Michael Irizarry, MD, MPH, on Tau NexGen Enrollment and E2814’s Potential in Alzheimer Disease

The senior VP of clinical research and deputy chief clinical officer of the neurology business group at Eisai spoke to the recent first enrollment in the Tau NexGen study of the investigational antimicrotubule binding region tau antibody, E2814.

Last week, Eisai announced that the first patient was enrolled in the phase 2/3 study of its investigational antimicrotubule binding region (MTBR) tau antibody, E2814, in individuals with dominantly inherited Alzheimer disease (DIAD).1 The study, dubbed the Tau NexGen study, is part of the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU), led by Washington University School of Medicine in St. Louis.

E2814 was selected as the first for the Tau NexGen study in March 2021 by the DIAN-TU, a collaboration between Eisai and University College London. The study will feature another agent as background antiamyloid therapy, Eisai and Boigen's lecanemab, which was submitted in a rolling biologics license application to the FDA in September 2021.2

To find out more about the Tau NexGen study and E2814 as the trial moves forward, NeurologyLive® inquired with Michael Irizarry, MD, MPH, senior VP of clinical research, and deputy chief clinical officer of the neurology business group, Eisai, who offered his insight for the clinical community.

NeurologyLive®: What background information should the clinical community know about E2814 ahead of this phase 2/3 trial?

Michael Irizarry, MD, MPH: E2814 is an antitau monoclonal antibody being investigated as a potential disease-modifying agent for the treatment of Alzheimer disease.

Pathologically, Alzheimer disease is characterized by the build-up of protein deposits in the brains of affected individuals. These deposits can form inside or outside of nerve cells. The deposits outside of the nerve cells are known as plaques, which are made up of a protein called ß-amyloid. The deposits inside the nerve cells, which are called neurofibrillary tangles, are made up of a protein called tau. It is now believed that in Alzheimer disease the tau “seeds” may be able to pass between nerve cells thus causing the disease to spread to unaffected regions of the brain and exacerbate the disease symptoms.

E2814 is a IgG1 antibody that targets microtubule-binding region (MTBR) of tau protein, which forms the major component of neurofibrillary tangles and is thought to be responsible for the spreading of tau seeds. It is hypothesized that by eliminating these seed competent forms of tau protein, E2814 may slow or stop progressive accumulation of neurofibrillary tangles and the associated decline in cognitive function that manifests in patients with AD.

Phase 1 clinical studies of E2814 are underway.

Is there anything about this trial design that is unique or will offer added perspective on efficacy or safety?

The DIAN-TU trial is the first trial aimed at identifying drugs to potentially prevent or slow Alzheimer disease in people with dominantly inherited mutation who are nearly certain to develop the disease due to genetic mutations. E2814 is the first antitau therapy to be evaluated in this trial.

The unique feature of this study design is inclusion of both asymptomatic and symptomatic subjects. Asymptomatic subjects are cognitively normal, prior to symptom onset of disease, and biologically characterized as accumulating tau seeds in the brain. Symptomatic subjects have early cognitive impairment and are characterized by neurofibrillary tangle spread. This approach will allow evaluation of E2814 treatment on inhibition of tau pathology leading to delay in onset or delay in progression of cognitive decline in subjects representing the continuum of AD from asymptomatic to early symptomatic stages.

The trial will also include Eisai’s investigational lecanemab as a background antiamyloid therapy. Evidence suggests that antiamyloid therapy, while effective at removing amyloid plaque that predisposes tau pathology and slows tau tangle spread, may not completely arrest tau tangle spread. By staggering the drugs in this way, the researchers will be able to evaluate the effects of the antitau drug along before assessing the effects of the 2 drugs together.

The trial will include 3 arms, each testing antitau therapy targeting different mechanism of tau pathology, including small molecule drug that inhibits tau aggregation and genetic treatment that reduces the production of tau protein. The 3 arms of the trial will share placebo groups, thus maximizing the number of people receiving active treatment.

Could you offer details on the criteria for inclusion in the trial? What key exclusionary criteria are there?

The study will enroll subjects with confirmed mutations in PSEN1, APP, or PSEN2 gene that is associated with dominantly inherited Alzheimer disease (or DIAD). Subjects will be within –10 years to +10 years of the predicted or actual age at cognitive symptom onset. Asymptomatic subjects will be CDR [Clinical Dementia Rating Scale] of 0 and symptomatic subjects will be CDR of 0.5-1.0.

Subjects will be excluded if they have a major or unstable illness that would prevent trial participation or are unable to complete main study related testing. Exclusions include MRI contraindications, required anticoagulation therapy, and pregnancy. Participants who know they are mutation noncarriers are not eligible.

What implications could this have if the trial is successful?

This will be the first trial aimed at demonstrating proof of concept of antitau therapy in people with dominantly inherited Alzheimer disease. If successful, the trial may demonstrate that targeting tau accumulation in asymptomatic stage of the disease delays the onset of cognitive impairment, whereas inhibiting tau spread at the early symptomatic stage may slow cognitive decline. This trial may also confirm the effect of concurrent removal of amyloid plague by antiamyloid treatment and direct targeting of tau pathology by antitau treatment, and its impact on delaying symptom onset and slowing disease progression.

Transcript edited for clarity.

REFERENCE
1. First Subject Enrolled in Phase II/III Study of Eisai’s Anti-mtbr Tau Antibody e2814 for Dominantly Inherited Alzheimer’s Disease (Diad), Conducted by Dian-Tu. News release. Eisai. January 18, 2022. Accessed January 21, 2022. https://www.prnewswire.com/news-releases/first-subject-enrolled-in-phase-iiiii-study-of-eisais-anti-mtbr-tau-antibody-e2814-for-dominantly-inherited-alzheimers-disease-diad-conducted-by-dian-tu-301463234.html
2. Eisai Initiates Rolling Submission to the U.S. FDA for Biologics License Application of Lecanemab (ban2401) For Early Alzheimer’s Disease Under the Accelerated Approval Pathway. Eisai. News release. September 28, 2021. Accessed January 21, 2022. https://eisai.mediaroom.com/2021-09-27-Eisai-Initiates-Rolling-Submission-To-The-U-S-FDA-For-Biologics-License-Application-Of-Lecanemab-BAN2401-For-Early-Alzheimers-Disease-Under-The-Accelerated-Approval-Pathway