At the AD/PD 2022 International Conference on Alzheimer’s Disease (AD) and Parkinson’s Disease (PD), Eisai presented new data from its lecanemab clinical programme during a session on amyloid beta (Aβ)-targeting therapies in AD on 18 March. A key theme from this session was highlighting how lecanemab’s mechanism of action differs from other Aβ monoclonal antibodies (mAbs) such as Biogen and Eisai’s Aduhelm (aducanumab) and Roche’s gantenerumab, as well as promising new data linking changes across various AD biomarkers in response to treatment.

There are a variety of forms of Aβ in the brain: monomers, which are not toxic; insoluble fibrils, which can aggregate into plaques; and soluble protofibrils, which are the most toxic form of Aβ, causing acute synaptotoxicity and inducing neurodegenerative processes. While all three mAbs demonstrated low affinity for Aβ monomers, data presented at AD/PD 2022 showed that lecanemab had the greatest affinity for protofibrils, while aducanumab and gantenerumab showed preferential binding for fibrils.

Not only is Eisai hoping this unique binding profile will result in better clinical outcomes for AD patients receiving lecanemab, but also in an improved safety profile. A known side effect of amyloid-lowering therapies is the development of amyloid-related imaging abnormalities (ARIAs), including ARIA related to underlying vasogenic oedema (ARIA-E). It has been hypothesised that ARIA-E is caused by a relative preference of binding to fibrils and therefore, since lecanemab shows preferential protofibril over fibril binding, it may result in less ARIA-E compared to aducanumab and gantenerumab, giving it an advantageous safety profile.

Indeed, data presented from the Phase IIb trial of lecanemab (NCT01767311) showed a low incidence of ARIA overall, with around 10% ARIA-E occurrence in patients receiving the highest dose of lecanemab biweekly. Most ARIA that did occur was asymptomatic, and when symptoms were present, around 90% were mild or moderate in severity. In addition, there was no sudden increase in ARIA in patients who enrolled in the open-label extension study when restarting treatment with lecanemab following a period of time without therapy.

During the same session, Eisai presented new biomarker results from the Phase II study. The data showed that lecanemab treatment resulted in a dose-dependent change in both central and peripheral amyloid and phosphorylated tau (p-tau) biomarkers. These biomarkers continued to be monitored after treatment was discontinued at the end of the trial period, which showed that the biomarkers gradually return to levels seen pre-treatment.

Eisai is now looking to use peripheral biomarkers to investigate long-term maintenance dosing of lecanemab beyond the 18-month placebo-controlled period of the Phase IIb trial as part of the ongoing open-label extension trial. Patients who have previously received lecanemab for 18 months or longer will switch from the biweekly dosing schedule to either once every four weeks or once every 12 weeks, and peripheral biomarkers will be measured to see how this new schedule affects their levels over time. This will provide a valuable assessment of what long-term maintenance treatment using lecanemab could look like in the future.

Interestingly, on 14 March, prior to the start of the AD/PD 2022 conference, Biogen and Eisai announced that they had amended their collaboration agreement regarding Aduhelm. From next year, Eisai will no longer share the global profits and losses from Aduhelm, instead receiving a tiered royalty based on net sales of the drug. In addition, Biogen will now have the sole decision making and commercialisation rights to Aduhelm worldwide. These collaboration changes, along with the themes of Eisai’s presentations at the AD/PD 2022 conference, indicate Eisai may be distancing itself from Aduhelm, whose approval and launch has been controversial, to instead fully focus on advancing lecanemab, which it may believe to be the more promising anti-Aβ candidate.