YIKES! FDA Approves Lecanemab Against Alzheimer’s

For decades the news about Alzheimer’s disease [AD] has been dismal. No medication has been shown to actually delay or reverse the symptoms of AD. On July 6, 2023 the FDA gave the latest anti-amyloid drug, lecanemab (Leqembi), full approval status. Many neuroscientists have hailed this drug as an important advance against dementia. The media has made it seem as if the drug is a breakthrough. Medicare says it will pay for the drug. That means millions of people with early dementia will get access to a pricey medication. How well will it work?

How Historic Is the FDA’s “Traditional” Approval of Lecanemab?

In its own words, the FDA stated on July 6, 2023:

“Leqembi is the first amyloid beta-directed antibody to be converted from an accelerated approval to a traditional approval for the treatment of Alzheimer’s disease. The drug works by reducing amyloid plaques that form in the brain, a defining pathophysiological feature of the disease.”

Let’s get one thing straight. Amyloid plaque is a “biomarker” for Alzheimer’s disease (AD). What the FDA is not saying is that everyone with amyloid plaque gets AD. We have known for years that some people with so-called Alzheimer’s brains that have lots of amyloid plaques do not develop Alzheimer’s disease (Stat, Feb. 27, 2020).

Here are more details:

“About 30% of older adults have brains littered with enough amyloid or tau, or both, to qualify for an Alzheimer’s diagnosis but without so much as a hint of dementia, said neuroscientist Timothy Hohman of Vanderbilt University Medical Center, who is leading the largest-ever study to identify genetic explanations for that resilience.

“’You can have abundant plaques and tangles without having Alzheimer’s disease,’ agreed neurologist Rudy Tanzi of Massachusetts General Hospital.”

Ooops! How does that happen?

Does Eliminating amyloid plaque “cure” Alzheimer’s disease? Not by a long shot! Reducing amyloid plaque in the brain does not mean that people suddenly get their memories back, recognize family members or avoid nursing homes.

The FDA states that the drug “has shown clinical benefit.” But what exactly does that mean? Here is a very technical description from the FDA.

Unfortunately, it does not tell you anything about the things people really care about:

“Leqembi demonstrated a statistically significant and clinically meaningful reduction of decline from baseline to 18 months on the primary endpoint, the Clinical Dementia Rating Scale Sum of Boxes score, compared to placebo. Statistically significant differences between treatment groups were also demonstrated on all secondary endpoints, which included the Alzheimer’s Disease Assessment Scale Cognitive Subscale 14, and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment.”

We will dig into the actual details of the clinical trial shortly. But first, what about adverse reactions?

The FDA Comments on Lecanemab Side Effects:

In its July 6, 2023 news release the FDA states:

“The most common side effects of Leqembi were headache, infusion-related reactions and amyloid-related imaging abnormalities (ARIA), a side effect known to occur with the class of antibodies targeting amyloid.  ARIA most commonly presents as temporary swelling in areas of the brain seen on imaging studies that usually resolves over time and may be accompanied by small spots of bleeding in or on the surface of the brain. Although ARIA is often not associated with any symptoms, symptoms can occur and include headache, confusion, dizziness, vision changes and nausea. ARIA can also infrequently present with serious and life-threatening brain edema that can be associated with seizures and other severe neurological symptoms. Intracerebral hemorrhages can occur in patients treated with this class of medications and can be fatal. A boxed warning is included in the prescribing information to alert patients and caregivers to the potential risks associated with ARIA.”

Boxed Warning?

I have been searching for the “boxed warning” or what has been called the “black box” warning for Leqembi. So far it has not been revealed in the official prescribing information for lecanemab.

I suspect it will say something about ARIA (amyloid-related imaging abnormalities). That is kind of vague. Most people will likely ignore it. Perhaps “brain swelling” and “bleeding” will also be mentioned. We will let you know when the black box warning becomes official.

Anti-Amyloid Drugs and Brain Shrinkage?

So, you have read about brain swelling. That does not seem like a good thing, but the FDA has made it seem as it it is a temporary problem that “usually resolves over time and may be accompanied by small spots of bleeding in or on the surface of the brain.” Don’t worry, be happy.

What you did not read in the FDA’s official announcement was anything about brain shrinkage. There is another disturbing fly in the anti-amyloid ointment. A study published in the journal Neurology (March 27, 2023) revealed that anti-amyloid drugs like lecanemab can cause brain shrinkage. The researchers call this accelerated “brain atrophy.” Such a reduction in brain volume is usually linked to worsening dementia.

We reported this unexpected complication after reading an article in Science (Dec. 7, 2022) titled “Brain Shrinkage As A Side Effect.”

The author refers to an article in STAT (Nov. 29, 2022) titled:

“Anti-amyloid drugs and the mystery of treatment-associated brain shrinkage.”

The neurologist who wrote this article works at the National Institute on Aging. He was reporting on early Phase II clinical trials of lecanemab.

Here is his assessment:

“The acceleration of brain shrinkage — also known as atrophy or reduction in brain volume — has been described in clinical trials of other anti-amyloid antibodies, including aducanumab (now FDA-approved as Aduhelm) and donanemab. It’s important to fully understand this phenomenon and its long-term implications, because in people with Alzheimer’s disease, brain shrinkage, typically measured on MRI scans as a reduction in brain volume or an increase in the volume of the brain’s fluid-filled spaces (known as ventricles), has been consistently associated with progression of the disease rather than slowing of symptoms.”

Researchers often perform autopsies on patients diagnosed with AD. That’s because the best way to prove someone actually died of Alzheimer’s disease is to look at the brain. Brain shrinkage can be measured by looking at ventricles. The bigger the ventricles the more atrophy there is in the brain. As shrinkage increases, AD tends to get worse (Brain, Sept, 2008).

A Systematic Review and Meta-Analysis of Anti-Amyloid Drugs:

The most recent study comes from scientists at the Institute of Neuroscience and Mental Health at the University of Melbourne, Australia (Neurology, March 27, 2023). They reviewed brain volume changes after patients were exposed to anti-amyloid drugs.

The authors analyzed data from 31 clinical trials of 14 anti-amyloid drugs. Both aducanumab and lecanemab were included in the analysis. The results of the study are startling!

The researchers report that their data:

“…reveal the potential for anti-Aβ [amyloid beta] therapies to compromise long- term brain health by materially accelerating brain atrophy and provide new insight into the adverse impact of ARIA [Amyloid-Related Imaging Abnormalities].”

The authors note that all of the drugs that reduce amyloid in the brain cause detectable “imaging abnormalities.” In other words, the structures within the brain are changed and not necessarily in a good way.

As they report:

“…loss of brain tissue is the proximate cause of cognitive dysfunction in AD and volume changes are supportive and objective evidence of disease progression.”

There are many unanswered questions about anti-amyloid drugs and the long-term benefits or risks of such medications. The authors of this research call for drug companies to release data from clinical trials so that other investigators can analyze the impact of brain shrinkage on clinical outcomes over time.

How Effective Are Anti-Amyloid Drugs Like Leqembi?

A lot depends upon how you define “effectiveness.” Drug companies and the FDA probably define drug effectiveness differently than you do.

Most of the news articles about the Leqembi emphasize that it “modestly” slows the decline of mental deterioration. What exactly does that mean and why did the FDA grant this drug “accelerated approval” status?

Accelerated Approval?

The FDA has a special category for drugs that might help hard-to-treat conditions.

It describes the process this way:

“The FDA instituted its Accelerated Approval Program to allow for earlier approval of drugs that treat serious conditions, and fill an unmet medical need based on a surrogate endpoint.  A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit. The use of a surrogate endpoint can considerably shorten the time required prior to receiving FDA approval.”

There is a huge problem with surrogate endpoints, though. Modifying them with a drug does not always produce the desired clinical outcome.

For example, the diabetes drug tolbutamide (Orinase) lowered blood glucose (a surrogate endpoint) but did not extend life. In fact, people getting the drug died faster than those who received placebo. You can read more about surrogate end point disappointments at this link.

Anti-Amyloid Drugs Have Been Disappointing:

Decades ago, leading neuroscientists fixated on amyloid plaque as the causative agent behind Alzheimer’s disease. A great many drugs have been developed that reduce the amyloid protein in the brain. Lowering beta amyloid is a classic example of a surrogate endpoint.

Until lecanemab, the billions that were spent on these drugs were mostly wasted. Although many medications were quite good at lowering amyloid in the brains of Alzheimer’s patients, none of these compounds reversed the significant symptoms of cognitive decline.

The experimental drugs did not help people resume normal activities of daily living. People were not able to go back to work. People with dementia were not able to avoid entering nursing homes by taking an anti-amyloid drug.

What About Leqembi?

There is no clinical data demonstrating that the newest anti-Alzheimer’s drug will help people resume normal activities of daily life. The drug companies involved in its development (Biogen and Eisai) have not proven Leqembi will restore forgotten memories for patients with Alzheimer’s disease. There is no evidence that it will keep patients with dementia out of nursing homes.

What they have proven is that like many drugs before it, Leqembi will lower amyloid plaque in the brains of patients with Alzheimer’s disease. There is also some evidence that it will have a modest impact on the rate of cognitive decline. Is that good enough for “traditional” approval?

FDA Got Spanked for the Way It Approved Aduhelm for Alzheimer’s Disease:

A related drug to lecanemab is aducanumab (Aduhelm). Both drugs are monoclonal antibodies. They work to rid the brain of amyloid plaque. On Dec. 29, 2022, two congressional committees released a joint investigation into the FDA’s handling of the Aduhelm approval. That drug got a green light against Alzheimer’s disease on June 7, 2021.

For reasons that are somewhat mysterious, the congressional report has seemingly disappeared. You can read an overview of the criticisms of both the FDA and the drug company (Biogen) at this link. I attempted to summarize the disturbing conclusions in a way you can understand. It’s worth taking a few minutes to learn why the FDA ended up in such hot water over its approval of Aduhelm.

Lecanemab Accelerated Approval:

The drug companies involved in the development of Leqembi have tried to put the most positive spin possible on the latest monoclonal antibody against amyloid plaque.

We heard last fall that lecanemab (Science, Sept. 29, 2022):

“…reduced cognitive decline by 27% in people with early-stage Alzheimer’s compared with those on a placebo after a year and a half.”

Headlines Endorse New Dementia Drug:

When news about lecanemab first appeared, newspaper editors had to decide how to present it. Usually, they love good news or bad news. If they can put a headline on a story that shouts drug breakthrough or drug disaster, they rejoice. It means people are likely to read the article. Nuance, statistics and balance are less likely to generate enthusiasm or eyeballs.

Here is an example of the headlines around the new dementia drug lecanemab:

“Experimental Alzheimer’s Drug Slows Cognitive Decline In Trial…” Washington Post

“Success of experimental Alzheimer’s drug hailed as ‘historic moment’” The Guardian

“Biogen Explodes Higher After Potential Mega Blockbuster Alzheimer’s Drug Succeeds” Investor’s Business Daily

Is lecanemab a “breakthrough”? Will the new dementia drug change the trajectory of Alzheimer’s disease? Read on to get the People’s Pharmacy Perspective.

New England Journal of Medicine, Jan. 5, 2023:

A study published in the New England Journal of Medicine describes the results of an 18-month clinical trial of lecanemab for Alzheimer disease. The researchers recruited nearly 1800 patients and assigned them randomly to receive either the anti-amyloid drug  or placebo. At the end of the study, people getting the drug had not declined quite as much as those on placebo.

That does not mean that the drug actually reversed their dementia, but it did slow the progression modestly. Some people experienced serious adverse reactions including brain inflammation. Three people taking the drug died.

OK…that is the quick and dirty summary. Here are the actual conclusions from the study in the New England Journal of Medicine, Jan. 5, 2023:

“Lecanemab reduced markers of amyloid in early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease.”

“Moderately less decline” is hardly a ringing endorsement. You will note that the researchers did not say the drug reversed Alzheimer’s disease. As far as we can tell, the drug did not improve memory or keep people out of nursing homes. The authors admit that “clinically meaningful effects” were not obvious.

No Surprises!

There was no question that lecanemab, like aducanumab, reduces levels of amyloid in the brain. But most drugs that reduce amyloid plaque in the brain have produced no practical benefits for patients’ daily lives. It is not obvious to me that lecanemab is any exception.

What Do We Know About the Clarity AD Clinical Trial?

The drug developers are touting the effectiveness of lecanemab, the latest anti-amyloid drug by stating that it can reduce clinical decline 27% as measured on a numeric scale. A 27% reduction in cognitive decline sounds pretty darned good. It has made headlines because of the FDA’s approval of Leqembi.

The Washington Post states on July 6, 2023):

“The Food and Drug Administration on Thursday gave full approval, for the first time, to a drug that modestly slows Alzheimer’s disease — a development that offers a degree of hope for treating the memory-robbing disease but also raises difficult questions about safety, effectiveness and cost.”

Let’s look at the data:

The CDR-SB Scale:

Let’s dig a bit deeper, though. The investigators used something called the CDR-SB scale to assess cognitive functioning. It stands for Clinical Dementia Rating sum of boxes. This assessment tool calculates things like problem solving ability and memory. It also analyzes personal care performance.

The scale runs from 0 to 18. Let me repeat that. This is an 18 point measurement scale. Someone who scores a 0 has virtually no cognitive impairment. A score of 18 is bad news and represents very severe cognitive decline. We’re talking full-blown dementia!

At the start of the clinical trial, patients averaged 3.2 on the CDR-SB scale. After a year and a half, most patients had higher scores. In other words, their cognitive performance declined.

How did the patients on lecanemab perform in absolute terms? The patients who got the drug instead of placebo improved their score by 0.45 points on the CDR-SB scale. Remember, though, this is an 18 point scale. The improved score over placebo was statistically significant. That is why the headlines were so positive.

The previous drug, aducanumab, improved participants’ scores by 0.39 points on the same scale. As you may recall, that drug disappointed scientists, even though the FDA did approve it for treating patients with Alzheimer’s disease.

How Good Is This New Dementia Drug in the Real World?

Although the Alzheimer’s Association has applauded the trial results and the FDA’s traditional approval, some experts are skeptical about whether the drug will make an important difference clinically.

Most importantly, will it keep patients with AD out of nursing homes? Will it help them remember family members? Could they resume work and drive safely? Those are the kinds of questions that families want answered. That is how I would define “effective” against Alzheimer’s disease.

What About Side Effects?

Roughly one in five of those on the drug had results on brain scans indicating swelling or bleeding. The drug companies reassured the public that actual symptoms of brain swelling and/or micro and macro hemorrhages were only 0.7% in the lecanemab group and 0.2% in the placebo group.

The article that reported on the clinical trial (Clarity AD) that appeared in the New England Journal of Medicine, Jan. 5, 2023 reported:

“Deaths occurred in 0.7% of the participants in the lecanemab group and 0.8% of those in the placebo group. No deaths were considered by the investigators to be related to lecanemab or occurred with ARIA [amyloid-related imaging disorders].”

That sounds OK. And yet on January 4, 2023, there was a report of “Multiple Cerebral Hemorrhages in a Patient Receiving Lecanemab Treated with t-PA for Stroke” published in the New England Journal of Medicine on January 4, 2023. The patient died. This makes the third death linked to the drug. Brain swelling or bleeding are recognized side effects of lecanemab.

It has been our experience that drug companies often try to explain away such serious adverse reactions. It will be interesting to see how the FDA responds to these deaths. They clearly did not slow the agency’s accelerated approval of Leqembi.

The People’s Pharmacy Perspective on This New Dementia Drug:

Relative risk reduction always seems impressive. Headlines that announce a 27% reduction in cognitive decline are impressive. A 0.45 difference between drug and placebo on an 18-point scale produces a lot less excitement.

Most prior anti-amyloid medications have disappeared into the waste bin of drug development. Perhaps Leqembi will be different. The price is expected to be $26,500 annually. We are being told that Medicare will pay for it! Of course that means your tax dollars at work. We will all be paying for Leqembi. If millions of people are prescribed this drug, Medicare will go deeper into the hole than before.

There are two more anti-amyloid antibodies waiting in the wings. Roche will soon offer the results of gantenerumab. Eli Lilly has already presented data for donanemab. You can read my take on this anti-amyloid monoclonal antibody at this link.

Should you be interested in a different theory of AD, here is a link to an article that discusses infection as a potential contributing factor. You may also find our podcast with Matthew Schrag, MD, PhD, of great interest. He has uncovered some serious questions about the amyloid theory of Alzheimer’s disease.

What do you think about the FDA’s “traditional” approval of Leqembi? Are you concerned about the reports of brain shrinkage linked to anti-amyloid drugs? Please share your thoughts in the comment section below.