The Food and Drug Administration (FDA) is the governing body of prescription medications in the United States. In order for a drug to gain FDA approval, it needs to demonstrate safety and efficacy. A thorough review process is conducted in order to assure this safety and efficacy. In June 2021, however, that process was questioned by the scientific community. In June of 2021, the FDA approved aducanumab (Aduhelm) for the treatment of Alzheimer’s disease. This is the first approval of a medication to treat Alzheimer’s disease since 2003. Although this medication was highly anticipated by the neurodegenerative disease community, the data was less than ideal. This medication is indicated in mild or moderate dementia or cognitive impairment. It utilizes a novel mechanism of action to aim to treat this devastating disease. Abucanumab is an amyloid beta-directed antibody.1
The recent FDA approval was based on data that suggests that aducanumab reduced the levels of cerebral amyloid plaques on PET scan.2 Many providers within the healthcare community are not convinced that amyloid plaques are characteristic of Alzheimer’s disease. The FDA granted approval based on the conclusion that the reduction of amyloid plaques is reasonably likely to cause some disease improvement. Amyloid plaques are not a validated endpoint in determining effects from Alzheimer’s disease. There have also been theories that decreases in the amyloid plaque is due to advanced cerebral disease, indicating more severe disease.2 The FDA advisory committee recommended against the approval of aducanumab on the basis of insufficient evidence. The FDA required the product’s manufacturer, Biogen, conduct more long term studies over the next 9 year in order to determine long-term clinical benefit. If these trials do not meet acceptable endpoints, the FDA could withdraw approval.3
On top of the lack of efficacy data, aducanumab is extremely expensive. It is estimated to cost over $56,000 per year to treat one patient. Being that most patients with dementia and Alzheimer’s are enrolled in Medicare services, the decision on whether CMS will cover the medication or not is a very important one. It is estimated that if Aduhelm is added to the CMS formulary, it will add billions of dollars to the federal government cost. Usually, FDA approval provides sufficient evidence to guarantee the safety and efficacy for CMS approval. Given the high critique of this medication, that is not enough. CMS would leave this coverage to the state Medicaid programs if they deny coverage of Aduhelm, which will drain funding. For legal reasons, Medicaid must cover most FDA approved medications. There are discussions on how to limit patients’ access to this medication. It has not been shown, concretely, to be beneficial. While there are still discussions on how to navigate this situation, there is also coverage for reform in the healthcare system. There are calls for changes in the laws that require CMS to cover medications if the states cannot afford to cover a medication. Especially with a medication that has no concrete benefit and a high cost, we are seeing how detrimental this could be on the healthcare systems.3
References:
Aduhelm. Package insert. Biogen; 2021.
Høilund-Carlsen PF, Alavi A. Aducanumab (Marketed as Aduhelm) Approval Is Likely Based on Misinterpretation of PET Imaging Data. J Alzheimers Dis. 2021 Oct 10.
Sachs R, Bagley, J. Medicare Coverage of Aducanumab — Implications for State Budgets. NEJM. 2021 Nov 20.
Alzheimer disease (AD) is a neurodegenerative disorder of uncertain cause and pathogenesis that primarily affects older adults and is the most common cause of dementia. The most essential and often earliest clinical manifestation of AD is selective memory impairment. While treatments are available that can improve some symptoms of the illness, there is no cure currently available, and the disease inevitably progresses in all patients.
AD is characteristically a disease of older age. It is unusual for AD to occur before age 60 and the incidence and prevalence of AD increase exponentially with age, essentially doubling in prevalence every 5 years after the age of 65 years.
Hallmark neuropathologic changes of AD include neuritic plaques, extracellular deposits of amyloid beta, and neurofibrillary degeneration. While the pathogenesis of AD remains unclear, all forms of AD appear to share overproduction and/or decreased clearance of a family of proteins known as amyloid beta peptides.
Cognitive deficits appear and progress insidiously. Memory impairment, specifically loss of memory of recent events, is the most frequent feature of AD and is usually its first manifestation. Other cognitive deficits appear with or after the development of memory impairment.
Neuropsychiatric symptoms are common in AD, particularly in the middle and late course of disease. These can begin with relatively subtle symptoms including apathy, social disengagement, and irritability. More problematic in patient management is the emergence of behavioral disturbances, including agitation, aggression, wandering, and psychosis (hallucinations, delusions, misidentification syndromes). A concomitant medical illness, medication toxicity, and other causes of delirium should be considered whenever new behavioral disturbances arise, especially if acute or subacute. Pyramidal and extrapyramidal motor signs, myoclonus, and seizures can occur in late stages of AD but are uncommon in early and middle stages.
AD should be suspected in any older adult with insidious onset, progressive decline in memory, and at least one other cognitive domain leading to impaired functioning. The diagnosis of AD is made in large part by this clinical assessment. Neuropsychological testing may provide confirmatory information and aid in patient management. A neuroimaging study should be obtained on every patient suspected of having AD.
For patients with newly diagnosed AD dementia, a trial of a cholinesterase inhibitor is recommended for symptomatic treatment of cognition and global functioning. Patients with AD have reduced cerebral content of choline acetyltransferase, which leads to a decrease in acetylcholine synthesis and impaired cortical cholinergic function. Cholinesterase inhibitors increase cholinergic transmission by inhibiting cholinesterase at the synaptic cleft and provide modest symptomatic benefit in patients with AD. The choice among donepezil, galantamine, and rivastigmine can be based upon ease of use, individual patient tolerance, cost, and clinician and patient preference, as efficacy appears to be similar.
In patients with moderate to advanced dementia, memantine can be added to a cholinesterase inhibitor, or be used alone in patients who do not tolerate or benefit from a cholinesterase inhibitor. In patients with severe dementia (MMSE <10), memantine can be continued given the possibility that memantine may be disease modifying. However, in some patients with advanced dementia, it may make sense to discontinue administration of medications to maximize quality of life and patient comfort.
Newly approved anti-amyloid antibody drugs, such as aducanumab and lecanemab, are approved for the treatment of mild AD. While they appear highly effective in reducing brain amyloid levels, it is uncertain that patients benefit clinically from treatment. In addition, there are known risks that require close monitoring with clinical and imaging assessments. At present, the routine use of anti-amyloid antibody drugs for patients with AD is not recommended. Shared decision-making must include discussions regarding both what is known and what is uncertain in regard to benefits, risks, burdens, and costs of therapy.
AD is inexorably progressive, but the rate of progression can vary. The average life expectancy after diagnosis has been reported to be between 8 and 10 years but may range from 3 to 20 years. Experts are cautious but hopeful about developing treatments that can stop or delay the progression of AD. Many drugs and medical devices in development aim to interrupt the disease process by impacting one or more of the brain changes associated with Alzheimer’s. These changes offer potential "targets" for new drugs or devices to slow or stop the progress of the disease. These promising targets include the buildup of beta-amyloid and tau protein, neuroinflammation, immune response, metabolic changes and more. Researchers believe that future treatments will involve a combination of medications or devices aimed at several targets, along with risk reduction strategies similar to current treatments for many cancers and AIDS.
References:
Press, D., & Buss, S. S. (2021, September 30). Treatment of Alzheimer disease. UpToDate. Retrieved from uptodate.com/contents/treatment-of-alzheimer-disease?search=alzheimers&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2#H2
Wolk, D. A., & Dickerson, B. C. (2021, October 8). Clinical features and diagnosis of Alzheimer disease. UpToDate. Retrieved from https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-alzheimer-disease?search=alzheimers&topicRef=5073&source=see_link#H13
Trinh NH, Hoblyn J, Mohanty S, Yaffe K. Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease: a meta-analysis. JAMA 2003; 289:210.
Raina P, Santaguida P, Ismaila A, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med 2008; 148:379.
Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt HP, van den Bussche H. Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials. BMJ 2005; 331:321.