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

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 55 millionTrusted Source people worldwide are currently living with dementia. Dementia most commonly affects those over the age of 65Trusted Source, and with people living longer, the WHO expects the number to reach around 140 million by 2050.

Alzheimer’s disease accounts for 60-70%Trusted Source of dementia cases. A characteristic of Alzheimer’s disease is the presence of beta-amyloid plaquesTrusted Source in the brain, which researchers have hitherto thought to disrupt the transmission of nerve impulses and cause many of the symptoms of Alzheimer’s.

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?

Plaque-clearing drugs

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 antibodiesTrusted Source (hMabs).

These are, according to their manufacturersTrusted Source, 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.

Aducanumab and lecanemab

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 lecanemabTrusted Source (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 ENGAGETrusted Source study into aducanumab. He also consulted for the FDA advisory committee on the clinical relevance of the data from the EMERGETrusted Source 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.”

Conflicting trial results for aducanumab

Two 18-month phase 3 trials of aducanumab, ENGAGE and EMERGE, were funded by the drug manufacturer Biogen.

ParticipantsTrusted Source 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 earlyTrusted Source 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 dataTrusted Source 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.”

Adverse effects

One concern with aducanumab was the frequency of side effects, particularly amyloid-related imaging abnormalitiesTrusted Source (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 alleleTrusted Source — 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 reactionsTrusted Source with lecanemab.

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