Anti-Tau Agent Diranersen Slows Cognitive Decline Across Multiple Endpoints in Phase 2 CELIA Trial, Biogen to Advance to Phase 3

Biogen presented full Phase 2 data from the CELIA study evaluating diranersen (BIIB080), an investigational intrathecally administered antisense oligonucleotide (ASO) targeting MAPT mRNA, in 416 adults with early Alzheimer's disease (AD) at the 2026 Alzheimer's Association International Conference (AAIC) in London.¹ Based on the data, Biogen plans to advance diranersen into confirmatory Phase 3 development.

Overall, diranersen demonstrated treatment effects on 5 of 6 clinical endpoints across all dose arms at 18 months, with the 60 mg dose given every 24 weeks (Q24W) showing the most consistent and largest clinical benefit.¹ Compared with placebo (n = 115), the 60 mg dose (n = 60) slowed clinical decline by 0.54 points (26%) on CDR-SB, 42% on ADAS-Cog13 (P = .01), 50% on MMSE (P = .02), 30% on modified iADRS, and 23% on ADCOMS. The majority of these endpoint differences achieved nominal statistical significance. Slowing of functional decline on the functional domains of CDR-SB also favored diranersen across all studied doses.

The 115 mg Q24W dose (n = 115) and the 115 mg Q12W dose (n = 116) also showed treatment effects, slowing decline by 14% and 9% on CDR-SB, 32% and 29% on ADAS-Cog13 (P = .04 for both), 34% and 38% on MMSE, and 29% and 18% on modified iADRS, respectively.¹ No separation from placebo was observed across any dose group on ADCS-ADL-MCI, a measure of daily functioning; long-term extension follow-up continues to assess whether longer treatment duration impacts this endpoint.

The study was designed with CDR-SB dose response as its primary endpoint, assessing whether higher doses could provide greater clinical benefit. That hypothesis was not supported: the lowest dose, 60 mg Q24W, demonstrated the largest treatment effect, and the primary dose-response endpoint was not met (P = .21). The investigators characterized this pattern as identifying an emerging optimal dose rather than a trial failure.

"The CELIA data provide some of the clearest evidence that reducing tau pathology can translate into clinically meaningful benefit," Catherine Mummery, MD, PhD, Professor of Clinical Neurology at the UCL Queen Square Institute of Neurology and Consultant Neurologist at University College London Hospitals NHS Foundation Trust, said in a statement.¹ "The magnitude of tau reduction and cognitive benefit observed in CELIA is among the most compelling reported to date in Alzheimer's disease drug development and supports advancing diranersen to Phase 3."

Biomarker Findings

Diranersen demonstrated robust and sustained reductions in CSF total tau across all studied doses, with mean reductions of 50% to 65% from baseline by week 72.¹ These reductions were consistent across the full study population and maintained throughout the placebo-controlled period.

In the tau PET imaging substudy (n = 131), decreases from baseline were observed across all evaluated brain regions for all diranersen doses, including medial and lateral temporal cortex, frontal cortex, parietal cortex, anterior and posterior cingulate cortex, occipital cortex, and whole brain grey matter.¹ Biogen described diranersen as 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.

Mechanism and Prior Data

Diranersen targets MAPT mRNA to suppress production of all tau isoforms, reducing both intracellular and extracellular tau protein. This upstream approach distinguishes it from antibody-based strategies targeting extracellular tau species, and from other tau lowering approaches that do not affect intracellular tau.

In the Phase 1b study (NCT03186989), diranersen was well tolerated, demonstrated CSF total tau target engagement, and showed numerically slower decline in the 60 mg and 115 mg groups on clinical scales at week 100 versus an external control, providing the initial proof of mechanism that supported CELIA's design.¹ In 2025, the FDA granted Fast Track designation to diranersen for the treatment of Alzheimer's disease.

Patient Population and Safety

CELIA enrolled 416 participants aged 50 to 80 years with MCI due to AD or mild AD dementia confirmed by amyloid PET or CSF, an MMSE score of 21 to 30, a CDR-GS of 0.5 to 1, and an RBANS Delayed Memory Index score of 85 or below. None had previously received anti-amyloid therapy. Mean age was 68 years, 51% were female, 60% had MCI, and 40% had mild AD dementia. ApoE4 carriers represented 69% of participants, including 23% homozygotes.¹

Of 416 randomized, 10 withdrew prior to dosing, leaving 406 in the full analysis set. Study completion rates were high: 87.0% in placebo, 86.7% in the 60 mg group, 83.5% in the 115 mg Q24W group, and 74.1% in the 115 mg Q12W group. Among those completing the placebo-controlled period, 94% elected to continue into the long-term extension.

All told, diranersen was generally well tolerated. Most adverse events (AEs) were mild or moderate, non-serious, and did not result in treatment discontinuation. The most frequent AEs were procedural pain, post-lumbar puncture syndrome, and confusional state. Most confusional state events occurred within a few days of dosing and resolved within a week.

Serious adverse events were highest in the 115 mg Q12W group (23.3%). Consistent with its tau-targeting mechanism, no amyloid-related imaging abnormality (ARIA) events were anticipated or observed. Two deaths occurred during the study: one in the placebo group and one in the 115 mg Q24W group; neither was related to study treatment.

Next Steps

Additional analyses and long-term extension data from CELIA will be presented at future conferences. Diranersen was originally discovered by Ionis Pharmaceuticals; Biogen exercised a worldwide exclusive license in December 2019.

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REFERENCES
1. Biogen presents Phase 2 CELIA data at AAIC demonstrating meaningful clinical outcomes and robust tau reduction with diranersen in early Alzheimer's disease. News release. Biogen Inc. July 14, 2026. Accessed July 14, 2026. https://investors.biogen.com/news-releases/news-release-details/biogen-presents-phase-2-celia-data-aaic-demonstrating-meaningful
2. Mummery CJ, Börjesson-Hanson A, Bhatt DL, et al. Diranersen in early Alzheimer's disease: results of a phase 1b/2a study. Nat Med. 2023;29(6):1437-1447. doi:10.1038/s41591-023-02326-3. https://doi.org/10.1038/s41591-023-02326-3