Aduhelm Puts Patients At The Helm, But At What Cost?

By Saami Zakaria

Image via Max Pixel
“I don’t think there’s sufficient evidence that it works, and there’s plenty of evidence that it can harm patients,” is not an expected response to a drug that has been approved by the stringent American Food and Drug Administration, or FDA; yet, this was the response that Dr. Greicius, a neurologist at Stanford University, had to the June 7th approval of a drug called Aducanumab. 

Aducanumab, marketed under the trade name Aduhelm, is the first drug for treating Alzheimer’s disease approved since 2003. Drug approvals, typically the end result of many years of research and clinical trials, are usually a joyous occasion. Aduhelm’s approval, however, set off a fire storm of controversy, with 3 members of the FDA advisory board that recommended against it resigning promptly after the decision to approve under the accelerated pathway. This pathway allows drugs to be approved based on surrogate end points rather than desired clinical outcomes such as memory and cognition improvements. In the case of Alzheimer’s disease, the surrogate end-point was the drug’s ability to remove beta-amyloid, a protein thought to be associated with the development of Alzheimer’s disease.   

The idea that beta-amyloid is associated with Alzheimer’s disease, also known as the “amyloid hypothesis,” is widely accepted and based on a few key studies and observations. The first study involved scientists identifying rare mutations in a few hundred extended families worldwide that virtually guaranteed that Alzheimer’s would develop in the individuals studied, where all the mutations were associated with beta amyloid. In the second, scientists genetically engineered mice to carry beta amyloid mutations, and then observed that these mice had trouble remembering mazes. The third observation was that Alzheimer’s disease is associated with Down syndrome, a syndrome characterized by an excess copy of the chromosome containing the amyloid precursor protein gene. However, evidence against the hypothesis include there being many elderly people with plenty of amyloid and no symptoms of Alzheimer’s as well as the failure of past monoclonal antibody treatment prospects against beta-amyloid, calling into question whether targeting amyloid is the correct approach. As of last year, there were 46 trials for Alzheimer’s disease, 30 of which that were not amyloid related.  

Image by stux via Pixabay
Biogen, the company behind Aduhelm, was almost another failed beta-amyloid story. Of the two randomized phase 3 trials for their drug, one showed slight benefit, though significantly so only in males, people over the age of 70, and those with a copy of a specific gene called ApoE4. The other study did not show a benefit at all, effectively ending the drug’s prospects. But Biogen was not ready to give up. They reanalyzed the trial that did not show any benefit by looking at only those patients receiving at least 14 treatment sessions with a high dose of their drug, or 24.5% of the original study population, and then found slight clinical benefits. The Peripheral and Central Nervous System Drugs Advisory Committee to the FDA, recognizing this as a normally frowned-upon and improper way to engage in science, was not impressed. To the surprise of many, the FDA later decided to approve the drug based on its ability to effectively clear beta-amyloid from the brain and not on its doubtful hope to slow or reverse Alzheimer’s symptoms, allowing Biogen to market their drug while now needing to conduct a post-approval trial that may lead to withdrawal of the drug years later.  

With approval cemented, a new reality has befallen on patients, providers, and the medical insurance world. Aduhelm comes at a sticker price of $56,000 annually, requires expensive scans before treatment to identify those with high levels of beta-amyloid, and requires periodic scans during treatment to monitor for side effects, including brain swelling and bleeds, headaches, falls, and altered mental status, putting all the stakeholders in a precarious position in choosing or allowing treatment.  

Alzheimer’s has been a notoriously difficult disease for the field of medicine to crack into, with one of the highest failure rates of any disease areas for prospective drug candidates. While the failure rate for cancer treatments sits at 81%, Alzheimer’s claims a 99.6% failure rate and over 200 failed trials. In 1992, the FDA decided to start considering accelerated approvals based on surrogate end points for cancer treatments. The move got drugs to patients desperate for help sooner and incentivized companies to work on more cancer treatments, which the FDA drug center’s director Patrizia Cavazzoni hopes to replicate with Alzheimer’s disease. However, the cancer treatments that got approved were not all useful. The FDA oncologic drugs advisory committee met recently to recommend withdrawal of treatment indications from 2 of 6 drugs given accelerated approval in the past five years, while other pharma giants, in consultation with the FDA, proactively withdrew indications from their drugs before this meeting even took place. 

Image by Paul Sableman via Flickr
“History has shown us that approvals of the first drug in a new category invigorates the field, increases investments in new treatments, and encourages greater innovation,” said Dr. Carillo, the chief science officer of the Alzheimer’s Association. This has already proven to be true, as drug giant Eli Lilly has now planned to file for accelerated approval of its Alzheimer’s drug without the data it thought it would need. But is it smart to chase a surrogate marker that we aren’t completely sure about? Is it invigorating the field in a way that will benefit patients in the long term? These are questions with no certain answers at this stage. However, the certainty is that the move shifts autonomy to the hands of individual patients and providers, a move of which many patient advocates approve. With accelerated approvals, patients are given a choice, albeit one at the expense of the rigorous scientific process once thought to be necessary for drugs to get to market and based on incomplete and perhaps incorrect evidence. 

“The question I asked myself is, ‘If this were available while my mother was still alive, would I have given her the drug?’ And the answer was, unequivocally yes,” said Dr. Lipton, a neurologist at the Albert Einstein College of Medicine whose mother died from Alzheimer’s. “And that is some mix of knowledge and emotion, and I’m not saying that it is a fully objective decision.” The floodgates have now been opened, and only time will tell if it was the right call.   


References 
  1. Associated Press (2021, June 27). Alzheimer’s Drug Stirs Hope for Patients, Worry for Doctors | U.S. News® | US News. US News & World Report. Retrieved June 28, 2021, from https://www.usnews.com/news/us/articles/2021-06-27/alzheimers-drug-stirs-hope-for-patients-worry-for-doctors 
  2. McGinley, L. (2021, June 17). Furor rages over FDA approval of controversial Alzheimer’s drug. Washington Post. https://www.washingtonpost.com/health/2021/06/17/alzheimers-drug-controversy/ 
  3. Alzheimer’s Association. (2017). Beta-amyloid and the Amyloid Hypothesis. 4. https://www.alz.org/national/documents/topicsheet_betaamyloid.pdf 
  4. Advisory Board “Crushing”: Another Alzheimer’s treatment trial has failed. What’s next? (2020, February 12). https://www.advisory.com/Daily-Briefing/2020/02/12/alzheimers-disease 
  5. Beaber, Brandon. (2021, June 10). Does Aducanumab (Aduhelm) Actually Work for Early Alzheimer’s Disease? [Neurologist Reviews Data]. Retrieved June 28, 2021, from https://www.youtube.com/watch?v=8oVOdKhNQs8 
  6. FDA. (2021). Aducanumab (marketed as Aduhelm) Information. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/aducanumab-marketed-aduhelm-information 
  7. Burke, M. (2014, July 14). Why Alzheimer’s Drugs Keep Failing. Scientific American. https://www.scientificamerican.com/article/why-alzheimer-s-drugs-keep-failing/ 
  8. Paul, L., & Riley, A. (2021, May 17). Is FDA cracking down on accelerated approval for oncology drugs? Here are our takeaways. Advisory Board. https://www.advisory.com/Blog/2021/05/fda-review 
  9. Scharre, D. (2021, June 7). FDA approves Aduhelm, first new Alzheimer’s disease treatment since 2003. Healio. https://www.healio.com/news/neurology/20210607/fda-approves-aduhelm-first-new-alzheimers-disease-treatment-since-2003 
  10. Taylor, N. P. (2021, June 24). Lilly to file for accelerated FDA approval of Alzheimer’s drug after Aduhelm OK opens the floodgates. FierceBiotech. https://www.fiercebiotech.com/biotech/lilly-to-file-for-accelerated-fda-approval-alzheimer-s-drug-after-aduhelm-ok-opens 
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Saami is a 4th year medical student at Thomas Jefferson University. Before starting medical school, he graduated with a B.S in Biomedical Engineering from the University of Virginia, and then completed a one year research fellowship at the National Institutes of Health. He has a strong interest in neurology and hopes to leverage and cultivate his background in engineering with the needs of the field of neurology moving forward to best serve his future patients.  





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Zakaria, S. (2021). Aduhelm Puts Patients At The Helm, But At What Cost? The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2021/07/aduhelm-puts-patients-at-helm-but-at.html. 

Comments

  1. The article is well done and covers a lot of territory. To get a better idea of how FDA sometimes proceeds on new drug approvals, one should read the recent book entitled "The Empire of Pain" which describes how one company Purdue-Fredrick, allowed and participated in the crises caused by Oxycodone and Oxycontin. The descriptions of FDA's role in all this should not be ignored; especially in think about the financial circumstances of giving a drug i.v. for the rest of the patient's life. This drug has not, by current clinical trial standards, been sufficiently evaluated for safe and efficacy. I have family also with dementia and I would not be so quick to give them the drug without more data and evaluation. Depending strictly on the company to run the trials and report objectively when so much money is to be made...is really courting danger and very likely, serious disappointment to patients and their caregivers.

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