New results presented this week at the Alzheimer's Association International Conference in London showed that the investigational drug diranersen (BIIB080), a tau-lowering therapy, slowed cognitive decline across multiple clinical measures in people with early Alzheimer's disease. Researchers describe the findings as the strongest evidence to date that targeting tau can alter the course of the disease and represent the first randomized, placebo-controlled evidence that lowering tau may provide a clinical benefit for patients.
For Erik D. Roberson, M.D., Ph.D., professor, Rebecca Gale Heersink Endowed Chair in the UAB Department of Neurology, and director of the UAB Frances Gorrie
Erik D. Roberson, M.D., Ph.D. Alzheimer’s Disease Center, the milestone traces back nearly two decades.
In 2007, while at the Gladstone Institutes, Roberson was first author of a landmark paper in Science that showed reducing tau levels protected mouse models of Alzheimer's disease from problems caused by amyloid, another key protein involved in the disease. The study was among the first to demonstrate that tau was not merely a bystander in Alzheimer's disease but played a central role in mediating amyloid's harmful effects.
"It's incredibly exciting to see work we did in mouse models of Alzheimer's disease translating into clinical trials with benefits for patients," Roberson said. "We showed in 2007 that genetically lowering tau protected mice from amyloid-induced memory deficits, seizure activity, and early death, without changing amyloid levels. Seeing a tau-lowering drug now produce both a biomarker effect and a cognitive benefit in a randomized trial in Alzheimer's patients is exactly what we hoped this biology would do."
The Phase 2 CELIA trial from Biogen evaluated diranersen, an antisense oligonucleotide designed to reduce production of the tau protein. In the study, participants receiving the lowest tested dose experienced 26 percent less decline on the Clinical Dementia Rating-Sum of Boxes, 42 percent less decline on the Alzheimer's Disease Assessment Scale-Cognitive Subscale, and 50 percent less decline on the Mini-Mental State Examination compared with placebo after 18 months. The results have prompted Biogen to advance the therapy into Phase 3 development.
The findings are significant because they validate a therapeutic strategy that has been under development for nearly 20 years.
"It is so important to see positive results from a tau-directed trial in Alzheimer’s disease," Roberson said. "The field has made substantial progress targeting amyloid, with new drugs now available that can remove amyloid, with some modest benefit. Tau pathology tracks much more closely with neurodegeneration and cognitive symptoms than amyloid does. So, a therapy that hits tau directly and shows benefit (even though the trial technically missed its target of showing higher doses work better than lower ones) gives us a validated approach to targeting tau, the other major culprit in Alzheimer's disease."
The findings are particularly meaningful because Alzheimer's research has long focused on amyloid. While amyloid plaques begin accumulating years before symptoms appear, tau abnormalities emerge later; thus, researchers increasingly view tau as a critical therapeutic target that complements amyloid-focused treatments.
"Amyloid plaques start forming about 15 years before symptoms appear, but plaque burden correlates poorly with how impaired a patient actually is,” Roberson explained. “Tau tangles show up later, spread through the brain in a pattern that tracks with disease stage, and correlate much more tightly with synapse loss and cognitive decline."
Roberson said the 2007 study helped answer two critical questions facing drug developers.
"Our 2007 paper addressed the two questions any drug developer needed answered before investing in a tau-lowering program," Roberson said. "First, does tau reduction help, even without removing amyloid? Second, and just as important, is partial tau reduction safe? Many in the field worried that lowering a protein with normal physiological roles in neurons might cause harm. We showed that mice with lower tau were protected, not harmed, and that even substantial tau reduction was well tolerated."
That evidence, he said, helped spur growing interest in tau-based therapies and ultimately contributed to efforts that have now reached late-stage clinical development.
While encouraged by the results, Roberson emphasized that diranersen is not yet available to patients and must still undergo additional testing before potential FDA approval.
"For the patients I see in clinic this week, nothing changes yet," he said. "This is a Phase 2 result, still headed toward the larger trials required for FDA approval, not an approved drug. But if it holds up, it gives us a treatment that works through a completely different mechanism than the amyloid antibodies already on the market."
Looking ahead, Roberson believes the future of Alzheimer's treatment will likely involve combination therapies.
"I think down the road many patients will end up on combination therapies targeting both amyloid and tau, which I suspect will be more effective than targeting either alone," he said.
For Roberson, the moment also highlights the importance of sustained investment in fundamental scientific research, even when the payoff takes decades.
"It took nearly 20 years to go from a genetic proof of concept in mice to a randomized trial showing clinical benefit in patients, and that timeline is normal for this kind of discovery."
Roberson credits colleagues, especially Lennart Mucke, M.D., as well as the academic and industry teams who helped advance tau reduction to clinical implementation.
"My lab at UAB has continued to work on understanding how tau reduction exerts its beneficial effects, and we are developing a related therapeutic approach to block key tau interactions," Roberson said. "We think that may capture many of the same benefits, but with a medicine that can be delivered in a pill instead of a lumbar puncture injection."