The number of people with Alzheimer’s disease is increasing rapidly. Some hail human monoclonal antibodies that clear beta-amyloid deposits from the brain as the first disease-modifying treatments for the condition. However, they are not without controversy — the Food and Drug Administration approved aducanumab despite a lack of evidence for its efficacy and concerns about adverse effects. Medical News Today spoke to a range of experts about the controversy.
According to the World Health Organization (WHO), at least
“Alzheimer’s disease is an extremely complex condition, which encompasses multiple inter-related, progressive destructive processes in the brain leading to [the] destruction of the function of certain brain cells and eventually widespread cell death, leading to end-stage dementia. However, the understanding of this complicated and intricate process is gradually becoming better understood by neuroscientists.”
– Dr. Emer MacSweeney, CEO and consultant neuroradiologist at Re:Cognition Health
Alzheimer’s disease accounts for
However, the role of beta-amyloid in the disease is still debated.
Medications that clear these plaques were hailed as a great breakthrough in the search for effective Alzheimer’s disease treatments, and several are in development and undergoing clinical trials.
But are they the wonder drugs patients, relatives, and researchers are hoping for?
Most Alzheimer’s disease treatments alleviate symptoms and help those with the disease to function for longer than they would without treatment.
There are many hMabs under investigation as Alzheimer’s disease treatments. They work by clearing the beta-amyloid plaques that build up in the brain of people with Alzheimer’s.
The theory behind them is that since these plaques interfere with the transmission of nerve impulses, clearing the plaques should improve the cognitive abilities of people with Alzheimer’s disease.
However, as yet there is no proof that clearing the beta-amyloid plaques protects individuals from cognitive and functional decline.
Some hMabs, such as bapineuzumab, failed after trials demonstrated no clinical efficacy in patients with mild to moderate Alzheimer’s disease. Many others are still going through trials.
Of these, two — aducanumab (marketed as Aduhelm) and
Dr. Anton Porsteinsson, professor and director of the Alzheimer’s Disease Care, Research and Education Program (AD-CARE) at the University of Rochester Medical Center, has been closely involved in many of the trials.
Having worked on bapineuzumab, he was one of 200 site investigators in the
He told Medical News Today why aducanumab seemed so promising:
“It was the first drug that showed a robust decrease in amyloid burden, to the degree where a majority of patients at the end of the double-blind phase of the study had full removal of beta-amyloid. It was an order of magnitude higher than anything we had seen before.”
Other hMabs had shown similar effects, but, he continued, “this was the first one that had a data set that got to the point that it was submitted to the FDA.”
Two 18-month phase 3 trials of aducanumab, ENGAGE and EMERGE, were funded by the drug manufacturer Biogen.
In the ENGAGE trial, aducanumab showed no benefit over placebo. In the EMERGE trial, the drug treatment showed a statistically significant benefit at a higher dose.
However, both studies were
However, Biogen continued to collect data for a further 3 months. A
“It’s very important to understand that the data set was impaired […] those studies were stopped prematurely. The reason for that, the company said, was lack of efficacy, then you had two studies with opposite results.”
— Dr. Anton Porsteinsson
He continued: “Biogen felt that they could make a good case for why the ENGAGE study was negative. Patients with adequate drug exposure had a favorable outcome. [The company felt that] EMERGE reflects what aducanumab does.”
One concern with aducanumab was the frequency of side effects, particularly
Although many ARIAs — around 65% — have no clinical symptoms, in some individuals, the effects can be severe and even fatal.
“In rare instances, these clinical symptoms can be severe. You can get a macro bleed. You can get a seizure. There is a small sub-group of people that can have a severe outcome.”
– Dr. Anton Porsteinsson
Dr. Porsteinsson advised that careful patient selection and clinical monitoring could minimize the risk of severe outcomes from ARIAs.
Patients with a particular genetic makeup — those with two copies of the
He did, however, point out that lecanemab has about one-third of the ARIA frequency of aducanumab for similar benefits, although patients are more likely to experience
In July 2021, aducanumab was approved by the FDA on its
According to the
Accelerated approval is given to a drug that has not yet shown proven clinical benefit, but is reasonably likely to do so because of a surrogate endpoint — in the case of aducanumab, the clearance of amyloid plaques.
A condition of accelerated approval is that further phase 3 studies are carried out to verify the drug’s clinical benefit.
Biogen is undertaking a post-approval confirmatory study. This phase 4 trial, ENVISION, should reach primary completion after 4 years, so it will be some time before we know whether aducanumab has significant clinical benefit.
The Alzheimer’s Association told MNT it supported the FDA’s decision:
“There is a dire and drastic need to offer relief and support to the millions of Americans impacted each day by the crushing realities of Alzheimer’s. This unmet need, combined with the publicly released data, justified aducanumab’s approval with a confirmatory trial.”
The drug’s manufacturer, Biogen, also applied for approval from the European Medicines Agency (EMA), but this was refused in December 2021. In April 2022, the company withdrew its application for marketing authorization in Europe.
Dr. Porsteinsson commented: “The reviews from the two European regulatory agencies [the EMA and UKMHRA] were more negative than the FDA. It doesn’t surprise me […] the Europeans are more critical, more rigorous. There are always different opinions.”
“Let’s not forget that in the last 10 years, there have been a number of situations where the shoe was on the other foot, where the European regulators have approved a drug that the FDA shot down,” he added.
Now, a congressional report has accused the FDA of failing “to follow their own guidance and practices.” Aducanumab was approved despite objections from the FDA’s panel of independent advisers, who did not believe the drug showed clinical benefit.
There was disquiet among many in the medical community at the rapid approval of the drug, as Dr. Porsteinsson told MNT:
“A meaningful number of my colleagues felt that this interaction [between Biogen and the FDA] was too close because of the data that they had to work with that was impaired by the early stop and the conflicting outcomes. In the view of many people, the FDA pulled a fast one.”
It has been proven that both aducanumab and lecanemab clear beta-amyloid plaques from the brains of people with Alzheimer’s disease. However, the issue is whether this leads to clinical improvement in the condition.
Until further trials are completed, there is no evidence of cognitive improvement in people with MCI or early Alzheimer’s who are treated with either drug.
Some participants in the lecanemab CLARITY trial did show a modest clinical response to the drug, with symptoms stablizing, although not improving.
Just before FDA approval of lecanemab, the Alzheimer’s Association commented: “The FDA is widely anticipated to approve lecanemab, which has the strongest evidence to date and will provide patients in the earliest stages of Alzheimer’s more time to participate in daily life and live independently.”
“Indeed,” they said, “there is growing consensus in the scientific and medical communities about the clinical benefits of thorough removal of amyloid from the brain for people living with mild cognitive impairment (MCI) and early-stage Alzheimer’s disease.”
These are not the only new medications for Alzheimer’s disease, as Dr. MacSweeney told MNT: “Currently, there are over 120 different potential new medications, for [Alzheimer’s disease], in clinical trials. […] This impressive pipeline of new medications targets the many different biological processes, which result in [Alzheimer’s disease] and its symptoms.”
“The aim for many of these medications is, through a variety of intermediate mechanisms, to reduce brain cell death, by reducing the abnormally accumulated amyloid or tau proteins, which are characteristically demonstrated in patients with [Alzheimer’s disease],” explained Dr. MacSweeney.
“New symptomatic treatment medications are also in development to boost cognitive function, without affecting the underlying pathology of [Alzheimer’s disease],” she added.
Despite the setbacks and controversies, the future is looking brighter for the treatment of Alzheimer’s disease. The Alzheimer’s Association, for one, is optimistic:
“There is an increasingly robust treatment landscape for Alzheimer’s disease. The progress we’ve seen in not only this class of treatments, but also in the diversification of targets over the past few years, is exciting and provides hope to those impacted by this devastating disease.”
And Dr. Porsteinsson agreed, while suggesting that the research focus would benefit from being widened: “I think disease-modifying monoclonal antibody treatments against beta-amyloid are a start, but we need to move beyond the ones we see coming up for approval in terms of improved efficacy and/ or safety and tolerability. This can be hMabs targeting the same structure but we also need small molecule oral agents.”
“Furthermore, we need to look beyond amyloid to tau, neuroinflammation, oxidative stress, other neuroprotective pathways, metabolic dysfunction, and non-pharmacological interventions targeting lifestyle, diet, exercise, and concomitant medical illnesses,” he added.