Lecanemab-irmb: Treatment for Alzheimer’s Materials

LECANEMAB-IRMB: A TREATMENT OPTION FOR THE EARLY STAGES OF ALZHEIMER’S DISEASE

Pamela Sardo, PharmD, B.S.

Pamela Sardo, PharmD, B.S., is a licensed pharmacist and Freelance Medical Writer at Sardo Solutions in Texas.

Topic Overview

Alzheimer’s disease (AD) is the most common cause of dementia and a leading cause of death among older populations. Globally, an estimated 55 million people are affected by dementia. Lecanemab-irmb is a drug approved by the Food and Drug Administration under an accelerated approval process. This drug is used in the early stages of AD. This drug targets amyloid protofibrils and reduces amyloid beta plaques in AD patients. In clinical trials, individuals with mild cognitive impairment or early AD, and evidence of amyloid beta plaques, received lecanemab-irmb, and after 18 months, reduced cognitive decline was reported. Further trials are needed to confirm the efficacy and safety of lecanemab in early Alzheimer's disease. Pharmacy teams are well- positioned to discuss lecanemab-irmb with healthcare professionals and patients suffering from Alzheimer’s disease.

Accreditation Statement:

RxCe.com LLC is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education.

Universal Activity Number (UAN): The ACPE Universal Activity Number assigned to this activity is 

Pharmacist  0669-0000-23-014-H01-P

Pharmacy Technician  0669-0000-23-015-H01-T

Credits: 1 hour of continuing education credit

Type of Activity: Knowledge

Media: Internet, Home Study Fee Information: $4.99

Estimated time to complete activity: 1 hour, including Course Test and course evaluation

Release Date: February 21, 2023 Expiration Date: February 21, 2026

Target Audience: This educational activity is for pharmacists.

How to Earn Credit: From February 21, 2023, through February 21, 2026, participants must:

Read the “learning objectives” and “author and planning team disclosures;”

Study the section entitled “educational activity;”

Complete the Course Test and Evaluation form. The Course Test will be graded automatically. Following successful completion of the Course Test with a score of 70% or higher, a statement of participation will be made available immediately. (No partial credit will be given.)

Credit for this course will be uploaded to CPE Monitor.

Learning Objectives: Upon completion of this educational activity, participants should be able to:

Describe the basic pathophysiology associated with Alzheimer's disease

Describe the proper indications and uses of lecanemab-irmb

Identify possible adverse effects associated with the use of lecanemab-irmb

Provide information to patients and caregivers about support and resources for Alzheimer’s patients

Disclosures

The following individuals were involved in the development of this activity: Pamela Sardo, PharmD, B.S., and Susan DePasquale, MSN, PMHNP-BC. Pamela Sardo, Pharm.D., B.S., was an employee of Rhythm Pharmaceuticals until March 2022 and has no conflicts of interest or relationships regarding the subject matter discussed. There are no financial relationships relevant to this activity to report or disclose by any of the individuals involved in the development of this activity.

ⓒ RxCe.com LLC 2022: All rights reserved. No reproduction of all or part of any content herein is allowed without the prior, written permission of RxCe.com LLC.

Introduction

Over 55 million people are living with dementia worldwide and this number is expected to grow. The projections are that by 2050, the number of people with Alzheimer’s disease dementia will triple. These staggering numbers highlight the need for the development of new treatments for patients with Alzheimer’s disease. Lecanemab-irmb is a newly approved drug for Alzheimer’s patients with mild cognitive impairment or mild dementia. Further trials are needed to confirm the efficacy and safety of lecanemab in early Alzheimer's disease. Pharmacy teams are well-positioned to discuss lecanemab-irmb with healthcare professionals and patients suffering from Alzheimer’s disease.

The History of Alzheimer’s Disease

In 1906, Dr. Alois Alzheimer reported on a patient he described as having a “peculiar severe disease process of the cerebral cortex.”1 The patient was a 50-year-old woman who was admitted to the Munich University Hospital for symptoms of “paranoia, progressive sleep and memory disturbance, aggression, and confusion.”1 Dr. Alzheimer treated the patient for five years.1 Her condition persisted until her death and after her death, an autopsy was performed that showed distinctive plaques and neurofibrillary tangles in her brain.1 In 1910, Dr. Alzheimer’s colleague, Emil Kraeplin, referred to the condition as “Alzheimer’s disease” for the first time in a medical book entitled Psychiatrie.1

In 1968, cognitive measurement scales were created, which permitted researchers to assess impairment and estimate the volume of damaged brain tissue. In 1983, the first National Alzheimer’s Disease Month declaration brought greater disease awareness.2

In 1993, a new therapeutic, tacrine, was approved by the Food and Drug Administration (FDA) and it was considered effective for mild-to-moderate Alzheimer’s disease (AD). The following year, President Ronald Regan announced that he had been diagnosed with AD, bringing greater attention to

the disease and its treatments.2 In 2003, memantine, a new N-methyl-D- aspartate (NMDA) receptor antagonist treatment, was approved.3 However, in spite of the new treatments and attention AD was receiving, by 2010, AD was listed as the sixth leading cause of death in the United States,2 and by May 2012, tacrine was withdrawn from the market due to concerns over its liver toxicity.4

Thereafter, additional pharmacotherapy agents were FDA-approved to treat Alzheimer’s symptoms, including cholinesterase inhibitors (donepezil, galantamine, and rivastigmine).5,6 In 2014, a combination of memantine and donepezil was FDA-approved.6-8 Subsequent research, including the first anti- amyloid beta (anti-Aβ) agent, failed to improve clinical symptoms. In 2020, the FDA Advisory Council met and voted on aducanumab, a drug designed to target and remove specific forms of beta-amyloid that accumulate into plaques within the brain. Approval was denied; however, unexpectedly, it received full FDA approval in 2021.9

Current conversations in the medical community include the role amyloid beta and beta-amyloid may play in the development of AD.10 Beta- amyloid (also referred to as amyloid beta, Aβ, by some researchers) is a normal peptide generated throughout life and a component of amyloid plaques. Amyloid plaques are a pathological characteristic in the brain of individuals with AD.11

Many questions remain about AD after its discovery over 100 years ago. The current view that amyloid plaques within Aβ1–42 play the prominent role in the development and progress of AD is in question. This is discussed in more detail below. Scientists continue to study the causes of AD and look for new treatments to prevent or control this debilitating disease.

Prevalence of Alzheimer’s Disease

More than 6 million Americans live with AD. Published data describes that, upon death, 1 in 3 seniors had Alzheimer’s or another dementia.2 In

2020, reports indicated over 55 million people are living with dementia worldwide.28

Pathophysiology in Mild Alzheimer’s Disease

The risk of AD doubles every five years after age 65, according to the Alzheimer’s Foundation of America. High amounts of two brain proteins - beta-amyloid and tau - are indicators of AD and they may cause brain cell damage. Researchers are assessing whether high levels of beta-amyloid and tau are symptoms, or causes, of AD.12

Alzheimer’s disease is a pathological process that develops into a clinical disease over decades. During the asymptomatic phase, amyloid accumulation can be detected using advanced neuroimaging or by cerebrospinal fluid examination.13

In AD, neuron communication is disrupted, neurons stop functioning, lose connections with other neurons, and die. Mild cognitive impairment (MCI) is referred to as the early stage of AD. Mild cognitive impairment represents a transitional period between normal aging and AD.14 Difficulty forming and retaining new memories is usually the earliest symptom of AD.7,15

In the early stages, neuritic plaques (neuron fragments surrounding a core of Aβ-protein) are present. This Aβ-protein comes in several different forms and they collect between neurons.10 However, there is growing support for a shift away from focusing on the amyloid plaques within Aβ1–42 as the primary cause of AD, and a greater focus on the oligomeric (repeating units in a molecule derived from smaller molecules) forms within this molecular structure.16-19 Fantini, et al. (2020) explained why there is a shift away from amyloid plaques.20 They argue that amyloid plaques are not specific to AD patients since they appear in the brains of cognitively normal individuals. It may be that the presence of amyloid plaques is necessary if a person is going to progress toward AD, or they may be indicative of an earlier, pre-AD state, but these assumptions are suspect since, for example, amyloid plaques are not always found in the brain of patients with inherited forms of AD.20 These

questions and different theories on the causes of AD will be studied and debated as scientists work toward a better understanding of AD, its treatment options, and a possible cure.

The early stages also present with neurofibrillary tangles. The tangles are abnormal accumulations of tau that collect inside neurons. Tau protein forms part of a microtubule, transporting nutrients and other substances from one nerve cell to another. In AD, the tau protein becomes abnormal and the microtubule collapses.21-23

Loss of basal forebrain cholinergic neurons also occurs.21 The brain's cholinergic system is associated with attention, information transmission, cognitive processing, and memory, so this loss can be debilitating. In summary, researchers are mainly focusing on the accumulation of amyloid plaques, leading to inflammation and brain cell destruction, and tau protein abnormalities, leading to neurofibrillary tangles.22,23 These processes are possible contributors to the presymptomatic stage, early impairment stage, or AD.24

New Pharmacotherapy Option: Lecanemab-irmb

Lecanemab-irmb (LEQEMBI) is an intravenous drug approved by the FDA in 2023 for the treatment of Alzheimer’s disease.25 It is indicated for patients with mild cognitive impairment or mild dementia, which was the population treated during clinical trials. At this time, safety and effectiveness data is not available on initiating treatment at earlier or later stages of the disease. This indication was approved under an accelerated approval process based on a reported reduction in amyloid beta plaques in patients. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial.25

Mechanism of Action

Lecanemab-irmb is directed against aggregated soluble and insoluble forms of Aβ. The accumulation of Aβ plaques in the brain is a defining

pathophysiological feature of Alzheimer’s disease and lecanemab-irmb reduces amyloid beta plaques.25

Dosing

Lecanemab-irmb is available as a 500 mg/5 mL (100 mg/mL) solution in a single-dose vial and a 200 mg/2 mL (100 mg/mL) solution in a single- dose vial. It should only be given after confirmation of the presence of Aβ pathology. The recommended dosage is 10 mg/kg which must be diluted in 250 mL of 0.9% Sodium Chloride Injection, USP. It is then administered as an intravenous infusion over approximately one hour, once every two weeks.25

Within one year before lecanemab-irmb treatment, a brain magnetic resonance imaging (MRI) scan should be obtained to evaluate whether pre- existing amyloid-related imaging abnormalities (ARIA) are present. Amyloid- related imaging abnormalities may present as edema or microhemorrhage. Magnetic resonance imaging scans are also recommended before the 5th, 7th, and 14th infusions.25

Clinical Trials

The accelerated approval of lecanumab-irmb by the FDA was based on the outcomes of the phase 2 data.25 The phase 2 data was referred to as Study

1 in the prescribing information. In this study, 161 participants were randomized to the recommended dosing regimen of 10 mg/kg every two weeks of lecanemab-irmb or placebo. The mean age at study entry was 73 years (ranging from 51 to 88 years). Enrollment was permitted with, or without, concomitant approved therapies (cholinesterase inhibitors and the N- methyl-D-aspartate antagonist memantine) for Alzheimer’s disease.25

Participant enrollment was based on a Clinical Dementia Rating (CDR) global score of 0.5 or 1.0 and a Memory Box score of 0.5 or greater.25 The CDR was obtained through interviews. The Clinical Dementia Rating–Sum of Boxes (CDR-SB) was considered a sensitive measure of cognitive and functional impairment simultaneously. Cognitive function was rated in 6

domains (box scores) of functioning, including memory, orientation, judgment, problem-solving, community affairs, home, hobbies, and personal care.25 Memory (M) was considered the primary category.26 The domains rating was either 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; or 3, severe impairment.25

All patients in the study had a Mini-Mental State Examination (MMSE) score of ≥22.25 The Mini-Mental State Exam is a 30-point test used to measure cognitive impairment. It measures orientation to time and place, ability to concentrate, and whether the patient can recall a series of items to test short- term memory. It also measures verbal memory and naming, visuospatial skills, and the ability to solve problems, such as spelling a simple word backward.27

The primary endpoint of the clinical trial was a change from baseline on a composite score consisting of items from the CDR-SB MMSE, and ADAS- Cog 14 (a cognitive subscale including 11 tasks) at Week 53.25 A prespecified success criterion of 80% was expected in the phase 2 study but lecanemab- irmb only had 64% success; i.e., there was a 64% likelihood of 25% or greater slowing of progression relative to placebo at Week 53. This did not meet.25 However, the secondary endpoints specified in the trial were met.24 Secondary endpoints “included the change from baseline in amyloid PET SUVR composite at Week 79 and change from baseline in the CDR-SB and ADAS-Cog14 at Week 79.”25

The Study 1 data was analyzed and lecanemab-irmb received FDA approval. Scientists then initiated a phase 3 trial.28 The newly published phase 3 Clarity AD trial data included a primary outcome of a change in CDR-SB after 18 months of treatment. Researchers published that patients on lecanemab- irmb experienced a mean increase in CDR-SB scores, indicating worsening dementia, of 1.21 points.26,28 Secondary endpoints in the phase 3 Clarity AD trial also evaluated changes from baseline at 18 months. Amyloid changes were measured using positron-emission tomography, and scores on the 14- item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS), the Alzheimer’s Disease Composite Score (ADCOMS), and the score on the

Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL).28-30

The phase 3 Clarity AD trial reported that patients on a placebo demonstrated a higher increase, of 1.66 points. According to the researchers, this difference represents a 27% relative slowing of dementia progression in patients receiving lecanemab-irmb.28

Review of Study 1 and the phase 3 Clarity AD trial has led some scientists to state that “the cognitive improvement associated with Lecanemab treatment is modest.”16 These studies may also be interpreted as a confirmation that scientists are on the right track, and that Aβ1–42 is the right molecular structure to target; however, as mentioned above, there is growing support for a shift away from the amyloid plaques within Aβ1–42 and greater focus on the oligomeric forms within this molecular structure.16

Adverse Events

Healthcare professionals should always consult the prescribing information for comprehensive safety and efficacy information. Common adverse reactions occurring in Study 1 are reported in Table 1. In Study 1, 15% of patients treated with lecanemab-irmb, compared to 6% of patients on placebo, stopped study treatment because of an adverse reaction. The most common adverse reaction leading to discontinuation of treatment was reported to be infusion-related reactions. Two percent of patients on treatment stopped lecanemab-irmb compared to 1% of patients on placebo.25

In Study 1, the majority of the infusion-related reactions shown in Table 1 reportedly occurred with the first infusion and were characterized as mild or moderate in severity. 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.25

Table 1. Adverse Reactions Reported in at Least 5% of Patients Treated with Lecanemab-irmb occurring at least 2% Higher than Placebo

*Amyloid-related imaging abnormalities with edema or effusion

Antibodies are generally protective proteins produced by the body’s immune system. They attach to antigens (foreign substances) and remove them from the body. Antibodies directed against aggregated beta-amyloid, including lecanemab-irmb, can cause abnormal brain MRI imaging, or ARIA, described above.25 These imaging abnormalities are divided into ARIA-E (abnormalities with edema), or ARIA-H (ARIA with hemosiderin deposition). Abnormalities with edema can be observed on an MRI as brain edema or effusions, and microhemorrhage appears with ARIA-H.

Amyloid-related imaging abnormalities are usually asymptomatic, although serious and life-threatening events, e.g., seizures can occur. Symptoms associated with ARIA may include headache, confusion, visual changes, dizziness, nausea, and gait difficulty. Focal neurologic deficits may also occur but they usually resolve over time.25

In Study 1, ARIA were observed in 12% of patients treated with lecanemab-irmb, compared to 5% of patients on placebo. If intracerebral hemorrhage, greater than 1 centimeter (0.39 inches) in diameter, was discovered during treatment with lecanemab-irmb, dosing was stopped until an MRI identified that the issue is resolved.25

Patients were excluded from Study 1 if they used anticoagulant medications. Distinct from anticoagulants, antiplatelet medications, such as aspirin and clopidogrel, were allowed in this study. The subsequent review of Study 1 results revealed that lecanemab-irmb patients receiving an

antithrombotic medication (aspirin, other antiplatelets, or anticoagulants) did not have an increased risk of ARIA-H compared to patients who received a placebo.25

Patient and Caregiver Education and Resources

Interactions with Alzheimer’s patients and caregivers are an important way to ensure that medicines are taken safely and correctly. A multidisciplinary approach to this disease provides broad opportunities to optimize care. June is Alzheimer’s and Brain Awareness Month and November is National AD Awareness Month which are effective times to provide resources and education that address the needs of the community and clinicians.

Table 2: Resources for Pharmacists and the Community*

*This list is not all-inclusive and does not endorse any specific organization or process. It provides resource options. It is not meant to delay or replace licensed professional medical advice.

What is Next?

Globally, the number of individuals with dementia is expected to almost double every 20 years, increasing the number of people with dementia to 78 million in 2030 and 139 million in 2050.31 In the U.S., the total number of people with AD dementia in 2050 is projected to be 13.8 million, with 7.0 million aged 85 years or older.32 The expectation is that compared to the number of people with AD dementia reported in 2010, the number will triple by 2050.32

The FDA will soon evaluate data from the newly published Phase 3 Clarity AD trial. This review is part of a Supplemental Biologics License Application (sBLA) for consideration of the traditional FDA approval pathway.33 The manufacturer is developing a program called Understanding ARIA™ to provide peer-to-peer education, individual and group educational sessions, and subject-matter-expert evaluation of case studies.33

Looking toward the future, a study is underway to evaluate the efficacy and safety of lecanemab-irmb in participants with preclinical Alzheimer's Disease and elevated amyloid. This study will also evaluate participants with early preclinical Alzheimer's Disease and intermediate amyloid.34 Another study will determine whether an experimental molecule, E2814, is superior to placebo, when each is concurrently administered with lecanemab-irmb, with the objective to prevent dementia.35 Future studies are also likely to focus on the role of amyloid plaques and oligomeric forms within Aβ1–42, in an effort to identify and address the root cause or causes of AD.16

Summary

Globally, over 55 million people are living with dementia worldwide. In the US, more than 6 million people live with AD. These numbers are expected to triple by 2050.

No effective cure is currently available for AD. Treatment options have had limited success but ecanemab-irmb was approved under an accelerated approval process because trials showed that it reduced amyloid beta plaques in patients. Lecanemab-irmb provides a new treatment option in a select group of patients.

Healthcare professionals, physicians, nurses, and pharmacy team members are well-positioned to recognize cases of cognitive decline in their patient populations. During counseling and education, they can provide essential evidence-based knowledge and offer support, and direct patients toward resources available for those with AD.

Course Test

Which of the following statements is or are true about Alzheimer’s disease (AD)?

It is a progressive neurologic disorder

It causes brain cell damage

Loss of brain cholinergic neurons occurs

All of the above

Which of the following statements is true about the pathophysiology of mild Alzheimer’s disease?

Low amounts of brain proteins, beta-amyloid, and tau, are indicators of AD

It is unknown whether high beta-amyloid is a symptom or cause of AD

Amyloid accumulation can be demonstrated using ultrasound and X- ray.

Mild cognitive impairment (MCI) is referred to as late-stage AD

Which of the following statements is true regarding the proper use of lecanemab-irmb?

Lecanemab-irmb is available as a 500 mg/5 mL (100 mg/mL) solution

It should be initiated in patients with advanced cognitive impairment

The dosage is 60 mg/kg diluted in 250 mL of 1.9% Sodium Cl.

Injection

Dose lecanemab-irmb as an IV infusion over 3 hours, twice every week

Adverse events reported with lecanemab-irmb include

sinusitis in 6% and clostridium difficile in 1%.

respiratory syncytial virus in 2% and cough in 2%.

infusion-related reactions in 9% and diarrhea in 4%.

infusion-related reactions in 20% and headache in 14%.

A home health aide, caring for a person with Alzheimer’s disease, asks for resources to learn more about the disease. What resources can be useful?

Bright Focus Foundation

Alzheimer’s Association

National Institute on Aging

All of the above

In Alzheimer’s disease,

neurons function but tau does not.

the neuron communication is disrupted.

connections with other neurons increase.

neuron fragments surrounding Aβ-protein disappear.

Which of the following statements should a clinician keep in mind when prescribing lecanemab-irmb?

ARIA can be identified in patients receiving lecanemab-irmb

Brain MRIs should be obtained in patients on lecanemab-irnb

Initiate lecanemab-irmb in patients with mild cognitive impairment

All of the above

A radiology technician student tells you they heard the word ARIA and would like to know what the initials stand for. How can you respond?

Alzheimer’s-related intelligence abnormalities

Abnormalities related to intense aneurysm

Amyloid-related imaging abnormalities

Antiplatelet-related imaging abnormalities

Which of the following statements is true regarding mild cognitive impairment (MCI)?

MCI always progresses to Alzheimer’s disease

Lecanemab-irmb is a new treatment to cure MCI

MCI is referred to as a period between normal aging and AD

Currently, MCI occurs in 78 million people globally

Which of the following statements describes data from lecanemab-irmb studies?

In Study 1, primary and secondary endpoints were met

Phase 2 study revealed a 90% likelihood of 50% slowing of progression

Clarity-AD demonstrated 27% relative slowing of dementia progression

Studies assessed CB-AB, MMNO, and AD-SM-RT composite measures

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https://clinicaltrials.gov/ct2/show/NCT05269394?term=lecanemab&dra w=2&rank=6 . Accessed January 26, 2023

DISCLAIMER

The information provided in this course is general in nature, and it is solely designed to provide participants with continuing education credit(s). This course and materials are not meant to substitute for the independent, professional judgment of any participant regarding that participant’s professional practice, including but not limited to patient assessment, diagnosis, treatment, and/or health management. Medical and pharmacy practices, rules, and laws vary from state to state, and this course does not cover the laws of each state; therefore, participants must consult the laws of their state as they relate to their professional practice.

Healthcare professionals, including pharmacists and pharmacy technicians, must consult with their employer, healthcare facility, hospital, or other organization, for guidelines, protocols, and procedures they are to follow. The information provided in this course does not replace those guidelines, protocols, and procedures but is for academic purposes only, and this course’s limited purpose is for the completion of continuing education credits.

Participants are advised and acknowledge that information related to medications, their administration, dosing, contraindications, adverse reactions, interactions, warnings, precautions, or accepted uses are constantly changing, and any person taking this course understands that such person must make an independent review of medication information prior to any patient assessment, diagnosis, treatment and/or health management. Any discussion of off-label use of any medication, device, or procedure is informational only, and such uses are not endorsed hereby.

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