Biogen's Tau-Targeting Diranersen Misses Its Primary Endpoint in Phase 2 but Cuts Brain Tau and Slows Alzheimer's Decline
Biogen's diranersen, an antisense drug aimed at tau, missed its Phase 2 dose-response endpoint but slowed cognitive decline and cut brain tau across all doses. Biogen is advancing to Phase 3.
Overview
Biogen presented detailed Phase 2 results for its experimental tau-targeting Alzheimer’s drug diranersen at the Alzheimer’s Association International Conference (AAIC) 2026 on July 14, according to Biogen. The data showed the drug slowed cognitive decline and cut levels of tau in the brain — but the trial, called CELIA, failed its primary goal, and its strongest benefits came at the lowest dose tested, an inversion that has left analysts both intrigued and wary, as reported by BioPharma Dive.
Diranersen, formerly known as BIIB080, “works by gumming up the genetic instructions cells use to create another Alzheimer’s-linked protein called tau,” BioPharma Dive reported, describing an antisense oligonucleotide originally developed by Ionis Pharmaceuticals. It is delivered by intrathecal injection — an infusion into the fluid around the spinal cord — according to Biogen. The therapy is designed to lower production of tau, the protein that forms the tangles found inside neurons in Alzheimer’s disease.
What We Know
CELIA enrolled 416 participants with mild cognitive impairment or mild dementia due to Alzheimer’s, according to Biogen, which said the participants were on average 68 years old, 51% female, and 69% carriers of the ApoE4 risk gene, with 60% having mild cognitive impairment and 40% mild dementia at baseline. The trial’s primary endpoint was a dose response for change from baseline on the Clinical Dementia Rating–Sum of Boxes (CDR-SB) at Week 76, and the study did not meet it, Biogen said.
The reason is a paradox at the center of the data: the primary goal was to show that diranersen’s effect grew as the dose rose, but the opposite happened. “Since the opposite occurred, the trial technically failed,” BioPharma Dive wrote.
According to Biogen, the 60 mg every-24-weeks group — the lowest-exposure arm — slowed decline on the CDR-SB by 0.54 points, or 26%, versus placebo, alongside reductions of 42% on the ADAS-Cog13, 50% on the MMSE, 30% on the modified iADRS and 23% on ADCOMS. The two higher-exposure arms fared worse on the CDR-SB, at 14% and 9%, meaning effect size shrank as exposure rose. BioPharma Dive independently reported that the effects “were most pronounced in the lowest dose arm, where clinicians reported a 26% slowing of decline” on the CDR-SB, and that across secondary tests “scores on several of these tests declined at least 23% and, by one measure, as much as 50% slower.”
On the biology, the results were more uniform. Biogen reported mean reductions of 50–65% in cerebrospinal fluid total tau across all doses and said diranersen was “the first tau-directed therapy to demonstrate reductions in both CSF total tau and brain tau pathology, as measured by PET, across all studied doses in a Phase 2 study.”
On safety, Biogen said most participants who experienced adverse events had events that were mild or moderate, most commonly procedural pain, post-lumbar puncture syndrome and confusional state that resolved within a week. The company added that amyloid-related imaging abnormalities, or ARIA, “are not anticipated with diranersen based on its tau-targeting mechanism of action” — a contrast with the brain-swelling and microbleed risks that accompany approved amyloid antibodies. BioPharma Dive likewise reported the drug “was generally well tolerated, with most adverse events being mild to moderate.”
What We Don’t Know
Because the primary dose-response endpoint failed, the cognitive results at 60 mg come from secondary analyses rather than a formally met primary outcome. The central open question, in BioPharma Dive’s words, is “why higher or more frequent dosing didn’t spur greater effects” — a pattern that could reflect a real biological effect or statistical noise in a mid-sized trial. Biogen has not published a peer-reviewed dataset, and whether removing tau slows decline over years — the question that ultimately decides approval — can only be answered in a larger, longer study.
Analysis
Biogen “disclosed this failure in mid-May, but said it would advance its drug into late-stage testing anyway because of the cognitive benefits and tau reductions that researchers observed,” BioPharma Dive reported. Priya Singhal, Biogen’s Executive Vice President and Head of Development, said in the company’s announcement: “If confirmed in Phase 3, diranersen could represent an important new therapeutic approach targeting one of the core pathologies of Alzheimer’s disease.”
The strategic interest lies in the target. The approved disease-modifying drugs cleared to date attack amyloid plaques; diranersen instead goes after tau, whose spread through the brain tracks more closely with the timing and severity of cognitive loss. A Biogen scientist, Diana Gallagher, told BioPharma Dive it was the first time anyone had shown tau reduction leading to a cognitive benefit at an effect that “looks comparable to amyloid lowering.” That would place diranersen alongside the amyloid-targeting antibodies already reaching patients, including the recently expanded at-home dosing for lecanemab that The Machine Herald previously reported.
Wall Street is divided. Mayank Mamtani of B. Riley Securities framed the CELIA readout as a key “de-risking event” for the field of tau drug development, according to BioPharma Dive. Others were skeptical: analysts at Cantor Fitzgerald led by Joshua Schmidt questioned why Biogen “would want to reopen its past can of worms,” warning the company was “making a very large bet on a neurodegenerative disease program that may be associated with a lower probability of success,” BioPharma Dive reported. Whether that bet pays off now hinges on a Phase 3 trial designed to avoid the dose-response trap that tripped CELIA.