Biogen (Nasdaq: BIIB) reported topline Phase II results for diranersen (BIIB080) in early Alzheimer's disease, marking the first randomized Phase II study of a tau-directed therapy to report both biomarker reductions and cognitive slowing — though the trial did not meet its primary endpoint. The CELIA study results, while not confirmatory, were sufficient for Biogen to announce plans to advance the asset into registrational development. The results provide one of the clearest clinical signals to date supporting tau reduction as a potential disease-modifying strategy in Alzheimer’s disease.
Trial specifics
The CELIA trial (NCT05399888) is an 18-month, randomized, double-blind, placebo-controlled, dose-ranging Phase II study enrolling 416 participants with mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia, all of whom were naive to prior anti-amyloid therapy. The study evaluated three intrathecal dosing regimens of diranersen — 60 mg every 24 weeks, 115 mg every 24 weeks, and 115 mg every 12 weeks — over a 76-week placebo-controlled treatment period. The primary endpoint was dose-response assessment for change from baseline on the Clinical Dementia Rating–Sum of Boxes (CDR-SB) at Week 76, which was not met.
Pre-specified analyses of cognitive endpoints showed slowing of clinical decline across all dose groups, with the most pronounced signal observed in participants receiving the lowest dose of 60 mg every 24 weeks. Diranersen also produced reductions in cerebrospinal fluid tau and tau pathology measured by positron emission tomography across all studied doses, with reductions maintained throughout the dosing period, the company said. On safety, adverse event incidence was comparable across dose groups, though a higher incidence of serious adverse events was observed at the highest dose studied. The overall safety and tolerability profile was described as generally consistent with the earlier Phase Ib study.
The CELIA trial's failure to demonstrate a statistically significant dose-response relationship on CDR-SB complicates interpretation of the cognitive findings. The pre-specified cognitive analyses showing slowing of decline are supportive observations, but they were not the basis of the primary hypothesis and carry the interpretive limitations typical of secondary and exploratory analyses in a study that missed its primary endpoint. Biogen has not disclosed full numerical results, confidence intervals, or p-values from these analyses; complete data are expected to be presented at the Alzheimer's Association International Conference in 2026. An ongoing long-term extension study continues to evaluate the durability and long-term safety of diranersen, and the company said it plans to engage with regulators on the path to registrational trials. The BIIB080 clinical trial program began with a Phase Ib study in mild Alzheimer's disease; exploratory clinical outcome analyses from that earlier work were published in Nature Aging in 2026, providing the preclinical and early clinical rationale that informed CELIA's design.
Diranersen (ISIS 814907) is an antisense oligonucleotide designed to target microtubule-associated protein tau (MAPT) mRNA, reducing tau protein production at its source. Unlike approaches targeting extracellular tau aggregates, the company says diranersen is designed to reduce both intracellular and extracellular tau.