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. Today, though, the FDA gave the latest anti-amyloid drug, lecanemab (Leqembi), accelerated approval status. In case you are wondering, Leqembi is pronounced leh-KEM-bee.
Will this new anti-amyloid drug be a breakthrough or a disappointment? 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?
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 accelerated approval?
Accelerated approval allowed the FDA to bypass its usual drug approval process. That involves an outside panel of experts. These advisory committee members get to vote thumbs up or thumbs down before the FDA makes a final drug approval decision.
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 new 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.
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.
Red Flags Flying Over New Dementia Drug:
Investigators are looking at some alarming red flags. In the Phase II trials, people taking the drug had more brain shrinkage or atrophy than those on placebo. In general, brain atrophy is an unwelcome development.
An article in Science (Dec. 7, 2022) was titled “Brain Shrinkage As A Side Effect.”
It describes atrophy as a complication of several anti-amyloid drugs:
“In general, though, it’s safe to say that brain volume reduction is considered to be a pathological sign associated with reduced cognition.”
“It really does merit attention, and seeing it accelerate with some anti-amyoid therapies is something to think about.”
Equally concerning are three deaths of trial subjects. In a study of the related drug, aducanumab, nine people taking the medication died. If anti-amyloid drugs are associated with a risk of death, physicians will probably be reluctant to prescribe them, and patients may be unwilling to take them unless the drugs make a huge difference in the progression of Alzheimer’s disease.
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 today because of the FDA’s accelerated approval of Leqembi.
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 accelerated 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. Will insurance companies or Medicare pay for it?
There are two more anti-amyloid antibodies waiting in the wings. Roche will offer the results of gantenerumab and Eli Lilly will present data for donanemab. Perhaps the amyloid-theory of Alzheimer’s disease will be resurrected after years of negative results.
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 accelerated approval of Leqembi? Do you think the FDA should have held an advisory committee meeting to get objective input from outside experts? Please share your thoughts in the comment section below.