Tuesday brought what was arguably the most anticipated presentation of the 2026 Alzheimer’s Association International Conference when Catherine Mummery, head of novel therapeutics at University College London’s Dementia Research Center, presented data from the phase II Celia trial of tau-lowering antisense oligonucleotide (ASO) diranersen (BIIB-080, Biogen Inc.).

Based on both clinical and biomarker data, “Celia establishes a proof of concept,” Mummery said, that reducing tau may slow the progression of Alzheimer’s disease.

Despite the fact that Celia missed its primary endpoint, which was to establish a dose-response relationship, the trial did not shake Biogen’s confidence. When the company reported top-line results via press release in May, it also announced that it was taking diranersen into phase III.

Now that the top-line analysis has been published, that decision looks to be attributable to the strength of the clinical data.

Patients treated with the 60-mg dose showed a slowing of cognitive decline as assessed by several tests. Decline slowed by 42% as measured by Alzheimer’s Dementia Assessment Scale – 13-item cognitive version (ADAS-Cog 13), 50% by mini-Mental State Examination (MMSE), and 26% as measured by Clinical Dementia Rating – Sum of Boxes (CDR-SB). Overall, five out of six clinical endpoints favored diranersen across all dose levels.

The magnitude of cognitive decline had been the most-anticipated indicator of diranersen’s possibility of success, with various researchers naming benchmarks of 25% to 30% as a strong enough effect to justify taking the drug forward despite its formal phase II miss.

Mummery also noted that patients across all doses showed “profound” reductions in tau, with mean reductions of 50% to 65% from baseline.

At a Monday session on “Clinical learnings from recent tau clinical trials,” session co-chair Günter Höglinger, director of the neurological clinic at the Ludwig Maximilians Universität, also highlighted the strong effect that diranersen had on tau levels as assessed by PET imaging.

In published brain imaging analyses published earlier in Lancet Neurology and exploratory analyses  of a diranersen phase Ib trial that were published in Nature Medicine in February, “from a biomarker perspective, the tau pet data [was] really convincing,” he said, though acknowledging that there were “a very low number of observations.”

Tau pathology is much more strongly correlated with cognitive decline than amyloid pathology, and in their February Nature Medicine paper, the authors wrote that “this result represents, to our knowledge, the first time that a reduction in aggregated tau has been observed across multiple brain regions in response to a disease-modifying therapy.” 

For amyloid-targeting antibodies, a disconnect has emerged between their ability to clear plaque, which they do extraordinarily well, and their ability to slow cognitive decline, which is more modest. Tau burden, Mummery said when presenting the data at AAIC, “correlates intimately with the progression of clinical symptoms.”

A global, randomized, double-blind, placebo-controlled and dose-ranging study, Celia enrolled 416 participants with mild cognitive impairment due to Alzheimer’s disease or mild Alzheimer’s disease dementia, all of whom had not previously received anti-amyloid therapy. Three doses were evaluated over the 76 weeks: 60 mg every 24 weeks, 115 mg every 24 weeks and 115 mg every 12 weeks. In addition to the primary endpoint, there were secondary and exploratory endpoints, including CSF tau biomarkers and tau positron emission tomography (PET). A long-term extension study is ongoing to evaluate safety, tolerability and durability.

A fly in the ointment is the unexplained reversal between the results in phase Ib, where stronger effects were seen with higher doses, and phase II, where it was the lowest, 60-mg dose that slowed cognitive decline the most. The results of the phase Ib trial had been sufficiently unambiguous to have Biogen choose a dose-response curve as Celia’s primary endpoint.

Another unexplained result is the ADCS-ADL-MCI, a measure of daily functioning, which did not improve in patients treated with the higher dose of 115 mg.

Still, Höglinger told BioWorld at the Monday tau session, there is always a tension between the scientific desire to understand causes, and the clinical desire to move forward with what looks like a promising dataset.  

Biogen will be holding a webcast from AAIC to discuss the data later today.