Breakthrough or Breakdown? Aducanumab’s Approval by the FDA with Comments from Neurologist Dr. Allan Levey

By Anna Zimmer 

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Alzheimer’s disease, a devastating, terminal, and progressive illness, currently affects nearly 6 million Americans (Matthews et al. 2019), and, as of 2016, nearly 44 million people worldwide (2019). Estimates for the next 40 years show the prevalence of Alzheimer’s disease in the United States surpassing 14 million (Matthews et al. 2019). Here, Alzheimer’s disease healthcare costs in 2020 were estimated to be 305 billion dollars (2020), making it one of the most costly health conditions (Hurd et al. 2013). Treatments are urgently needed. Yet, aducanumab (Aduhelm), the newest drug approved by the FDA to treat Alzheimer’s disease in almost 20 years, may not be effective.  

Aducanumab is an antibody that helps clear amyloid (FDA 2021a), a substance present in the brain that is  associated with the pathology of Alzheimer’s disease (Abeysinghe, Deshapriya, and Udawatte 2020). If and how it causes the clinical symptoms or contributes to disease progression has been uncertain.  Given a potential relationship between amyloid accumulation and clinical progression, the FDA approved the drug for use on an accelerated pathway. This approval is unique in that it used the scientific understanding of amyloid’s role as a biomarker of the pathology in brain of rather than clinical evidence that the drug produces benefits for its approval – one clinical trial found marginal benefit while another found no benefit (Cavazzoni 2021). Compounding matters, the primary side effect of the drug was brain swelling and other imaging abnormalities  that, for some, required hospitalization (Belluck 2021). In short, the FDA approved aducanumab despite limited evidence of its clinical effectiveness and despite known risks (FDA 2021b).  

Dr. Allan Levey, the Director of Emory Goizueta Alzheimer's Disease Research Center, and Professor of Neurology at Emory University School of Medicine, weighed in on the recent FDA approval of aducanumab.  

(The responses below are edited for clarity and have been approved by Dr. Levey.)   

What were your initial reactions to the approval of aducanumab?  

I was not terribly surprised; it was really 50:50. The biggest issue, I think, is the pressure that advocacy groups put on the FDA on behalf of patients and families who are desperate for effective treatments. They are very, very powerful and they have been extraordinarily influential in the field.  

What impact, if any, do you think the approval of aducanumab will have on the healthcare practitioner trust in the FDA? Public trust in the FDA?   

This is a great question. I’m sure you know that several colleagues resigned from the advisory committee. Now people will know if they are asked to serve, they are rightly just advisory. It also probably makes the broader scientific community more skeptical. You really want the FDA to be unbiased and consistent - I lost some faith in both of those.  

From your perspective, what sort of precedent do you think that the approval of aducanumab will set? Is this new precedent something you’re worried about? 

I’m very much worried about the possibility that this will set a precedent for approval of drugs based on changing a biomarker rather than having a clinical benefit. . .But I am sort of happy about it, too, as it could encourage more drug development. But again, it is up to the FDA to hold precedent. . .Assuming they do use precedent as an important issue, it will lower the bar to get other drugs approved, which could be a good thing to attract more research which is urgently needed.  

As a physician, one of your goals is to reduce human suffering. How does the approval of aducanumab fit into this goal?   

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Clearly reducing suffering is a first goal, and I remind myself of that every time I see a patient; do no harm is part of that equation. This is where this FDA decision becomes fairly complicated. The first issue  is the drug approval. I don’t view the FDA having approved this on clinical efficacy – the science still needs to speak. I try to communicate that to patients, that this is still conditional, and the scientific studies still need to occur. I don’t think it’s clear we are going to reduce suffering. However, given that we don’t have a treatment and we know patients are universally suffering, I’m definitely okay administering the drug and offering it to patients that are within a narrowly defined group similar to those participating in the clinical trials.  That is, I would only prescribe the treatment for my patients who are only mildly symptomatic, have biomarker confirmation of Alzheimer’s disease by spinal fluid or PET imaging analyses, and are able and willing to have monthly infusions and undergo several MRI brain scans. Moreover, they need to have full understanding of the risks and benefits. We need to make sure people have the same level of understanding as they would for participation in a clinical trial.  

I’m also really concerned about the ethical issues raised by unrealistic expectations of patients and families, the insufficient expertise of some prescribing doctors and potential financial motivations to provide an expensive treatment. . .There are a lot of people interested in accessing the drug either who may not understand that there is no evidence for any benefit of treatment at earlier stages of Alzheimer’s disease than has been studied in the clinical trials. The patients on the early side of the disease are affected by the way the FDA approved the labeling for the indication as “Alzheimer’s disease.” Because Alzheimer’s is not defined, and there are unfortunately varying definitions based on either pathological or clinical features, it’s going to open up a lot of opportunities for inappropriate prescribing. At one extreme, there is nothing to stop people from prescribing for asymptomatic individuals who have positive biomarkers for Alzheimer’s disease – of which there are an estimated 48 million in the US alone. What could be more devastating than treating an otherwise healthy 70-year-old with biomarkers for Alzheimer’s and a family history, who, like everybody, is going to have some age-related memory changes? We might learn later, after 30 years, that he/she would have never progressed to Alzheimer’s. But that same person would have 30% chance of ARIA (amyloid-related imaging abnormalities) if they are treated.  

And at the other end of the spectrum, doctors will need to avoid prescribing treatment that could add risk despite no evidence of benefits, or potentially even prolong survival at terminal stages of disease. . .In the best case, someone with confirmed early stages of Alzheimer’s disease treated with aducanumab will continue to progress, and it is not clear how long treatment should be continued. The evidence to date is that Aducanumab at best will slow down disease progression by ~30%. So, on the flip side, this means that someone with Alzheimer’s is still going to progress 70% over the course of a year of what they would have otherwise without treatment. 

Thus, how you draw a line for treatment is one of the biggest problems clinicians will face in my view. Are we going to stop it if their mini mental state brings them outside initial inclusion criteria? We also have no way of knowing if the drug is working on an individual level. It’s going to be an individual decision with the patient and family to determine what’s best for them. Having had a mother in this situation, there is no way we would have wanted to slow it down when she was later in the course. Earlier, sure, but not later. 

Knowing that a year’s worth of aducanumab is $56,000 for the drug alone, there has (understandably) been a lot of discussion about the fairness (or lack thereof) of this cost. How would you navigate a situation where a patient does not meet your criteria for treatment but insists on paying out of pocket?  

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In that situation I would not treat the patient and inform them that they would need to seek care elsewhere. It’s actually the flip side of this ethical issue that really bothers me; it’s more the people that want it and are appropriate candidates and can’t afford it. It’s going to exacerbate health disparities. Minorities with less access to healthcare in general have far lower rates of identification of disease, and without a diagnosis and access to specialists they will not receive treatment. 

One positive about the decision is that it will hopefully drive some necessary change in healthcare like widespread screening for cognitive impairment. The US Prevention Task Force even this past year has deemed that there is insufficient evidence to support widespread screening for cognitive impairment, which has been in part driven by lack of treatment options. Now that there is a treatment, I hope that screening for cognitive impairment and Alzheimer’s disease will be recommended so that people will have the opportunity to be evaluated at early stages when reversible causes of memory loss can be identified, or treatments initiated when they can be most promising, and when individuals have the capacity to understand the implications of the diagnosis and plan with their families.   

I can only imagine how challenging this approval has been professionally, knowing the likely negative consequences of aducanumab’s approval.  

Actually, it’s really energizing because it’s bringing a lot of attention to this area of research. This approval is generating interest in getting pharmaceutical companies motivated, especially regarding the use of biomarkers. Previously, there had been very little enthusiasm for clinical care. This is generating all sorts of new opportunities and I am optimistic that the approval of Aducanumab is the necessary first step in helping healthcare systems and communities learn how to provide the much-needed support for patients and families and accelerate the next generation of more effective treatment. 

References

1. 2019. "Global, regional, and national burden of Alzheimer's disease and other dementias, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016."  Lancet Neurol 18 (1):88-106. doi: 10.1016/s1474-4422(18)30403-4. 
2. 2020. "2020 Alzheimer's disease facts and figures."  Alzheimer's & Dementia 16 (3):391-460. doi: https://doi.org/10.1002/alz.12068. 
3. Abeysinghe, Aadt, Rdus Deshapriya, and C. Udawatte. 2020. "Alzheimer's disease; a review of the pathophysiological basis and therapeutic interventions."  Life Sci 256:117996. doi: 10.1016/j.lfs.2020.117996. 
4. Belluck, Pam. 2021. "Many Alzheimer’s Experts Say Use of Aduhelm Should Be Sharply Limited." The New York Times, June 21. https://www.nytimes.com/2021/06/21/health/aduhelm-alzheimers-drug.html. 
5. Cavazzoni, Patrizia. 2021. "FDA’s Decision to Approve New Treatment for Alzheimer’s Disease." U.S. Food and Drug Administration, Last Modified June 7, accessed June 24. https://www.fda.gov/drugs/news-events-human-drugs/fdas-decision-approve-new-treatment-alzheimers-disease. 
6. FDA. 2021a. "Aducanumab (marketed as Aduhelm) Information." accessed June 22. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/aducanumab-marketed-aduhelm-information. 
7. FDA. 2021b. FDA Grants Accelerated Approval for Alzheimer’s Drug. In FDA News Release. FDA.gov. 
8. Hurd, M. D., P. Martorell, A. Delavande, K. J. Mullen, and K. M. Langa. 2013. "Monetary costs of dementia in the United States."  N Engl J Med 368 (14):1326-34. doi: 10.1056/NEJMsa1204629. 
9. Matthews, Kevin A., Wei Xu, Anne H. Gaglioti, James B. Holt, Janet B. Croft, Dominic Mack, and Lisa C. McGuire. 2019. "Racial and ethnic estimates of Alzheimer's disease and related dementias in the United States (2015–2060) in adults aged ≥65 years."  Alzheimer's & Dementia 15 (1):17-24. doi: https://doi.org/10.1016/j.jalz.2018.06.3063. 

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Anna Zimmer is a fourth year medical student and master’s in bioethics candidate at Emory University. She will be pursuing a neurology and/or psychiatry residency on her way to becoming a palliative care physician. Academically, Anna is concentrating on the ethics of pain management, especially in sickle cell disease.   

 

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Zimmer, A. (2021). Breakthrough or Breakdown? Aducanumab’s Approval by the FDA with Comments from Neurologist Dr. Allan Levey. The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2021/07/breakthrough-or-breakdown-aducanumabs.html