Advice |  Ask a Doctor: Who Will the New Alzheimer's Drug Help?

Advice | Ask a Doctor: Who Will the New Alzheimer’s Drug Help?


Q: Who will lecanemab, an experimental Alzheimer’s drug that has been shown to moderately slow the effects of the disease, help? Is it safe? Is there reason to be hopeful about the future of dementia/Alzheimer’s therapy?

A: My father passed away last year from Alzheimer’s disease. As a son, I well remember the despair I felt when he refused. I was desperately looking for something – anything – that could help slow or reverse his decline. Judging from my experience, I think it’s possible that patients and their caregivers will turn to lecanemab, an experimental drug for Alzheimer’s disease, as a lifeline.

Lecanemab, however, is unlikely to benefit patients with dementia other than Alzheimer’s disease, about one-third of the dementia population, or those in the later stages of Alzheimer’s disease, when significant brain damage have already happened.

Researchers announced this week that lecanemab slowed cognitive decline in patients with early stage disease. After 18 months of treatment in a clinical trial with nearly 1,800 participants, the reduction in score on a clinical dementia scale that assesses mental functions such as memory, judgment and problem solving was 27% lower in patients treated with lecanemab than in those receiving a placebo. .

Lecanemab, a monoclonal antibody given intravenously every two weeks, targets and eliminates buildups of beta-amyloid, an abnormal protein commonly thought to damage the brain in Alzheimer’s disease. The trial, published Tuesday in the New England Journal of Medicine, provides the first definitive evidence that removing beta-amyloid in patients with Alzheimer’s disease provides clinical benefit. Both groups in the trial experienced worsening of their symptoms over 18 months, but the group receiving the placebo declined faster.

Experts cautioned, however, that the slowing of cognitive decline with lecanemab, which amounted to about half a point on an 18-point scale, was a modest effect that may not be noticeable to patients. The result was statistically significant, but it is uncertain whether it is clinically significant.

Is Alzheimer’s disease drug lecanemab safe?

Participants treated with lecanemab experienced severe side effects. Almost 13% showed signs of mild to moderate brain swelling, which was also seen with other amyloid-removing drugs, but was not life-threatening. Seventeen percent also experienced brain bleeds, compared to 9% of placebo participants. In a follow-up study, two patients who received the drug died of brain hemorrhage. Although Biogen and Eisai, the companies that make the drug, have denied the bleeding was due to lecanemab, the deaths add to concerns that the drug is safe for patients on blood thinners.

Given the cognitive benefits seen with lecanemab, the Food and Drug Administration is expected to grant “accelerated approval” to the drug in early January. This status would allow the drug to be given to patients in the general population, but may require Biogen and Eisai to conduct further trials of the drug to gain full approval.

The lecanemab results come after decades of failures in Alzheimer’s disease research. Hundreds of experimental drugs have fallen into the trash heap of failed Alzheimer’s disease therapies. Even drugs that targeted beta-amyloid did not help patients or delay disease progression (and, in some cases, impaired cognitive performance). The only drugs approved to treat the condition, such as Aricept, primarily treated symptoms such as memory loss (and even then with minimal effectiveness). They did nothing to slow or reverse the progression of the disease.

There have also been controversies. In late 2020, a panel of experts advising the FDA almost unanimously concluded that aducanumab, an amyloid-suppressing drug similar to lecanemab and also made by Biogen, was not worthy of approval. In 2019, Biogen ended two late-stage studies of the drug after concluding that it produced no benefit over a placebo. A few months later, however, the company unexpectedly resurrected the drug after analyzing a larger data set that allegedly showed that aducanumab did indeed reduce cognitive decline in patients with early Alzheimer’s who were receiving higher doses.

The FDA panel flatly rejected this interpretation. This decision seemed to dash not only the hopes of treating the more than 6 million patients in the United States – and approximately 30 million worldwide – living with Alzheimer’s disease, but also in many ways the very logic of the program of current research. This rationale—removing amyloid-beta clumps from patients’ brains will lead to better clinical outcomes, often referred to as the “amyloid hypothesis”—has been the basis of Alzheimer’s disease drug research for several decades.

In granting tentative approval for aducanumab, the FDA overruled the advice of its own panel of advisors, but many experts interpreted the trial results as the nail in the coffin for the amyloid hypothesis. (Medicare also decided to severely limit its coverage of aducanumab, citing uncertain risks and benefits.)

But now, with data released this week, the amyloid hypothesis appears to have been confirmed for the first time in a clinical trial.

What future for treatments for Alzheimer’s disease?

Beta-amyloid continues to underpin most Alzheimer’s disease research, but it is becoming clear that the dogma that Alzheimer’s disease is simply driven by accumulations of beta-amyloid must give way to a broader conceptualization of disease.

Other culprits such as brain inflammation are being examined by researchers. Recent evidence suggests that overactivity of brain immune cells called microglia, which devour unknown pathogens and dead brain tissue, can accelerate brain degeneration. Several research groups and companies are trying to understand how to influence the genes that control inflammatory microglial activity. Indeed, small studies of anti-inflammatory drugs have shown some benefit in reducing the risk of developing Alzheimer’s disease.

Other research suggests that infectious agents such as herpes viruses or bacteria that cause gum disease may play a role in initiating amyloid buildup. These hypotheses may open new avenues of investigation and treatment, including the use of antibiotics. In the modern view, then, clinical Alzheimer’s disease may be the last common pathway of disease processes initiated by a host of problems.

We need to develop new approaches in addition to amyloid removal as the population continues to age and a dementia epidemic looms before us.

Sandeep Jauhar is a physician at Northwell Health in New York and a writer. He is the author of “Heart: a story» and the forthcoming book «My Father’s Brain: Life in the Shadow of Alzheimer’s Disease.”

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