Ionis and Biogen Report Positive Phase 2 Results for Diranersen in Early Alzheimer’s Disease, Supporting Advancement to Phase 3
Ionis Pharmaceuticals, Inc. has announced that its long-standing collaboration partner, Biogen, presented new data from the Phase 2 CELIA clinical trial evaluating diranersen, an investigational antisense oligonucleotide (ASO) therapy designed to target the tau protein in individuals with early Alzheimer’s disease. The findings were presented at the Alzheimer’s Association International Conference (AAIC) 2026, providing additional evidence that the therapy may slow clinical disease progression while significantly reducing biomarkers associated with Alzheimer’s pathology.
The newly released data build upon previously reported topline results and provide what the companies describe as Phase 2 proof of concept for diranersen’s tau-directed mechanism of action. The study demonstrated meaningful improvements across multiple measures of cognition and daily functioning, alongside substantial reductions in cerebrospinal fluid (CSF) tau levels and brain tau pathology measured through positron emission tomography (PET) imaging.
Based on the growing body of evidence generated from both the Phase 1b and Phase 2 clinical programs, Biogen has announced plans to advance diranersen into confirmatory Phase 3 clinical development, marking a significant milestone for one of the industry’s leading tau-targeting therapeutic candidates.
Advancing a New Approach to Alzheimer’s Disease
Alzheimer’s disease remains the most common cause of dementia worldwide and continues to represent one of medicine’s greatest unmet challenges. While recent therapeutic advances have primarily focused on reducing amyloid-beta plaques in the brain, increasing scientific evidence suggests that abnormal accumulation of the tau protein plays a central role in neuronal degeneration and cognitive decline.
Tau proteins normally help stabilize the internal structure of nerve cells. In Alzheimer’s disease, however, abnormal chemical changes cause tau proteins to become misfolded and aggregate into neurofibrillary tangles. These tangles disrupt communication between neurons, contribute to cell death, and closely correlate with worsening cognitive impairment.
Diranersen has been specifically designed to address this process.
Unlike monoclonal antibodies that target extracellular proteins, diranersen is an antisense oligonucleotide that works by reducing production of tau protein at the messenger RNA level. By lowering the amount of tau produced within neurons, researchers hope to slow or prevent the progressive neurodegeneration that characterizes Alzheimer’s disease.
Ionis Highlights Progress of RNA-Based Therapeutics
Ionis Pharmaceuticals discovered diranersen using its RNA-targeted drug discovery platform before partnering with Biogen for continued clinical development.
Holly Kordasiewicz, Ph.D., Executive Vice President and Chief Development Officer at Ionis Pharmaceuticals, said the latest findings reinforce both the therapeutic potential of tau reduction and the broader capabilities of antisense technology.
“The CELIA data presented at AAIC provide important new insights into the potential of diranersen to markedly lower all forms of tau and meaningfully improve outcomes in early Alzheimer’s disease,” Kordasiewicz said.
She added that Ionis is proud to have discovered the investigational therapy and continues to support Biogen as the program advances toward Phase 3 development.
According to Kordasiewicz, the progress achieved with diranersen reflects the strength of Ionis’ RNA-targeted platform and the company’s extensive experience developing innovative therapies for complex neurological disorders.
Encouraging Clinical Benefits Across Multiple Endpoints
The Phase 2 CELIA study evaluated several dosing regimens of diranersen administered intrathecally and assessed patients over an 18-month treatment period.
Across all evaluated doses, investigators observed evidence of clinical benefit using multiple established measures of cognitive performance, functional ability, and overall disease progression.
Among the prespecified secondary endpoints were:
- Clinical Dementia Rating–Sum of Boxes (CDR-SB)
- Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog13)
- Mini-Mental State Examination (MMSE)
- Modified Integrated Alzheimer’s Disease Rating Scale (iADRS)
- Alzheimer’s Disease Composite Score (ADCOMS)
These assessments collectively measure memory, thinking ability, daily functioning, and overall progression of Alzheimer’s disease.
Strongest Response with 60 mg Every Six Months
The most favorable clinical outcomes were observed among participants receiving 60 mg of diranersen every six months.
This treatment group included 60 participants and was compared with 115 participants receiving placebo.
At 18 months, the therapy demonstrated:
- 26% slowing of clinical decline on CDR-SB, corresponding to a difference of 0.54 points
- 42% slowing on ADAS-Cog13
- 50% slowing on MMSE
- 30% slowing on modified iADRS
- 23% slowing on ADCOMS
According to Biogen, the majority of these differences reached nominal statistical significance compared with placebo.
These findings suggest that reducing tau production may translate into measurable improvements across several dimensions of Alzheimer’s disease progression.
Benefits Observed Across Additional Dose Groups
Clinical improvements were not limited to a single dosing schedule.
Participants receiving 115 mg every six months also demonstrated favorable outcomes relative to placebo.
This regimen produced:
- 14% slowing of decline on CDR-SB
- 32% improvement on ADAS-Cog13
- 34% slowing on MMSE
- 29% slowing on modified iADRS
- 21% slowing on ADCOMS
A third treatment arm receiving 115 mg every three months likewise demonstrated measurable benefit.
Compared with placebo, this regimen showed:
- 9% slowing on CDR-SB
- 29% slowing on ADAS-Cog13
- 38% slowing on MMSE
- 18% slowing on modified iADRS
- 7% slowing on ADCOMS
Although the magnitude of benefit varied between dose groups, investigators reported evidence of efficacy across all studied regimens.
Primary Endpoint Not Achieved
Despite encouraging clinical outcomes across numerous secondary endpoints, the CELIA study did not meet its primary endpoint.
The trial had been specifically designed to determine whether increasing the dose of diranersen would produce progressively greater improvements on the CDR-SB scale after 18 months.
Researchers did not observe the expected dose-response relationship, meaning higher doses did not consistently outperform lower doses.
As previously reported, this resulted in the study formally missing its predefined primary endpoint.
Nevertheless, the overall collection of efficacy data, together with biomarker findings and safety results, provided sufficient evidence for Biogen to continue advancing the program into Phase 3 development.
Robust Biomarker Evidence Supports Mechanism
One of the most significant aspects of the CELIA study involved evaluation of biological markers demonstrating whether diranersen successfully engaged its intended target.
Across every treatment group, investigators observed substantial reductions in total tau protein within cerebrospinal fluid.
Mean reductions ranged between 50% and 65% from baseline, confirming strong suppression of tau production.
Researchers also conducted a tau PET imaging substudy involving 131 participants.
Brain imaging demonstrated reductions in tau pathology across all evaluated brain regions for every studied dose of diranersen.
According to the companies, diranersen is the first tau-directed therapy to demonstrate reductions in both cerebrospinal fluid total tau and brain tau accumulation measured by PET imaging across all evaluated doses in a Phase 2 clinical study.
These biomarker findings provide strong support for the drug’s proposed mechanism of action and reinforce confidence that the therapy is effectively targeting one of Alzheimer’s key pathological processes.
Favorable Safety Profile
The safety findings from CELIA were generally consistent with previous studies of diranersen.
Most participants who experienced adverse events reported events that were:
- Mild or moderate in severity
- Non-serious
- Not associated with treatment discontinuation
- Not responsible for withdrawal from the study
The most commonly reported adverse events included:
- Procedural pain
- Post-lumbar puncture syndrome
- Confusional state
Investigators noted that episodes of confusional state generally occurred within several days following dosing and typically resolved within approximately one week.
Importantly, more than 90% of participants who completed the placebo-controlled portion of the study chose to continue into the ongoing long-term extension study, suggesting strong participant willingness to remain on therapy.
No Evidence of ARIA
Unlike amyloid-targeting therapies, diranersen is not expected to produce amyloid-related imaging abnormalities (ARIA), a potentially serious side effect involving brain swelling or microhemorrhages.
Because diranersen specifically targets tau rather than amyloid plaques, researchers anticipated that ARIA would not occur.
The CELIA results were consistent with that expectation, with no unexpected ARIA findings reported during the study.
This distinction could represent an important clinical advantage if future studies continue to demonstrate favorable efficacy and safety.
Representative Early Alzheimer’s Population
The Phase 2 trial enrolled participants representative of patients commonly diagnosed during the early stages of Alzheimer’s disease.
Baseline characteristics were generally balanced across treatment groups.
Among enrolled participants:
- Mean age was approximately 68 years
- 51% were women
- 60% had mild cognitive impairment
- 40% had mild Alzheimer’s disease dementia
Approximately 69% of participants carried at least one ApoE4 genetic variant, a well-established risk factor for Alzheimer’s disease.
Among these individuals, approximately 23% were ApoE4 homozygotes, representing patients with particularly elevated genetic risk.
The encouraging combination of clinical improvements, robust biomarker reductions, and favorable safety findings has positioned diranersen as one of the most advanced investigational therapies targeting tau biology in Alzheimer’s disease.
Biogen plans to initiate confirmatory Phase 3 clinical trials to further evaluate whether reducing tau production can meaningfully slow disease progression in a larger patient population. Meanwhile, researchers will continue analyzing data from the CELIA trial and its ongoing long-term extension study, with additional findings expected to be presented at future scientific meetings.
As the Alzheimer’s treatment landscape continues to evolve beyond amyloid-targeting approaches, diranersen represents a promising RNA-based strategy aimed at addressing another fundamental driver of neurodegeneration. If future Phase 3 studies confirm the benefits observed in Phase 2, the therapy could become an important addition to the growing arsenal of disease-modifying treatments for patients living with early Alzheimer’s disease.
About diranersen (IONIS-MAPTrx/BIIB080)
Diranersen (IONIS-MAPTrx/BIIB080) is an investigational antisense oligonucleotide (ASO) therapy designed to target microtubule-associated protein tau (MAPT) mRNA to reduce the production of tau protein. Unlike many investigational approaches that have focused on targeting extracellular tau, diranersen is designed to reduce both intracellular and extracellular tau.
Diranersen is being investigated as a potential treatment for early Alzheimer’s disease. In 2025, the U.S. Food and Drug Administration (FDA) granted Fast Track designation to diranersen for the treatment of Alzheimer’s disease.
In December 2019, Biogen exercised a license option with Ionis Pharmaceuticals and obtained a worldwide, exclusive, royalty-bearing license to develop and commercialize diranersen. Diranersen was discovered by Ionis.
About the CELIA Study
CELIA is a global Phase 2 randomized, double-blind, placebo-controlled, dose-ranging study evaluating the efficacy, safety, and tolerability of diranersen in individuals with early Alzheimer’s disease. The study enrolled 416 participants with mild cognitive impairment due to Alzheimer’s disease or mild Alzheimer’s disease dementia. All participants enrolled in CELIA had not previously received anti-amyloid therapy.
The study evaluated three doses of diranersen administered intrathecally over an 18-month placebo-controlled treatment period: 60 mg every six months, 115 mg every six months, and 115 mg every three months.
The primary endpoint of CELIA was assessment of dose response for change from baseline on the Clinical Dementia Rating–Sum of Boxes (CDR-SB) at Week 76. Secondary and exploratory endpoints included additional clinical, biomarker, and imaging measures, including cerebrospinal fluid tau biomarkers and tau positron emission tomography (PET). Additional information on the study design is available in the ClinicalTrials.gov listing for the CELIA study.
An ongoing long-term extension (LTE) study is continuing to evaluate the long-term safety, tolerability, and durability of diranersen’s clinical benefit in early Alzheimer’s disease.
About Ionis Neurology
Ionis has been at the forefront of discovering and developing leading neurological disease medicines, including SPINRAZA® (nusinersen), the first approved treatment for spinal muscular atrophy, WAINUA® (eplontersen), a medicine to treat hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN), and QALSODY® (tofersen) for SOD1-ALS.
The clinical-stage portfolio includes 13 investigational medicines, of which six are wholly owned by Ionis. Ionis’ investigational portfolio includes medicines for which there are few or no disease modifying treatments, such as rare diseases including Alexander disease, Angelman syndrome, prion disease, multiple system atrophy and Huntington’s disease, as well as more common conditions such as Alzheimer’s disease.
About Ionis Pharmaceuticals, Inc.
For more than three decades, Ionis has invented medicines that bring better futures to people with serious diseases. Ionis currently has marketed medicines and a leading pipeline in neurology, cardiometabolic disease and select areas of high patient need. As the pioneer in RNA-targeted medicines, Ionis continues to drive innovation in RNA therapies in addition to advancing new approaches in gene editing. A deep understanding of disease biology and industry-leading technology propels our work, coupled with a passion and urgency to deliver life-changing advances for patients.