Sunday, October 2, 2022

New drug for AZ

 Earlier this week, the pharmaceutical companies Biogen and Eisai announced encouraging results from a clinical trial for patients with Alzheimer’s disease: a monoclonal antibody treatment, called lecanemab, reduced cognitive decline by 27% in people with early-stage Alzheimer’s compared with those on a placebo after a year and a half. Outside observers say the trial could offer hope to some of the millions of people afflicted worldwide, who are largely bereft of treatments.

Amid the excitement, however, many questions linger, including why this treatment shows promise when others based on a similar strategy have failed. For years, researchers have tried to target a signature feature of the illness: a buildup of amyloid plaques in the brain, clumps of protein that disrupt neurons and other cells. But drugs that break down or otherwise inhibit these plaques haven’t clearly subdued symptoms. The new treatment is, apparently, the first to do so.

The field has been roiled in controversy: Another Biogen drug, aducanemab, was approved by the Food and Drug Administration (FDA) last year over concerns that, despite clearing away amyloid plaques, the evidence it alleviates patients’ symptoms was unconvincing. No other approved Alzheimer’s treatment targets the disease’s presumed roots, only its symptoms. Before aducanumab, U.S. officials hadn’t greenlighted an Alzheimer’s drug for almost 20 years.

Science spoke with Alzheimer’s experts about this week’s announcement and what’s next for lecanemab and the field.

What did the clinical trial find?

In a press release, Biogen and Eisai shared outcomes of their study, which included 1795 people with early-stage Alzheimer’s disease. The participants were randomly assigned to either receive lecanemab or a placebo, given via an intravenous infusion every other week for 18 months. The primary test was comparing cognitive decline between the two groups, based on a classic dementia scale called Clinical Dementia Rating-Sum of Boxes (CDR-SB). “I grew up using it and love it,” says Joy Snider, a neurologist at Washington University in St. Louis, of the assessment tool, which was developed at her institution. She heads the Knight Alzheimer’s Disease Research Center Clinical Trials Unit there, which enrolled nine patients in the lecanemab study. One advantage of this assessment, Snider says, is that it includes information from family members on how patients are faring, along with other measures.

In the study, people getting lecanemab still had cognitive decline, but it progressed 27% slower than in those on a placebo. That translates to 0.45 points on the 18-point CDR-SB. Although the difference is modest, it’s spawning hope. “This does make us feel a little better. These drugs do work,” Snider says.

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Lecanemab had side effects, most notably certain brain abnormalities seen with other antiamyloid therapies, including swelling and small hemorrhages in the brain. Neuroimaging turned up these concerns in about 21% of patients on lecanemab, and 9% of those on the placebo. Although these abnormalities often produce no symptoms, about 3% of those getting lecanemab did have symptoms from them.

Doctors aren’t sure how the apparently gentler slope of cognitive decline would be perceived by patients and their families. “Does that mean that grandma is going to have a few better days, a few better months, a few better years?” asks Jonathan Jackson, a cognitive neuroscientist at Massachusetts General Hospital (MGH). “It’s still an open question.” He and others hesitate to make grand pronouncements, especially after last year’s flameout of aducanemab. “We’re all feeling a sense of wariness and caution,” Jackson says. “We want to dig into the data before we make any large conclusions.”

Why did this drug meet its goals, whereas others failed?

No one knows for sure, but there are some theories. One is that lecanemab works a bit differently from other antiamyloid drugs. Some “try to bind or remove amyloid once it has aggregated into these large plaques,” Jackson says. Aducanemab, for example, primarily binds to amyloid protein after it has clumped together. Lecanemab, on the other hand, swoops in at an earlier stage, targeting “protofibrils,” strands that will consolidate into plaques but haven’t yet. Evidence across many trials and other research suggests the earlier in the disease process one goes after amyloid plaques, the better. For that reason, says Jackson—who describes himself as an amyloid skeptic—lecanemab “has always been one we had a lot of hope for,” even years ago when it was in early development.

The length of the lecanemab trial also made it easier to detect differences between patients not getting the experimental treatment and those who were. Assuming an Alzheimer’s drug works, the effect “will be bigger the longer your trial happens,” says Bart De Strooper, director of the UK Dementia Research Institute at University College London. And indeed, Biogen and Eisai noted that lecanemab failed to show a meaningful impact on cognition after 12 months, but did at 18 months.

The trial also included only people who had evidence of amyloid in the brain—something that’s been true of more recent trials but not older ones studying antiamyloid therapies, De Strooper says.

Does a diverse trial population matter?

One notable feature of the lecanemab trial was that about 25% of its participants were either Black or Hispanic, a relatively high number in the world of clinical trials, where marginalized groups are woefully underrepresented. “We’d like to think that people have equal access to our science,” says Jason Karlawish, co-director of the Penn Memory Center at the University of Pennsylvania, but practically speaking, they often don’t.

Furthermore, these populations also have a higher risk of Alzheimer’s disease than non-Hispanic white people, for reasons researchers don’t fully understand. “We want a drug that works in everybody,” Snider says, another reason trial diversity is so important.

For Jackson, who studies the impact of diversity and inclusion in human subjects research and directs the Community Access, Recruitment, and Engagement Research Center at MGH and Harvard Medical School, the new trial’s population presents an opportunity to research this disparity. According to one theory, dementia risk might be greater in Black and Hispanic people because they have higher rates of diabetes and cardiovascular disease, which can impact the brain, he explains. Probing how well lecanemab—“an antiamyloid therapy which really focuses on a pure presentation of Alzheimer’s disease”—worked in Black and Hispanic participants could offer biological insights into their illness. “I think this is going to be the first opportunity for us to have enough data on ethnic and racial minorities” in an Alzheimer’s trial to tease apart that information, Jackson says.

What will be the impact on the Alzheimer’s field?

Lecanemab is “not a cure, it doesn’t make people better,” Snider cautions. But she’s excited that it’s targeting known disease pathology and has some effectiveness in patients. (Still, scientists caution that especially after the aducanumab experience, they’ll feel more comfortable once the companies release more complete trial data.)

Other antiamyloid antibodies are in trials, and De Strooper says he’d love to see the development of small molecule drugs that can be swallowed instead of injected. Lecanemab’s impact on patients so far appears modest, but Jackson hopes emerging therapies “out in 3 or 4 years may be much more significant shots on goal.” Superior performance could come from researchers learning how to build better and safer antiamyloid therapies, he says, as well as determining who is best suited to receive them.

That said, “I still think we can’t just focus on amyloid,” Snider says. Future antiamyloid treatments may be an improvement over this one—or they may not. “This drug may be just as good as we can do” with that strategy on its own, she says, especially in people who already have symptoms. “We don’t treat cancer with one drug, we have a cocktail,” she says. Physicians need a similarly diverse toolkit for Alzheimer’s disease, where inflammation and other factors are also key drivers.

What questions remain?

A lot! First, researchers want to see more data from the lecanemab trial, which the companies say they’re planning to release in late November. Biogen and Eisai have applied for accelerated FDA approval. If it’s granted, there’s much interest—and some trepidation—about how the rollout of lecanemab will proceed in the real world. Snider wonders whether people on anticoagulant drugs, which reduce blood clots and which many older people take, may be at higher risk of brain bleeding from lecanemab. “That’s going to be a big question,” she says.

Karlawish wants more information on how patients fare long-term. Right now, assuming the companies’ announcement aligns with their trial data, the therapy seems “worth taking” or at least considering by those for whom it’s designed. But, “What haunts you in clinical practice is how long does the drug work and how long should you continue it.” He and others also worry that Alzheimer’s clinics aren’t equipped to handle a therapy like this, which requires infusions for potentially many patients and likely imaging to look for side effects. Karlawish would love to see a registry that tracks people on the treatment in order to help guide doctors and families facing difficult choices. “We don’t have an adequate workforce to roll this drug or a drug like it out into clinical practice,” where patients have enough trouble just getting a diagnosis, he says. 

Lecanemab is now being tested in people with evidence of amyloidsand, often, familial or genetic risk factors—but without symptoms. A burning question is whether the therapy can stave off dementia. At least a decade before glaring symptoms, there must be subtle signs of disease, De Strooper says. Preventing them from worsening is another frontier.

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