Biogen (BIIB) investor relations material

Key clinical findings and data highlights

• Diranersen demonstrated robust tau lowering and reduction of tau tangles in the brain, with substantial impact on multiple clinical endpoints in early Alzheimer's disease, including cognition and function, as shown in the CELIA phase II study.

• The 60 mg twice-yearly dose showed the largest and most consistent benefit across nearly all endpoints, with effects on CDR Sum of Boxes similar to anti-amyloid therapies and unprecedented cognitive efficacy signals.

• Biomarker data revealed significant reductions in CSF tau and tau PET, with tau pathology accumulation reduced from baseline in all diranersen arms, a first for tau-directed agents.

• Safety profile was favorable, with most adverse events mild or moderate and no ARIA observed; confusional state events were dose-related, mild to moderate, and resolved quickly.

• High patient retention was observed, with 94% of completers entering the long-term extension study.

Study design, dose selection, and future plans

• CELIA was an 18-month, randomized, placebo-controlled phase II study in early Alzheimer's, testing three diranersen doses and measuring multiple cognitive and functional endpoints.

• No typical dose response was observed, but all doses favored diranersen over placebo; the 60 mg dose emerged as optimal based on the totality of efficacy and safety data.

• Subgroup analyses showed consistent efficacy across demographics, including APOE4 carriers, with no significant differences identified.

• Long-term extension is ongoing to assess durability, with two-year data expected by end of 2026; phase III study design is underway, engaging regulators and external experts.

• Future development may include combination or sequential therapy with anti-amyloid agents, but initial phase III will focus on tau monotherapy.

Mechanistic insights and broader implications

• Diranersen is an antisense oligonucleotide targeting MAPT gene translation, reducing all tau isoforms inside cells and impacting both intracellular and extracellular tau pathology.

• The lack of a clear dose response may reflect the need for a therapeutic 'sweet spot' in tau reduction, as tau has physiological roles in the brain.

• Functional benefit on ADCS-ADL-MCI was not observed at 18 months, but other composite endpoints showed both cognitive and functional improvements; longer-term data may clarify functional effects.

• The confusional state adverse event was not temporally linked to tau reduction and typically resolved quickly, suggesting it is not an on-target effect.

• The commercial potential is significant, with a differentiated profile versus anti-amyloid therapies and the possibility of twice-yearly administration.