Days after Johnson & Johnson’s posdinemab failed to slow clinical decline in patients with Alzheimer’s disease, Eisai Chief Clinical Officer Lynn Kramer expressed unwavering conviction in his company’s own anti-tau asset, while others suggest the Alzheimer’s field is heading in a completely different direction.
In a space where strikeouts are unfortunately common, Alzheimer’s therapies targeting tau have had a particularly bad batting average. Johnson & Johnson’s recent whiff with posdinemab’s mid-stage failure is just the latest in a series of disappointing readouts that could turn some away from the target.
Last November, UCB’s anti-tau Alzheimer’s candidate bepranemab was unable to improve cognition and function in a Phase II trial—a month after Roche terminated a collaboration for the molecule. And earlier in 2024—just a month after winning approval for its anti-amyloid Alzheimer’s drug Kisunla—Eli Lilly failed to see the same success with its anti-tau drug LY3372689.
Eisai Chief Clinical Officer Lynn Kramer has a theory as to why the recent cadre of anti-tau candidates has been unsuccessful.
In an interview with BioSpace prior to the Clinical Trials on Alzheimer’s Disease (CTAD) 2025 conference, he expressed unwavering conviction in his company’s own anti-tau asset, pointing to its unique tau-specific target. Of the flopped anti-tau candidates, “We’ve never expected them to succeed because if you don’t have the right target you can’t succeed.”
The “critical” region when it comes to stopping Alzheimer’s is an area of the tau protein that is involved in seeding its own spread, Kramer explained. Pointing to a slide on his computer, he said, “J&J, as you see, doesn’t hit that seeding region.”
Eisai—which along with Biogen brought to market Leqembi after the companies’ Aduhelm—hopes etalanetug will turn the tide against tau. Etalanetug, which Eisai is developing in collaboration with University College London, targets the R2-R4 regions within the tau microtubule binding region (MTBR). In an oral presentation Monday at CTAD, Eisai presented Phase Ib/II data showing that the treatment reduced all measurable forms of MTBR-tau243—a specific biomarker of tau tangle pathology in Alzheimer’s—in the cerebrospinal fluid and plasma of seven patients with mild-to-moderate disease.
Kramer said that the key to etalanetug’s success is binding at the seed location to stop this “spreading phenomenon” that is unique to Alzheimer’s disease. “[In] almost all tauopathies, tau builds up in the neuron,” he said. “It doesn’t spread across to the next like an infection.”
Eisai is not alone in its continued pursuit of tau-targeting Alzheimer’s treatments, despite the setbacks. Bristol Myers Squibb, Merck and more continue their campaigns against tau. BMS’s BMS-986446 binds to the R1-R3 regions within the MTBR, while Merck’s MK-2214, which targets phosphorylated serine 413 (pS413) tau, was granted FDA fast track designation earlier this month.
Kramer noted that tau is a better marker for cognitive impairment than amyloid because it builds up over time. Amyloid, by contrast, is found at roughly the same levels in the brains of people who are and are not cognitively impaired, according to Leqembi’s trials AHEAD 3-45 and CLARITY-AD.
But tau therapies have something to prove, especially in the wake of the recent clinical disappointments. Howard Fillit, co-founder and chief science officer at the Alzheimer’s Drug Discovery Foundation, told BioSpace that most of the data currently available in this space is from animal models. “It’s still probably a bit early days with anti-tau and anti-tangle therapies.”
The Next Frontier?
Anti-tau therapies are far from the only strategy being undertaken for Alzheimer’s. For Fillit, the next important Alzheimer’s target to watch is inflammation. “My personal view is that inflammation is a very important target in this illness, both systemic and neuroinflammation,” he said.
This theory has already clocked its first failure, however, after Novo Nordisk’s semaglutide was unable to reduce Alzheimer’s disease progression in a pair of closely watched trials last month.
There are over 30 other active clinical trials in Alzheimer’s with anti-inflammatory targets, according to Fillit. ADDF has invested in some of these companies, including Houston-based Coya Therapeutics. Coya is studying COYA 302 in a Phase II trial for amyotrophic lateral sclerosis, but the regulatory T cell (Treg)-targeted therapy is also in early-stage development in frontotemporal dementia, Alzheimer’s and Parkinson’s disease.
Therini Bio, meanwhile, is targeting vascular dysfunction to treat Alzheimer’s. Therini’s lead candidate, THN391, targets the “inflammatory epitope” on fibrin deposits outside of blood vessels and prevents the activation of microglia and macrophages, which cause destructive neuroinflammation, according to the biotech’s website. Its Alzheimer’s program is in Phase I.
“We’ve had such a focus for 40 years on amyloid and tau,” Fillit said, but “now it seems like the focus is just starting to change.” While five years ago, 70% of clinical trials in Alzheimer’s were targeting amyloid and tau, today, 70%-75% of targets are novel, he continued, with inflammation being the primary one.
That said, there is still interest in those traditional targets. A former and suddenly resurgent competitor of Eisai and Biogen’s, Lilly presented new data Monday from a Phase I/II study of trontinemab, its next-generation bispecific 2+1 amyloid-beta antibody, at CTAD. While not targeted toward tau, biomarker analysis showed that trontinemab had a potential effect on the accumulation of tau protein in the brain.
Overall, Fillit described the tone at CTAD 2025 as “very exciting, because we really have breakthroughs and multiple pathways and a lot of drugs in Phase II and even a number in Phase III. Forty years of research is finally paying off.”
