Biogen Advances Tau-Targeting Alzheimer’s Drug Diranersen Despite Phase II Dose Uncertainty

Detailed CELIA trial results show Biogen and Ionis’ diranersen slowed cognitive decline in early Alzheimer’s disease, but questions remain over why the lowest dose delivered the strongest clinical benefit.

Biogen is moving ahead with plans to advance its investigational Alzheimer’s disease therapy diranersen (BIIB080) into Phase III development, despite new data from a Phase II study raising questions around the optimal dose and the scale of potential clinical benefit.

Detailed results from the CELIA study presented at the Alzheimer’s Association International Conference (AAIC) showed that diranersen slowed cognitive decline in patients with early Alzheimer’s disease, but the strongest effect was observed at the lowest dose tested.

The findings have prompted renewed debate around the programme’s future, with analysts questioning why higher doses did not translate into greater clinical improvement despite producing similar or greater reductions in tau protein levels.

Following the presentation, Biogen’s shares fell approximately 8%. CELIA Trial Evaluated Diranersen in Early Alzheimer’s Disease

The Phase II CELIA trial enrolled 416 patients with:

• Mild cognitive impairment due to Alzheimer’s disease

• Mild Alzheimer’s dementia
  

The study evaluated diranersen, an antisense oligonucleotide (ASO) developed in partnership with Ionis Pharmaceuticals, designed to reduce production of tau protein.

Tau accumulation is considered one of the key pathological features of Alzheimer’s disease, alongside amyloid-beta plaque formation.

Unlike currently approved anti-amyloid therapies, diranersen targets tau pathology, representing a different approach to slowing disease progression.

The trial aimed to determine whether higher doses of diranersen would deliver greater clinical benefit over an 18-month treatment period.

However, the results did not demonstrate a clear dose-response relationship.

Lowest Diranersen Dose Showed Greatest Cognitive Benefit

The strongest clinical results came from the lowest dose tested.

Patients receiving 60mg of diranersen administered intrathecally every 24 weeks experienced:

• A 26% slowing of cognitive decline compared with placebo based on the Clinical Dementia Rating–Sum of Boxes (CDR-SB)

• A 0.54-point improvement difference versus placebo
  

The magnitude of benefit was comparable with results reported for existing Alzheimer’s disease therapies.

For comparison:

• Biogen and Eisai’s Leqembi (lecanemab) demonstrated approximately a 27% reduction in decline in its pivotal trial

• Eli Lilly’s Kisunla (donanemab) reported a 35% reduction
  

Additional cognitive measures also showed positive trends with the 60mg dose, including:

• 42% slowing on Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog13)

• 50% slowing on Mini-Mental State Examination (MMSE)

• 30% slowing on modified Integrated Alzheimer’s Disease Rating Scale (iADRS)

• 23% slowing on Alzheimer’s Disease Composite Score (ADCOMS)
  

Biogen noted that statistical significance for many of these secondary measures was nominal compared with placebo.

Higher Doses Raise Questions Around Treatment Strategy

The CELIA study also evaluated higher doses of diranersen:

• 115mg every 24 weeks

• 115mg every three weeks
  

However, neither produced stronger clinical outcomes than the lower dose.

The higher-dose groups showed:

• 14% slowing of decline on CDR-SB for the every-24-week regimen

• 9% slowing for the every-three-week regimen
  

The lack of a traditional dose-response pattern has become one of the main questions surrounding the programme.

RBC Capital Markets analyst Brian Abrahams said the results "leave more questions than answers", noting that tau reduction appeared greater at higher doses despite weaker clinical outcomes.

The analyst questioned whether the observed treatment effect would be considered sufficiently meaningful if larger Phase III studies produce more moderate results across different dosing groups.

Diranersen Successfully Reduced Tau Biomarkers

Despite uncertainty around dosing, Biogen highlighted evidence that diranersen successfully achieved its intended biological effect.

Across all treatment groups, the therapy reduced tau levels in cerebrospinal fluid by approximately 50% to 65% from baseline.

The company said these findings provide proof-of-concept that tau reduction can translate into clinical benefit.

Biogen’s head of development, Priya Singhal, said the CELIA results demonstrated that diranersen’s tau-reduction mechanism could represent an important new therapeutic approach if confirmed in Phase III trials.

Safety Profile Differs From Anti-Amyloid Alzheimer’s Therapies

The safety profile of diranersen was generally consistent with previous studies.

The most common adverse events reported in the CELIA trial included:

• Procedural pain

• Post-lumbar puncture syndrome

• Confusional state
  

Biogen said confusion-related events occurred shortly after dosing and resolved within approximately one week.

The company also highlighted that amyloid-related imaging abnormalities (ARIA), a key safety concern associated with anti-amyloid Alzheimer’s therapies, are not expected with diranersen because of its different mechanism targeting tau rather than amyloid.

What Diranersen Means for the Future of Alzheimer’s Treatment

The Alzheimer’s treatment landscape is rapidly evolving, with the first generation of disease-modifying therapies focused primarily on targeting amyloid plaques.

However, many researchers believe future treatment approaches may require addressing multiple disease pathways, including tau accumulation.

A successful tau-targeting therapy could potentially complement existing anti-amyloid medicines or provide an alternative treatment approach for patients where amyloid therapies are unsuitable.

The challenge for Biogen and Ionis will be demonstrating that diranersen’s cognitive benefits are consistent, clinically meaningful and scalable in Phase III development.

Summary

Biogen’s diranersen programme remains one of the most closely watched tau-targeting approaches in Alzheimer’s disease.

Phase II CELIA data showed the therapy slowed cognitive decline, with the strongest results observed at the lowest dose tested.

However, the unexpected dose-response pattern has raised questions about the optimal treatment strategy and whether the level of benefit can be replicated in larger trials.

As Biogen prepares for Phase III development, diranersen could become an important test of whether targeting tau can deliver the next major advance in Alzheimer’s disease treatment.

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