Alzheimer’s Disease (AD) is the most common type of dementia and is characterized by changes in the brain. While the specific causes of Alzheimer’s are not fully known, the changes include senile plaques composed of amyloid β protein (Aβ) and neurofibrillary, or tau, tangles. Resulting in a loss of neurons and their connections, these changes affect a person’s ability to remember and think.
In January 2023, the U.S. Food and Drug Administration (FDA) indicated that the number of Americans affected by AD had surpassed 6.5 million. At the same time, the FDA announced the approval of Leqembi (lecanemab-irmb), via the Accelerated Approval pathway, for treating AD. A Phase III randomized, controlled clinical trial confirmed the drug’s clinical benefit. Leqembi is the second FDA-approved drug in a new category of medications, anti-amyloid monoclonal antibodies (MABs), the first disease-modifying category of drugs for AD. MABs target and affect AD’s fundamental pathophysiology rather than treat disease symptoms.
What is Leqembi?
Leqembi, also known as Lecanemab, is a humanized IgG1 MAB that targets soluble aggregated Aβ species (protofibrils). Intervening in the fundamental biological processes of AD, Leqembi demonstrates robust brain fibrillar amyloid reduction and slows clinical decline in patients with early AD by delaying the inevitable progression of AD into more severe cognitive impairment. Aβ plaque, a marker for AD, is quantified using positron emission tomography (PET) imaging. According to the prescribing information, Leqembi is indicated for treating AD and should be initiated in patients with mild cognitive impairment or mild dementia stage of the disease. The FDA cautions that Leqembi includes a warning for amyloid-related imaging abnormalities (ARIA) and a risk of infusion-related reactions, e.g., flu-like symptoms, nausea, vomiting, and changes in blood pressure.
Cummings et al. (2023) cite the application of neuroscience knowledge to the success of MABs in redefining AD therapeutics and anticipates that MABs will accelerate the development of more anti-amyloid MABs, other types of anti-amyloid therapies, and new approaches to the treatment of other neurodegenerative disorders.
Clinical Research and Evidence for Leqembi
In clinical research by McDade et al. (2022), researchers evaluated Leqembi in a double-blind, placebo-controlled, parallel-group, dose-finding study of 856 patients with AD. The study provided detailed results in biomarker, cognitive, and clinical effects from the randomized and open-label extension of the Phase II proof-of-concept study. Patients receiving the approved dose of Leqembi had a significant reduction in brain amyloid plaques and a slowing of clinical decline. In contrast, patients in the placebo arm had no decrease in Aβ plaque. McDade et al. (2022) concluded that the rapid and pronounced amyloid reduction indicates clinical benefit and potential disease-modifying effects, in addition to the potential use of plasma biomarkers to monitor Leqembi treatment effects.
To further study the impact of Leqembi in early AD, van Dyck et al. (2023) conducted a multicenter, double-blind, Phase III trial. The trial involved persons with early AD with evidence of amyloid on PET or by cerebrospinal fluid testing. Study results demonstrated that at 18 months, Leqembi reduced amyloid markers and resulted in moderately less decline in cognition and function than placebo, but was associated with adverse events. The authors recommend longer trials to determine the safety and efficacy of Leqembi in early AD.
Qiao et al. (2023) published a systematic review and meta-analysis of randomized clinical trials on the cognitive effectiveness and safety of Leqembi in patients with AD. The authors found that the drug showed significant positive statistical efficacy for cognition, function, and behavior in patients with early AD; however, the authors indicated that the actual clinical significance had yet to be established.
Long-term effects of Leqembi
To study the long-term health outcomes of Leqembi in early AD, Tahami Monfared et al. (2023) conducted an evidence-based patient-level disease simulation model. The model compared Leqembi plus standard of care (SoC) and SoC alone. Study findings demonstrated the potential clinical value of Leqembi for early AD by slowing down disease progression and prolonging time in earlier stages of the disease, significantly benefiting patients, caregivers, and society overall.
Implications for Health Systems
As an unprecedented and transformative agent, Cummings et al. (2023) also note that the introduction of Leqembi will impact health systems as a whole. Considerations should be made on the impact of Leqembi use on patients with AD, their care partners, clinicians, and payers.
Looking ahead, Verger et al. (2023) considered the implications of Leqembi and potential widespread amyloid PET use from the perspective of geographies yet to approve it. Citing studies that use amyloid PET as an inclusion criterion and a secondary endpoint, including a sub-study where patients were monitored exclusively by amyloid PET, Verger et al. (2023) caution that the introduction of amyloid PET–guided Leqembi treatment will be a challenge for health systems. The authors recommend that the nuclear medicine community prepare for the anticipated increase in demand for amyloid PET radiotracers, PET imaging infrastructure, and training for image reading.
Economic Value of Leqembi
To further understand the value of Leqembi, several studies aimed to predict the economic and societal value of the introduction of Leqembi for patients with early AD. Tahami Monfared et al. (2023) used simulation modeling to estimate the societal value of Leqembi. The economic study estimated the long-term societal value of Leqembi plus SoC versus SoC alone from both the U.S. payer and societal perspectives. Study findings suggest that Leqembi plus SoC would improve health and quality of life outcomes while reducing the economic burden for patients and caregivers.
A patient-level simulation was conducted by Igarashi et al. (2023) to predict the societal value of Leqembi in early AD in Japan. The study compared Leqembi plus SoC versus SoC alone against a range of willingness-to-pay (WTP) thresholds from a healthcare and societal perspective in Japan. Similar to the Tahami Monfared et al. (2023) study, the findings suggest that using Leqembi plus SoC would improve health and quality of life outcomes with a reduced economic burden for patients and caregivers with early AD in Japan.
From the European Alzheimer’s Disease Consortium Executive Committee (EADC-EC) viewpoint, Jönsson et al. (2023) considered the affordability of Lecanemab for AD in Europe. Estimating the population potentially eligible for treatment in the 27 EU countries to be 5.4 million individuals, the authors anticipate treatment costs above EUR$133 billion per year if the drug were priced similarly to the U.S. (i.e., over half the total EU pharmaceutical expenditure). The EADC-EC seeks pricing policies that will allow eligible patients across Europe to access innovations while supporting continued research and development investments.
Learn more about exciting developments in the treatment of nervous system disorders and the future of neurology.
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