The Tau Next Generation (Tau NexGen) clinical trial will now be evaluating an anti-amyloid antibody in addition to an anti-tau antibody as a potential treatment for early onset Alzheimer’s disease, according to a press release.

BioArctic and Eisai‘s investigational treatment lecanemab has been selected as the background anti-amyloid agent to be used for the first arm of the trial, the researchers announced.

Lecanemab was chosen by the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU), the network of scientists leading the trial, upon agreement with the U.S. Food and Drug Administration and the European Medicines Agency.  According to the DIAN-TU, there is a possibility this anti-amyloid beta protofibril antibody will be used for subsequent trial arms.

Each antibody will target either tau or amyloid protein, both of which accumulate into toxic clumps throughout the brain and are implicated in the neurodegeneration observed in Alzheimer’s.

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The Tau NexGen study was originally designed to focus on therapies that target the tau protein. However, increasing evidence has shown that targeting amyloid protein also can reduce biomarkers of Alzheimer’s.

“With growing evidence that removing amyloid plaques has biologically beneficial effects on amyloid and tau, we believe that targeting both Alzheimer’s disease pathologies — amyloid plaques and tau tangles — at the same time can provide the highest chance of success,” Randall J. Bateman, MD, director of DIAN-TU and a professor at Washington University, in Missouri, said in another press release.

The study is designed to evaluate the safety, tolerability, biomarker, and cognitive efficacy of these investigational therapies in patients with gene mutations that may cause the neurodegenerative disease — such as those seen in early onset Alzheimer’s.

Researchers will investigate whether treatment with these investigational therapies can slow the rate of disease progression and improve disease-related biomarkers in patients with this inherited form of early onset Alzheimer’s.

DIAN-TU had previously chosen Eisai’s anti-tau antibody E2814 as the first investigational therapy to be evaluated in the study.

Under the newly revised protocol, all participants will now receive lecanemab, while half also will receive E2814 and half the placebo. The timing of each therapy administration will depend on whether participants have started experiencing Alzheimer’s symptoms. Notably, those who are symptomatic will receive lecanemab for six months before receiving either E2814 or a placebo.

Presymptomatic participants will receive E2814 or a placebo for a year before being given lecanemab. This type of design will allow researchers to understand not only if clearing amyloid can improve the efficacy of an anti-tau antibody but also the effects of an anti-tau antibody alone versus in combination with an amyloid-targeting therapy.

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The trial is designed to have three arms, each one investigating a therapy that targets the tau protein and that works in different ways. E2814 specifically targets the spread of tau throughout the brain.

While the first arm will evaluate lecanemab and E2814, the other two arms will study other tau therapies that work differently, including those that inhibit tau aggregation, or clumping, or reduce its production. Future arms also may combine anti-amyloid therapies.

The trial’s primary endpoint is the slowing of tau accumulation in the brain in symptomatic patients. The secondary endpoint will be the evaluation of the therapies’ effect on the levels of a type of tau (phosphorylated tau 217) in the cerebrospinal fluid — the liquid that surrounds the brain and spinal cord — of presymptomatic patients.

If both primary and secondary endpoints are met, the trial will continue for an additional two years to assess whether these therapies can slow cognitive decline and if they have additional effects on tau buildup.