The search for effective treatments for Alzheimer’s disease has long been challenging, with most drug candidates failing to make it through clinical trials. Despite a 99% failure rate in past efforts, recent approvals of drugs such as Biogen and Eisai’s Leqembi and Eli Lilly’s Kisunla have renewed optimism in the field.
This new sense of possibility has encouraged companies to develop early-stage therapies using different scientific approaches, including gene silencing, antisense platforms, and advanced drug delivery methods. Experts suggest that a combination of these strategies may eventually be necessary to manage Alzheimer’s effectively.
Patrick Trucchio, managing director of Equity Research at H.C. Wainwright, told BioSpace: “KOLs . . . expect it will take a combination of anti-amyloid, anti-tau and then some sort of neuroinflammatory drug to address the disease. In terms of tau-targeting, I think the next two years will determine which candidates and which type of approach is going to be paired with the amyloid drugs.”
Several companies are focusing on targeting tau protein, which forms toxic tangles in the brains of people with Alzheimer’s. Among these efforts is Biogen’s BIIB080, an antisense oligonucleotide (ASO) therapy currently in Phase II trials after receiving FDA Fast Track designation last year. Early trial data showed significant reductions in soluble tau protein levels among participants. The company reported full enrollment for its Phase II CELIA trial in April 2025, with results expected this year.
Laura Nisenbaum, executive director of drug development at the Alzheimer’s Drug Discovery Foundation (ADDF), said: “So far, the drug appears to be safe and to reduce tau levels in the brain. What we’re looking to see next is whether this holds across more individuals, continues to be safe and possibly has an impact on cognitive symptoms.”
Arrowhead Pharmaceuticals is developing ARO-MAPT, an RNA interference therapy also aimed at reducing tau protein. Unlike previous approaches that use antibodies or small molecules—methods that have struggled to reach intracellular tau—ARO-MAPT targets tau mRNA expression within neurons via subcutaneous injection.
James Hamilton, chief medical officer at Arrowhead Pharmaceuticals, explained: “Tau monoclonals do not adequately target intracellular tau neurofibrillary tangles, which are one of the key drivers of disease biology.” He added that initial data from ongoing studies should become available later this year but cautioned that early-phase trials are unlikely to show cognitive benefits until larger studies are conducted.
Alnylam Pharmaceuticals is also pursuing RNA interference-based therapies for Alzheimer’s. Its siRNA therapy mivelsiran is being tested in Phase I trials targeting amyloid proteins; another asset aims at tau proteins specifically. Tim Mooney, program lead for mivelsiran at Alnylam, stated: “With RNAi, we can target amyloid-beta and tau at their genetic source... This upstream approach may be able to more comprehensively address drivers of Alzheimer’s progression compared to other modalities.” He added that future treatment will likely require multiple combined approaches and highlighted potential roles for diagnostic screening using blood-based biomarkers.
Alector Therapeutics is developing AL137—a preclinical antibody against amyloid beta—paired with its proprietary brain carrier technology designed to improve delivery across the blood-brain barrier (BBB). This technology uses receptor-mediated transcytosis to help therapeutics reach brain tissue more effectively while aiming to reduce side effects associated with current anti-amyloid antibodies.
Trucchio commented on these advancements: “ARIA prevention is now becoming a key differentiator that companies in this space hope to achieve,” referring to amyloid-related imaging abnormalities—a known side effect targeted by new delivery technologies.
As companies like Roche attempt comebacks with new delivery methods for their antibody trontinemab and others invest further into novel therapeutic strategies, experts note increased enthusiasm among developers entering the field today compared with five years ago.
“With the success of anti-amyloid therapies and the development and approval of blood-based biomarker tests, we’ve seen renewed excitement and a greater willingness from drug developers to enter this space,” Nisenbaum said.
