Treatment goals of disease-modifying treatments

As of August 2023, there are two FDA approved DMTs available for the treatment of AD.^4,5 Aducanumab, the first novel therapy approved for AD since 2003, is a monoclonal antibody selective for aggregated forms of amyloid-b.^4,6 Since its discovery, several experimental studies and clinical trials have been conducted to assess the effectiveness and safety of the drug.⁷ Conflicting findings from two identically designed studies (ENGAGE and EMERGE), alongside the lack of evidence that brain Ab reduction correlates with clinical improvement, resulted in non-approval from the EMA for the drug.⁸ However, despite the conflicting results, the FDA granted the drug accelerated approval in 2021.⁴

Lecanemab is a humanized monoclonal antibody that binds with high affinity to soluble Ab protofibrils.⁹ In early 2023, lecanemab was granted accelerated approval by the FDA, which was then converted to traditional approval later in the year.^5,10 This conversion was following evidence from a Phase 3 trial in which lecanemab demonstrated a statistically significant and clinically meaningful reduction of decline from baseline to 18 months on the primary endpoint (the Clinical Dementia Rating Scale sum of boxes score) compared with placebo.¹⁰ A statistically significant difference between treatment groups was also demonstrated on secondary endpoints, which included the Alzheimer’s Disease Assessment Scale Cognitive Subscale 14, and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment.¹⁰

References:
1. Van Dam D, De Deyn PP. Drug discovery in dementia: the role of rodent models. Nat Rev Drug Discov 2006; 5 (11): 956–970.

2. Kennedy GJ. From symptom palliation to disease modification: implications for dementia care. Primary Psychiatry 2007; 14 (11): 30–34.

3. Tolar M, Abushakra S, Hey JA, et al. Aducanumab, gantenerumab, BAN2401, and ALZ-801 – the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval. Alzheimers Res Ther 2020; 12 (1): 95.

4. FDA press release 7 June 2021. 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. Accessed 1 June 2023.

5. FDA press release 6 January 2023. FDA grants accelerated approval for Alzheimer’s disease treatment. Available at: https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-disease-treatment. Accessed 11 August 2023.

6. Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 2016; 537 (7618): 50–56.

7. Rahman A, Hossen MA, Chowdhury MFI, et al. Aducanumab for the treatment of Alzheimer’s disease: a systematic review. Psychogeriatrics 2023; 23 (3): 512–522.

8. Vaz M, Silva V, Monteiro C, Silvestre S. Role of aducanumab in the treatment of Alzheimer’s disease: challenges and opportunities. Clin Interv Aging 2022; 17: 797–810.

9. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer’s Disease. N Engl J Med 2023; 388 (1): 9–21.

10. FDA press release 6 July 2023. FDA converts novel Alzheimer’s disease treatment to traditional approval. Available at: https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval. Accessed 1 August 2023.