How Early Intervention and a Treatment Can Help Early Alzheimer’s Disease

Sponsored by Eisai Inc. and Biogen

Alzheimer’s disease (AD) is widely recognized as a progressive and debilitating fatal neurodegenerative condition that substantially affects cognition and daily functioning.¹ AD progresses from asymptomatic (or preclinical AD) to mild cognitive impairment (MCI) due to AD, then to mild, moderate, and severe dementia.¹ The term ‘early AD’ is used often to refer to the beginning stages of symptomatic disease progression, and includes people with MCI due to AD who are at the stage at which mild cognitive symptoms appear, but may not interfere with daily abilities.¹ Early AD also includes mild AD dementia, which is the stage at which cognitive symptoms interfere with some daily activities.¹ The earlier MCI due to AD and mild AD dementia are diagnosed and treated, the greater the opportunity for benefit.¹

Jonathon Liss, M.D., neurologist and founder of the Columbus Memory Center and David Weisman, M.D., neurologist at Abington Neurological Associates, discuss the science behind AD and what physicians need to know about a new treatment option for patients with early AD.

Dr. Liss: While many factors contribute to impaired brain cell function and cognitive decline associated with AD, emerging evidence suggests that AD may result from accumulation of two different proteins: amyloid-beta (Aβ) and tau.² The Aβ protein clumps together to form plaques that build up between nerve cells. The tau protein forms twisted strands, or tangles, inside the neurons. These plaques and tangles accumulate in the brain and are thought to disrupt cell function.^2,3

Although the amyloid cascade is one piece of the complex AD disease process, which also includes tau, synaptic dysfunction, neuroinflammation and other components, there is strong scientific evidence that alterations in the amyloid cascade can contribute to neurodegeneration.^4,5 Abnormal Aβ accumulation results in the development of amyloid plaques through a continuous process where individual Aβ proteins join together, latching onto each other, one at a time, like adding links to a chain.³ In the early part of this process these small chains of Aβ are soluble and are toxic to the neurons within the brain.⁴

The most toxic of the soluble chains is called a protofibril.⁴ At the center of the amyloid cascade model, continuous accumulation of toxic protofibrils contributes to neurodegeneration and eventually to neuronal death. Once you lose neurons to AD, you cannot get them back.⁶ The Aβ cascade also triggers downstream molecular pathways, including tau pathology, which further contribute to neurodegeneration.⁷

AD-related pathophysiological changes in the brain may begin up to 25 years prior to diagnosis, but many patients are diagnosed only after advanced symptom onset.⁸ A prompt diagnosis of AD and early intervention are important.¹ Intervening early can delay disease progression.¹

Dr. Weisman: With this new understanding of the science of AD, there is a treatment option for patients with early AD that targets both toxic protofibrils and amyloid plaques. When it comes to the treatment of AD, we are living in a very exciting time. We have witnessed the FDA approval of LEQEMBI (lecanemab-irmb) under the traditional approval pathway. This makes LEQEMBI the first approved anti-amyloid AD treatment shown to slow disease progression in a clinically meaningful way in early AD patients.⁹ Medicare also covers anti-amyloid AD treatments with traditional FDA approval, including LEQEMBI, contingent upon provider participation in the CMS National Patient registry or another CMS-approved study.¹⁰ In the Phase 3 Clarity AD trial, LEQEMBI met its primary endpoint - demonstrating statistically significant slowing of cognitive and functional decline with continued treatment at 18 months compared with placebo, as measured by the Clinical Dementia Rating Sum of Boxes (CDR-SB), a cognitive and functional scale (-0.45 [-27%], p<0.0001).¹¹ Please see Important Safety Information below and accompanying full Prescribing Information, including Boxed WARNING for Amyloid Related Imaging Abnormalities (ARIA).

Clarity AD was an 18-month, global, placebo-controlled, double-blind, parallel-group, randomized clinical trial of 1795 patients with MCI due to AD (n=528/859) or mild AD dementia (n=331/859) with confirmed Aβ pathology. Patients were randomized 1:1 to receive LEQEMBI 10 mg/kg (IV infusion) or placebo (IV infusion) once every 2 weeks.¹¹

Dr. Liss: Decades of research have led to the emergence of LEQEMBI as a treatment option for Alzheimer’s disease. LEQEMBI works to clear more than just amyloid plaque. LEQEMBI is dual-acting meaning it supports neuronal function by clearing the highly toxic protofibrils that can continue to cause neuronal injury and death even after plaques are cleared.^4,7,11-15

Lecanemab-irmb is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble forms (oligomers and protofibrils) and insoluble forms (fibrils) of amyloid beta.

Dr. Liss: LEQEMBI is indicated for the treatment of Alzheimer’s disease. Treatment with LEQEMBI should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. It is important to confirm the presence of amyloid beta pathology prior to initiating treatment with LEQEMBI.¹¹ Cerebrospinal fluid (CSF) tests or amyloid positron emission tomography (PET) are used to confirm amyloid beta pathology.^16,17

Dr. Weisman: An important treatment aspect we need to consider as we evaluate our patients is safety. Antibodies targeting amyloid plaques, including LEQEMBI, can cause ARIA.¹¹ ARIA is most commonly seen as temporary swelling in areas of the brain that usually resolves over time and can be managed during treatment with dosing interruptions. ARIA is subdivided into ARIA-E which can be observed on MRI as brain edema or sulcal effusions or ARIA hemosiderin deposition (ARIA-H) seen with MRI as microhemorrhages and superficial siderosis.¹¹ While the incidence and timing of ARIA vary among treatments, ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events can occur on rare occasions.

Serious intracerebral hemorrhages >1 cm, some fatal, have been observed with this class of medications. Another important topic to consider is the ApoE ε4 genetic component. Patients who are ApoE ε4 homozygotes (which is ~15% of AD patients) treated with this class of medications have a higher incidence of ARIA, including symptomatic, serious, and severe radiographic ARIA, compared to heterozygotes and noncarriers. Testing and discussion for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prescribers should inform patients that this is a physician-patient decision. Patients can still be treated with LEQEMBI if genotype testing is not performed; however, it cannot be determined if they are ApoE ε4 homozygotes and at higher risk for ARIA. It’s also important to note LEQEMBI is contraindicated in patients with serious hypersensitivity to lecanemab-irmb or to any of the excipients of LEQEMBI. Reactions have included angioedema and anaphylaxis.

Recent baseline brain MRI prior to initiating treatment with LEQEMBI and prior to the 5th, 7th and 14th infusions should be performed to monitor for ARIA. Patients should be informed that most people with swelling in areas of the brain do not experience symptoms, however, some people may experience symptoms such as headache, confusion, dizziness, vision changes, nausea, aphasia, weakness, or seizure. Symptoms associated with ARIA usually resolve over time.¹¹

Dr. Liss: In the Clarity AD trial for LEQEMBI, we saw that the incidence of ARIA-E was 13% compared to 9% for patients on placebo, and the incidence of ARIA-H was 17% for patients on LEQEMBI compared to 9% for patients in the placebo group. Including the incidence of asymptomatic radiographic events, ARIA was observed in 21% of LEQEMBI treated patients (191/898), compared to 9% of patients on placebo (84/897).¹¹ It's important that patients work with their doctors to consider the benefits of LEQEMBI for the treatment of Alzheimer’s disease and evaluate the potential risks of serious adverse events associated with ARIA.¹¹ Please see Safety Information continued below.

Dr. Weisman: So, what do you think is next for Alzheimer’s disease treatments?

Dr. Liss: Well, as you said, it is a very exciting time in Alzheimer’s disease research. LEQEMBI is the first approved treatment shown to reduce the rate of disease progression and slow cognitive and functional decline in adults with early Alzheimer’s disease (MCI due to AD and mild AD).^9,11 I think emerging combination therapies that target Aβ and tau hold promise. I’m eager to see more advancements regarding prevention in the Alzheimer’s disease space.

We also need to continue to pursue the development of biomarkers and early testing. We may eventually be able to implement interventions that prevent progression to the stage of dementia altogether. We still have much work to be done on this front, but every step towards this goal is a step in the right direction.

To learn more about LEQEMBI, visit www.LEQEMBIHCP.com.

INDICATION AND IMPORTANT SAFETY INFORMATION

INDICATION
LEQEMBI is indicated for the treatment of Alzheimer’s disease. Treatment with LEQEMBI should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATION
LEQEMBI is contraindicated in patients with serious hypersensitivity to lecanemab-irmb or to any of the excipients of LEQEMBI. Reactions have included angioedema and anaphylaxis.

WARNINGS AND PRECAUTIONS

AMYLOID RELATED IMAGING ABNORMALITIES

• LEQEMBI can cause ARIA-E and ARIA-H. ARIA-E can be observed on MRI as brain edema or sulcal effusions, and ARIA-H as microhemorrhage and superficial siderosis. ARIA can occur spontaneously in patients with Alzheimer’s disease. ARIA-H associated with monoclonal antibodies directed against aggregated forms of beta amyloid generally occurs in association with an occurrence of ARIA-E. ARIA-H and ARIA-E can occur together.
• ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events, including seizure and status epilepticus, rarely can occur. Reported symptoms associated with ARIA may include headache, confusion, visual changes, dizziness, nausea, and gait difficulty. Focal neurologic deficits may also occur. Symptoms associated with ARIA usually resolve over time.

ARIA Monitoring and Dose Management Guidelines

• Obtain recent baseline brain magnetic resonance imaging (MRI) prior to initiating treatment with LEQEMBI. Obtain an MRI prior to the 5th, 7th and 14th infusions.
• Recommendations for dosing in patients with ARIA-E and ARIA-H depend on clinical symptoms and radiographic severity. Depending on ARIA severity, use clinical judgment in considering whether to continue dosing, temporarily discontinue treatment, or permanently discontinue LEQEMBI.
• Enhanced clinical vigilance for ARIA is recommended during the first 14 weeks of treatment with LEQEMBI. If a patient experiences symptoms suggestive of ARIA, clinical evaluation should be performed, including MRI if indicated. If ARIA is observed on MRI, careful clinical evaluation should be performed prior to continuing treatment.
• There is no experience in patients who continued dosing through symptomatic ARIA-E or through asymptomatic, but radiographically severe, ARIA-E. There is limited experience in patients who continued dosing through asymptomatic but radiographically mild to moderate ARIA-E. There are limited data in dosing patients who experienced recurrent ARIA-E.

Incidence of ARIA

• In Study 2, symptomatic ARIA occurred in 3% (29/898) of LEQEMBI-treated patients. Serious symptoms associated with ARIA were reported in 0.7% (6/898) of patients treated with LEQEMBI. Clinical symptoms associated with ARIA resolved in 79% (23/29) of patients during the period of observation.
• Including asymptomatic radiographic events, ARIA was observed in LEQEMBI: 21% (191/898); placebo: 9% (84/897). ARIA-E was observed in LEQEMBI: 13% (113/898); placebo: 2% (15/897). ARIA-H was observed in LEQEMBI: 17% (152/898); placebo: 9% (80/897). There was no increase in isolated ARIA-H for LEQEMBI vs placebo.

ApoE ε4 Carrier Status and Risk of ARIA

• In Study 2, 16% (141/898) of patients in the LEQEMBI arm were ApoE ε4 homozygotes, 53% (479/898) were heterozygotes, and 31% (278/898) were noncarriers.
• The incidence of ARIA was higher in ApoE ε4 homozygotes (LEQEMBI: 45%; placebo: 22%) than in heterozygotes (LEQEMBI: 19%; placebo: 9%) and noncarriers (LEQEMBI: 13%; placebo: 4%). Among patients treated with LEQEMBI, symptomatic ARIA-E occurred in 9% of ApoE ε4 homozygotes compared with 2% of heterozygotes and 1% of noncarriers. Serious events of ARIA occurred in 3% of ApoE ε4 homozygotes, and approximately 1% of heterozygotes and noncarriers.
• The recommendations on management of ARIA do not differ between ApoE ε4 carriers and noncarriers.

Radiographic Findings

• The majority of ARIA-E radiographic events occurred early in treatment (within the first 7 doses), although ARIA can occur at any time and patients can have more than 1 episode. The maximum radiographic severity of ARIA-E in patients treated with LEQEMBI was mild in 4% (37/898), moderate in 7% (66/898), and severe in 1% (9/898). Resolution on MRI occurred in 52% of ARIA-E patients by 12 weeks, 81% by 17 weeks, and 100% overall after detection. The maximum radiographic severity of ARIA-H microhemorrhage in LEQEMBI-treated patients was mild in 9% (79/898), moderate in 2% (19/898), and severe in 3% (28/898) of patients; superficial siderosis was mild in 4% (38/898), moderate in 1% (8/898), and severe in 0.4% (4/898). Among LEQEMBI-treated patients, the rate of severe radiographic ARIA-E was highest in ApoE ε4 homozygotes 5% (7/141), compared to heterozygotes 0.4% (2/479) or noncarriers 0% (0/278). Among LEQEMBI-treated patients, the rate of severe radiographic ARIA-H was highest in ApoE ε4 homozygotes 13.5% (19/141), compared to heterozygotes 2.1% (10/479) or noncarriers 1.1% (3/278).

Intracerebral Hemorrhage

• Intracerebral hemorrhage >1 cm in diameter was reported in 0.7% (6/898) of patients in Study 2 after treatment with LEQEMBI compared to 0.1% (1/897) on placebo. Fatal events of intracerebral hemorrhage in patients taking LEQEMBI have been reported.

Concomitant Antithrombotic Medication:

• In Study 2, baseline use of antithrombotic medication (aspirin, other antiplatelets, or anticoagulants) was allowed if the patient was on a stable dose. The majority of exposures to antithrombotic medications were to aspirin. Antithrombotic medications did not increase the risk of ARIA with LEQEMBI. The incidence of intracerebral hemorrhage was 0.9% (3/328 patients) in patients taking LEQEMBI with a concomitant antithrombotic medication at the time of the event compared to 0.6% (3/545 patients) in those who did not receive an antithrombotic. Patients taking LEQEMBI with an anticoagulant alone or combined with an antiplatelet medication or aspirin had an incidence of intracerebral hemorrhage of 2.5% (2/79 patients) compared to none in patients who received placebo.
• Because intracerebral hemorrhages >1 cm in diameter have been observed in patients taking LEQEMBI, additional caution should be exercised when considering the administration of anticoagulants or a thrombolytic agent (e.g., tissue plasminogen activator) to a patient already being treated with LEQEMBI.

Other Risk Factors for Intracerebral Hemorrhage:

• Patients were excluded from enrollment in Study 2 for findings on neuroimaging that indicated an increased risk for intracerebral hemorrhage. These included findings suggestive of cerebral amyloid angiopathy (prior cerebral hemorrhage >1 cm in greatest diameter, >4 microhemorrhages, superficial siderosis, vasogenic edema) or other lesions (aneurysm, vascular malformation) that could potentially increase the risk of intracerebral hemorrhage. The presence of an ApoE ε4 allele is also associated with cerebral amyloid angiopathy, which has an increased risk for intracerebral hemorrhage. Caution should be exercised when considering the use of LEQEMBI in patients with factors that indicate an increased risk for intracerebral hemorrhage and in particular for patients who need to be on anticoagulant therapy.

HYPERSENSITIVITY REACTIONS
Hypersensitivity reactions, including angioedema, bronchospasm, and anaphylaxis, have occurred in LEQEMBI-treated patients. Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity reaction, and initiate appropriate therapy.

INFUSION-RELATED REACTIONS

• In Study 2, infusion-related reactions were observed in LEQEMBI: 26% (237/898); placebo: 7% (66/897), and the majority of cases in LEQEMBI-treated patients (75%, 178/237) occurred with the first infusion. Infusion-related reactions were mostly mild (69%) or moderate (28%) in severity. Infusion-related reactions resulted in discontinuations in 1% (12/898) of LEQEMBI-treated patients. Symptoms of infusion-related reactions included fever and flu-like symptoms (chills, generalized aches, feeling shaky, and joint pain), nausea, vomiting, hypotension, hypertension, and oxygen desaturation.
• In the event of an infusion-related reaction, the infusion rate may be reduced, or the infusion may be discontinued, and appropriate therapy initiated as clinically indicated. Prophylactic treatment with antihistamines, acetaminophen, nonsteroidal anti-inflammatory drugs, or corticosteroids prior to future infusions may be considered.

ADVERSE REACTIONS

• In Study 2, the most common adverse reaction leading to discontinuation of LEQEMBI was ARIA-H microhemorrhages that led to discontinuation in 2% (15/898) of patients treated with LEQEMBI compared to <1% (1/897) of patients on placebo.
• In Study 2, the most common adverse reactions reported in ≥5% of patients treated with LEQEMBI (N=898) and ≥2% higher than placebo (N=897) were infusion-related reactions (LEQEMBI: 26%; placebo: 7%), ARIA-H (LEQEMBI: 14%; placebo: 8%), ARIA-E (LEQEMBI: 13%; placebo: 2%), headache (LEQEMBI: 11%; placebo: 8%), superficial siderosis of central nervous system (LEQEMBI: 6%; placebo: 3%), rash (LEQEMBI: 6%; placebo: 4%), and nausea/vomiting (LEQEMBI: 6%; placebo: 4%).

Please see full Prescribing Information for LEQEMBI, including Boxed WARNING.

References

1. Alzheimer’s Association. 2023 Alzheimer’s Disease Facts and Figures. Alzheimers Dement 2023;19. Retrieved November 12, 2023, from https://www.alz.org/media/Documents/alzheimers-facts-and-figures.pdf
2. U.S. Department of Health and Human Services. (2022). What happens to the brain in Alzheimer’s disease? National Institute on Aging. Retrieved November 12, 2023, from https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease
3. Alzheimer’s Association. (2022). Brain Tour Part 2 - Alzheimer’s Effect. Retrieved November 12, 2023, from https://www.alz.org/alzheimers-dementia/what-is-alzheimers/brain_tour_part_2
4. Hampel, H., Hardy, J., Blennow, K. et al. The Amyloid-β Pathway in Alzheimer’s Disease. Mol Psychiatry 26, 5481–5503 (2021). https://doi.org/10.1038/s41380-021-01249-0
5. Walsh DM, Hartley DM, Kusumoto Y, et al. Amyloid beta-protein fibrillogenesis. Structure and biological activity of protofibrillar intermediates. J Biol Chem. 1999;274(36):25945-25952.
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7. Ono K, Tsuji M. Protofibrils of Amyloid-β are Important Targets of a Disease-Modifying Approach for Alzheimer's Disease. Int J Mol Sci. 2020;21(3):952. doi: 10.3390/ijms21030952. PMID: 32023927; PMCID: PMC7037706.
8. Bateman RJ, Xiong C, Benzinger TLS, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367(9):795-804.
9. U.S. Food and Drug Administration. FDA Converts Novel Alzheimer’s Disease Treatment to Traditional Approval. Retrieved November 13, 2023, from https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval
10. Centers for Medicare and Medicaid Services. Statement: Broader Medicare Coverage of Leqembi Available Following FDA Traditional Approval. Retrieved November 13, 2023, from https://www.cms.gov/newsroom/press-releases/statement-broader-medicare-coverage-leqembi-available-following-fda-traditional-approval
11. LEQEMBI US Prescribing Information under Traditional Approval
12. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer’s Disease. New England Journal of Medicine. 2023;388(1):9-21. doi:10.1056/NEJMoa22d12948.
13. Brendza RP, et al. Anti-Aβ antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice. J Clin Invest. 2005;115(2):428-433. https://doi.org/10.1172/JCI23269.
14. Söllvander S, Nikitidou E, Brolin R, et al. Accumulation of amyloid-β by astrocytes result in enlarged endosomes and microvesicle-induced apoptosis of neurons. Mol Neurodegener. 2016;11(1):38.
15. Hartley DM, Walsh DM, Ye CP, Diehl T, Vasquez S, Vassilev PM, Teplow DB, Selkoe DJ. Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci. 1999;19(20):8876-84. doi: 10.1523/JNEUROSCI.19-20-08876.1999. PMID: 10516307; PMCID: PMC6782787.
16. Schindler SE, Bollinger JG, Ovod V, et al. High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis. Neurology. 2019;93(17):e1647-e1659.
17. Nakamura A, Kaneko N, Villemagne VL, et al. High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature. 2018;554(7691):249-254.

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