New Analyses on Lecanemab Suggest Sustained Benefits Even After Discontinuation

Clinical Landscape

In Asia Pacific, the number of people suffering from dementia is set to triple from 23 million in 2015 to 71 million by 2050. Globally, the number of cases is estimated to reach 135 million by 2050, with more than half of them living in the Asia Pacific Region1.

Although there are different forms of dementia, Alzheimer’s Disease (AD) is the most common, accounting for 60-70% of global cases2. AD is a progressive neurodegenerative disease with pathophysiology involving extracellular beta-amyloid deposits (in neuritic plaques) and intracellular neurofibrillary tangles of abnormally phosphorylated tau proteins3. The accumulation of amyloid plaques and neurofibrillary tangles of tau protein triggers a cascade of events resulting in neuronal cell death, loss of neuronal synapses, and progressive neurotransmitter deficits, leading to the clinical symptoms of dementia3,4. 

Treatment Options 

Guidelines5 state that the primary goal of current medication treatment in AD is to delay the progression of cognitive symptoms or manage mood and behavioural-related symptoms. Disease-modifying treatments are currently the most investigated in AD drug development, including anti-amyloid beta (anti-Aβ) monoclonal antibodies (mAbs) which make up 15.4% and anti-tau mAbs making up 10.6% of the considered agents6.

MAbs Approval Status & Mechanism of Action

Anti-Aβ agents have been researched for at least 15 years7, and even though some evidence suggests that amyloid removal slows the progression of the disease8, the lack of clinical benefits has prevented marketing authorization, except for Biogen’s Aducanumab (Aduhelm)9 in July 202110 and Eisai and Biogen’s Lecanemab (Leqembi) under FDA’s accelerated approval pathway in January 202311. 

While Aβ can exist in different forms, including monomers (non-toxic) and insoluble fibrils which can aggregate into plaques, soluble protofibrils are the most toxic form of Aβ12. Soluble protofibrils can trigger acute synaptotoxicity and neurodegenerative processes. Compared to the other mAbs such as aducanumab or gantenerumab, lecanemab (Leqembi) had the highest binding to small and large soluble protofibrils, demonstrating the highest level of protofibril depletion efficiency as compared to the other mAbs12. 

Leqembi is currently indicated for the treatment of AD, for those with mild cognitive impairment or mild dementia stage of disease11 in the United States. 

New Analyses from Phase II Study 201 of Leqembi (Lecanemab)13,14

In the newest analysis released by Eisai and Biogen, AD patients who were administered Leqembi maintained the benefits even after discontinuation of the anti-Aβ mAb. Further analysis suggested that patients in the Leqembi group had slower disease progression even when off treatment for an average of two years. 

These patients were AD patients who had stopped taking Leqembi after 18 months in the mid-stage phase II trial (Study 201). They resumed treatment during the open-label extension (OLE) portion after a gap period of around two years. The analysis compared these patients to a group that received a placebo.

According to researchers, the difference in disease progression rates between the Leqembi and placebo group were maintained during the gap period, keeping the same absolute separation obtained at the end of treatment. However, no further added benefits were observed while off-treatment. Researchers also found that brain amyloid reaccumulated slightly (average increase of about 6 centiloids) during the gap period, while soluble Aβ42/40 decreased by 47% and plasma p-tau181 levels increased by 24%.

Existing Literature 

Previous analysis of Study 201 has demonstrated that the Leqembi group exhibited a reduction in amyloid plaque and a consistent decline of clinical symptoms, as compared to the placebo group. The current ongoing phase III trial (Clarity AD) has shown reduced AD markers and lesser decline in cognition and function measures, as compared to placebo at 18 months15.

However, in the Clarity AD trial, Leqembi was associated with adverse events in such as infusion-related reactions (26.4% of participants in Leqembi group), amyloid-related imaging abnormalities (ARIA) with cerebral microhemorrhages, cerebral microhemorrhages or superficial siderosis (17.3%), brain oedema (ARIA-E) (12.6%), headache (11.1%) and falls (10.4%)15. An open-label extension of the Clarity AD trial is currently underway to study the safety and efficacy data of Leqembi beyond 18 months15.

In individuals with AD, Lecanemab demonstrated reduced amyloid levels that translated to a reduction in clinical decline, with sustained effects even after discontinuation. However, further data is necessary to evaluate its safety before its potential eventual implementation into clinical practice. 

References

1. Dementia warning for the Asia-Pacific region. Lancet Neurol. 2015 Jan;14(1):1. doi: 10.1016/S1474-4422(14)70312-6. PMID: 25496878.
2. Dementia (2023) World Health Organization. World Health Organization. Available at: https://www.who.int/news-room/fact-sheets/detail/dementia#:~:text=Alzheimer%20disease%20is%20the%20most%20common%20form%20and%20may,60%E2%80%9370%25%20of%20cases Accessed: April 18, 2023
3. Huang, J. (2023) Alzheimer disease – neurologic disorders, MSD Manual Professional Edition. MSD Manuals. Available at: https://www.msdmanuals.com/en-sg/professional/neurologic-disorders/delirium-and-dementia/alzheimer-disease Accessed: April 18, 2023
4. Jenny Lam, Jakub Hlávka, Soeren Mattke The Potential Emergence of Disease-Modifying Treatments for Alzheimer Disease: The Role of Primary Care in Managing the Patient Journey The Journal of the American Board of Family Medicine Nov 2019, 32 (6) 931-940; DOI: 10.3122/jabfm.2019.06.180328
5. APA Work Group on Alzheimer’s Disease and other Dementias; Rabins PV, Blacker D, et al. American Psychiatric Association practice guideline for the treatment of patients with Alzheimer’s disease and other dementias. Second edition. Am J Psychiatry. 2007 Dec;164(12 Suppl):5-56. PMID: 18340692.
6. Cummings J, Lee G, Zhong K, Fonseca J, Taghva K (2021) Alzheimer’s disease drug development pipeline: 2021. Alzheimers Dement (N Y) 7, e12179.
7. Tian Hui Kwan A, Arfaie S, Therriault J, Rosa-Neto P, Gauthier S (2020) Lessons learnt from the second generation of anti-amyloid monoclonal antibodies clinical trials. Dement Geriatr Cogn Disord 49, 334-348.
8. Avgerinos KI, Ferrucci L, Kapogiannis D. Effects of monoclonal antibodies against amyloid-Œ≤ on clinical and biomarker outcomes and adverse event risks: a systematic review and meta-analysis of phase III RCTs in Alzheimer’s disease. Ageing Res Rev 2021;68:101339-101339.
9. Food & Drug Administration. FDA news release. FDA Grants Accelerated Approval for Alzheimer’s Drug. Available at: https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug. Last updated June 7, 2021, Accessed on February 9, 2022
10. Food & Drug Administration. FDA news release. FDA’s Decision to Approve New Treatment for Alzheimer’s Disease. Available at: https://www.fda.gov/drugs/news-events-human-drugs/fdas-decision-approve-new-treatment-alzheimers-disease. Last updated July 6, 2021. Accessed on April 18, 2023 
11. FDA accepts Eisai’s filing of a supplemental biologics license application and grants priority review for traditional approval of LEQEMBI™ (lecanemab-irmb) for the treatment of alzheimer’s disease (no date) Biogen. Available at: https://investors.biogen.com/news-releases/news-release-details/fda-accepts-eisais-filing-supplemental-biologics-license#:~:text=LEQEMBI%20was%20approved%20under%20accelerated,U.S.%20on%20January%2018%2C%202023 Accessed: April 18, 2023
12. Söderberg, L., Johannesson, M., Nygren, P. et al. Lecanemab, Aducanumab, and Gantenerumab — Binding Profiles to Different Forms of Amyloid-Beta Might Explain Efficacy and Side Effects in Clinical Trials for Alzheimer’s Disease. Neurotherapeutics (2022). https://doi.org/10.1007/s13311-022-01308-6
13. McDade, E., Cummings, J.L., Dhadda, S. et al. Lecanemab in patients with early Alzheimer’s disease: detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study. Alz Res Therapy 14, 191 (2022). https://doi.org/10.1186/s13195-022-01124-2
14. Additional detailed analyses from phase 2 study 201 of LECANEMAB published as three papers in peer-reviewed journals: News release：2023 (no date) Eisai Co., Ltd. Available at: https://www.eisai.com/news/2023/news202324.html Accessed: April 18, 2023
15. van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, Kanekiyo M, Li D, Reyderman L, Cohen S, Froelich L, Katayama S, Sabbagh M, Vellas B, Watson D, Dhadda S, Irizarry M, Kramer LD, Iwatsubo T. Lecanemab in Early Alzheimer’s Disease. N Engl J Med. 2023 Jan 5;388(1):9-21. doi: 10.1056/NEJMoa2212948. Epub 2022 Nov 29. PMID: 36449413.