Following the hard-won success of early anti-amyloid drugs, a new generation of Alzheimer’s modalities—from tau-targeting gene silencers to blood-brain barrier delivery platforms—is entering the pipeline to anchor future combination therapies.
The development of treatments for Alzheimer’s disease has been marked by consistent disappointment, with a demoralizing 99% candidate failure rate. However, recent market entrants—beginning with Biogen and Eisai’s ill-fated Aduhelm, then their more prosperous Leqembi and Eli Lilly’s Kisunla—have defied these odds.
With proof that progress is possible in this space, a new wave of treatments has emerged in the early-stage pipeline. Many of these candidates are taking novel approaches to the disease, whether through gene silencing, antisense platforms or improved drug-delivery technologies.
Having various modalities with different targets coming through the pipeline could be especially important as the treatment landscape matures, with a combination of approaches likely to be key to managing Alzheimer’s disease, Patrick Trucchio, managing director of Equity Research at H.C. Wainwright, told BioSpace. Several companies, including Eisai, Bristol Myers Squibb and Merck, are working on another common Alzheimer’s target: the tau protein.
“KOLs . . . expect it will take a combination of anti-amyloid, anti-tau and then some sort of neuroinflammatory drug to address the disease,” he said. “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.”
Against this backdrop, attention is turning to the next generation of Alzheimer’s drugs that could form the backbone of future combination therapies.
Biogen’s BIIB080
Antisense oligonucleotide
Biogen was there in the beginning, and the company remains in the thick of the next generation of Alzheimer’s R&D. BIIB080, a tau-targeting antisense oligonucleotide (ASO) granted FDA Fast Track designation last year, is currently being evaluated in Phase II trials. A popular target, the tau protein forms into toxic tangles in the brains of individuals living with Alzheimer’s.
Phase Ib data presented at the International Conference on Alzheimer’s and Parkinson’s Diseases in 2023 showed BIIB080 reduced soluble tau protein in cerebrospinal fluid (CSF) in patients with early-stage Alzheimer’s. The clinical study was the first to show a reduction of this magnitude in tau PET across brain regions, Biogen said in its press release at the time. The ASO therapy reduced biomarkers of tau in all dose groups by approximately 60% compared to baseline. Biogen announced in April 2025 that the Phase II CELIA trial of BIIB080 was fully enrolled. The study’s completion date is set for May, with readouts expected this year.
This readout will be one of the most significant for Alzheimer’s in 2026, Laura Nisenbaum, executive director of drug development at the Alzheimer’s Drug Discovery Foundation (ADDF), told BioSpace.
“So far, the drug appears to be safe and to reduce tau levels in the brain,” she said. “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’ ARO-MAPT
RNA interference therapy
California-based Arrowhead is also working on a tau-targeting asset, an investigational RNA interference therapeutic called ARO-MAPT. Arrowhead launched a Phase I/IIa trial of the treatment in Alzheimer’s and other tauopathies last month.
Traditional methods of targeting tau, such as antibodies and small molecules, have had difficulty in modulating the protein, which makes it ideal for a siRNA-mediated knockdown approach, James Hamilton, chief medical officer at Arrowhead, told BioSpace in an email.
The primary reason for the other approaches’ struggles, Hamilton said, is that “tau monoclonals do not adequately target intracellular tau neurofibrillary tangles, which are one of the key drivers of disease biology.” ARO-MAPT, on the other hand, “targets tau mRNA expression in neurons and is administered by a subcutaneous injection,” he explained.
Arrowhead is hoping its study will show reductions in CSF translating into lower levels of regional brain tau, Hamilton said. He noted that the study will also include cognitive measures and other disease-relevant rating scales but cautioned that the trial is likely too small to show an effect on cognition, with this set to be assessed in Phase II trials.
The company is anticipating initial data from the first parts of the study in the second half of this year, Hamilton said in the December press release announcing the trial’s launch.
With Arrowhead’s and other significant readouts expected this year, Trucchio referred to 2026 as “the year of tau,” adding that 2027 will also be crucial. The data from these trials will be important because they will help confirm the most appropriate approach, Trucchio said, likening the different methods of tau reduction to either “a chisel or a sledgehammer.”
Alnylam’s Mivelsiran
RNA interference therapy
Alnylam’s mivelsiran, also an siRNA therapy, is being tested in Phase I trials for Alzheimer’s disease. Plans were underway to initiate a Phase II trial during the fourth quarter of 2025, according to the biotech’s third-quarter 2025 earnings report, but as of publication no such trial was listed on ClinicalTrials.gov.
While part of the same class as ARO-MAPT, mivelsiran is delivered via intrathecal rather than subcutaneous injection. Alnylam is targeting amyloid in its Phase I trial, while a further asset, ALN-5288, also a siRNA, is being explored to target tau.
“With RNAi, we can target amyloid-beta and tau at their genetic source, addressing both intracellular and extracellular pools of these problematic proteins,” Tim Mooney, program lead for mivelsiran at Alnylam, told BioSpace in an email. “This upstream approach may be able to more comprehensively address drivers of Alzheimer’s progression compared to other modalities.”
Echoing Trucchio, Mooney said Alnylam expects the future of Alzheimer’s treatment to comprise a variety of approaches and combinations to provide “a more comprehensive effect.” This includes looking at approaches that extend beyond targeting amyloid and/or tau proteins, he added, with Alnylam “exploring multiple mechanisms” to address the disease.
“Looking further into the future, we anticipate that diagnostic screening with blood-based biomarkers may eventually play a role in helping to identify individuals at risk of developing AD who could benefit from treatment with targeted therapeutic approaches like ours to prevent the onset of dementia altogether,” Mooney said.
Alector Therapeutics’ AL137
Next-gen antibody paired with brain carrier technology
Alector suffered two setbacks to its neurodegenerative pipeline, experiencing clinical trial failures in its partnerships with both AbbVie and GSK in a 13-month span. The biotech is still developing AL101 alongside GSK for Alzheimer’s but has pivoted its approach in its earlier-stage pipeline.
AL137, a preclinical anti-amyloid beta antibody, is being paired with Alector’s “brain carrier” (ABC) delivery technology to target Alzheimer’s disease. This design is intended to counter one of the major barriers to administering treatments for Alzheimer’s by navigating the blood-brain barrier (BBB).
Alector’s ABC technology uses receptor-mediated transcytosis to cross the BBB, targeting specific receptors of endothelial cells to facilitate the delivery of therapeutics. This delivery technology is designed to improve drug delivery and also to reduce dose levels whilst maintaining efficacy, according to the company’s website.
Navigating the BBB could help to prevent one of the key known side effects of the anti-amyloid antibody class: amyloid-related imaging abnormalities (ARIA), Trucchio said. Last July, Lilly’s Kisunla received a label update for its dosing schedule to reduce the likelihood of ARIA.
ARIA prevention is now becoming a key differentiator that companies in this space hope to achieve, Trucchio said, adding that analysts will be looking to the next-generation anti-amyloid therapies or delivery platforms to deliver this.
As the potential for improved delivery of Alzheimer’s treatments becomes clear, companies emerging later into the space—or those on the rebound, such as Roche with its antibody trontinemab—are leveraging this as a means to catch up to the early frontrunners.
The progress currently being seen in the Alzheimer’s space is lifting the negativity that existed in the field five years ago, Nisenbaum said.
“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.”
