Alzheimer’s disease is not the only cause of dementia, but it is the most common. The many other types of dementia, e.g., Lewy body, vascular or frontotemporal, mostly affect older adults. Collectively, dementias are terrible diseases striking at the essence of what makes us human beings. I wonder if dementia, Alzheimer’s disease particularly, is the true Emperor of All Maladies (with all due respect to what is a wonderful book). The story of Alzheimer’s disease is a story of health inequity and the impact of social determinants of health. Black Americans are roughly twice as likely to suffer dementia compared to White Americans. Women account for nearly 2/3 of all dementias. Nearly 3/4 of all Alzheimer’s disease sufferers are 75 or older. Hispanic Americans are nearly 1 1/2 times as likely to suffer dementia as White Americans. In the first 20 years of this century, deaths from heart disease decreased by 7.3 percent, and cancer deaths decreased by 27 percent (although they are still the #1 and #2 causes of death in the U.S.). Contrast this with the 145 percent increase in deaths from Alzheimer’s disease over the same period. In aggregate, heart disease and cancer will claim more victims than Alzheimer’s disease – but already, Alzheimer’s disease (and other dementias) claims more senior victims than prostate and breast cancer combined. If the currently estimated 6.2M Americans aged 65 and older suffering from Alzheimer’s disease does more than double as projected to nearly 13M by 2050, the already substantial impact and burden of Alzheimer’s disease on victims, their loved ones, and society will increase substantially. The progression of Alzheimer’s disease can be slow and unpredictable. With current therapies, the cost for treatment of Alzheimer’s disease may consume 1/3 of all Medicare spending by 2050. Treating dementia may be a $1 trillion business on its own in the next quarter-century. Is it any wonder the possibility of hope, even just a little hope, associated with a breakthrough treatment becomes a very big deal? The FDA approved Biogen’s new Alzheimer’s monoclonal antibody treatment (marketed as Aduhelm) in what looks to be the continuation of a degrading process. Not only were the clinical trials, called ENGAGE and EMERGE, exempted from Phase II trials, but a 2019 futility analysis also did not support continuing the trials. In other words, the results of the trials indicated the cost (both financial and side effects) was not worth the potential benefit. There was a re-do of the analysis based on newly obtained data. Even after the new results, the Peripheral and Central Nervous System Advisory Committee did not recommend approval. In fact, the committee did not just fail to recommend approval; not a single committee member voted for approval. The FDA approved it anyway. Three committee members resigned in protest. Dr. Aaron Kesselhiem, a committee member who resigned, said the approval decision “was probably the worst drug approval decision in recent U.S. history.” A consumer advocacy group, Public Citizen, demanded the immediate removal or resignation of the acting head of the FDA. The time from approval on June 7, 2021, to the first patient receiving treatment on June 16 was barely more than a week. Meanwhile, Biogen stock went from $286 a share on June 4 to $395 on June 7, the day of the approval announcement. Aduhelm targets amyloid deposits in the brain, but there is debate about the amyloid hypothesis. Beta-amyloid deposits are the primary feature of senile plaques, and senile plaques along with neurofibrillary tangles are the neuropathologic findings that typify Alzheimer’s disease. But, senile plaques may be present in the brains of some normal elderly and absent from the brains of some who suffered severe Alzheimer’s disease. Differentiating Alzheimer’s disease from other dementias is difficult, and often diagnostic certainty is not attainable even with post-mortem pathologic analysis. In one study, neuropathologists incorrectly identified 3/4 of brain tissue samples for people who had no cognitive decline as having Alzheimer’s disease. Some potential exists for amyloid PET scans to identify these plaques, but a positive scan is also not a definitive diagnosis of Alzheimer’s disease. In addition to the amyloid hypothesis, scientists are only beginning to understand other possible etiologies, such as limbic-predominant age-related TDP-43 encephalopathy which can mimic Alzheimer’s disease. The causes of and effective treatments for Alzheimer’s disease remain elusive. Aduhelm is likely to cost $56,000 a year for monthly infusions. Treating 10,000 patients a year with Aduhelm could cost $560M – not far below the total Medicare budget. Biogen indicates it could provide 1M patients with Aduhelm annually. Yet, Biogen says it wants Aduhelm to be affordable for patients and sustainable for health systems. If you think this is socially responsible of Biogen, consider that the revenue associated with treating 1M patients every year would be $56B, a 400+ percent increase in Biogen’s 2020 revenue. The research and development process is very expensive. Arriving at the end of a clinical trial with at best equivocal data means pharmaceutical companies can make $100M investments in development and wind up with nothing to show for it. In the run-up to developing a SARS-CoV-2 vaccine, there were worries about political interference in the FDA approval process. What appears to be true is the political and social pressures on the FDA to speed the board’s approval process over the years eroded the scientific basis for drug approvals. When combined with the intense financial risk taken to pursue drug development, today’s result is not the same FDA that prevented thalidomide birth defects in the U.S. As the costs for drug development continue to increase, the stakes grow ever higher. Corporate financial risk is real, to be sure, and a concern. We need pharmaceutical companies investing in investigation and developing new treatments for the vast array of maladies affecting people. Sufferers of diseases, particularly terrible ones like Alzheimer’s disease, and their loved ones need and deserve something better than science can deliver today. However, the scientific rigor of the clinical trials process where approval is only granted to drugs with a clear benefit in excess of risk needs to return. Imagine the position this puts neurologists in today. Having a conversation with an Alzheimer’s disease patient and family about why prescribing Aduhelm does not make sense. The only thing they would likely hear is they are being robbed of hope, false though it may be. And yet, if the American Academy of Neurology were to actively advise against using Aduhelm and every neurologist in the U.S. treating Alzheimer’s disease sufferers were to refuse to prescribe it, the message to the pharmaceutical industry and the FDA would be crystal clear. Alas, it is too late for that as the first patients are already receiving Aduhelm and Biogen has nine years to demonstrate benefit before the FDA will reconsider its approval. We live in a time now where money and politics supersede science as the foundation for decisions concerning Americans’ health, safety, and welfare. The many billions, probably hundreds of billions, that we will spend on Aduhelm in the 2020s will drive stock prices up and increase the bottom lines of health systems. Meanwhile, we will surely see more unproven treatments speed through the approval process because the measure of benefit now is not proven efficacy; it is simply ROI. Source
