Alzheimer's drug approval raises the alarm

Data shows treatment can lead to 'brain shrinkage'

The US Food and Drug Administration (FDA) has granted an accelerated approval of a new treatment for Alzheimer’s disease, which aims to clear toxic amyloid protein build-up in the brain.

At a cost of $26,500 per year in the US (not covered by Medicare or Medicaid), people with early Alzheimer’s disease can receive a twice-monthly monoclonal antibody infusion called lecanemab (marketed as LEQEMBI™), co-developed by Eisai, a Japanese biotech firm, and Biogen.

In the lead up to the FDA’s approval, there was intense lobbying for the drug.

A ‘consensus statement’ signed by over 200 scientists, many of whom had financial ties to the drug companies, described lecanemab as a “foundational gamechanger” for the disease, calling for “no barrier” to the widespread availability of the treatment.

Now that the drug has been approved, advocacy groups like the Alzheimer’s Association, which are heavily funded by the drug industry, have welcomed the news, saying the FDA made “the right decision.”

But critics doubt the benefits of lecanemab outweigh its harms, and are dismayed that the FDA approved the drug without input from its own advisory panel.

Kim Witczak, a drug safety advocate, and member of the FDA’s Psychopharmacologic Drugs Advisory Committee, says she is “shocked" by the latest FDA stunt. 

“By approving this new drug without a public advisory committee meeting, the FDA once again has shown a lack of concern for the public, patients, and healthcare providers. Convening its advisory panel would have helped reassure everyone that the FDA’s decision was scientifically sound and transparent,” said Witczak.

“Advisory committee meetings offer the opportunity to discuss the data in an open and public forum, to challenge methods, study endpoints (surrogate vs clinically meaningful), and safety findings before the general committee member discussion. But in this case, none of that was possible,” she added.

FDA repeating its mistakes?

The FDA’s accelerated approval process used to green-light lecanemab is known for accepting lower evidentiary standards for drug efficacy, so that patients can gain access to experimental drugs sooner.

Critics say its reminiscent of the FDA’s approval of aducanumab - Biogen’s other Alzheimer’s drug. It was approved on the basis of lowering amyloid protein (a surrogate marker) in the brain, despite no clinically meaningful benefit for patients.

At the time, the controversial decision led to the resignation of FDA advisory member Aaron Kesselheim, who labelled it “probably the worst drug approval decision in recent U.S. history.”

Linda Furlini, a research ethics advisor based in Montreal, Canada says it essentially gives the rubber stamp to similar drugs down the track. “Once you grant accelerated approval of a drug in that class, then it’s easier to get the second drug, and then the third drug approved.”

Jessica Adams, an expert in drug regulatory affairs, agrees. She said, “Lecanemab’s approval shows the power of precedent in regulatory approvals. This is why I scoff whenever the FDA says it still reviews drugs on a case-by-case basis.”

What are the benefits?

The industry-funded study published in the New England Journal of Medicine, involving almost 1800 people with early Alzheimer’s disease, found that lecanemab could slow the decline of cognition and function by 27% over 18 months compared to placebo.

They used a “Clinical Dementia Rating” scale to show lecanemab patients declined by 1.21 points compared to 1.66 point in the placebo group – a 0.45 point difference in lecanemab’s favour.

But experts question whether the small difference will have any impact on how the patient actually feels.

Madhav Thambisetty, a neurologist at Johns Hopkins University and the National Institute on Aging said, “The benefit appears to be quite small, and it’s unclear how meaningful this might be for patients.”

In fact, the FDA’s own statistician Dr Tristan Massie was uncertain whether “the treatment effect on amyloid is reasonably likely to predict change on the clinical outcome” and considered the results of the study to be “exploratory”.

The harms?

As a physician who cares for people with Alzheimer’s disease, Thambisetty spoke about the harms of the drug. “These patients can experience headaches, falls, confusion, vision disturbances and it’s unclear if patients will be able to see obvious benefits on a day-to-day basis,” he said.

The data showed an increased risk of brain bleeds and swelling, i.e. amyloid-related imaging abnormalities (ARIA) occurred in 126 (14.0%) of subjects in the lecanemab group and only 69 (7.7%) of subjects in the placebo group.

This prompted the FDA to include a warning on the drug about the risk of swelling and bleeding in the brain.

The drugmakers have also highlighted that people carrying two copies of the APOE4 gene (which predisposes someone to Alzheimer’s) puts them at a particularly “high risk of life-threatening brain haemorrhage.”

Three deaths have been reported in people taking lecanemab; an 80-yr old phase 3 trial participant who suffered intracranial haemorrhage, a 65-yr old who experienced brain swelling and bleeding and a 79-yr old who reportedly had seizures and brain bleed in the open-label phase of the trial.

Two of the three people who died were taking blood thinners, and experts who reviewed the lecanemab death cases suggested that anticoagulant use may have exacerbated the fatal outcomes.

Furlini’s research career has focused on the need to educate and support caregivers of people with dementia-type illnesses.

“You read the list of side effects - you might have gait problems, you might have brain swelling, visual disturbances… I mean, what are we doing here?” asks Furlini, “The patient is already confused and losing their cognitive capacity. How are these serious side effects helping them? It runs counter to any ethical semblance of what is wanted or expected.”

What about brain shrinkage?

Thambisetty has also expressed concerns about the “brain shrinkage” seen in trial participants taking either lecanemab or aducanumab – increasing doses of the drug correlate to a decrease in brain volume.

“The observation of brain shrinkage is worrisome because, in the absence of compelling evidence to the contrary, it suggests a potential worsening of degenerative changes in the brains of people with Alzheimer’s disease,” wrote Thambisetty in a recent opinion piece for STAT.

The observation has been explained away by researchers who say that a reduced brain volume is due to the clearance of amyloid protein from the brain. But Thambisetty says there is little empirical evidence to support this theory.

Instead, he points to an Australian study which calculated that the clearance of amyloid plaque from the brain was too small to represent a plausible explanation for the loss of brain volume.

Another blow to FDA credibility

US lawmakers launched an investigation into the FDA after the agency’s controversial approval of aducanumab. Last month, a US House of Representatives panel released the report following an 18-month investigation.

The report said the process was “rife with irregularities” and that FDA officials “inappropriately collaborated” with the drugmaker during the approval process which “exceeded the norm in some respects.”

Representatives from the FDA and Biogen engaged in over 100 phone calls or meetings dating back to 2019 in order to expedite the drug’s approval, which lawmakers say, “consisted of atypical procedures and deviated from the agency’s own guidance."

The congressional report recommended the agency “must take swift action to ensure that its processes for reviewing future Alzheimer’s disease treatments do not lead to the same doubts about the integrity of FDA’s review.”

But critics now say, it’s too late for an agency that has not taken accountability for its actions.

“These drug approvals have just created confusion, uncertainty, fear and misinformation. Then they wonder why people have no trust in their institutions, like the FDA. The world looks to the FDA for leadership. That it does not fulfill its responsibilities, remains the challenge of our times,” said Furlini.

A new direction?

Furlini has followed this area of research for decades and says the drug industry needs to move on from the ‘amyloid theory’ of Alzheimer’s disease and refocus its attention on other causes.

“After so many years, I’m fed up with the exclusive focus on the amyloid theory to the exclusion of other research theories, it’s a disservice to people with Alzheimer's, and their families,” said Furlini

“There are a lot of buzzwords and marketing propaganda being put out there. And they justify it by saying that you have to give people hope. But you're giving people false hope. It plays with people's emotions, which I find horrendous,” added Furlini.

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