LONDON — Diranersen is an investigational antisense oligonucleotide developed by Biogen that targets microtubule-associated protein tau (MAPT) RNA. It is designed to reduce both intracellular and extracellular tau by binding to messenger RNA produced from the MAPT gene, leading to its degradation. The drug is administered via intrathecal injection into the fluid surrounding the spinal cord.

The CELIA trial was a randomized, placebo-controlled study evaluating diranersen in people with early Alzheimer's disease. It enrolled 416 participants with a mean age of about 68 years, approximately half of whom were women. All participants had either mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's dementia, with amyloid pathology confirmed by PET or cerebrospinal fluid (CSF) tests. The trial evaluated three dosing regimens over a 76-week treatment period: 60 mg every 24 weeks, 115 mg every 24 weeks, and 115 mg every 12 weeks.

The primary endpoint of the trial was to determine whether higher doses of diranersen provided greater clinical benefit as measured by Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. Diranersen did not meet this endpoint because it failed to demonstrate a clear dose response—meaning that higher doses did not consistently produce better outcomes than lower ones. However, every dose of diranersen slowed cognitive decline compared with placebo. The lowest dosage (60 mg every 24 weeks) performed best in slowing cognitive decline.

Participants receiving the 60-mg dose showed 26% less decline in CDR-SB scores at week 76 compared with those on placebo. They also experienced 42% less decline on the cognitive subscale of the Alzheimer's Disease Assessment Scale and 50% less decline in Mini-Mental State Examination scores. Functional scores on the Alzheimer's Disease Cooperative Study-Activities of Daily Living for Mild Cognitive Impairment, however, showed an inconsistent pattern across diranersen doses.

All doses of diranersen reduced tau PET signals and CSF tau levels. Participants taking the drug had mean reductions in CSF tau of 50% to 65% from baseline across all doses. A tau PET substudy confirmed decreases in tau signals in all evaluated brain regions for all doses of diranersen, indicating a consistent biomarker effect regardless of dosage.

Catherine Mummery, MBBS, PhD, of University College London, presented the data at the Alzheimer's Association International Conference in London. “Diranersen works upstream of tau deposition,” Mummery said. She added, “Effectively, it's a synthetic oligonucleotide that binds to the messenger RNA produced from the gene, leads to its degradation, and therefore reduces the production of tau across all forms of tau, including toxic elements, and across all compartments.” Mummery also noted, “However, there was consistency in treatment effect across all dose arms and consistent favorable trends seen across all secondary cognitive and composite measures.”

Laura Nisenbaum, PhD, interim chief science officer at the Alzheimer's Drug Discovery Foundation, described the findings as for the field. “These are the first data to show a tau-targeting drug producing both a robust biomarker effect and a signal of clinical benefit, and that is a meaningful step forward for the field,” she said. Nisenbaum also emphasized the complexity of interpreting the results, stating, “The fact that greater reduction of tau pathology at higher doses did not translate into greater clinical benefit tells us that the relationship between biomarker and clinical response is more complex than we initially assumed.” She added, “What the data make clear, however, is that we still have important work to do in understanding how much tau reduction is needed to produce a meaningful clinical effect,” and concluded, “Answering that question is essential not just for diranersen, but for the next generation of tau-targeting therapies.”

The safety profile of diranersen in the CELIA trial was consistent with prior findings. Most adverse events were mild or moderate and included procedural pain, post-lumbar puncture syndrome, and confusional state. Adverse events such as confusional state often resolved within a week.

The safety data were generally consistent with those observed in the earlier Phase Ib study. An ongoing long-term extension study continues to evaluate diranersen's long-term safety, tolerability, and durability.

Diranersen represents one of the first tau-targeting therapies to show both a robust reduction in tau biomarkers and a measurable signal of cognitive benefit in a controlled clinical trial. Its advancement to Phase III despite missing the primary endpoint underscores the scientific community’s interest in tau as a therapeutic target in Alzheimer’s disease, particularly in early-stage patients. The unexpected finding—that the lowest dose produced the strongest clinical effect—challenges assumptions about dose-response relationships in neurodegenerative drug development and may influence the design of future trials for similar agents. Biogen’s decision to proceed to Phase III reflects confidence that optimizing dosing and confirming durability of effect could yield a meaningful treatment for early Alzheimer’s.