The Complex Landscape of Alzheimer’s Treatments: A Deep Dive into Efficacy, Safety, and Hope
In recent years, the quest for effective Alzheimer’s treatments has seen significant advancements, but not without controversy and debate. The FDA-approved drug Donanemab has come under scrutiny due to concerns about its safety and efficacy. An investigation revealed potential design flaws in the clinical trials and undisclosed financial conflicts among the FDA-appointed advisers who recommended its approval. Critics argue that the data used to evaluate Donanemab’s impact on Alzheimer’s progression might be misleading, raising questions about the drug’s true effectiveness. This scrutiny is crucial as Donanemab belongs to a new class of anti-amyloid drugs that target beta amyloid, a protein believed to cause Alzheimer’s disease.
When the FDA initially denied approval of Donanemab in January 2023, they cited a high rate of missing data and concerns about long-term safety. The drug showed a higher rate of treatment discontinuation due to adverse events, including brain hemorrhage and swelling, compared to the placebo. Eli Lilly, the pharmaceutical company behind Donanemab, acknowledged three deaths among patients on the drug, while an independent company found two additional deaths in the Donanemab arm and five in the placebo arm. These findings have fueled debates about the reliability of the clinical trial data and the methods used by the independent company to assess the drug’s safety.
The investigation also highlighted financial conflicts of interest among the FDA-appointed advisers who reviewed Donanemab. Seven out of eight doctors had financial ties to drug companies, with three having connections to Eli Lilly, two to Roche (Lilly’s development partner), and two holding patents on amyloid antibodies. The eighth doctor had research funding from Janssen for another Alzheimer’s drug. The public database OpenPayments revealed that these advisers received up to $62,000 in fees and up to $10.5 million in research grants from 2017 through 2023. Despite these revelations, the FDA declined to comment on the financial conflicts among its advisors, raising further concerns about the transparency and integrity of the approval process.
During the clinical trials, the primary outcome measure for Donanemab was changed from a widely accepted scale to Lilly’s own scale. Despite the results not showing a clinically meaningful difference between the drug and placebo, Lilly claims that Donanemab slows the progression of Alzheimer’s by 22 percent and has promoted it as slowing decline by 35 percent. However, experts in clinical epidemiology and healthcare research argue that this is a misleading statement, as it represents a relative difference that may sound impressive but translates to a small absolute difference. The investigation, published by the BMJ group, underscores the need for more transparency in clinical trials and the evaluation of potential conflicts of interest among decision-makers.
Amidst the controversies surrounding Donanemab, another Alzheimer’s treatment, Leqembi, has been making headlines for its positive impact on patients. Approved by the FDA, Leqembi helps improve cognition in patients in the early stages of Alzheimer’s. Administered through routine infusions twice a month, the drug targets beta-amyloid plaques in the brain, which are linked to cognitive decline. By removing these plaques, Leqembi has shown promise in improving cognitive function. Local health facilities in Abilene, Texas, are equipped to administer the treatment, and patients like Ken Woodard have reported significant improvements in their quality of life after starting Leqembi.
Ken Woodard’s story is a testament to the potential benefits of Leqembi. Accompanied by his daughter, Amy Gibbs, Woodard made lifestyle changes and decided to try the new treatment. Since starting Leqembi, Woodard has experienced a renewed sense of hope and a significant improvement in his daily life. His family now looks forward to making more happy memories together, thanks to the positive impact of the drug. The annual ‘Walk to End Alzheimer’s’ benefit in Abilene aims to raise funds for research, highlighting the community’s commitment to finding effective treatments for Alzheimer’s disease.
Another promising development in Alzheimer’s treatment is the drug Kisunla, manufactured by Eli Lilly and Company. A Pennsylvania woman named Karen Chung, aged 63, became one of the first patients to receive this new FDA-approved treatment for early symptomatic Alzheimer’s disease. Administered through intravenous (IV) infusions at Abington Neurological Associates, Kisunla works by removing amyloid plaque and excessive build-up of the amyloid protein in the brain. Doctors believe that this build-up is responsible for memory and thinking issues in Alzheimer’s patients. Dr. Dan Gzesh, a neurologist at Abington Neurological Associates, considers Kisunla a game changer, as it targets the underlying cause of Alzheimer’s rather than just the symptoms.
Before the approval of Kisunla, the only option for patients was to participate in clinical trials. According to Dr. Gzesh, Kisunla can slow down cognitive deterioration, although it cannot stop it completely. Similar drugs to Kisunla already exist, but this one requires only one visit per month to the doctor’s office. However, MRIs are required after several sessions to monitor for brain swelling, a potential side effect. Karen Chung is excited about the potential of this treatment, as it will allow her to enjoy her family and travel without the limitations of her disease. Her story offers hope to many others living with Alzheimer’s and their families.
Despite the advancements in Alzheimer’s treatments, there are still significant divisions within the medical community regarding their efficacy and safety. Lecanemab, a monoclonal antibody that targets amyloid-beta, received FDA approval in 2023 and subsequent regulatory approval in countries like Japan, China, South Korea, and Israel. However, the European Medicines Agency (EMA) refused marketing approval for lecanemab, citing concerns that its potential harm outweighs its benefits. One potential harm is the development of amyloid-related imaging abnormalities (ARIA), which can range from mild to fatal and require close monitoring. On the other hand, the UK Medicines and Healthcare products Regulatory Agency (MHRA) approved lecanemab for use in early Alzheimer’s disease, except for those with a particular genetic risk.
The National Institute for Health and Care Excellence (NICE) in the UK determined that while lecanemab had a significant impact on slowing cognitive decline, it was not cost-effective due to factors such as diagnostics, genetic testing, and frequent MRI scans. Slowing cognitive decline can greatly improve the quality of life for caregivers, but it is unclear if NICE is equipped to accurately measure this effect in their cost analysis. It is also important to collect longer-term data beyond 18 months to determine if the disease-modifying effects of lecanemab continue over time. Public consultation for NICE’s evaluation is set to end soon, with final guidance expected in 2025. The manufacturer of lecanemab, along with clinicians and medical societies, has appealed the EMA’s decision, and a final ruling is anticipated soon.
For stakeholders, including regulators, clinicians, and patients, it is essential to have an open discussion about how lecanemab can be made safely and more cost-efficiently available. Innovations such as blood tests to measure a protein called phosphorylated tau have shown to be as effective as cerebrospinal fluid (CSF) testing in diagnosing Alzheimer’s, potentially replacing expensive amyloid PET scans. Additionally, a subcutaneous formulation of lecanemab is under fast-track review by the FDA, which could offer benefits to patients and reduce costs. Faster MRI sequencing may also provide a more practical way to monitor for adverse effects. Managed access to lecanemab in high-risk populations, such as those with early-onset Alzheimer’s, may provide valuable information for further research and development.
It is important to address the common misconception that dementia is a normal part of aging. Alzheimer’s disease is a deadly condition, claiming almost 2 million lives worldwide each year. Changes must be made in how people with cognitive issues are referred for specialist care and access to biomarker testing to ensure proper diagnosis and management of the disease. Public awareness campaigns and educational programs can help dispel myths about Alzheimer’s and encourage early detection and intervention. By fostering a better understanding of the disease, we can improve the quality of life for those affected and their families.
In conclusion, the landscape of Alzheimer’s treatments is complex and evolving. While drugs like Donanemab, Leqembi, and Kisunla offer hope, they also come with challenges related to safety, efficacy, and cost. Ongoing research, transparency in clinical trials, and addressing potential conflicts of interest are crucial for developing effective treatments. As we continue to navigate this challenging terrain, it is essential to remain open to new evidence and advancements that could greatly benefit those living with Alzheimer’s disease. By working together, we can strive towards a future where Alzheimer’s is no longer a devastating diagnosis but a manageable condition with effective treatments.