In Alzheimer’s disease soluble, toxic amyloid beta aggregates are believed to contribute to the neurodegenerative process. Lecanemab, a anti amyloid-beta protofibril antibody, selectively binds to these forms of amyloid beta and eliminates them. The antibody’s unique profile is highly selective for amyloid beta oligomers/protofibrils in the brain. BioArctic’s belief is that lecanemab’s unique binding profile is important and differentiates it from other amyloid beta antibodies.
Lecanemab is in clinical development as the company’s first immunotherapy developed with BioArctic’s patented technology. The project is based on research from Uppsala University, Sweden. BioArctic’s partner Eisai is responsible for the clinical development of lecanemab in Alzheimer’s disease. The confirmatory Phase 3 study, Clarity AD, with lecanemab in early Alzheimer’s disease is currently ongoing and Eisai expect to have the topline results by the end of September 2022.
The unique binding profile of lecanemab has been confirmed in data presented at several international congresses. All in all, the results strengthen BioArctic’s conviction that lecanemab ’s unique binding profile is important and that it differs from other amyloid beta antibodies. Professor Lars Lannfelt has presented details on the binding profile at the AAIC Conference (Alzheimer’s Association International Conference®) in July 2019 and at the CTAD conferences (Clinical Trials on Alzheimer’s Disease) in December 2019 and November 2021.
Clinical development of lecanemab in early Alzheimer’s disease
Eisai is conducting two global Phase 3 studies with lecanemab, one in patients with early Alzheimer’s disease (Clarity AD) and one in cognitively unimpaired individuals with intermediate or elevated amyloid levels in the brain who have not yet developed symptoms of Alzheimer’s disease (AHEAD 3-45).
Clarity AD is the pivotal and confirmatory Phase 3 study. It is based on the Phase 2b study with lecanemab in 856 patients with early Alzheimer’s disease which demonstrated dose dependent, clinically meaningful, and statistically significant effects of lecanemab on several clinical endpoints and on biomarkers and showed good tolerability.
Clarity AD is a global placebo-controlled, double-blind, parallel-group, randomized study in 1,795 patients with early Alzheimer’s disease i.e. mild cognitive impairment (MCI) due to Alzheimer’s disease or mild Alzheimer’s disease. Patients are allocated in a 1:1 ratio to receive intravenous infusion twice a month, either with placebo or with lecanemab 10 mg/kg. The primary endpoint is the change from baseline in the cognition and function scale Clinical Dementia Rating-Sum of Boxes (CDR-SB) at 18 months of treatment. Changes in the clinical scales AD composite score (ADCOMS) and AD Assessment Scale-Cognitive Subscale (ADAS-Cog) are key secondary endpoints together with brain amyloid levels as measured by amyloid-PET. According to Eisai, the aim is to obtain the primary endpoint data from the study by the end of September 2022 and thereafter apply for a full market approval.
An open-label extension study, without placebo control, with continued treatment with lecanemab with the highest study dose for all participants in the Phase 2b study is in progress. During 2020 Eisai presented data from the study showing that the patients who had previously received placebo in the Phase 2b study had rapidly and continually decreasing amyloid levels in the brain after three, six and twelve months of treatment with lecanemab. Additionally, with treatment with lecanemab less than 10 percent of patients experienced ARIA-E side effects, consistent with previously reported data. This picture was further strengthened in March 2021 when Eisai presented results showing that the effects of lecanemab on reducing amyloid in the brain on average persist for at least two years following discontinuation of treatment. At the same time, it was verified that when lecanemab is administered in a dose of 10 mg/kg every other week, amyloid levels in the brains of more than 80 percent of patients decreased to levels under those that define Alzheimer’s disease. These results were achieved in both the primary study and in the open-label extension study. In July 2021, Eisai presented data for the first time from a small cohort of participants in the open-label Phase 2b extension study. The results showed responses to treatment on clinical scales such as ADCOMS, CDR-SB and ADAS-Cog among patients with early Alzheimer’s disease who had been recently treated with lecanemab or previously treated with placebo. The data provided additional support for the efficacy results seen in the large placebo-controlled Phase 2b study.
Lecanemab has a unique binding profile that distinguishes it from other amyloid beta antibodies and its unique binding profile has been confirmed in laboratory analyses, which are ongoing in parallel with the clinical development program. BioArctic has an ongoing research collaboration with Eisai in order to further deepen the knowledge about the drug candidate lecanemab’s unique binding profile.
Lecanemab was selected by the Alzheimer’s Clinical Trials Consortium (ACTC) and Eisai to be evaluated in a second clinical Phase 3 program which aims to evaluate the effects of lecanemab on preclinical asymptomatic Alzheimer’s disease (AHEAD 3-45). The program, that was started 2020, include individuals that are at a very early stages of Alzheimer’s disease with a high risk of developing the disease. The program consists of two clinical sub-studies: A3 and A45. After a joint screening process, the participants are included in one of the randomized, double-blind and placebo-controlled sub-studies based on amyloid levels in the brains of the specific individuals. AHEAD 3-45 is a global program that is expected to include approximately 1,400 individuals.
In June 2021 lecanemab was granted Breakthrough Therapy designation, an FDA program intended to facilitate and accelerate the development and review of drugs for serious or life-threatening conditions. This status includes more intensive guidance from the FDA on an efficient development program and eligibility for rolling review and potentially priority review.
In September 2021, Eisai announced that the company had initiated a rolling application to the FDA for approval of lecanemab in early Alzheimer’s disease. The application for market approval, which was submitted for review under the Accelerated Approval Program, is based primarily on clinical, biomarker and safety data from the Phase 2b study of lecanemab in persons with early Alzheimer’s disease and confirmed Aβ pathology. Data from the open-label Phase 2b extension study and blinded safety data from Clarity AD will also be included to support the application for market approval.