Phase 2/3 Study of Tau-Targeting Agent E2814 in Alzheimer Disease Enrolls First Patient

Michael Irizarry, MD, MPH

According to an announcement, the first patient has been enrolled in the phase 2/3 Tau NexGen study, which will evaluate the effect of Eisai’s investigational anti-microtubule bind region (MTBR) tau antibody E2814 in dominantly inherited Alzheimer disease (DIAD).¹

Announced in March 2021, E2814 became the first investigational antitau drug selected by the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) to be in its next-generation program, which will evaluate 3 antitau drugs in clinical studies. Led by investigators at Washington University School of Medicine in St. Louis, the study aims to determine whether such drugs affect tau phosphorylation, tau tangles, and their damage caused, thereby slowing or stopping the progress of AD.

Tau NexGen, originally developed from a research collaboration between Eisai and University College London, will include patients who are both presymptomatic and symptomatic, who have an AD-causing gene mutation. In November 2021, the clinical trial was amended to include the company’s investigational antiamyloid-ß (Aß) protofibril antibody lecanemab, as the background antiamyloid therapy, a decision that was made off increasing evidence that the drug showed it can reduce biomarkers of AD.

"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," Michael Irizarry, MD, MPH, senior VP of clinical research, and deputy chief clinical officer of the neurology business group, Eisai, told NeurologyLive^®. "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."

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Symptomatic participants in the study will receive lecanemab for 6 months before being randomly assigned to also receive E2814 or placebo. The company noted that, "since amyloid plaques accumulate before tau tangles in AD, this study design allows the researchers to assess whether amyloid removal clears the way for the anti-tau drug to function most effectively."

By randomly assigning presymptomatic patients to either E2814 or placebo for 1 year prior to lecanemab, investigators will be able to tell the true effect of the anti-tau drug. If at 2 years into treatment, both primary and secondary end points are positive, the study will be extended for an additional 2 years to evaluate its effects on cognitive decline and tau pathology.

When asked about the possible implications of this first DIAD-focused proof of concept antitau trial, if successful, Irizarry told NeurologyLive^®, "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."

E2814 is a humanized, monoclonal immunoglobulin antibody that recognizes an HVPGG epitope in the MTBR domain near the mid-domain of tau and is developed as a disease-modifying agent for tauopathies including sporadic AD. It is intended to bind extracellular tau, prevent cell-to-cell propagation of pathogenic species, and mediate clearance by microglia.

Eisai completed a phase 1 study evaluating the safety and tolerability of a single intravenous infusion of E2814 in healthy adults in August 2020, with the results presented at the 2020 Clinical Trials on Alzheimer Disease (CTAD) conference. Investigators evaluated 3-mg/kg, 10-mg/kg, and 30-mg/kg doses of the drug, with secondary outcomes that included serum and cerebrospinal fluid pharmacokinetics (PK) and immunogenicity.²

After the 4-month follow-up, treatment resulted in no significant drug-related clinical changes or dose-limiting events. Headache, nausea, and vomiting were the most reported side effects related to the drug, and 1 participant in the 30-mg/kg group had elevated C-reactive protein 2-3 days after receiving study drug, which produced no symptoms and returned to baseline. PK results indicated there was a dose-related increase in serum and CSF exposures. Additionally, the median time to maximum E2814 concentrations in serum was 1.5 to 2 hours.²

Secondary peaks were observed in the individual PK profiles, particularly during the terminal disposition phase. The anti-tau agent presented a large volume of distribution of 36 L, a clearance of 0.06 L/hour, and a half-life of 20 days. These CSF concentrations produced by the study drug remained elevated for 24 hours up to the last time-point of 672 hours (Day 29). The target engagement analysis between E2814 and MTBR-tau suggested a dose-related increase that was sustained for up to Day 29.²

E2814 was originally discovered in the lab of Rohan de Silva, MSc, DPhil, who is currently a professor of molecular neuroscience at the University of College London. Rohan de Silva senior authored a 2020 paper that described the preclinical generation and characterization of the antitau agent, which led to its proposal for clinical development. He and his colleagues concluded that E2814 bounds to different types of tau filaments that was shown by immunogold labelling and recognized pathological tau structures by immunohistochemical staining. Additionally, tau fragments that contained HVPGG epitopes were also found to be elevated in AD brains compared to progressive supranuclear palsy or control.³

REFERENCES

1. First subject enrolled in phase 2/3 study of Eisai’s anti-MTBR tau antibody E2814 for dominantly inherited Alzheimer 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. Aceves P, Giroux M, Boyd P, et al. A phase 1, first-in-human, single ascending dose study of the novel anti-tau therapeutic antibody E2814 in healthy volunteers. Presented at 2020 Clinical Trials in Alzheimer Disease annual meeting. Poster LB23.

3. Roberts M, Sevastou I, Imaizumi Y, et al. Pre-clinical characterization of E2814, a high-affinity antibody targeting the microtubule-binding repeat domain of tau for passive immunotherapy in Alzheimer disease. Acta Neuropathol Commun. 2020;8(13). doi:10.1186/s40478-020-0884-2