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
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.
Written by Justin Ayob and Antonio Ortega Aduhelm’s Latest Coverage News On April 7, 2022 the Centers for Medicare & Medicaid Services (CMS) released its national coverage determination of the FDA approved Alzheimer’s drug aducanumab (Aduhelm), limiting Medicare payments to patients enrolled in clinical trials. Medicare will provide coverage for patients enrolled in any FDA- or NIH- approved trial. Any new drugs that, unlike Aduhelm, receive traditional FDA approval, may be available in care settings that Medicare-covered patients can use such as outpatient departments or infusion centers. Coverage would ultimately be restricted to participation in CMS-approved studies, such as data collection either through clinical practice or registries for these future medications. CMS posted a fact sheet on their coverage decision along with the decision memorandum and a Question & Answer document, stating that even though their decision was not favorable to Biogen, the decision was made based on research including more than 10,00 stakeholder comments and 250 peer-reviewed documents, providing the American public with a transparent, trusted, and evidence-based decision. Biogen took a very strong stance against the CMS’ decision to limit aducanumab’s coverage. The pharmaceutical company stated that the set restrictions for coverage have never been applied to any other FDA-approved medication in any therapeutic area regardless off accelerated or traditional approval. The Alzheimer’s Association also sided with Biogen and released a public statement detailing their deep disappointment with CMS’ latest decision. Chief executive officer of the Alzheimer’s Association stated that unnecessary barriers for patients with Alzheimer’s disease are being created and their needs are being ignored, further adding that patients with Alzheimer’s disease deserve the same access to therapies as others living with cancer and heart disease. Their final dispute was that years of research and funding have led to tremendous progress and innovation but may face a halt as developers would need to question if there is a pathway leading to coverage approval. References:
· Dooley Young, Kerry. "Final CMS Aducanumab Decision Limits Coverage To Clinical Trials". Medscape, 2022, https://www.medscape.com/viewarticle/971813#vp_1.
· Sevigny, Jeff et al. “The antibody aducanumab reduces Aβ plaques in Alzheimer's disease.” Nature vol. 537,7618 (2016): 50-6. doi:10.1038/nature19323
Alzheimer’s is a type of dementia that can severely impact memory, thinking, and behavior. Symptoms usually progress to a point that interfere with daily tasks. Dementia is a general term for memory loss or cognitive decline serious enough to affect a person’s quality of life. Alzheimer’s disease makes up about 60-80 percent of dementia cases. Majority of Alzheimer’s patients are over 65 years old. Increasing age is the greatest risk factor for this condition. In the beginning stages of Alzheimer’s, patients may experience mild memory loss. However, over the years, individuals may lose the ability to carry on a conversation and respond to their environment. It is the sixth leading cause of death in the United States. Patients with Alzheimer’s live above 4 to 8 years on average after diagnosis. One of the worst things about Alzheimer’s is that there is no cure for it and there are very limited treatment options. In 2021, aducanumab, under the brand name “Aduhelm,” was approved by the United States Food and Drug Administration for the treatment of Alzheimer’s disease. This drug is an anti-amyloid monoclonal antibody drug that works by binding to amyloid beta fibrils and soluble oligomers in the brain that are thought to contribute to Alzheimer’s disease. This drug has the proper intention, and the concept makes sense, but hasn’t proved itself to be efficacious. The approval of this drug sparked a ton of controversy. Throughout the clinical trials, aducanumab didn’t show any clear efficacy benefits when being used to treat Alzheimer’s. There was almost no evidence that convincingly showed that the drug can slow cognitive decline. However, on June 7th 2021, the Food and Drug Administration approved the drug anyway and received many responses from Alzheimer’s experts and other scientists. They also received many requests to investigate how a drug that provides so little benefit to patients can get approved. When questioned about how this drug got approved, the FDA responded by saying “the decision was informed by science, medicine, policy, and judgement, in accordance with applicable legal and regulatory standards.” When Biogen, the company that manufactured Aduhelm, was asked their response was “Biogen stands 100 percent behind Aduhelm and the clinical data that supported its approval. The reasoning to defend the approval of this drug is that the drug targets a key protein that clumps in the brains of patients with Alzheimer’s. Many experts disagreed with this statement because they say there isn’t enough evidence to prove that reducing this protein, amyloid, slows memory or thinking problems. Since the cause of Alzheimer’s isn’t well known, this concept shouldn’t be the basis of approval. After further investigation, the found that FDA officials collaborated on publications and presentations with employees of Biogen while the application was pending before those very officials. This was also being heavily criticized and was said to unprofessional and harmful to FDA credibility. Overall, this drug may lead to more research o Alzheimer’s even though it doesn’t directly treat it. I applaud the intention of making this drug especially since there is no other known treatments for Alzheimer’s disease.
1. Belluck, Pam, et al. “How an Unproven Alzheimer's Drug Got Approved.” The New York Times, The New York Times, 20 July 2021, https://www.nytimes.com/2021/07/19/health/alzheimers-drug-aduhelm-fda.html.
2. “What Is Alzheimer's?” Alzheimer's Disease and Dementia, https://www.alz.org/alzheimers-dementia/what-is-alzheimers.
The approval of Aducanumab in mid-2021 by the U.S FDA caused great controversy that is not usually attached to the approval of novel drug therapies. The clinical trials that supposedly backed the approval failed to show that the therapy improved cognitive function. As a matter of fact, the two pivotal trials were stopped early because no benefit was shown. After analyzing and poring over the data from the trials, Biogen, the manufacturing company found one small improvement in a subgroup of patients and used this to push the approval. Before its approval, an independent expert panel was gathered to review the effectiveness and make a recommendation to the FDA. All but one member of the panel voted against the approval. Even with the opinion of this expert panel, approval was granted. With accelerated approval granted by the FDA in June because of the scarcity of drugs to treat Alzheimer’s, the manufacturing company had high hopes in the impact this drug would have across the world. With accelerated approval still comes the burden of proving the effectiveness of the therapy as time goes on. More research is still needed to prove the clinical benefit.
It is widely thought that there is a connection between the loss of amyloid protein in the brain and Alzheimer’s disease. This direct correlation has yet to be fully scientifically proven. The pathogenesis of the disease is not yet fully understood, which is what makes Alzheimer’s so difficult to treat. Aducanumab targets these amyloid plaques further building into the question of if this drug is actually effective because it is targeting a protein in which there is no evidence of a solid connection to Alzheimer’s. Because of the controversy, once approval was granted, the drug has been extremely slow to reach patients. The biggest barrier to this is lack of insurance coverage. Most, if not all, insurance companies utilize something called a formulary list. This formulary list is a comprehensive list of drugs that the insurance will cover and for what amount. Many times, there are steps to the formulary list meaning that if a patient fails one therapy treating a disease state, only then will their insurance cover another and more likely, more expensive one.
Medicare, the government insurance program that covers many people with Alzheimer’s has set out to decide if they want to cover the therapy later in 2022 and add it to their formulary. Many private insurance companies are waiting on the government’s decision before they make their own. This in-between, where the drug is neither turned down nor accepted, speaks volumes for the state of aducanumab and what there is to come. Many families who are looking for any type of therapy and are at their last resort are paying tens of thousands of dollars out of pocket for the therapy. Interestingly, the Alzheimer’s Association supports the use of the drug, but many hospitals are refraining from prescribing it to patients.
1. Hamilton J. Cost and controversy are limiting use of new alzheimer's drug. NPR. https://www.npr.org/sections/health-shots/2021/11/08/1052833252/cost-and-controversy-are-limiting-use-of-new-alzheimers-drug. Published November 8, 2021. Accessed January 31, 2022.
2. Erin Hull & Morgan deBlecourt September 20, deBlecourt EH& M. What you need to know about aducanumab. Duke Health. https://www.dukehealth.org/blog/what-you-need-know-about-aducanumab. Published September 20, 2021. Accessed January 31, 2022.