Andrew Budson, MDChief of Cognitive and Behavioral Neurology at the VA Boston Healthcare System; Associate Director and Leader of Education at Boston University Alzheimer’s Disease Research Center; Lecturer at Harvard Medical School. Dr. Budson discloses that his lab received research funding from Biogen, the manufacturer of aducanumab, in 2020. The funds were received by the Veterans Affairs Boston Health Care System and did not contribute to his salary. He also received funds for a one-day consultation meeting with Sage Pharmaceuticals (manufacturer of the antidepressant brexanolone) in February 2020. Dr. Carlat has reviewed the content of this interview and determined that there is no commercial bias as a result of these financial relationships.
CGPR: How does aducanumab work?
Dr. Budson: Aducanumab (Aduhelm), which is given intravenously once a month, is a monoclonal antibody directed against amyloid plaques that are associated with Alzheimer’s disease. The idea is that aducanumab will stick to the plaques in the brain. Once there’s an antibody on a plaque, the immune system signals the body’s defense mechanisms to remove it.
CGPR: Does aducanumab slow the progression of Alzheimer’s disease?
Dr. Budson: The studies clearly show that aducanumab removes plaques from the brain, but they have not consistently demonstrated whether aducanumab does anything to the progression of cognitive impairment. According to the publicly available data on the FDA’s website, there are two large studies, each with about 1,000 participants. In one of the studies, aducanumab looked like it could slow down the disease by three months over an 18-month trial. In this study, high-dose aducanumab treatment was associated with a 22% slowing of decline on the primary outcome measure, the CDR-SB (a composite measure with cognitive and functional components), compared to placebo. But the other study showed the opposite—not only did aducanumab not work, but the patients in the placebo group outperformed the aducanumab group on cognitive tests by the equivalent of three months (www.tinyurl.com/yhszhmya). The effect size was about the same in both studies, one of them in the positive direction and the other in the negative direction.
CGPR: Which patients are eligible for aducanumab?
Dr. Budson: Individuals with mild cognitive impairment and individuals in the mild stage of Alzheimer’s disease are eligible. In the original studies, patients had a Mini-Mental State Examination of 24 or above. But the FDA’s ruling was for the mild stage, which is a little more lenient. A person in the mild stage of Alzheimer’s disease might experience difficulty with instrumental activities of daily living, such as paying bills, managing medications, or grocery shopping. But they should not have difficulty with their basic activities of daily living, such as dressing, bathing, or maintaining their hygiene.
CGPR: What are the side effects of aducanumab?
Dr. Budson: Side effects included headaches, confusion, dizziness, and nausea. Microhemorrhages (bleeding in the brain) were seen 12% more often in those taking aducanumab compared to those taking placebo. Having many of these brain bleeds can impair a person’s cognition.
CGPR: Any other side effects?
Dr. Budson: Aducanumab caused amyloid-related imaging abnormalities (ARIAs) in about 40% of people. Approximately 35% of people in the high-dose group had “ARIA-E” or amyloid-related vasogenic edema (www.tinyurl.com/yhszhmya). ARIA-E is not necessarily destructive, but it causes brain swelling. It’s important to note that the study data excluded individuals with a history of heart attack, transient ischemic attack or stroke, or kidney disease, as well as people on blood thinners. Since many people meet these criteria, the reported rates of ARIAs are likely underestimates.
CGPR: How concerned should we be when we see ARIAs on imaging?
Dr. Budson: Most of the time this type of brain swelling resolves without any permanent damage, although sometimes it leads to a stroke if the tissue is too compressed or the swelling is too great. I’m always very cautious when I see ARIAs on a scan, and my rule of thumb is that a person with ARIAs is done from the study, and they don’t get rechallenged.
CGPR: What’s the cost of aducanumab, and will insurance cover it?
Dr. Budson: The cost is estimated to be around $28,000 a year, as aducanumab is titrated according to a patient’s body weight. Thus far no insurance company covers it. The US Department of Veterans Affairs (VA) has chosen not to cover it and not to include it in the VA formulary. The Centers for Medicare and Medicaid Services (CMS) has issued a final decision to pay for aducanumab only in the setting of a clinical trial in order to obtain more information about risks and benefits.
CGPR: Do you think it’s likely that CMS will pay for aducanumab outside of clinical trials in the near future?
Dr. Budson: I would hope they don’t, based on everything I know about the data. CMS does not cover amyloid PET scans, which is the easiest way to determine if someone has Alzheimer’s disease, and a sure diagnosis is necessary to administer this drug. Then there is the cost of repeated MRI scans, which cost $1,325 on average and would be necessary to monitor for microhemorrhages and swelling in the brain. MRIs are recommended prior to initiation and prior to the fifth, seventh, and 12th doses (or if symptoms suggestive of ARIAs occur). And even if CMS does cover the medication, patients are still responsible for 20% of the price tag.
CGPR: People who are carriers of the APOE4 gene appear to be at higher risk for the development of ARIAs. Should we be screening patients for their carrier status to potentially administer a lower dose of aducanumab?
Dr. Budson: The benefit of aducanumab was only apparent when people received the highest dose; the low dose was not effective. In the negative trial, not enough individuals received the highest dose, even if they were APOE4 positive.
CGPR: Given the cost of the medication and the potential side effects, do you think that aducanumab will get much use?
Dr. Budson: I don’t think so, at least not until there is proof that it works. If aducanumab is shown to be safe and effective (using clinically meaningful outcomes) in a diverse population with Alzheimer’s disease, and its cost doesn’t limit use to the wealthy, then I think a lot of people will use it, and I would be in favor of using it as well. There have now been a few deaths that were likely due to aducanumab, which changes the question of how we perceive the danger of ARIAs. Many patients may think, “Well, maybe it’s not going to help me, but it can’t hurt.” When they hear that people have died, they’ll be less likely to try it.
CGPR: Can you speak about the controversy associated with aducanumab’s accelerated approval?
Dr. Budson: The FDA can approve medications based on a biomarker or other indication that the medication might work. It can approve a medication with the reasoning that it might help some people even though a definitive study has not been done. This FDA decision was controversial for two reasons: 1) One study was positive and the other was negative, so the obvious conclusion is that we need at least one more study to determine if the drug works; 2) The FDA’s own advisory panel recommended that the drug not be approved. Every member of the FDA advisory panel either voted not to approve or abstained. The FDA’s accelerated approval led to the resignation of three members of its advisory panel. The approval was so controversial that two congressional committees, plus the Health and Human Services Office of Inspector General, are conducting independent investigations to better understand the decision.
CGPR: Do you think aducanumab’s approval is opening the floodgates for the approval of other amyloid-clearing therapies?
Dr. Budson: I hope not, unless there’s more consistent evidence—in which case, we should definitely approve them. The amyloid hypothesis is controversial because it has repeatedly failed therapeutically; this is why meaningful outcomes are critically important. I hope the FDA realizes that they did not do the right thing. Whether they will retract their approval or not, I don’t know. They already retracted one part of their initial ruling, which said that aducanumab was FDA approved for people at any stage of Alzheimer’s; it now only includes people in the mild stage of disease (which makes sense since this was the population studied).
CGPR: If patients are interested in an aducanumab trial, where can they go?
Dr. Budson: People in the mild or very mild stages of Alzheimer’s disease can sign up for a clinical trial at one of the 33 NIH-funded Alzheimer’s disease research centers across the country. Patients can research trials at www.clinicaltrials.gov.
CGPR: Can centers administer aducanumab without a trial?
Dr. Budson: Yes, centers and individual neurologists and other providers are free to prescribe aducanumab if a patient can pay out of pocket.
CGPR: What else do you recommend to patients with Alzheimer’s disease?
Dr. Budson: I recommend the standard treatments to help memory for Alzheimer’s disease, including the cholinesterase inhibitors. Those have been shown to turn the clock back on cognitive decline by six to 12 months (Cummings JL, Am J Geriatr Psychiatry 2003;11(2):131–145). These medications can’t stop the clock from ticking down, and they can’t change the rate at which the clock ticks down, but turning the clock back six to 12 months is still pretty good. To put this in perspective, it’s actually better than the positive subgroup analysis of aducanumab that may turn the clock back three months.
CGPR: What do you mean by “turning the clock back six to 12 months”?
Dr. Budson: This is extrapolated from a JAMA article in which the researchers looked at changes in the scores of tests like the ADAS-COG: the Alzheimer’s Disease Assessment Scale—Cognitive Subscale (Cummings, 2003). They compared people who took cholinesterase inhibitors and placebos to the expected decline on the test every year due to progression of the illness. The researchers found that people taking cholinesterase inhibitors improved by an amount equivalent to raising their score to where they were cognitively six months ago, or for some people to where they were a year ago.
CGPR: And what would that look like—a drug-placebo difference of two or three points on the 70-point ADAS-COG?
Dr. Budson: Right, a very tiny difference. We don’t have a good understanding of how this translates to daily functioning.
CGPR: Do you have additional recommendations for people with Alzheimer’s disease?
Dr. Budson: I recommend engaging in aerobic exercise for at least 30 minutes a day five days a week. I also recommend a Mediterranean menu of foods such as fish, olive oil, fruits and vegetables, nuts and beans, whole grains, and chicken. Everyone can also benefit from engaging in social activities, along with doing something novel with their brain. And finally, having a positive mental attitude toward aging and life in general has been shown to be important (Levy BR and Myers LM, Prev Med 2004;39(3):625–629). People with a positive attitude are more likely to be outgoing, to participate in social activities, and to take care of themselves by eating right and engaging in physical activity.
CGPR: How do these recommendations fare in terms of patient outcomes as compared to medications?
Dr. Budson: I don’t know of any study that has compared these recommendations, but the effects of diet, exercise, and social activities are very powerful. In studies that looked at a combination of lifestyle changes, when people made healthy lifestyle changes in middle age, even if they later developed dementia, they did so at a later age compared to those who did not engage in healthy activities (Rosenberg A et al, J Prev Alzheimers Dis 2020;7(1):29–36).
CGPR: Thank you for your time, Dr. Budson.
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