The lineup at the Alzheimer’s Association International Conference will provide critical insight into where the industry is headed with regard to targets being explored to vanquish the elusive neurodegenerative disease.
A lot has changed in the Alzheimer’s disease treatment landscape over the last few years. Where once anti-amyloid treatments reigned supreme, therapies aimed at tau are now getting their time to shine.
The Alzheimer’s Association International Conference (AAIC) in London next week will feature shifting mindsets around disease targets and specified approaches.
“We’re at the dawn of disease-modifying treatments,” Al Sandrock, CEO of Voyager Therapeutics and a longtime leader in the space, told BioSpace.
The 2023 approval of Eisai and Biogen’s Leqembi and the subsequent 2024 go-ahead for Eli Lilly’s Kisunla marked the beginning of that new era as the first two drugs approved to clear amyloid plaque, thought to be one of the major drivers of Alzheimer’s disease. And while those therapies blazed a trail, questions about their safety and degree of efficacy loom, with drugmakers and industry watchers keeping their eyes trained on the next wave.
For Sandrock, formerly chief scientific officer at Biogen, there’s plenty to look forward to.
“We’re all waiting for whether or not earlier treatment with anti-amyloid drugs works better, and there are some big trials reading out over the next year or so,” he said. “And then we’re asking, what’s the second wave? It took years for amyloid to be validated, and now, to me, tau is the next important target.”
Tau tangles in the brain have long been considered the other hallmark of Alzheimer’s disease, alongside amyloid plaques, and drugmakers are increasingly leaning toward tau as a major target for new treatments. From industry titans such as Biogen, Eisai and Lilly, to rising stars like Voyager, the field is celebrating a litany of programs as they mature in the clinic, both for tau and amyloid.
As for new mechanisms to fight Alzheimer’s, most agree there is no silver bullet. And AAIC will showcase the myriad approaches that could eventually serve to treat different stages of the disease.
Sandrock, for one, believes that within a decade, early detection and treatment with a combination of targeted therapies could lead to “a world where we may not have to worry about Alzheimer’s disease at all.”
The rise of tau
Occupying center stage at AAIC is Biogen’s tau targeting candidate diranersen, which “has implications across the industry as a new modality,” Andrew Tsai, analyst and managing director at Jefferies, told BioSpace.
“I think tau thematically could make a splash this year,” Tsai said, pointing to the potential for tau-targeting therapies to avoid the most prominent side effect of anti-amyloid treatments called ARIA, which is a swelling of the brain.
“Given the context of the tau therapies that have failed in the past, [diranersen] seems to be the first one that could maybe succeed, and people (like me) are generally tired of talking about amyloid, so a new mechanism could be somewhat intriguing.”
Early attempts at tau-targeting treatments for Alzheimer’s encountered efficacy hurdles in the clinic. The most recent among them was a mid-stage candidate from Johnson & Johnson called posdinemab, with the company halting a Phase 2 trial when it failed to slow clinical decline. J&J will share full data from the study at AAIC.
Biogen’s tau candidate—licensed exclusively from longtime partner Ionis—is also front and center for Paul Matteis, managing director and head of therapeutics research at Stifel. The company has committed to a Phase 3 trial based on biomarker and clinical signals observed in a mid-stage study that missed the dementia-related primary endpoint, making Matteis and other analysts curious to see the data for themselves.
“About 90% of my focus is going to be on this full Biogen tau data, to understand whether the data make sense,” Matteis said. “Biogen, from our dialogues with them over the past year, has had a semi-high bar to advance the program because of how hard the [Leqembi] launch has been. How will they frame it? And what does it look like?”
For many, Biogen’s diranersen results could be an important bellwether for tau’s effectiveness overall.
“This is the first time that we’re seeing a tau targeting drug have an effect both on biology as well as a potential signal on the clinical effects … and this is the first signal that we might be able to move beyond amyloid,” Laura Nisenbaum, interim Chief Science Officer at the Alzheimer’s Drug Discovery Foundation, told BioSpace.
Biogen won’t be the only company touting tau at AAIC. Voyager’s candidate, which last month received IND clearance to begin clinical trials, is an adeno-associated virus (AAV) gene therapy called VY1706 that makes use of capsid technology to cross the blood-brain barrier and target tau proteins.
“Neurotherapeutics has gotten to the point where we know the targets we want to go after, but the problem is many of the targets are undruggable if you only have small molecules at your disposal, because small molecules are the only ones that can cross the blood-brain barrier,” said Voyager’s Sandrock. “With [VY1706], you could have a one-time gene therapy that is a potential game-changer.”
Voyager will present a poster July 13 with data from its IND-enabling study.
Keeping the amyloid hypothesis alive
Currently, however, anti-amyloid drugs remain the only approved disease-modifying therapies for Alzheimer’s, and Eisai and Biogen are determined to demonstrate Leqembi’s ongoing usefulness in the treatment landscape.
Eisai has learned from its experience with the pair’s first FDA-approved anti-amyloid drug Aduhelm, which endured regulatory and reimbursement challenges before the companies removed it from the market in January 2024. Now, the focus is primarily on Leqembi, which comprises a sizable portion of more than 50 presentations Eisai is bringing to AAIC.
One of the most prominent Leqembi trials is a three-year, real-world study of more than three hundred patients. Leqembi’s long-term studies have shown that the anti-amyloid mechanism works best in earlier-stage patients, Eisai Chief Clinical Officer Lynn Kramer told BioSpace.
They have also showed the interplay between amyloid and tau.
“As we start to understand the disease biology, we understand when you can interfere at what stage of the disease,” Kramer said. “Alzheimer’s is a disease that speeds up over time, and once you get over the edge of the cliff, amyloid agents don’t work very well, because now tau has taken over the process.”
The link between tau and amyloid is becoming clearer, with the presence of amyloid indicating early signs of developing Alzheimer’s disease while tau accompanies cognitive decline, according to both Kramer and Sandrock.
Among the dozens of studies involving Leqembi, Eisai will also present treatment durability, biomarker data and, critically, data on ARIA side effects. Kramer noted that, over time, the brain swelling associated with anti-amyloid drugs has diminished from more than 12% of patients in earlier clinical trials to 8% in the larger population.
Some smaller companies are working on new approaches to amyloid. This includes ProMIS Neurosciences, which uses a computational model to discover patterns of misfolded amyloid proteins that CEO Neil Warma said could help treatments avoid the ARIA problem.
Still in early stages, ProMIS will present a poster highlighting its lead amyloid candidate PMN310’s Phase 1b trial, which has gained FDA Fast Track designation, with safety data that shows no drug-related serious adverse events, Warma said. A cleaner side effect profile could help set the drug apart in the clinic and, potentially, the market, he added.
“What folks are looking for, whether it’s patients or pharma or investors, is something that’s truly differentiated, with the potential to modify the disease,” Warma said. “Part of that challenge is to identify a certain species of the amyloid beta protein that seems to be the toxic driver.”
