FDA Advisory Panel Unanimously Approves Donanemab for Alzheimer’s Disease


A significant stride in the battle against Alzheimer’s disease emerged as the US Food and Drug Administration (FDA) advisory committee granted unanimous approval to donanemab, a drug developed by Eli Lilly. This marks a crucial step towards making donanemab available in clinical settings. If approved, donanemab will become the second drug on the US market aimed at slowing cognitive decline caused by Alzheimer’s disease. Despite its promise, donanemab’s effects are modest, and it does not reverse symptoms. The FDA may also impose restrictions on its usage.

On June 10, 2024, at the FDA’s headquarters in Silver Spring, Maryland, all 11 members of an FDA independent scientific advisory committee voted in favor of donanemab’s effectiveness for treating Alzheimer’s, particularly in its early stages. The committee concluded that the benefits of donanemab outweigh its risks. This meeting surprised many observers who had anticipated a swift FDA approval without convening an advisory committee. Instead, the FDA chose to delay its decision to address concerns regarding the drug’s efficacy in individuals with specific Alzheimer’s markers. Ultimately, the meeting was highly positive, with neurologist David Knopman of the Mayo Clinic noting that it would have been challenging to object based on the available data.

Donanemab is an antibody that targets amyloid, a sticky protein that accumulates in the brains of Alzheimer’s patients. In data submitted to the FDA, Eli Lilly reported that the 860 trial participants who received donanemab experienced a slower decline in cognitive abilities over 18 months compared to those who received a placebo. However, the drug did not reverse the disease. Research indicates that donanemab slows symptoms similarly to its rival drug lecanemab, developed by Eisai and Biogen. Unlike previous monoclonal antibody trials, Eli Lilly’s trial included only participants whose brains contained both amyloid and another protein called tau, associated with cognitive decline. Donanemab appeared more effective in individuals with low to moderate tau levels at the start of the trial compared to those with high levels. The FDA noted that the disease might have progressed more slowly in the lower-tau group than in those with higher tau.

Advisory committee members were generally supportive of donanemab, though some expressed concerns about the lack of evidence for its efficacy in individuals with minimal tau. Despite this, the committee decided against restricting the drug’s usage based on tau levels, citing the complexity and cost of tau screening, which would prevent many from accessing the drug.

The panel also raised concerns about a condition known as amyloid-related imaging abnormalities (ARIA), which can cause brain bleeding and seizures. ARIA, potentially fatal, is believed to occur when antibodies weaken blood vessels in the brain. Eli Lilly recorded more ARIA-related deaths among donanemab recipients than in the placebo group. Although lecanemab is also associated with ARIA, the increased risk appears significantly higher with donanemab.

The approval of donanemab is a positive development for amyloid-targeting Alzheimer’s drugs, following several controversies. The FDA approved the first such drug, Biogen and Eisai’s aducanumab, in 2021 despite objections from its advisory committee, leading to the resignation of three committee members. A subsequent US Congressional investigation found that the FDA had improperly guided the manufacturers through the approval process. Many insurers were unconvinced of aducanumab’s efficacy, resulting in most refusing to cover it. Biogen ceased production of the drug earlier this year, and three individuals died from ARIA-related conditions during lecanemab’s clinical trials.

The donanemab committee emphasized the need for further research, including the optimal duration of treatment and its efficacy in individuals with varying tau levels. Knopman pointed out that it remains to be seen whether the drug’s modest effect will persist over years. The committee also recommended more research on donanemab’s efficacy in people of color, as over 90% of Lilly’s trial participants were white, and in individuals with Down’s syndrome or genetic mutations that predispose them to ARIA. Committee member Kathleen Poston, a neurologist at Stanford University Medical Center, stressed the importance of obtaining these data to ensure the drug’s benefits can be extended to all Alzheimer’s patients. The FDA’s final decision on donanemab is anticipated later this year.

The development and approval of donanemab reflect broader trends and challenges in Alzheimer’s research and treatment. Alzheimer’s disease, a progressive neurodegenerative disorder, affects millions globally, with the number of cases expected to rise as the population ages. The disease’s complexity has made it difficult to develop effective treatments, with many promising drugs failing in clinical trials.

Amyloid plaques and tau tangles are hallmark features of Alzheimer’s pathology. Amyloid plaques form when fragments of the amyloid-beta protein accumulate and clump together in the brain, disrupting cell function. Tau tangles occur when tau proteins, which stabilize microtubules in neurons, become abnormally modified and form tangles inside neurons, leading to cell death. These pathological changes are associated with cognitive decline and dementia in Alzheimer’s patients.

The focus on amyloid-targeting therapies, such as donanemab and lecanemab, stems from the amyloid hypothesis, which posits that amyloid-beta accumulation initiates a cascade of events leading to Alzheimer’s pathology. However, the failure of many amyloid-targeting drugs to produce significant clinical benefits has led to debates within the scientific community about the validity of the amyloid hypothesis. Some researchers argue that targeting tau pathology or other mechanisms, such as neuroinflammation, might be more effective approaches.

Donanemab’s approval highlights the complexities and risks associated with amyloid-targeting therapies. ARIA, a serious side effect involving brain swelling and bleeding, poses significant risks to patients. Understanding and mitigating these risks is crucial for the safe use of these drugs. The increased incidence of ARIA-related deaths with donanemab compared to lecanemab underscores the need for careful patient monitoring and selection.

Furthermore, the disparity in trial participants’ demographics points to a broader issue in clinical research— the need for diverse participant representation. Genetic, biological, and environmental factors can influence drug efficacy and safety, making it essential to include diverse populations in clinical trials. The committee’s call for more research on donanemab’s effects in people of color and those with Down’s syndrome or genetic predispositions to ARIA reflects a growing recognition of this need.

The economic implications of new Alzheimer’s treatments are also significant. Alzheimer’s disease imposes a substantial economic burden on healthcare systems and families, with costs expected to increase as the population ages. Effective treatments that slow disease progression could potentially reduce this burden, but they also come with high costs. Balancing the benefits and costs of new therapies is a critical consideration for policymakers, insurers, and healthcare providers.

Eli Lilly’s donanemab represents a step forward in Alzheimer’s treatment, offering hope for patients and families affected by this devastating disease. However, its modest effects and associated risks highlight the ongoing challenges in developing effective Alzheimer’s therapies. Continued research, including studies on long-term efficacy, safety, and diverse patient populations, is essential to fully understand donanemab’s potential and optimize its use in clinical practice.

The broader context of Alzheimer’s research and treatment involves multiple avenues of investigation. Researchers are exploring various strategies, including targeting tau pathology, neuroinflammation, and synaptic health. Advances in biomarker development are improving early diagnosis and monitoring of disease progression, which is critical for the timely initiation of treatments.

In addition to pharmacological approaches, non-pharmacological interventions such as cognitive training, lifestyle modifications, and support for caregivers play crucial roles in managing Alzheimer’s disease. A holistic approach that integrates these strategies with pharmacological treatments is likely to provide the most comprehensive care for Alzheimer’s patients.

The approval process for new Alzheimer’s drugs, including donanemab, also raises important regulatory and ethical considerations. Balancing the urgency of providing new treatments to patients with the need for thorough evaluation of their safety and efficacy is a complex task for regulatory agencies like the FDA. Transparency, rigorous scientific standards, and effective communication with the public are essential components of this process.

As the field of Alzheimer’s research continues to evolve, collaboration among researchers, healthcare providers, patients, and policymakers will be crucial. Sharing data, insights, and resources can accelerate progress and ensure that new treatments are developed and implemented effectively. Public awareness and education about Alzheimer’s disease and the importance of participating in clinical trials can also support research efforts and improve outcomes for patients.

In conclusion, the unanimous approval of donanemab by the FDA advisory committee represents a hopeful development in the fight against Alzheimer’s disease. While the drug’s modest effects and associated risks underscore the challenges in developing effective treatments, donanemab offers a new option for slowing cognitive decline in early-stage Alzheimer’s patients. Continued research and a comprehensive approach to Alzheimer’s care are essential to fully realize the potential of new treatments and improve the lives of those affected by this disease. The FDA’s final decision on donanemab, expected later this year, will be a critical milestone in this ongoing effort.

reference link : https://www.nature.com/articles/d41586-024-01726-w#:~:text=At%20a%2010%20June%20meeting,the%20disease%2C%20and%20that%20its


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