Tau-Targeting Alzheimer’s Drug Shows Promise in Trial
A new experimental drug that targets a different brain protein than current treatments has shown promising results in slowing cognitive decline in early Alzheimer’s disease, according to data presented Tuesday at the Alzheimer’s Association International Conference (AAIC) in London. The drug, diranersen, developed by Biogen in partnership with Ionis Pharmaceuticals, targets the tau protein — a markedly different approach from existing therapies that focus on clearing amyloid plaques.
A New Frontier in Alzheimer’s Treatment
Alzheimer’s disease is characterized by two hallmark brain pathologies: amyloid plaques and tau tangles. For decades, drug development has focused almost exclusively on amyloid, leading to the approval of drugs like Leqembi (lecanemab) and Kisunla (donanemab), which modestly slow cognitive decline. However, many scientists believe amyloid buildup alone is insufficient to cause Alzheimer’s — it is the subsequent abnormal tau tangles that more closely correlate with cognitive symptoms.
Diranersen, an antisense oligonucleotide (ASO), works by instructing the tau-producing gene (MAPT) to produce less protein, reducing both normal and abnormal tau at its source. Unlike antibody-based approaches that target extracellular tau, ASOs reduce tau throughout the cell. The drug is administered via intrathecal injection — directly into the spinal fluid — to bypass the blood-brain barrier.
The CELIA Trial Results
The Phase 2 CELIA study enrolled 416 patients with mild cognitive impairment due to Alzheimer’s or mild Alzheimer’s disease. While the study missed its primary endpoint of demonstrating a statistically significant dose-response on the CDR-SB scale, the results have been hailed as a potential breakthrough.
At the lowest dose tested — 60 mg administered every six months — diranersen produced a 26% reduction in cognitive decline on the CDR-SB scale, comparable to the effect seen with amyloid-targeting drugs. The drug also demonstrated robust reductions in both cerebrospinal fluid total tau (50-65%) and brain tau pathology as measured by PET scans — a first for any tau-directed therapy.
“As a clinician, I am excited to see that we now can target successfully another core pathology of Alzheimer’s disease,” Dr. Szofia Bullain, vice president of Alzheimer’s disease and dementia clinical development at Biogen, told BioSpace ahead of the presentation.
Dr. Cath Mummery of University College London, who led the study, explained the mechanism: “If you lower tau production, you are lowering the amount of the abnormal tau that needs to be cleared by the microglia, by the clearance mechanism in the brain. And so you are enabling the normal clearance mechanism to have more capacity to clear the tau.”
Safety and Tolerability
Importantly, diranersen showed no signs of ARIA (amyloid-related imaging abnormalities) — brain inflammation that can affect recipients of anti-amyloid drugs. Side effects included injection site pain and a temporary state of confusion that could appear a few days after the shot and last about a week.
Expert Reactions
Independent experts expressed cautious optimism about the findings. “This is really quite promising if it were to hold up” in next-step testing, said Jessica Langbaum of the Banner Alzheimer’s Institute in Phoenix.
Dr. Reisa Sperling of Mass General Brigham added a note of measured enthusiasm: “This is early days. But I think it will reinvigorate interest and investment in lots of tau mechanisms, and the field needs that.”
Laura Nisenbaum, interim chief science officer at the Alzheimer’s Drug Discovery Foundation, called the results “the first signal that we might be able to move beyond amyloid.”
The Road Ahead
Biogen has announced plans to advance diranersen to a Phase 3 trial to confirm the drug’s benefit. The company has precedent for navigating unconventional regulatory pathways — both its Alzheimer’s drug Aduhelm and its ALS drug Qalsody received FDA approval despite missed endpoints, suggesting flexibility with ASO therapies supported by strong biomarker evidence.
Meanwhile, the broader tau-targeting landscape is expanding. The University of California, San Francisco, recently launched the Alzheimer’s Tau Platform trial, a first-of-its-kind study funded by the National Institutes of Health that will test anti-tau therapies both alone and in combination with existing amyloid treatments.
Implications for the Field
The CELIA results represent a potential paradigm shift in Alzheimer’s treatment. For the first time, a drug targeting tau has demonstrated cognitive benefits comparable to amyloid therapies, validating tau as a therapeutic target. If confirmed in Phase 3, diranersen could be used alone or in combination with amyloid-targeting drugs, potentially offering patients a more comprehensive approach to treating this devastating disease.
As Biogen’s head of development, Dr. Priya Singhal, put it: “These results are not by chance.” The question now is whether they will hold up in the larger trials to come.