First Evidence That Targeting Tau May Slow Cognitive Decline

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First Evidence That Targeting Tau May Slow Cognitive Decline

LONDON — The investigational tau-targeting therapy diranersen (BIIB080) reduced tau pathology and showed evidence of slowing cognitive decline in people with early Alzheimer's disease (AD) in the phase 2 CELIA trial. 

Although the study did not meet its primary endpoint, it demonstrated robust biomarker effects across all doses, with the strongest clinical benefit observed at the lowest dose evaluated.

The new results follow a phase 1b study that showed the drug had a robust impact on tau biomarkers.

“This is the first randomized phase 2 trial of a tau-targeting agent to show that a reduction in tau pathology, which has been clearly and consistently shown across both trials, may slow early Alzheimer's progression,” said study investigator Catherine Mummery, PhD, professor of clinical neurology at the University College London (UCL) Queen Square Institute of Neurology.

Key Points

• Diranersen (BIIB080) ↓ tau pathology in early AD; phase 2 CELIA.
• Primary endpoint missed; no significant dose-response on CDR-SB (P=.21).
• 60-mg dose showed best clinical signal: CDR-SB ↓26%, ADAS-Cog13 ↓42%, MMSE ↓50%.
• CSF total tau ↓50%-65%; tau PET signal also ↓ across all doses.
• Generally well tolerated; AEs mainly lumbar puncture-related, mild-moderate.

What tau reduction threshold predicts cognitive benefit in early AD?

How does intrathecal tau ASO compare with anti-amyloid therapy?

Which biomarkers best monitor response to tau-lowering therapy?

The findings were presented July 14 at the Alzheimer's Association International Conference (AAIC) 2026.

‘Clear Target Engagement’

AD is a progressive neurodegenerative disorder characterized by the accumulation of amyloid plaques and pathological tau, the latter of which is more closely associated with disease progression and clinical symptoms, Mummery said. 

Although anti-amyloid therapies are available, no tau-targeting therapies have been approved for AD.

Diranersen is an investigational intrathecally administered antisense oligonucleotide (ASO) designed to reduce production of tau protein by targeting microtubule-associated protein tau (MAPT) messenger RNA, thereby lowering both intracellular and extracellular tau.

In a phase 1b study in patients with early AD, diranersen was well tolerated, produced robust reductions in tau biomarkers, and showed favorable trends on exploratory cognitive endpoints. 

"There was a dose-dependent reduction in levels of total tau," with levels falling to about 40% of baseline by week 48 in the 60-mg group and remaining at that level, Mummery said. "So there was a clear target engagement."

The double-blind phase 2 CELIA trial enrolled 416 adults aged 50-80 years with mild cognitive impairment due to AD or mild AD dementia and confirmed amyloid pathology. 

Participants were randomly assigned to intrathecal diranersen 60 mg every 24 weeks, 115 mg every 24 weeks, 115 mg every 12 weeks, or placebo for 76 weeks. Although the numbers were small, exploratory analyses showed positive trends on cognitive tests. 

Baseline characteristics were well balanced across treatment groups. The mean participant age was 68 years, which Mummery noted is slightly younger than that of a typical AD population. 

Primary Endpoint Not Met

Approximately 60% of participants had mild cognitive impairment (MCI) due to AD, while 40% had mild AD dementia. Participants underwent quarterly cerebrospinal fluid (CSF) sampling throughout the placebo-controlled phase of the trial. 

At its conclusion, all participants were invited to enroll in a 2-year long-term extension (LTE) study.

Overall, study retention was high. More than 80% of participants completed the placebo-controlled phase, and 94% enrolled in the long-term extension study, suggesting people “weren't put off by having quarterly intrathecal administration of the drug," Mummery said. 

The primary endpoint was dose response for change from baseline to week 76 in the Clinical Dementia Rating — Sum of Boxes (CDR-SB), a global measure of cognition and daily function. 

Although the 60-mg dose slowed decline on the CDR-SB by 26% compared with placebo, the trial did not meet its primary endpoint of demonstrating a dose-response relationship across treatment groups (P = .21).

Analyses of the CDR-SB subdomains also showed consistent improvements in both cognitive and functional domains with the 60-mg dose, Mummery said.

Although the trial missed its primary endpoint, secondary cognitive outcomes consistently favored diranersen. On the 13-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), all three dose groups showed less decline than placebo, with the greatest effect seen in the 60-mg group (42% slower decline; P = .01). A similar pattern was observed on the Mini-Mental State Examination (MMSE), where the 60-mg dose slowed decline by 50% vs placebo (P = .01).

In contrast, the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory for Mild Cognitive Impairment (ADCS-ADL-MCI) showed no significant difference between the 60-mg dose and placebo, suggesting that the functional findings warrant further study, Mummery said. 

‘Unprecedented’ Tau Reduction

Biomarker analyses showed robust target engagement. Cerebrospinal fluid (CSF) total tau levels remained stable in the placebo group but fell by 50% to 65% from baseline across all three diranersen dose groups. Most of the reduction occurred during the first 12 months and was sustained through the remainder of the study, Mummery reported.

Tau PET standardized uptake value ratio (SUVR) analyses showed the expected increase in whole-brain gray matter tau burden in the placebo group over time. In contrast, all three diranersen dose groups showed reductions in tau PET signal, which Mummery described as "unprecedented."

Referring to a brain scan from a participant receiving the 60-mg dose, Mummery highlighted the drug's effect on tau pathology. "In brain areas with particularly high levels of tau, like the lateral temporal and inferior parietal, you see quite a marked reduction," she said.

The drug was generally well tolerated. Most adverse events were mild to moderate in severity and did not result in treatment discontinuation or study withdrawal.

The most common adverse events were procedural pain, post-lumbar puncture syndrome (including headache and low back pain), and confusional state. Mummery noted that post-lumbar puncture syndrome is "incredibly common" in trials involving intrathecal administration. 

In 2025, the FDA granted Fast Track designation to diranersen for the treatment of AD. 

During the discussion, a conference delegate asked about the episodes of confusion reported in the trial. Mummery said investigators "are actively collecting data to try and understand more about it." She emphasized that most cases were mild or moderate, resolved within a week, and rarely led to treatment discontinuation. 

Asked whether a threshold of tau reduction is needed before a clinical benefit emerges, Mummery said important questions remain. "The fact that we're starting to see changes on tau-PET is really exciting, but we're going to learn a huge amount more about what the threshold is and how long it takes for that to mean something," she said.

Encouraging Findings, Important Caveats

The most interesting and noteworthy aspect of the study is that it demonstrates diranersen's ability to effectively reduce tau production, Jessica Langbaum, PhD, senior director of Alzheimer's prevention and research at Banner Alzheimer's Institute, told Medscape Medical News. 

Langbaum said the findings could open the door to therapies for other tauopathies, particularly if future technologies enable tau-targeting drugs to cross the blood-brain barrier and be administered subcutaneously. 

These findings provide the first evidence from a randomized trial that a tau-targeting therapy can produce both robust biomarker effects and a signal of clinical benefit, Laura Nisenbaum, PhD, interim chief science officer at the Alzheimer's Drug Discovery Foundation, said in a press release.

“Tau is one of the two defining pathologies of Alzheimer’s disease and has long been difficult to target, which makes these results all the more notable.”

However, Nisenbaum said the discordance between the biomarker and clinical findings raises important questions about the optimal degree of tau reduction and the dose of diranersen that should be evaluated in future studies. "Those questions will be central to designing the strongest possible phase 3 program."

Mummery has served as a consultant to Alector, Aerska, Biogen, Eisai, Ionis, Lilly, MSD, Neuroimmune, Novartis, Prevail, Roche/Genentech, Switch, Voyager, and Wave. She has received honoraria for teaching and educational activities from Biogen, Eisai, and Lilly, and an academic research funding award from Biogen. She is supported by the NIHR University College London Hospitals Biomedical Research Centre.