Ionis and Biogen Report Promising Phase 2 Results for Tau-Targeting Alzheimer’s Therapy Diranersen
Ionis Pharmaceuticals and Biogen have announced encouraging topline findings from the Phase 2 CELIA clinical study evaluating diranersen (IONIS-MAPTRx/BIIB080), an investigational antisense oligonucleotide (ASO) therapy designed to target tau protein in patients with early Alzheimer’s disease. The results mark an important milestone in Alzheimer’s research, providing what the companies describe as the first evidence from a randomized Phase 2 study showing that a tau-directed therapy can produce both strong biomarker improvements and measurable cognitive benefits in individuals with early-stage disease.
The findings from CELIA are significant because Alzheimer’s disease research has long focused heavily on amyloid-beta plaques, while therapies directly targeting tau pathology have faced major scientific and clinical challenges. Tau accumulation inside neurons is considered one of the key drivers of neurodegeneration and cognitive decline in Alzheimer’s disease. By demonstrating both biological activity and clinical signals in a controlled study, diranersen may represent a meaningful advancement in the search for more effective disease-modifying therapies.
According to the companies, pre-specified analyses of cognitive endpoints showed slowing of clinical decline across all doses evaluated in the study. The strongest effects appeared in participants receiving the lowest dose regimen of diranersen, consisting of 60 mg administered once every 24 weeks. Researchers also observed substantial reductions in cerebrospinal fluid (CSF) tau levels as well as reductions in tau pathology measured through positron emission tomography (PET) imaging. Importantly, these biomarker reductions were sustained throughout the treatment period, suggesting a durable biological effect on tau production and accumulation.
Despite these encouraging findings, the study did not achieve its primary endpoint, which evaluated dose response for change from baseline on the Clinical Dementia Rating–Sum of Boxes (CDR-SB) scale at Week 76. The CDR-SB is a widely used assessment tool for measuring cognitive and functional decline in Alzheimer’s disease. Although the formal primary endpoint was not met, the broader dataset generated optimism among investigators and company executives because of the consistency between biomarker reductions and observed cognitive trends.
Holly Kordasiewicz, Ph.D., executive vice president and chief development officer at Ionis Pharmaceuticals, emphasized the importance of the findings for both the company and the broader Alzheimer’s research field. She stated that the topline results reinforce the potential value of targeting tau as a strategy capable of meaningfully improving outcomes for patients with early Alzheimer’s disease.
Kordasiewicz noted that the results further validate Ionis’ growing neurology pipeline, which currently includes 13 medicines in clinical development, six of which are wholly owned by the company. She also highlighted the role Ionis played in discovering diranersen and expressed appreciation to the patients, caregivers, researchers, and clinical teams involved in the study.
The CELIA trial has attracted significant attention within the neuroscience and Alzheimer’s communities because it evaluates a first-in-class ASO therapy specifically designed to reduce production of tau protein at its source. Antisense oligonucleotides are short synthetic strands of nucleic acids engineered to selectively bind RNA molecules and alter protein production. This therapeutic approach has already shown success in several neurological diseases, including spinal muscular atrophy and hereditary transthyretin amyloidosis.
Diranersen works by targeting messenger RNA associated with tau production, thereby reducing the formation of both intracellular and extracellular tau proteins. Scientists believe this mechanism may offer advantages over some previous approaches that focused primarily on extracellular tau aggregates after they had already accumulated.
In healthy brains, tau plays an essential role in stabilizing microtubules and supporting normal neuronal function. However, in Alzheimer’s disease, tau proteins can become abnormally modified and aggregate into neurofibrillary tangles inside neurons. These tangles disrupt cellular function, contribute to neuronal death, and are strongly associated with worsening cognitive impairment and disease progression.
Because tau pathology correlates more closely with cognitive decline than amyloid plaque burden, many researchers believe effective tau-directed therapies could become critical components of future Alzheimer’s treatment strategies. Nevertheless, translating that biological rationale into successful clinical outcomes has proven difficult, making the CELIA data especially noteworthy.
Priya Singhal, M.D., M.P.H., executive vice president and head of development at Biogen, described the results as unprecedented for a tau-directed therapy studied in a randomized early Alzheimer’s disease trial. She said the convergence of efficacy signals and biomarker improvements provides confidence to move diranersen into registrational-stage development.
Singhal added that Biogen plans to engage with regulatory authorities and the broader Alzheimer’s community to discuss the next steps for the program. She also acknowledged the contributions of study participants, caregivers, investigators, and research staff who supported the pioneering trial.
Safety findings from CELIA were generally consistent with observations from earlier clinical studies of diranersen. The therapy demonstrated a safety and tolerability profile that aligned with previous Phase 1b results and the known characteristics of the investigational treatment. The incidence of adverse events was broadly similar across the various dose groups studied, although the highest dose cohort experienced a greater frequency of serious adverse events.
The companies did not provide detailed numerical efficacy or safety data in the topline announcement, indicating that additional analyses are ongoing. More comprehensive findings are expected to be presented at future scientific conferences and potentially published in peer-reviewed medical journals.
The results emerge at a time of renewed momentum in Alzheimer’s drug development. In recent years, regulatory approvals for amyloid-targeting therapies have helped demonstrate that disease-modifying treatment approaches may be feasible. However, many experts believe that combination approaches targeting multiple pathological pathways, including both amyloid and tau, may ultimately be necessary to produce substantial and sustained clinical benefit.
The development of diranersen also highlights the growing importance of RNA-targeting therapeutics in neurology. Ionis has been a pioneer in antisense technology for decades, and its collaborations with companies such as Biogen have helped advance several neurological treatment programs. Success in Alzheimer’s disease would represent one of the most significant achievements yet for ASO-based medicine because of the complexity and scale of the disease.
Alzheimer’s disease remains one of the largest unmet medical needs globally, affecting millions of individuals and placing enormous emotional and economic burdens on families and healthcare systems. Current therapies provide limited symptomatic relief or modest slowing of progression, underscoring the urgent demand for innovative treatments capable of altering the underlying biology of the disease.
While additional clinical evaluation will be necessary to confirm the findings from CELIA, the topline results have generated optimism among researchers and industry observers who have long sought effective tau-targeting therapies. If future studies validate these early signals, diranersen could become an important addition to the evolving landscape of Alzheimer’s disease treatment and potentially open a new chapter in neurodegenerative disease therapeutics.
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. Abnormal accumulation of tau in the brain is a hallmark of Alzheimer’s disease (AD) associated with neurodegeneration and cognitive decline.
Diranersen is being investigated as a potential treatment for early AD. In 2025, the U.S. Food and Drug Administration (FDA) granted Fast Track designation to diranersen for the treatment of AD.
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 (AD). The study enrolled 416 participants with mild cognitive impairment due to AD or mild AD dementia. All participants enrolled in CELIA had not previously received anti-amyloid therapy.
The study evaluated three doses of diranersen administered intrathecally over a 76-week placebo-controlled treatment period: 60 mg every 24 weeks, 115 mg every 24 weeks and 115 mg every 12 weeks.
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 CELIA 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 in early AD.
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 Angelman syndrome, prion disease, multiple system atrophy, Huntington’s disease and Alexander disease, as well as more common conditions such as Alzheimer’s disease.
About Ionis Pharmaceuticals, Inc.
For 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.
