Biogen’s Alzheimer’s Tau Drug Splits Experts: Can Diranersen Challenge Leqembi?

Biogen is pushing its experimental Alzheimer’s drug diranersen into Phase 3 trials despite missing the primary dose-response goal in its 416-patient CELIA study, after the lowest tested dose paradoxically delivered the strongest results—slowing cognitive decline on the CDR-SB scale by 26% over 18 months. Unlike traditional antibodies that attempt to clear extracellular tau proteins and have repeatedly failed in Phase 2, the Ionis-licensed antisense oligonucleotide blocks intracellular tau production at the genetic level, achieving a clinical efficacy signal nearly identical to approved anti-amyloid treatments like Leqembi while avoiding their signature brain-swelling side effects.

A Trial Designed to Prove Dose Response, and Didn’t

Biogen’s CELIA study set out to answer a specific question: would higher doses of diranersen, an experimental therapy that targets the Alzheimer’s-linked protein tau, produce a bigger clinical benefit than lower doses? The 416-patient, 18-month Phase 2 trial tested three regimens of the drug, an antisense oligonucleotide licensed from Ionis Pharmaceuticals, against placebo in people with early Alzheimer’s disease. The study’s primary endpoint — a dose-response relationship on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale — was not met, Biogen disclosed.

The reason it failed was not that diranersen didn’t work — it was that the lowest of the three doses tested worked best. The 60 mg dose, given every six months, slowed decline on CDR-SB by 26% relative to placebo, versus 14% and 9% for the two higher-dose regimens, according to detailed data Biogen presented at the Alzheimer’s Association International Conference (AAIC) in July. Despite missing its primary goal, the company said the totality of the data gave it enough confidence to move diranersen into Phase 3, registrational development.

What the Data Actually Show

The low dose’s advantage held across multiple measures, not just CDR-SB: a 42% slowing on the ADAS-Cog13 cognitive scale and 50% on the MMSE, compared with 32%–34% and 29%–38% for the higher doses on the same tests, respectively. All three doses, however, produced similar reductions in cerebrospinal fluid tau, of 50% to 65%, and similar reductions in brain tau measured by PET scan — meaning the drug engaged its target equally at every dose, but that engagement did not translate into a proportionally bigger clinical effect as the dose increased.

The 26% slowing on CDR-SB at the low dose invites a direct comparison to Leqembi, the amyloid-targeting antibody from Biogen and Eisai, whose pivotal trial showed a 27% slowing on the same scale over the same 18-month window. The comparison is illustrative rather than definitive: CELIA was a mid-stage, dose-ranging study, not a pivotal trial designed and powered to establish efficacy against a fixed statistical bar, and cross-trial comparisons between different patient populations carry real limitations.

A Field With a Rocky History

Alzheimer’s disease is associated with two hallmark proteins: amyloid, which clumps into plaques between neurons, and tau, which tangles inside them. The two approved Alzheimer’s antibodies, Leqembi and Eli Lilly’s Kisunla, both target amyloid. Attempts to target tau have had a rockier history: UCB’s bepranemab, J&J’s posdinemab, and Eli Lilly’s LY3372689 all reached Phase 2 but failed to deliver significant cognitive or clinical benefits.

Diranersen works differently. Rather than mopping up tau outside cells with an antibody, it is designed to block the genetic instructions cells use to produce the protein in the first place, reducing both the intracellular and extracellular forms — a distinction researchers say may explain why it succeeded where earlier antibody approaches did not.

The Competitive Field Heats Up

CELIA’s results landed just days after Johnson & Johnson’s antibody posdinemab failed to slow clinical decline in its own Alzheimer’s trial, sharpening the contrast between antibody and antisense approaches to tau. UCB’s antibody bepranemab has also reported weaker data than CELIA in a similar population, results researchers said support the idea that intracellular tau knockdown may be a materially different approach from the monoclonal antibodies that have repeatedly failed.

Attention is now turning to earlier-stage rivals: Denali Therapeutics‘ DNL628, which also targets the MAPT gene and is in Phase 1b testing, and programs at Eisai and Eli Lilly. Biogen and Ionis’ head start, and the size of the CELIA dataset, give diranersen a meaningful lead in a field that had, until this year, produced mostly disappointment.

Outside physicians were largely positive. Dr. Jeff Cummings, a professor of brain sciences at the University of Nevada, Las Vegas, said the results mark meaningful progress toward “shaping the next generation of Alzheimer’s disease treatments,” he said in Biogen’s release. Laura Nisenbaum, interim chief science officer at the Alzheimer’s Drug Discovery Foundation, called CELIA “the first data from a randomized trial to show a tau-targeting drug producing both a robust biomarker effect and a signal of clinical benefit”.

Not everyone is treating the inverted dose-response as settled science. CELIA was designed and sized to detect whether effects scaled up with dose, not to determine which single arm was statistically superior, meaning a divergence this pronounced sits at the edge of what the trial can reliably distinguish from chance. Biogen’s own disclosure offers one possible clue: the incidence of serious adverse events was higher in the highest-dose group than in the other arms, though overall tolerability was described as consistent across doses. Whether that safety difference, a true biological ceiling effect, or statistical noise best explains the pattern will likely only be resolved with a larger, purpose-built Phase 3 trial.

What Happens Next: Diranersen’s Phase 3 Path and Potential Safety Advantage

Biogen has said it will advance diranersen into confirmatory Phase 3 development and engage regulators on next steps, though it has not disclosed a start date or trial design for the pivotal program. The drug’s tau-targeting mechanism means it is not expected to cause ARIA, the brain swelling and micro-bleeding that limits use of the approved amyloid antibodies — a potential differentiator if the effect holds up in a larger trial.

More than 90% of CELIA participants who completed the placebo-controlled period chose to continue into a long-term extension study now underway, and Biogen has said additional analyses and data will be presented at future scientific conferences as the drug’s regulatory and clinical path becomes clearer.

Author

Bernice Lottering