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Alzheimer’s Drug Gets Full FDA Approval Despite Safety Concerns

An anatomical model of a human brain in cross-section.
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The U.S. Food and Drug Administration (FDA) has this week converted the accelerated approval of the Alzheimer’s disease (AD) drug lecanemab to a traditional approval. This follows the results of a Phase 3 clinical trial published in January that demonstrated a modest ability to slow cognitive decline in the disease’s early stages. However, concerns regarding side effects warranting a black-box warning – the FDA’s highest level – weighed against limited clinical benefits raise concerns surrounding its use.

A first traditional approval

AD is a progressive brain disorder that affects over 6.5 million Americans. It is the most common cause of dementia, leading to worsening memory loss, confusion and communication difficulties that limit patients’ abilities to carry out simple tasks.

Changes in the brain such as the accumulation of abnormal proteins – amyloid-beta plaques and tau tangles – are key characteristics of the disease and are thought to be involved in its progression by destroying neurons and their connections.

Lecanemab, an amyloid-beta–directed antibody from biotech and pharmaceutical giants Biogen and Eisai, works by targeting and reducing these plaques, and is now the first of its class to be converted from an accelerated to a traditional FDA approval for the treatment of AD.

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Accelerated approval was granted in January 2023, via an FDA pathway that permits the approval of drugs for serious conditions with unmet medical needs based on clinical data reasonably likely to predict benefit for patients, known as a “surrogate endpoint”. For lecanemab, reducing the level of amyloid-beta plaques in the brain indicated its potential clinical benefit, with the FDA requiring a confirmatory study to validate anticipated clinical benefits.

On June 9, all members of the Peripheral and Central Nervous System Drugs Advisory Committee voted that the study’s results confirmed lecanemab’s benefit for AD treatment in a meeting convened by the FDA.

The efficacy of lecanemab was evaluated using the results of a randomized, placebo-controlled Phase 3 clinical trial involving 1,795 patients in which the presence of amyloid-beta plaques had been confirmed as well as either mild dementia due to AD or mild cognitive impairment (considered a precursor to dementia).

Bi-weekly intravenous doses of either placebo or lecanemab over 18 months showed a small but statistically significant “slowing” of cognitive decline in the lecanemab-treated group. This was measured using the Clinical Dementia Rating–Sum of Boxes (CDR-SB), an 18-point scale in which a higher score indicates greater impairment. CDR-SB scores in the placebo group increased by an average of 1.66 points, compared to 1.21 points in the lecanemab group. Though this does indeed represent a 27% “slowing” in cognitive decline, the importance of a 0.45-point reduction across an 18-point–wide scale is controversial.

A major breakthrough, or not clinically meaningful?

The approval was met with a mixed reaction – including exuberant statements from researchers who have dedicated their careers to proving that dementias can be treated by removing proteins like amyloid from the brain. Prof. Bart de Strooper, director of the UK Dementia Research Institute who received the 2018 Brain Prize for his work on AD’s molecular origin, commented, “This is a major step forward for the field and a triumph for basic research that has provided the basis for this breakthrough.”

This sentiment was echoed by Alzheimer’s charities, who have largely been strong supporters of the new wave of antibody drugs, including lecanemab, which have provided the first positive signals in a field where clinical trials have routinely delivered costly failures over the last two decades. Dr. Richard Oakley, associate director of research and innovation at the Alzheimer's Society, called the approval “incredibly encouraging."

Conversely, Dr. Robert Howard, a professor of old age psychiatry at University College London, gave short shrift to the data in an interview with Technology Networks. “It’s obviously not clinically meaningful,” he said. Howard pointed out that the apparent “slowing” of the disease’s progress was not a measure that the trial was originally set up to detect. Instead, Howard suggests the focus should be on the differences between individual time points. At 18 months, Howard says, “the differences are about half of what we would consider to be the minimum clinically important difference at that stage in AD.”

That limited clinical benefit becomes even more compromised considering the drug’s potential side effects. The FDA’s most stringent “black-box” warning is included in the prescribing information, highlighting the potential risks identified in the study, such as amyloid-related imaging abnormalities (ARIA) – potentially serious events known to occur with amyloid-targeting antibodies – and brain bleeds (hemorrhages).

ARIA often presents as temporary brain swelling that usually resolves with time, but can cause symptoms such as headache, confusion and dizziness, sometimes accompanied by small areas of bleeding. However, a small number of cases can present with serious and life-threatening brain swelling linked to seizures.

“I think about 1% of people on these drugs will have an ARIA event which is basically life-changing,” said Howard. “We’re balancing those tiny benefits with those very real risks.”

The black-box warning also recommends exercising caution for those who may be at a higher risk of ARIA or brain hemorrhages. For example, recommending genetic testing for patients before starting lecanemab to identify those with two copies of the ApoE ε4 allele (~2–5% of AD patients) who are at higher risk of severe ARIA, as well as careful consideration of the use of anticoagulants that could increase the risk of hemorrhages.

When asked about weighing the contrasting opinions on this drug for those with family members or who they themselves are struggling with dementia, Howard said: “Be really careful of making a decision that is based on your desperation, because sometimes that could lead you to do something that wasn’t in your best interests or in the best interests of someone that you love and care for.”

Professor Robert Howard was speaking to Ruairi J Mackenzie, Senior Science Writer for Technology Networks.