Progress and controversy in Alzheimer’s research: Aducanumab’s FDA approval

Most Alzheimer’s disease treatments alleviate symptoms and help those with the disease to function for longer than they would without treatment.

Two new drugs that have recently received much attention, aducanumab and lecanemab, are human monoclonal antibodies (hMabs).

These are, according to their manufacturers, the first “disease-modifying” drugs for Alzheimer’s disease.

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.

Several trials, despite showing a reduction in plaques, have shown little or no difference in symptoms between patients on hMabs and controls on placebo.

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 lecanemab (Leqembi) — have now received accelerated approval from the Food and Drug Administration (FDA). Aducanumab received approval in July 2021, and lecanemab in January 2023.

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 ENGAGE study into aducanumab. He also consulted for the FDA advisory committee on the clinical relevance of the data from the EMERGE study.

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.

Participants in the trials had mild cognitive impairment (MCI) or early dementia, and an average age of 70 years. Although the two trials were almost identical in design, the results were rather different.

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 terminated early after analysis of data from the first 50% of participants, as Dr. Porsteinsson explained: “Both studies were actually stopped prematurely because interim analysis suggested they were not going to meet their endpoints.”

However, Biogen continued to collect data for a further 3 months. A reanalysis of the data confirmed the lack of benefit from the drug in the ENGAGE study, but suggested some cognitive benefit in patients given a higher dose of aducanumab in the EMERGE study.

“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 amyloid-related imaging abnormalities (ARIAs). These side effects are very common and dose-dependent with hMabs. In the aducanumab trials about one-third of the participants developed ARIAs.

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 APOE E4 allele — as well as those taking anticoagulants, or people who have a history of brain bleeds are at higher risk, so should be carefully monitored during treatment.

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 infusion reactions with lecanemab.

In July 2021, aducanumab was approved by the FDA on its accelerated approval pathway.

According to the FDA, “[p]atients receiving the treatment had significant dose-and time-dependent reduction of amyloid beta plaque, while patients in the control arm of the studies had no reduction of amyloid beta plaque.”

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.

Some have questioned why the FDA gave accelerated approval to aducanumab, rather than waiting for results from further trials. It has even been suggested that there was too much collaboration between Biogen and the FDA.

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.