A Dab of MAB: Lecanemab, Aducanumab vs Standard of Care Treatment for Alzheimer Disease

Background

With more than 50 million patients with Alzheimer disease (AD) worldwide and more than 100 years of research on record, newly approved modern monoclonal antibody (MAB) treatments have provided a breakthrough hope for a brighter future of treatment after years of no new approvals. Under the umbrella of dementia lies this progressive neurodegenerative disease, which leads to impaired cognition, memory loss, and functional capacity.

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Part of the underlying pathology of this disease is the accumulation of the protein amyloid beta (Aβ) leading to plaques in the brain.¹ Along a continuum of interference with daily activities, AD can be defined from preclinical AD to severe dementia due to AD based on the progression of this plaque deposition.³

An additional aspect of pathology is the hyperphosphorylation of the protein tau, which forms neurofibrillary tangles (NFTs) that lead to synaptic and neuronal loss.⁴ In an attempt to define the etiology, the cholinergic hypothesis emphasizes the reduction in acetylcholine biosynthesis as a result of cholinergic synaptic loss and reduction in acetylcholine receptors.¹

The amyloid hypothesis focuses on the role amyloid plays when abnormal folding and accumulation occurs. The increasing ratio of peptides Aβ₄₀ and Aβ₄₂ specifically, implicate amyloid fibril formation, which has downstream effects of neurotoxicity and neuronal cell death.¹

Notably, a heavily implicated genetic marker in this disease is the Apolipoprotein (ApoEε4) allele of a highly expressed glycoprotein involved in receptor-mediated endocytosis in the liver and brain astrocytes. The presence of this particular allele has been shown to be associated with higher rates of vascular damage and senile plaque Aβ deposition.¹

Standard of Care Treatment

Cholinesterase Inhibitors

Cholinesterase inhibitors, in accordance with the cholinergic hypothesis, treat symptoms related to memory, cognition, language, and judgment. Their mechanism targets supporting the communication between nerve cells with the inhibition of acetylcholine degradation.

The most commonly prescribed medications are donepezil (Aricept), approved for all stages of AD, and rivastigmine (Exelon) and galantamine (Razadyne), approved for mild-to-moderate AD.^5,6 In comparison, donepezil reversibly binds acetylcholinesterase (AchE) to block hydrolysis, whereas rivastigmine is a pseudo-irreversible inhibitor of AchE to prevent metabolism.

Galantamine acts by competitive inhibition of AchE and can bind at a non-active site on the nicotinic acetylcholine receptors to activate them.^5,6 Adverse effects (AEs) of this drug class can include loss of appetite, increased bowel movements, and nausea.

N-methyl D-aspartate (NMDA) Antagonists

NMDA antagonists such as memantine (Namenda) are approved for moderate-to-severe AD and target a different pathway involved in glutamate regulation. Overactivation of NMDA receptors can lead to excess glutamate, an excitatory amino acid, ultimately resulting in excitotoxicity and neuronal cell death.

Memantine is a low affinity noncompetitive antagonist of the NMDA receptor. It has shown efficacy in being used alone or in combination with a cholinesterase inhibitor.^5-8 AEs can include the previous listed plus headache, constipation, and confusion.

Evidence for Aducanumab

How do the new MABs compare to the standard of care treatment? Previous trials have attempted to create the next anti-Aβ MAB, but it wasn’t until aducanumab (Aduhelm) was approved in June 2021 that the first MAB made it to market. It all began with the PRIME phase 1b study that resulted in dose- and time-dependent reduction in Aβ plaques along with slowed clinical decline.⁹

This allowed for the identical, randomized, placebo-controlled EMERGE and ENGAGE phase 3 trials to move forward in assessing the efficacy and safety of intravenous aducanumab in patients with early onset AD. Both trials included patients aged 50-85 years who met clinical criteria for mild cognitive impairment (MCI) due to AD or mild AD dementia and who had confirmed amyloid pathology upon a PET scan.

They excluded patients with use of any antiplatelet or anticoagulant medications. Groups of participants were randomized (1:1:1) to receive placebo, low dose (3 mg/kg), or high dose (6 mg/kg or 10 mg/kg) aducanumab and were stratified by site and ApoEε4 carrier status.⁹

The primary endpoint was based on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) and the change from baseline at week 78.¹⁰ The CDR-SB is a functional and cognitive scale used to identify the progression of impairment that aligns with a corresponding dementia stage.

EMERGE was able to show a statistically significant slowing of clinical decline in the high-dose arm of the study, meeting the primary endpoint (Table 1).¹⁰ However, ENGAGE did not meet its primary or secondary endpoints.

An impactful limitation to both trials was the fact that they were stopped in March 2019 for the poor outcomes of a futility analysis. The controversy surrounding the approval of this drug has prompted a 24-month, open-label, single-arm phase 3b study called EMBARK to evaluate the long-term safety and tolerability of aducanumab.^10-12

Evidence for Lecanemab

With researchers taking an even closer look into MABs, lecanemab (Leqembi) quickly became the next breakthrough drug to gain accelerated approval in January 2023, which was converted to a full traditional approval in July 2023 with its verified clinical benefit through the confirmatory CLARITY-AD trial. CLARITY-AD was a phase 3 trial for use of lecanemab in early AD and reflected similar patient population criteria to aducanumab trials except for the use of antiplatelet medications being included.^13-15

The design of this trial was an 18 month, multicenter, double-blind, placebo-controlled, parallel group study in which participants aged 50-90 years were randomized in a 1:1 ratio. Stratification was based on clinical subgroup, the presence of concomitant approved medications for AD symptom management, ApoEε4 carrier status, and geographic region.^15,16 The primary endpoint was a change in baseline of the CDR-SB at 18 months similar to EMERGE and ENGAGE.

The results showed that the primary endpoint was met, meaning lecanemab reduced brain amyloid levels and was associated with less clinical decline when compared to placebo (Table 1).^15,16 When discussing the limitations of these recent studies, it’s important to note that CLARITY-AD had a 17.2% dropout rate and was only 18 months long.

Table 1. Comparison of Primary Endpoints for Aducanumab and Lecanemab Trials

Comparison of New MAB Therapies

With the knowledge that these new MABs have some evidence of slowing disease progression, it’s important to understand how these play a role in practice. Both drugs are immunoglobulin gamma1 (IgG1) monoclonal antibodies dosed through IV infusion therapy for people living with MCI or mild dementia due to AD, which differs from the indications of some standard of care treatments.

No data exist for safety and efficacy on initiating treatment at earlier or later stages of disease progression. The dosing for lecanemab is 10 mg/kg once every 2 weeks, whereas aducanumab allows for a titration regimen up to the seventh infusion to target 10 mg/kg IV every 4 weeks.^17,18

Both drugs have a mechanistic action directed at aggregated soluble and insoluble forms of amyloid beta. The most common AE seen in both trials was amyloid-related imaging abnormalities (ARIA) that can further be differentiated into hemorrhagic (ARIA-H) or edematous (ARIA-E).

ARIA manifests on magnetic resonance imaging (MRI) as temporary swelling of the brain and/or small spots of bleeding that are usually asymptomatic but can lead to serious complications. Unique to lecanemab was the predominance of infusion-related reactions on top of ARIA incidence in the CLARITY-AD trial (Table 2).¹⁶

Table 2. Overview of Aducanumab and Lecanemab

As for EMERGE and ENGAGE, the incidence of AEs was similar across both studies showcased by ARIA-E events being more prevalent in the high-dose arms and higher in ApoEε4 carriers compared to non-carriers with 98% of incidents resolving on study.⁹ Enhanced clinical vigilance for ARIA is recommended during the first 8 doses of aducanumab and the first 14 weeks of treatment with lecanemab.^19,20

Both monoclonal antibodies require that amyloid beta pathology is confirmed by a recent MRI prior to treatment and subsequent MRIs be taken at infusions specific to each drug.^19,20 No contraindications are listed for either drug.

The Role Pharmacists Can Play

Staying up to date on new MABs as they come out and extension studies on the MABs already approved will be important. The multicenter, randomized, double-blind, placebo-controlled, phase 2 TRAILBLAZER-ALZ trial was completed in 2021 followed by a phase 3 study completed in May 2023 for the MAB donanemab showing positive results.^21,22

A phase 3 extension study for lecanemab, the AHEAD study, is underway as well to assess the efficacy in preclinical AD and timing of initiation of treatment.¹⁶ Staying up to date on studies goes hand-in-hand with the role of being an advocate for increased diversity in these clinical trials as well.

Because pharmacists are financially driven when it comes to medication management, it will be important to connect patients with payment resources and accessible treatment locations due to the large cost of these treatments.

About the Authors

Author: McKenzie Erwin, PharmD candidate, University of Texas at Austin College of Pharmacy, Class of 2025.

Preceptor: Ashley Sturm, PharmD, BCPS, Clinical Pharmacist, Mayo Clinic Medical Center-St. Mary’s Campus.

References

1. Breijyeh Z, Karaman R. Comprehensive Review on Alzheimer's Disease: Causes and Treatment. Molecules. 2020 Dec 8;25(24):5789. doi: 10.3390/molecules25245789. PMID: 33302541; PMCID: PMC7764106.
2. Alzheimer's Association. Milestones. Alzheimer’s Disease and Dementia. Published 2019. https://www.alz.org/alzheimers-dementia/research_progress/milestones
3. 2020 Alzheimer's disease facts and figures. Alzheimer's Dement., 16: 391-460. https://doi.org/10.1002/alz.12068
4. Lane CA, Hardy J, Schott JM. Alzheimer's disease. Eur J Neurol. 2018 Jan;25(1):59-70. doi: 10.1111/ene.13439. Epub 2017 Oct 19. PMID: 28872215.
5. Medications for memory, cognition and dementia-related behaviors. Alzheimer’s Disease and Dementia. Accessed July 5, 2023. https://www.alz.org/alzheimers-dementia/treatments /medications-for-memory#Types%20of%20drugs
6. Management. Alzheimer’s Disease and Dementia. Published 2021. https://www.alz.org/professionals/health-systems-medical-professionals/management
7. Petersen, R. C., Lopez, O., Armstrong, M. J., Getchius, T. S. D., Ganguli, M., Gloss, D., Gronseth, G. S., Marson, D., Pringsheim, T., Day, G. S., Sager, M., Stevens, J., & Rae-Grant, A. (2018). Practice guideline update summary: Mild cognitive impairment: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology, 90(3), 126–135. https://doi.org/10.1212/WNL.0000000000004826
8. Reitz, C., & Mayeux, R. (2014). Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochemical pharmacology, 88(4), 640–651. https://doi.org/10.1016/j.bcp.2013.12.024
9. S. Budd Haeberlein, P.S. Aisen, F. Barkhof, et al. Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer’s Disease. J Prev Alz Dis 2022;2(9):197-210; http://dx.doi.org/10.14283/jpad.2022.30
10. Dhillon S. (2021). Aducanumab: First Approval. Drugs, 81(12), 1437–1443. https://doi.org/10.1007/s40265-021-01569-z
11. Yuksel, J. M., Noviasky, J., & Britton, S. (2022). Aducanumab for Alzheimer's Disease: Summarized Data From EMERGE, ENGAGE, and PRIME Studies. The Senior care pharmacist, 37(8), 329–334. https://doi.org/10.4140/TCP.n.2022.329
12. ClinicalTrials.gov. A Study to Evaluate Safety and Tolerability of Aducanumab in Participants With Alzheimer’s Disease Who Had Previously Participated in the Aducanumab Studies 221AD103, 221AD301, 221AD302 and 221AD205 2020. https://clinicaltr ials.gov/ct2/show/NCT04241068?term=aducanumab&draw= 2&rank=2. Accessed 11 Jun 2023
13. FDA grants accelerated approval for alzheimer’s disease treatment. U.S. Food and Drug Administration. January 6, 2023. Accessed July 5, 2023. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-disease-treatment
14. 1. FDA approves LEQEMBITM (lecanemab-irmb) under the accelerated approval pathway for the treatment of alzheimer’s disease. Biogen News. January 6, 2023. Accessed July 5, 2023. https://investors.biogen.com/news-releases/news-release-details/fda-approves-leqembitm-lecanemab-irmb-under-accelerated-approval.
15. Swanson CJ, Zhang Y, Dhadda S, Wang J, Kaplow J, Lai RYK, Lannfelt L, Bradley H, Rabe M, Koyama A, Reyderman L, Berry DA, Berry S, Gordon R, Kramer LD, Cummings JL. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimers Res Ther. 2021 Apr 17;13(1):80. doi: 10.1186/s13195-021-00813-8. Erratum in: Alzheimers Res Ther. 2022 May 21;14(1):70. PMID: 33865446; PMCID: PMC8053280.
16. 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.
17. Lexicomp. (n.d.). Lecanemab: Drug Information. UpToDate. Retrieved June 19, 2023, from https://www.uptodate.com/contents/lecanemab-druginformation?source=auto suggest&selectedTitle=1~1---1~4---lecanemab&search=lecanemab
18. Lexicomp. (n.d.). Aducanumab: Drug Information. UpToDate. Retrieved June 19, 2023, from https://www.uptodate.com/contents/aducanumabdruginformation?source=autosuggest&selectedTitle=1~1---1~4---aducan&search=aducanumab
19. HIGHLIGHTS OF PRESCRIBING INFORMATION. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761269Orig1s000lbl.pdf
20. HIGHLIGHTS OF PRESCRIBING INFORMATION. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761178s005lbl.pdf
21. Mintun, M. A., Lo, A. C., Duggan Evans, C., Wessels, A. M., Ardayfio, P. A., Andersen, S. W., Shcherbinin, S., Sparks, J., Sims, J. R., Brys, M., Apostolova, L. G., Salloway, S. P., & Skovronsky, D. M. (2021). Donanemab in Early Alzheimer's Disease. The New England journal of medicine, 384(18), 1691–1704. https://doi.org/10.1056/NEJMoa2100708
22. Lilly’s Donanemab significantly slowed cognitive and functional decline in phase 3 study of early alzheimer’s disease. Eli Lilly News. May 3, 2023. Accessed July 5, 2023. https://investor.lilly.com/news-releases/news-release-details/lillys-donanemab-significantly-slowed-cognitive-and-functional