Novel Alzheimer’s Drug Targeting Tau Shows Promise in Mid-Stage Trial

The tau-targeting agent diranersen did not meet the primary endpoint of the phase II CELIA trial, but that isn’t stopping the drug from moving forward.

The placebo-controlled study is the first to show a cognitive benefit and a reduction in tau pathology in people with early Alzheimer’s disease, reported Catherine Mummery, MBBS, PhD, of University College London, in a presentation at the Alzheimer’s Association International Conference (AAIC).

All diranersen doses tested in CELIA reduced tau PET signals and cerebrospinal fluid (CSF) tau in people with mild cognitive impairment or mild dementia due to Alzheimer’s disease, Mummery said. Every dose slowed cognitive decline.

Because the lowest dosage performed best, the drug missed its primary endpoint of demonstrating a clear dose response.

“However, there was consistency in treatment effect across all dose arms and consistent favorable trends seen across all secondary cognitive and composite measures,” Mummery said. Based on that, diranersen will advance to a phase III trial.

“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,” observed Laura Nisenbaum, PhD, interim chief science officer at the Alzheimer’s Drug Discovery Foundation in New York City.

“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,” Nisenbaum told MedPage Today.

“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 pointed out. “Answering that question is essential not just for diranersen, but for the next generation of tau-targeting therapies.”

The Alzheimer’s drug pipeline is entering a new phase, with tau-targeted trials gaining momentum after the recent approvals of anti-amyloid agents lecanemab (Leqembi) and donanemab (Kisunla). An AAIC session reviewing the treatment landscape identified 14 tau-targeting approaches in development, led primarily by small molecules, monoclonal antibodies, and vaccines. Other researchers reported encouraging findings showing that the investigational therapy etalanetug reduced plasma levels of eMTBR-tau243, a marker closely tied to Alzheimer’s tau tangle pathology.

Diranersen is an investigational antisense oligonucleotide targeting microtubule-associated protein tau (MAPT) RNA. It is designed to reduce both intracellular and extracellular tau.

“Diranersen works upstream of tau deposition,” Mummery said. “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.”

In a phase Ib study, diranersen was well tolerated and demonstrated target engagement, she noted.

The randomized CELIA trial 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 study included 416 participants with a mean age of about 68 years; approximately half were women.

Participants met criteria for mild cognitive impairment due to Alzheimer’s disease or mild Alzheimer’s dementia. All had amyloid pathology confirmed by PET or CSF tests.

The primary goal of this study was to determine whether higher doses of diranersen could provide greater clinical benefit from baseline as measured by Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. All doses showed less decline in CDR-SB scores compared with placebo at week 76, with the strongest effect seen with 60 mg every 24 weeks.

The difference in CDR-SB scores was similar to that seen in phase III trials of lecanemab and donanemab. Compared with placebo, patients on the 60-mg dose had 26% less decline in CDR-SB scores, 42% less decline in scores on the cognitive subscale of the Alzheimer’s Disease Assessment Scale, and 50% less decline in Mini-Mental State Examination scores.

However, functional scores on the Alzheimer’s Disease Cooperative Study-Activities of Daily Living for Mild Cognitive Impairment showed an inconsistent pattern across diranersen doses.

Participants taking diranersen had mean reductions in CSF tau of 50% to 65% from baseline across doses. A tau PET substudy showed decreases in all evaluated brain regions for all doses.

Most adverse events were mild or moderate and included procedural pain, post-lumbar puncture syndrome, and confusional state, which often resolved within a week.

Safety profiles were generally consistent with the phase Ib diranersen study, Mummery noted. An ongoing long-term extension study is continuing to evaluate the drug’s long-term safety, tolerability, and durability.

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