Biogen Advances Diranersen to Phase 3 After Positive CELIA Data

Biogen has reported detailed Phase 2 results from the CELIA trial evaluating diranersen (BIIB080), an investigational antisense oligonucleotide (ASO) therapy for early Alzheimer’s disease. Presented at the Alzheimer’s Association International Conference (AAIC) 2026, the findings showed consistent clinical benefit across multiple cognitive endpoints and substantial reductions in tau biomarkers, supporting Phase 3 development of the therapy.

Although CELIA did not meet its primary endpoint of demonstrating a dose-response relationship on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the study provided evidence that tau lowering translated into measurable clinical benefit across several prespecified outcomes.

Diranersen Targets Tau Production at the RNA Level

Diranersen targets microtubule-associated protein tau (MAPT) messenger RNA, reducing the production of all tau protein isoforms. Unlike therapies that primarily target extracellular tau, the ASO lowers both intracellular and extracellular tau, addressing a central pathological hallmark of Alzheimer’s disease.

Tau accumulation closely correlates with neurodegeneration and cognitive decline, making it an important therapeutic target alongside amyloid-directed treatments.

Phase 2 CELIA Demonstrated Broad Clinical and Biomarker Activity

The global, randomized, double-blind, placebo-controlled Phase 2 CELIA study (NCT05399888) enrolled 416 patients with mild cognitive impairment due to Alzheimer’s disease or mild Alzheimer’s disease dementia. None of the participants had previously received anti-amyloid therapy. The trial evaluated three intrathecal dosing regimens of diranersen over an 18-month placebo-controlled treatment period: 60 mg every six months, 115 mg every six months, and 115 mg every three months.

Among the treatment groups, the 60 mg dose administered every six months produced the strongest clinical response. Compared with placebo, this regimen slowed clinical decline by 26% on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), 42% on ADAS-Cog13, 50% on the Mini-Mental State Examination (MMSE), 30% on the modified Integrated Alzheimer’s Disease Rating Scale (iADRS), and 23% on the Alzheimer’s Disease Composite Score (ADCOMS). Most of these treatment differences reached nominal statistical significance.

The two 115 mg dosing regimens also demonstrated clinical benefit compared with placebo, although increasing the dose did not result in greater slowing of disease progression. As a result, the study did not meet its predefined primary endpoint, which evaluated whether higher doses produced a stronger treatment effect on CDR-SB at Week 76.

Diranersen also showed consistent biological activity across all dose groups. Cerebrospinal fluid total tau concentrations declined by an average of 50% to 65% from baseline, while the tau positron emission tomography (PET) imaging sub study demonstrated reductions in brain tau pathology across all evaluated brain regions. According to Biogen, diranersen is the first tau-directed therapy to demonstrate reductions in both cerebrospinal fluid total tau and brain tau pathology measured by PET across all studied doses in a Phase 2 Alzheimer’s disease trial.

Most of these differences achieved nominal statistical significance

Higher-dose groups also favored diranersen over placebo, although greater doses did not produce greater clinical benefit. Consequently, CELIA did not meet its predefined primary endpoint assessing dose response on CDR-SB at Week 76.

Diranersen also produced robust biomarker effects across all dose groups. Mean cerebrospinal fluid total tau levels declined by 50% to 65%, while tau PET imaging demonstrated reductions in brain tau pathology. According to Biogen, diranersen is the first tau-directed therapy to show reductions in both CSF total tau and brain tau pathology across all studied doses in a Phase 2 Alzheimer’s disease trial.

Safety Profile Supports Continued Development

Diranersen was generally well tolerated throughout the placebo-controlled period. Most adverse events were mild or moderate and did not lead to treatment discontinuation.

The most common adverse events included procedural pain, post-lumbar puncture syndrome, and transient confusional state, with most episodes resolving within one week after dosing. No amyloid-related imaging abnormalities (ARIA) were observed, consistent with the therapy’s tau-directed mechanism.

More than 90% of participants completing the placebo-controlled phase enrolled in the ongoing long-term extension study.

Phase 3 Program Planned

Biogen said the combined clinical, biomarker, and safety findings provide Phase 2 proof of concept for tau reduction as a therapeutic strategy in Alzheimer’s disease. Building on data from both Phase 1b and Phase 2 studies, the company plans to advance diranersen into confirmatory Phase 3 clinical development while continuing long-term follow-up through the ongoing extension study.

What This Means for Patients

The Phase 2 CELIA results suggest that diranersen may help slow cognitive decline in people with early Alzheimer’s disease by targeting tau, one of the key proteins involved in disease progression. The study also showed substantial reductions in tau biomarkers and brain tau pathology, supporting the drug’s biological activity. While the trial did not meet its primary dose-response endpoint, the overall clinical, biomarker, and safety findings were strong enough for Biogen to advance diranersen into Phase 3 testing. Patients should note that diranersen remains an investigational therapy and is not yet approved for clinical use. Larger Phase 3 studies will determine whether these benefits can be confirmed and support future regulatory approval.

Reference

Biogen Presents Phase 2 CELIA Data at AAIC Demonstrating Meaningful Clinical Outcomes and Robust Tau Reduction with Diranersen in Early Alzheimer’s Disease | Biogen