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

Daranersen and the CELIA 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.

Study Findings

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.

Consistency Across Doses

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

Significance of Findings

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.

The data make clear, however, that there is still important work to do in understanding how much tau reduction is needed to produce a meaningful clinical effect, she noted.

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 initially assumed. Answering that question is essential not just for diranersen, but for the next generation of tau-targeting therapies.

The Evolving Treatment Landscape

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. Encouraging findings were also reported from other researchers demonstrating that the investigational therapy etalanetug reduced plasma levels of eMTBR-tau243, a marker closely tied to Alzheimer’s tau tangle pathology.

Mechanism of Diranersen

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, according to Mummery. Effectively, it’s a synthetic oligonucleotide that binds to the messenger RNA produced from the gene, leading to its degradation, and therefore reduces the production of tau across all forms, including toxic elements.

Clinical Trial Details

In a phase Ib study, diranersen was well tolerated and demonstrated target engagement, noted Mummery. The randomized CELIA trial evaluated three doses of diranersen administered intrathecally over a 76-week placebo-controlled treatment period. Participants met criteria for mild cognitive impairment due to Alzheimer’s disease or mild Alzheimer’s dementia, with amyloid pathology confirmed by PET or CSF tests.

The primary goal of this study was to determine whether higher doses could provide greater clinical benefit. All doses showed less decline in Clinical Dementia Rating-Sum of Boxes (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.

Adverse Events and Next Steps

Most adverse events were mild or moderate, including procedural pain and post-lumbar puncture syndrome. Safety profiles were generally consistent with the phase Ib study, and a long-term extension study is continuing to evaluate the drug’s long-term safety and tolerability.

Disclaimer

Esta información es para propósitos educativos y no debe considerarse como un consejo médico. Siempre consulte a un profesional de la salud para preguntas sobre condiciones médicas y tratamientos.

Fuente: https://www.medpagetoday.com/meetingcoverage/aaic/122186