine, which aims to enhance cognition and function by improving sleep quality, thereby reducing amyloid beta aggregation.

Cassava Sciences’ simufilam seeks to restore brain function by stabilizing the protein filamin A, but the company faces legal scrutiny over data integrity related to its clinical trials. Despite this, simufilam has shown promise in maintaining cognitive scores over two years of continuous treatment.

Given the complex nature of Alzheimer’s, a combination of treatments targeting different mechanisms could be more effective. Experts anticipate that future treatment strategies may involve integrating various FDA-approved therapies with brain-healthy lifestyles to address the disease comprehensively.

In conclusion, the landscape of Alzheimer’s therapeutics is evolving, with innovative approaches and diverse clinical trials offering hope for more effective management of this challenging disease.