Alzheimer's Disease

Alzheimer’s disease (AD) is a slow progressive brain disease that affects approximately 6.5 million Americans, women more commonly than men. AD is the most common cause of dementia, accounting for an estimated 60% to 80% of cases and is the sixth leading cause of death. AD is usually diagnosed in persons older than 65 years, and its prevalence increases every decade thereafter. On average, a person with Alzheimer's lives four to eight years after diagnosis, but can live as long as 20 years.(2,3,4) The hallmark pathologies of Alzheimer’s disease are the accumulation of the protein beta-amyloid plaques and twisted strands of the protein tau (tangles) inside neurons in the brain. These changes are accompanied by the death of neurons and damage to brain tissue. Alzheimer's is a slowly progressive brain disease that begins many years before symptoms emerge.(3)

Like other types of dementia, it is characterized by progressive memory loss and cognitive decline. Difficulty remembering recent conversations, names or events is often an early symptom; apathy and depression are also often early symptoms. Later symptoms include impaired communication, disorientation, confusion, poor judgment, behavioral changes and, ultimately, difficulty speaking, swallowing and walking.(2,3)

The National Institute on Aging and Alzheimer’s Association (NIA-AA) defines three stages of AD as preclinical, mild cognitive impairment (MCI), and dementia phase. The preclinical phase is characterized by neuropathologic changes that already present in the brain but not yet clinically expressed. Patients in this phase are asymptomatic and cognitively normal. People living with AD begin to accumulate beta-amyloid in the brain in the preclinical phase up to 15 years prior to the onset of symptoms.(4,6)

MCI may occur as a prodrome to several neurodegenerative dementias, as well as non-neurodegenerative conditions (e.g., depression, medicine effects). Therefore, the specific designation of MCI due to AD is used when a biomarker associated with AD (e.g., amyloid imaging, functional scan consistent with AD, or cerebrospinal fluid (CSF) testing of beta-amyloid, tau, and phospho-tau) is present in the affected patient. Using the NIA-AA criteria on a cohort of research subjects with MCI, individuals with cognitive impairment and both amyloid and neuronal injury biomarkers had an approximately 60% conversion rate to AD dementia over three years. Individuals are diagnosed with Alzheimer’s dementia when there is impairment of two cognitive domains and these deficits significantly interfere with the ability of the patient to function independently at work or at home. At this stage, a person typically needs a caregiver.(4,5,6)

The U.S. Food and Drug Administration (FDA) has approved drugs for the treatment of Alzheimer’s disease. The majority of these drugs (i.e., donepezil, rivastigmine, galantamine, memantine and memantine combined with donepezil) temporarily treat Alzheimer’s symptoms. Current treatment of AD is focused on supportive care, which may include treatment of dementia symptoms with medications that do not alter the course of the disease. Because of the devastating burden of AD, there is a great need for disease-modifying treatments (DMT) that slow or stop progression of the disease. Aducanumab (Aduhelm), a human monoclonal antibody, was the first putative disease modifying drug to obtain accelerated approval from the FDA in June 2021, based on PET documented removal of amyloid from the brain. Although aducanumab was approved for the treatment of AD in June 2021, there remain substantial uncertainties about its benefits and harms.(3,4)

Clinical Trials and FDA Review

Leqembi is an amyloid beta-directed antibody indicated for the treatment of Alzheimer’s disease (AD). Leqembi has high selectivity for soluble aggregated species of amyloid beta as compared with monomeric amyloid, with moderate selectivity for fibrillar amyloid; this profile is considered to target the most toxic pathologic amyloid species. 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. There are no safety or efficacy data on initiating treatment at earlier or later stages of the disease than were studied. This indication is approved under accelerated approval based on reduction in amyloid beta plaques observed in patients treated with Leqembi.(1,7) 

Study 201

Leqembi, an IgG1 monoclonal antibody, preferentially targets soluble aggregated amyloid beta, with activity across oligomers, protofibrils, and insoluble fibrils. Study 201, a randomized double-blind clinical trial, utilized a Bayesian design with response-adaptive randomization to assess 3 doses across 2 regimens of Leqembi versus placebo in early Alzheimer’s disease, mild cognitive impairment due to AD) and mild AD dementia. Study 201 aimed to establish the effective dose 90% (ED90), defined as the simplest dose that achieves greater than 90% of the maximum treatment effect.(1,8)

A total of 854 randomized subjects were treated (lecanemab, 609; placebo, 245). At 12 months, the 10-mg/kg biweekly ED90 dose showed a 64% probability to be better than placebo by 25% on Alzheimer’s Disease Composite Score (ADCOMS), which missed the 80% threshold for the primary outcome. At 18 months, 10-mg/kg biweekly Leqembi reduced brain amyloid (−0.306 SUVr units) while showing a drug-placebo difference in favor of active treatment by 27% and 30% on ADCOMS, 56% and 47% on ADAS-Cog14, and 33% and 26% on CDR-SB versus placebo according to Bayesian and frequentist analyses, respectively. CSF biomarkers were supportive of a treatment effect. Leqembi was well-tolerated with 9.9% incidence of amyloid-related imaging abnormalities-edema/effusion at 10 mg/kg biweekly.(1,8)

Leqembi did not meet the 12-month primary endpoint. However, prespecified 18-month Bayesian and frequentist analyses demonstrated reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints. Proof of concept was supported through prespecified key secondary endpoint analyses, where Leqembi treatment resulted in a dose dependent and consistent reduction in clinical decline relative to placebo across a number of clinical endpoints according to Bayesian and frequentist approaches. These effects were accompanied by a dose-dependent reduction in brain amyloid PET over 18 months of treatment and were reinforced by additional CSF biomarker results. Taken together, the findings in this double-blind trial on multiple cognitive endpoints and biomarkers are supportive of the therapeutic concept for the targeting specific oligomeric species (protofibrils) in the process of pathophysiological amyloid generation in AD. The confirmation of the effects of Leqembi were evaluated in the Phase 3 Clarity AD study in early AD.(1,8)

Clarity AD

Clarity AD was a Phase III placebo-controlled randomized controlled trial that evaluated the efficacy of 10 mg/kg of intravenous Leqembi administered every two weeks versus placebo for 18 months, with an open label extension phase with all participants receiving Leqembi for an additional 27 months. The primary outcome was change from baseline in CDR-SB at 18 months. The CDR-SB score is a validated outcome measure used in clinical trials of AD that is obtained by interviewing patients and their care partners and captures cognition and function. Total scores range from 0 to 18, with a score of 0.5 to 6 indicating early AD.(1,9)

The open label extension phase examined treatment-emergent adverse events and change in CDR-SB. Participants were included if they were aged between 50 and 90 years and had a mild cognitive impairment due to AD disease or mild AD disease dementia, objective impairment in episodic memory, amyloid positivity as determined by PET or CSF, objective impairment in episodic memory, had a Mini-Mental State Exam (MMSE) score of 22-30, BMI 17-35, and, if they were receiving any treatment for AD symptoms, were on a stable dose for 12 weeks prior to baseline.(1,9)

In this phase 3 trial, the change from baseline at 18 months in the CDR-SB score (primary end point) was less with Leqembi than with placebo, favoring Leqembi. Results for secondary clinical end points were in the same direction as those for the primary end point. After 18 months of treatment in the amyloid substudy, the mean amyloid level of 22.99 centiloids in the Leqembi group was below the threshold for amyloid positivity of approximately 30 centiloids, above which participants are considered to have elevated brain amyloid levels. In the CSF substudy and in plasma analyses involving the overall population, markers of amyloid, tau, neurodegeneration, and neuroinflammation (plasma GFAP) were reduced to a greater extent with Leqembi than with placebo, with the exception of NfL, which is less sensitive to neurodegeneration than the other markers and has a slower time course for change than the others.(1,9)

In persons with early AD, Leqembi reduced brain amyloid levels and was associated with moderately less decline on clinical measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of Leqembi in early AD. On January 6, 2023, the FDA approved lecanemab under the Accelerated Approval pathway, based on evidence of effect on the surrogate endpoint of amyloid removal in the Phase 2 trial, and a reasonable likelihood of clinical benefit. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial.(1,9)

Amyloid-related Imaging Abnormalities (ARIA) and Adverse Events

The most common adverse reactions (at approximately 10% and higher incidence compared to placebo): infusion-related reactions, headache, and ARIA-edema.

In Study 201, 6% (10/161) of patients in the Leqembi group were apolipoprotein E 4 (ApoE 4) homozygotes, 24% (39/161) were heterozygotes, and 70% (112/161) were noncarriers. The incidence of ARIA was higher in ApoE 4 homozygotes than in heterozygotes and noncarriers among patients treated with Leqembi. Of the 5 patients treated with Leqembi who had symptomatic ARIA, 4 were ApoE 4 homozygotes, 2 of whom experienced severe symptoms. In addition, an increased incidence of symptomatic and overall ARIA in ApoE 4 homozygotes compared to heterozygotes and noncarriers in patients taking Leqembi has been reported in other studies.(1,8)

Enhanced clinical vigilance for ARIA is recommended during the first 14 weeks of treatment with Leqembi. Risk of ARIA, including symptomatic ARIA, was increased in apolipoprotein E 4 homozygotes compared to heterozygotes and noncarriers. If a patient experiences symptoms suggestive of ARIA, clinical evaluation should be performed, including MRI scanning if indicated.(1)

Similar rates of death were reported in the lecanemab and placebo treatment arms (0.7% and 0.8%,respectively). No deaths were considered to be related to the use of lecanemab or involved ARIA-related events, according to the study's authors. Three deaths from brain hemorrhage have been reported in the Clarity open-label extension. Two of the three people had received blood thinners. In Clarity, macrohemorrhages, defined as any brain bleed larger than 1 cm, occurred in 0.6% in the treatment group, and 0.1% in the placebo group. For people on anticoagulants and Leqembi, the rate increased to 2.4%.(7,9)

Number

Reference

1

Leqembi prescribing information. Eisai Inc. July 2023.

2

Winslow BT, et al. Treatment of Alzheimer disease. Am Fam Physician. 2011 Jun 15;83(12):1403-12. Erratum in: Am Fam Physician. 2014 Aug 15;90(4):209. PMID: 21671540.   

3

Alzheimer’s Association. 2022 Alzheimer’s Disease Facts and Figures. Alzheimers Dement 2022;18. 

4

Institute for Clinical and Economic Review (ICER) Draft Evidence Report. Beta-Amyloid Antibodies for Early Alzheimer's Disease. Published December 22, 2022.

5

Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011; 7(3):270-279. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3312027/

6

National Institute on Aging. Alzheimer’s Disease Diagnostic Guidelines. Available at: https://www.nia.nih.gov/health/alzheimers-disease-diagnostic-guidelines.

7

Leqembi. ALZFORUM. https://www.alzforum.org/therapeutics/leqembi. Last Updated January 2023.

8

van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer's Disease. N Engl J Med 2022 November 29. DOI:10.1056/NEJMoa2212948

9

Swanson, Chad J., Yong Zhang, et al., A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimer's Research & Therapy (2021) 13:80. Available at: https://doi.org/10.1186/s13195-021-00813-8.

10

Center for Drug Evaluation and Research (CDER). Summary review. Application number: 761269Orig1s000. Leqembi(lecanemab-irmb). January 6, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/summary_review/2023/761269Orig1s000SumR.pdf

Target Brand Agent(s)

Target Generic Agent(s)

Strength

Client Formulary

Leqembi

lecanemab-irmb iv soln

200 MG/2ML ; 500 MG/5ML