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.
In 2022, lecanemab was shown to slow down the decline in memory and thinking skills of people living with early Alzheimer’s disease by 27%. Now news has broken about another drug called donanemab, that appears to be more effective at slowing down memory and thinking decline in Alzheimer’s disease.
Donanemab and lecanemab are both immunotherapies. Although both drugs target amyloid protein, they target it at different stages in how it builds up in the brain. Lecanemab targets amyloid as it begins to form fibres, whereas donanemab binds to amyloid once these fibers have clumped together to become a larger build-up or plaque in the brain. This may be partly why we see a difference in how effective both drugs are at slowing down the disease.
Eli Lilly and Company (NYSE: LLY) announced on May 3, 2023 positive results of the TRAILBLAZER-ALZ 2 Phase 3 study showing that donanemab significantly slowed cognitive and functional decline in people with early symptomatic Alzheimer's disease. TRAILBLAZER-ALZ 2 is a randomized, double-blind, placebo-controlled study that evaluated the safety and efficacy of donanemab, an investigational amyloid plaque targeting therapy. The study enrolled people with early symptomatic AD, which includes mild cognitive impairment (MCI) and the mild dementia stage of disease, with the confirmed presence of AD neuropathology, and participants completed their course of treatment with donanemab once they reached a prespecified level of amyloid plaque clearance.
As with all drug treatments, there have been some side effects associated with donanemab. There were no differences in the serious adverse events when comparing the Donanemab and placebo groups (19.85% vs. 20%). In the safety population, 119 of 131 participants (90.8%) in the donanemab group and 113 of 125 participants (90.4%) in the placebo group had at least one adverse event during the double-blind intervention period. However, as with other amyloid-clearing drugs, the incidence of ARIA-E was significantly higher in the donanemab group than in the placebo group (26.7% vs. 0.8%). This is mostly asymptomatic or only causes mild symptoms, and usually gets better by itself. Unfortunately, there were three deaths in the trial related to brain swelling and 1.6% of participants had serious symptoms relating to brain swelling.
Donanemab met the primary endpoint of change from baseline until 18 months on the integrated Alzheimer's Disease Rating Scale (iADRS). The primary endpoint of iADRS measures cognition and activities of daily living such as managing finances, driving, engaging in hobbies, and conversing about current events. All secondary endpoints of cognitive and functional decline were also met and showed highly statistically significant clinical benefits with similar magnitude. The primary endpoint showed 35% slowing of decline (p<0.0001), and an important key secondary endpoint (Clinical Dementia Rating-Sum of Boxes, or CDR-SB) showed 36% slowing of decline (p<0.0001) over 18 months. Based on these results, Lilly will proceed with global regulatory submissions as quickly as possible and anticipates making a submission to the U.S. FDA yet this quarter. Lilly will work with the FDA and other global regulators to achieve the fastest path to traditional approvals.
There are currently 488 ongoing clinical trials aimed at improving the quality of life among patients with Alzheimer’s disease. With the plethora of ongoing trials, Donanemab adds one more therapy line to the mix. Slowing the progression of the disease has been a large unmet need of our time. While Alzheimer’s disease therapies have largely been controversial in their approval status by the FDA, the future needs more accessible and effective therapies. Anti-amyloid treatments are one of the first phase III trials to be performed in preclinical Alzheimer’s disease. With upcoming trials and patient dissemination of novel therapeutics, it is essential that all clinical testing carries out considerable planning, longitudinal assessments, data storage, and management. The findings of ongoing work will help in revealing the success of Ddnanemab in a more population-based setting to improve the diversity and retention of the intervention, along with the rates of referrals to clinical trials.
References:
Lilly’s Donanemab Significantly Slowed Cognitive and Functional Decline in Phase 3 Study of Early Alzheimer’s Disease. (2023, May 3). Eli Lilly and Company. Retrieved from https://investor.lilly.com/news-releases/news-release-details/lillys-donanemab-significantly-slowed-cognitive-and-functional
Mintun, M. A., et al. (2021, May 6). Donanemab in Early Alzheimer’s Disease. The New England Journal of Medicine. Retrieved from https://www.nejm.org/doi/full/10.1056/NEJMoa2100708
Rashad, A., Rasool, A., Shaheryar, M., Sarfraz, A., Sarfraz, Z., Robles-Velasco, K., & Cherrez-Ojeda, I. (2022). Donanemab for Alzheimer's Disease: A Systematic Review of Clinical Trials. Healthcare (Basel, Switzerland), 11(1), 32. https://doi.org/10.3390/healthcare11010032
Alzheimer’s disease is an irreversible, progressive brain disorder affecting more than 6.5 million Americans that slowly destroys memory and thinking skills and, eventually, the ability to carry out simple tasks. While the specific causes of Alzheimer’s are not fully known, it is characterized by changes in the brain - including amyloid beta plaques and neurofibrillary, or tau, tangles - that result in loss of neurons and their connections. These changes affect a person’s ability to remember and think. The accumulation of soluble and insoluble aggregated amyloid-beta (Aβ) may initiate or potentiate pathologic processes in Alzheimer’s disease.
Lecanemab (Leqembi™), a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils, is being tested in persons with early Alzheimer’s disease.
Lecanemab was approved in January 2023 using the Accelerated Approval pathway. Researchers evaluated lecanemab’s efficacy in a double-blind, placebo-controlled, parallel-group, trial that involved 1,795 participants with early-stage, symptomatic Alzheimer’s. Lecanemab slowed clinical decline by 27% after 18 months of treatment compared with those who received a placebo and study participants who received the treatment had a significant reduction in amyloid burden in imaging tests, usually reaching normal levels by the end of the trial. Participants also showed a 26% slowing of decline in a key secondary measure of cognitive function and a 37% slowing of decline in a measure of daily living compared to the placebo group.
These results support the accelerated approval of lecanemab, which is based on the observed reduction of amyloid beta plaque, a marker of Alzheimer’s disease. Amyloid beta plaque was quantified using positron emission tomography (PET) imaging to estimate the brain levels of amyloid beta plaque in a composite of brain regions expected to be widely affected by Alzheimer’s disease pathology compared to a brain region expected to be spared of such pathology.
The prescribing information for Leqembi includes a warning for amyloid-related imaging abnormalities (ARIA), which are known to occur with antibodies of this class. ARIA usually does not have symptoms, although serious and life-threatening events rarely may occur. ARIA most commonly presents as temporary swelling in areas of the brain that usually resolves over time and may be accompanied by small spots of bleeding in or on the surface of the brain, though some people may have symptoms such as headache, confusion, dizziness, vision changes, nausea and seizure.
The most common adverse events (>10%) in the lecanemab group were infusion reactions (lecanemab: 26.4%; placebo: 7.4%), ARIA-H (combined cerebral microhemorrhages, cerebral macrohemorrhages, and superficial siderosis; lecanemab: 17.3%; placebo: 9.0%), ARIA-E (edema/effusion; lecanemab: 12.6%; placebo: 1.7%), headache (lecanemab: 11.1%; placebo: 8.1%), and fall (lecanemab: 10.4%; placebo: 9.6%). Infusion reactions were largely mild-to-moderate (grade 1-2: 96%) and occurred on the first dose (75%).
During the study period, deaths occurred in 0.7% and 0.8% of participants in the lecanemab and placebo groups, respectively and no deaths were related to lecanemab or occurred with amyloid-related imaging abnormalities (ARIA) in the 18-month double-blind study period. Serious adverse events were experienced by 14.0% of participants in the lecanemab group and 11.3% of participants in the placebo group. Treatment-emergent adverse events occurred in 88.9% and 81.9% of participants in the lecanemab and placebo groups, respectively. Treatment-emergent adverse events leading to drug withdrawal occurred in 6.9% and 2.9% of participants in the lecanemab and placebo groups, respectively.
On June 9, 2023, the U.S. Food and Drug Administration (FDA) advisory committee decided that data from the Phase 3 Clarity AD trial are sufficient to confirm the clinical benefits of lecanemab for the treatment of early Alzheimer’s disease. The FDA now will consider the unanimous opinion of the committee when deciding whether Leqembi should receive full (traditional) approval for the treatment of early Alzheimer’s, an indication for which it earned conditional approval in January.
References:
FDA Grants Accelerated Approval for Alzheimer’s Disease Treatment. (2023, January 6). U.S. Food and Drug Administration. Retrieved from fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-disease-treatment
Lecanemab in Early Alzheimer’s Disease. (2023, January 5). The New England Journal of Medicine. Retrieved from https://www.nejm.org/doi/full/10.1056/NEJMoa2212948
Eisai Presents Full Results of Lecanemab Phase 3 Confirmatory Clarity Ad Study for Early Alzheimer’s Disease At Clinical Trials On Alzheimer’s Disease (Ctad) Conference. (2022, November 29). Biogen. Retrieved from https://investors.biogen.com/news-releases/news-release-details/eisai-presents-full-results-lecanemab-phase-3-confirmatory
Alzheimer’s disease (AD) causes the cells in the brain to get sick and eventually die, which leads to symptoms like memory loss. To treat AD, we need to find effective drugs that are able to slow down or stop it. These drugs are often called ‘disease-modifying' treatments. Existing drugs only treat the symptoms of AD. They do not treat the root cause of the disease and so do not slow down how quickly it gets worse.
In the brains of people living with Alzheimer’s disease, a protein called amyloid builds up into plaques. These plaques are thought to be toxic and damage the cells of the brain. These drugs are called immunotherapies. They target the amyloid plaques in the brains of people with Alzheimer’s disease to try and help break them down. Researchers believe that by clearing amyloid plaques from the brain, they will be able to slow down how quickly Alzheimer’s disease gets worse.
Aducanumab, a new drug approved by the FDA to treat Alzheimer's for the first time since 2003, is a monoclonal antibody that targets the buildup of amyloid protein plaques in the brain, which are believed to be a cause of Alzheimer’s disease. Since its approval in June 2021, there has been ongoing controversy about aducanumab’s efficacy and side effects.
The newly updated label in February 2023 warns patients on aducanumab about the potential risks of brain bleeding, which can be significant and life-threatening. The FDA has updated its safety-related labeling for aducanumab, an anti-amyloid therapy approved for early AD, to better characterize the risk of potential bleeding in the brain while on the therapy.
Approved by the FDA Center for Drug Evaluation and Research (CDER), the update cited events of intracerebral hemorrhage greater than 1 cm in diameter in patients on aducanumab, and stated that the use of antithrombotic or thrombolytic medications while on the therapy may increase the risk of bleeding in the brain.
Aducanumab gained FDA approval in June 2021 based on 2 phase 3 trials—EMERGE (NCT02484547) and ENGAGE (NCT02477800)—1 of which met its primary endpoint and 1 that did not. In addition to its efficacy in question, the most common adverse event (AE) observed in these studies were ARIA-edema, occurring at rates of 25.7% and 25.4% in the EMERGE and ENGAGE low-dose groups, respectively, and rates of 34.0% and 35.5% in the EMERGE and ENGAGE high-dose groups, respectively. Comparatively, the placebo group experienced respective ARIA-E rates of 2.2% and 3% in EMERGE and ENGAGE.
Although ARIA can occur in any patient treated with aducanumab, the label informs patients that there is an increased risk in patients who are apolipoprotein (APOE) e4 homozygotes, and that there are tests available to determine APOE e4 genotype. Additionally, the updated patient counseling information encouraged patients to participate in the Alzheimer’s Network for Treatment and Diagnostics (ALZ-NET), a voluntary provider-enrolled patient registry that collects information on treatments for AD, including aducanumab.
In the medication guide section of the updated labeling changes, the FDA pointed out that most people with ARIA-type swelling in the brain do not get symptoms; however, some may experience symptoms such as headache, nausea, confusion, difficulty walking, dizziness, vision changes, and seizures. "Instruct patients to notify their healthcare provider if these symptoms occur," the label stated. MRI scans are typically performed before and during treatment with aducanumab to check for ARIA. This was the second time changes were made to the safety labeling of aducanumab, the first coming in April 2022. The first revisions formally recognized that seizures are a potential adverse effect.
Since aducanumab was approved under the accelerated approval pathway, Biogen is required to conduct phase 4 studies to confirm aducanumab’s efficacy. In June 2022, the company began its phase 4 ENVISION trial (NCT05310071), enrolling 1500 people with early AD who will be assessed for an 18-month treatment period. A long-term extension will last up to 4 years, with results expected by 2026.
REFERENCES
1. Drug Safety-related Labeling Changes: Aduhelm. FDA. https://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges/index.cfm?event=searchdetail.page&DrugNameID=2616#. Updated February 8, 2023.
2. Biogen plans regulatory filing for aducanumab in Alzheimer’s Disease based on new analysis of larger dataset from phase 3 studies. News release. Biogen and Eisai. October 22, 2019. Accessed February 15, 2023. https://www.biospace.com/article/releases/biogen-plans-regulatory-filing-for-aducanumab-in-alzheimer-s-disease-based-on-new-analysis-of-larger-dataset-from-phase-3-studies
3. Budd Haeberlein S, von Hehn C, Tian Y, et al. EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s disease. Presented at: 12th Annual CTAD Meeting; December 4-7, 2019; San Diego, CA.
4. Drug Safety-related Labeling Changes: Aduhelm. FDA. https://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges/index.cfm?event=searchdetail.page&DrugNameID=2616
5. Biogen Submits Final Protocol for ADUHELM® (aducanumab-avwa) Phase 4 ENVISION Trial to FDA. News release. Biogen. March 30, 2022. Accessed February 15, 2023. https://www.biospace.com/article/releases/biogen-submits-final-protocol-for-aduhelm-aducanumab-avwa-phase-4-envision-trial-to-fda/
6. Meglio, M. (2023, February 13). Aducanumab’s Label Updated to Include Risks on Brain Bleeding. NeurologyLive. Retrieved from https://www.neurologylive.com/view/aducanumab-label-updated-include-risks-brain-bleeding-amyloid-related-imaging-abnormalities
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.
References:
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.
Aducanumab Now
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.
References:
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.