Earlier this week, 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 to those taking a placebo. after a year and a half.
Outside observers say the trial could offer hope to some of the millions of afflicted people around the world, who are largely without treatment.
Amid the excitement, however, many questions remain, including why this treatment shows promising results when others based on a similar strategy have failed.
For years, researchers have been trying to target a defining feature of the disease: a buildup of plaque amyloids in the brain, lumps of proteins that destroy neurons and other cells.
But drugs that break down or otherwise inhibit these plaques don’t have clearly attenuated symptoms. The new treatment is, apparently, the first to do so.
The field has been the subject of controversy: Another Biogen drug, aducanemab, was approved by the Food and Drug Administration (FDA) last year with concerns that, despite the removal of amyloid plaques, the evidence that it relieves the patients’ symptoms was not convincing.
No other approved Alzheimer’s treatment targets the alleged roots of the disease, only its symptoms. Prior to aducanumab, US officials had not given the green light for an Alzheimer’s drug for almost 20 years.
Science spoke to Alzheimer’s experts about this week’s announcement and future prospects for lecanemab and the industry.
Alzheimer’s: What Did the Clinical Trial Discover?
In a press release, Biogen and Eisai shared the results of their study, which included 1,795 people with early-stage Alzheimer’s disease. Participants were assigned randomly to receive lecanemab or a placebo, given as an intravenous infusion every other week for 18 months.
The main test was to compare the 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 I love it”says Joy Snider, a neurologist at Washington University in St. Louis, of the assessment tool, which was developed at her institute. She directs the clinical trials unit of the Knight Alzheimer’s Disease Research Center there, which enrolled nine patients in the lecanemab study.
One benefit of this assessment, Snider says, is that it includes information from family members about how patients are doing, along with other measures.
In the study, people taking lecanemab still had cognitive decline, but it progressed 27% slower than those taking a placebo.
This translates to 0.45 points on the 18-point CDR-SB. Although the difference is modestis generating hope. “This makes us feel a little better. These drugs work “says Snider.
Lecanemab had side effects, particularly some brain abnormalities seen with other antiamyloid therapies, including swelling and small bleeding in the brain. Neuroimaging raised these concerns in approximately 21% of patients treated with lecanemab and in 9% of those treated with placebo.
Although these abnormalities often did not produce symptoms, about 3% of those taking lecanemab had symptoms. Doctors aren’t sure how the apparently gentler slope of cognitive decline would be perceived by patients and their families.
“Does that mean grandma will have better days, better months, better years?” asks Jonathan Jackson, a cognitive neuroscientist at Massachusetts General Hospital (MGH). “It’s still an open question”.
He and others are hesitant to make big statements, especially after last year’s aducanemab shutdown. “We all feel a sense of distrust and caution”Jackson says. “We want to dig into the data before drawing big conclusions.”
Why has this drug achieved its goals while others have failed?
Nobody knows for sure, but there are some theories. One is that lecanemab works slightly differently than other antiamyloid drugs. Some “They try to bind or remove the amyloid once it has aggregated in these large plaques”Jackson says.
Aducanemab, for example, mainly binds to the amyloid protein after it has aggregated. Lecanemab, on the other hand, comes forward at an earlier stage, targeting the “Protofibrils”threads that will consolidate in plates but they are not yet.
Evidence in many studies and other research suggests that the earlier in the disease process you go after amyloid plaques, the better. For this reason, says Jackson, who describes himself as a skeptic on the amyloid, lecanemab “It has always been what we hoped for”even years ago, when it was in early development.
The length of the lecanemab study also made it easier to detect differences between patients who did not receive the experimental treatment and those who were. Assuming an Alzheimer’s drug works, the effect “It will be greater the longer it develops”,
says Bart De Strooper, director of the UK’s Dementia Research Institute at University College London. And indeed, Biogen and Eisai noted that the lecanemab does not showed a significant impact on cognition after 12 months, but did so at 18 months.
The trial also included only people who had evidence of amyloid in their brains, something that was true for more recent studies but not for older ones studying antiamyloid therapies, says De Strooper.
Is a diverse test population important?
A notable feature of the lecanemab study was that approximately 25% of its participants were black or Hispanic, a relatively high number in the clinical trial world, where marginalized groups are sadly underrepresented.
“We would 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 in practice they often don’t.
Furthermore, these populations also have a higher risk of Alzheimer’s than to non-Hispanic whitesfor reasons that researchers do not fully understand. “We want a drug that works for everyone”says Snider, another reason why process diversity is so important.
For Jackson, who studies the impact of diversity and inclusion in human subject research and heads the Community Access, Recruitment, and Engagement Research Center at MGH and Harvard Medical School, the new study’s population represents an opportunity to research this. disparity.
According to one theory, the risk of dementia may be higher in blacks and Hispanics because they have higher rates of diabetes and cardiovascular disease, which they can impact the brainexplains.
Probe how well the lecanemab, “An antiamyloid therapy that really focuses on a pure presentation of Alzheimer’s disease”it worked in black and Hispanic participants could offer biological insights into their disease.
“I think this will be the first opportunity for us to have sufficient data on ethnic and racial minorities” in an Alzheimer’s trial to question this information, Jackson says.
What will be the impact of Alzheimer’s on the ground?
Lecanemab “It’s not a cure, it doesn’t improve people”, Snider warns. But he is thrilled that he targets a known condition and has some effect in patients.
However, scientists warn that, especially after the experience with aducanumab, they will feel more comfortable once companies release more complete test data.
Other antiamyloid antibodies are being tested, and De Strooper says he would like to see the development of small-molecule drugs that can be ingested rather than injected.
The impact of Lecanemab on patients so far it seems modestbut Jackson hopes emerging therapies “In 3 or 4 years they may be more within range”.
Higher 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.
Said this, “I still think we can’t just focus on amyloid”says Snider. Future antiamyloid treatments may be an improvement over this, or not.
“This drug could be as effective as we can do” with that strategy alone, he says, especially in people who already have symptoms. “We don’t cure cancer with a drug, we have a cocktail”He says.
Doctors need an equally diverse toolkit for Alzheimer’s disease, in which Inflammation and other factors are also key factors.
What questions remain?
Many! First, the researchers want to see more data from the lecanemab trial, which the companies say they want to release in late November. Biogen and Eisai have requested expedited approval from the FDA.
If it were granted, there would be a lot of interest, and some trepidationon how the launch of lecanemab in the real world will proceed.
Snider wonders if people who take anticoagulant drugs, which reduce blood clots, and which many older people take, may be at increased risk of brain haemorrhage from lecanemab. “It will be a great question”He says.
Karlawish wants more information on how long-term patients are doing. Right now, assuming the companies’ announcement is in line with their trial data, the therapy appears “be worth” or at least take it into consideration by those for whom it was designed.
But “What haunts you in clinical practice is how long the drug works and how long you should continue taking it”.
He and others also fear Alzheimer’s clinics are not equipped to handle therapy like thiswhich requires infusions for potentially many patients and possibly imaging to look for side effects.
Karlawish would like to see a registry that tracks people on treatment in order to help guide doctors and families facing difficult choices.
“We do not have an adequate workforce to bring this drug or a similar drug into clinical practice”where patients have enough trouble getting a diagnosis, he says.
Lecanemab is now being tested in people with evidence of amyloids and, often, family or genetic risk factors, but without symptoms. A burning question is whether therapy can prevent dementia. At least a decade before symptoms manifest, there must be subtle signs of disease, says De Strooper. Stopping them from getting worse is another frontier.
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