How promising are the latest monoclonal antibodies targeting amyloid-ß for the treatment of early Alzheimer's disease?

INTRODUCTION: Monoclonal antibodies targeting amyloid-ß are the first disease-modifying treatments for Alzheimer disease to have received FDA-approval. There are three different drugs approved or pending FDA-approval: aducanumab, lecanemab, and donanemab. These three drugs are each in different stages of regulatory approval by the FDA. AREAS COVERED: We discuss the development of these drugs, the data regarding their clinical efficacy, their dosing regimens, and side effects. In addition, we examine pragmatic issues with their potential implementation as common treatments to slow the rate of decline in Alzheimer disease, and what unanswered questions remain regarding this new class of drugs. EXPERT OPINION: We conclude that these new monoclonal antibodies that target amyloid-ß represent a genuine advance in the treatment of Alzheimer disease. However, questions remain regarding their clinical significance. Additionally, it is presently unclear which patients would most benefit from these expensive drugs given the risk of side effects and the logistical difficulties concerning administration and the determination of eligibility.

Profiling lecanemab as a treatment option for Alzheimer's disease.

INTRODUCTION: In July 2023, the U.S. Food and Drug Administration (FDA) granted full approval to lecanemab for the treatment of mild cognitive impairment (MCI) due to Alzheimer's disease (AD) and mild AD dementia. Considering the limited treatment options for AD, the approval of lecanemab offers hope and opens the door for other disease-modifying therapies in the pipeline. AREAS COVERED: In this review, the authors summarize the FDA treatment guidelines, other anti-amyloid agents, and drug information relevant to prescribers, such as pharmacology and pharmacokinetics. Relevant clinical trial outcomes are discussed along with their significance and controversies. EXPERT OPINION: While questions remain about the magnitude of lecanemab's clinical impact, its approval signifies major progress in addressing the underlying pathology of AD. The authors have confidence in lecanemab as a promising treatment option and foresee exciting advancements on the 5-year horizon. Yet, further research is needed regarding trials beyond 18 months, post-marketing surveillance, and lecanameb in combination with existing treatments and lifestyle interventions.

Pharmacokinetic evaluation of donanemab for the treatment of Alzheimer's.

INTRODUCTION: Donanemab is a humanized monoclonal antibody that significantly reduces cerebral amyloid plaques in Alzheimer's Disease (AD). It can delay disease progression and cognitive decline, making it one of the most promising disease-modifying treatments in the current treatment landscape. AREAS COVERED: This paper covers the current literature available on pharmacokinetics, pharmacodynamics, safety, and tolerability of donanemab. Publications from PubMed and Google were reviewed. A summary of regulatory approvals and current clinical data is also provided. EXPERT OPINION/COMMENTARY: Donanemab as a therapy for AD has more effective disease-modifying effects compared to lecanemab. Donanemab appears generally well-tolerated; however, it may have higher rates of severe side effects, such as amyloid-related imaging abnormalities (ARIA), that could lead to death. Guidelines for frequency of MRI monitoring for ARIA/safety are pending but will be integral to determining its use. Despite some limitations, donanemab is expected to receive FDA approval, giving clinicians access to another disease-modifying drug. Overall, more data is needed about donanemab, especially relating to safety, efficacy, cost, and integration with other treatments, but its development signifies progress in AD treatment.

Alzheimer's Disease (AD) is a brain disorder that severely impacts memory, behavior, and thinking. The most common treatments manage symptoms but do not slow disease progression or improve function. Accumulation of proteins called amyloid-beta plaques in the brain are one of the main causes of the disease. Donanemab is an antibody that helps the body remove these plaques. This review summarizes what is currently known about the safety of donanemab, how it works, and the extent to which it can help people with AD.Results suggest that donanemab significantly decreases the amount of plaques in the brain, delays disease progression, and improves cognition. Treatment can prevent reaccumulation of plaques for an extended period of time. There are some side effects associated with treatment, but they are generally manageable and resolve when the drug is stopped. In rare cases, more serious side effects were reported. These require careful monitoring and an evaluation of potential risk compared to benefit. Overall, current information on donanemab is extensive and shows promise. However, to help caregivers and people with AD make informed decisions on using the drug, further research is needed to fully explore donanemab's safety, cost, and efficacy compared to other therapies in the same class.

The donepezil transdermal system for the treatment of patients with mild, moderate, or severe Alzheimer's disease: a critical review.

INTRODUCTION: Cholinesterase inhibitors, along with memantine, are the mainstay of symptomatic treatment for AD (Alzheimer's disease); however, these medications are typically administered orally, which can be difficult for people with AD and their caregivers. AREAS COVERED: In this drug profile and narrative review, the authors trace the development of the new FDA-approved transdermal donepezil. The authors discuss the studies showing its bioequivalence with the oral formulation, including two double-blinded placebo controlled non-inferiority trials. The authors also compare the patch to the only other transdermal cholinesterase inhibitor on the market, rivastigmine, and highlight the potential advantages and disadvantages between these two treatments. EXPERT OPINION: While the patch is bio-equivalent, it is rather large and may not be affordable for some patients. In addition, there is no high dose (e.g. 23 mg) equivalent. Nevertheless, transdermal donepezil will be useful for people with AD and their caregivers, given its effectiveness and potential convenience.

The aquaporin-4 water channel and updates on its potential as a drug target for Alzheimer's disease.

INTRODUCTION: Although there are several FDA-approved treatments for Alzheimer's disease (AD), only recently have disease-modifying therapies received approval for use in patients. In this narrative review, we examine the history of aquaporin-4 (AQP4) as a therapeutic target for NMOSD (neuromyelitis optica spectrum disorder) and as a potential therapeutic target for AD. AREAS COVERED: We review the basic science and discovery of AQP4, a transmembrane water-channel essential to regulating water balance in the central nervous system (CNS). We also review the pathogenesis of NMOSD, an autoimmune disease characterized by the destruction of cells that express AQP4. Then, we review how AQP4 is likely involved in the pathogenesis of Alzheimer's disease (AD). Finally, we discuss future challenges with drug design that would modulate AQP4 to potentially slow AD development. The literature search for this article consisted of searching Google Scholar and PubMed for permutations of the keywords 'Alzheimer's disease,' 'aquaporin-4,' 'neuromyelitis optica,' and their abbreviations. EXPERT OPINION: We place research into AQP4 into context with other recent developments in AD research. A major difficulty with drug development for Alzheimer's is the lack of strategies to cleanly target the early pathogenesis of the disease. Targeting AQP4 may provide such a strategy.

Alcohol is a predictor of mortality in motor vehicle collisions.

INTRODUCTION: It is well recognized that driving while intoxicated increases the probability of a motor-vehicle collision (MVC). The effect of alcohol on the chance of surviving the MVC is less clear. METHOD: Using data from the Fatality Analysis Reporting System (FARS) we conducted analyses for the outcome of mortality using alcohol and other variables as predictors. We also selected alcohol positive (AP) and alcohol negative (AN) persons from the same MVC and vehicle to control for confounding characteristics. RESULTS: The odds ratio (OR) for mortality for alcohol positive drivers was 2.57, (p < 0.001 for all the following OR). Other harmful predictive factors were age OR 1.01 per year, vehicle age OR 1.05 per year, male sex OR 1.23, avoidance maneuver OR 1.09, speed related OR 2.89, rollover mechanism OR 2.75, and collision with a fixed object OR 6.70. Protective factors were proper restraint use - OR 0.19 and collision with another moving vehicle, OR 0.21. In the multivariate analysis the OR of mortality for AP vs AN was 1.46. Proper restraint use (OR 0.27) remained protective along with collision with another moving vehicle. When AP and AN persons from the same MVC and the same vehicle were compared, the adjusted OR's for mortality were 1.46 and 2.08, respectively. CONCLUSIONS: Alcohol is an independent predictor of mortality in an MVC. Proper restraint use is the strongest protective factor. This finding allows a more complete understanding of the risks of driving while intoxicated, not only a higher probability of an MVC, but decreased survival once the MVC occurs. Practical Applications: Identification of alcohol as an independent predictor of mortality in an accident may improve risk assessment and influence drivers to avoid driving while intoxicated.