A New Drug Could Slow Alzheimer’s Disease, Data Show

Over the past few years, Alzheimer’s patients and their caregivers have been on a roller-coaster ride full of highs and lows in the search for treatments—and new research presents another emotionally thrilling loop.

In data presented at the annual Clinical Trials in Alzheimer’s Disease meeting in San Francisco, and published in the New England Journal of Medicine, scientists from the Japanese pharmaceutical company Eisai showed that its drug for Alzheimer’s led to improvements in people’s cognitive functions.

The improvements weren’t huge, or even the first to be reported with an Alzheimer’s medication. But they do come from the most comprehensive and advanced study on Alzheimer’s patients to date. In a phase 3 trial, Eisai researchers showed that people taking the drug lecanemab, which targets the amyloid protein that builds up in the brain during Alzheimer’s, slowed cognitive decline by 27%, as measured by standard clinical tests, compared to people assigned to a placebo. Those results mean that lecanemab is a disease-modifying drug: one that impacts the course of Alzheimer’s, rather than simply treat its symptoms, which all but one of the approved drugs for the condition do.

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But as encouraging as the results are, they come at a bewildering time for the Alzheimer’s community, which has been buoyed by hopeful news only to have those expectations dashed in short order. In June 2021, the Food and Drug Administration (FDA) approved the first drug to treat Alzheimer’s, aducanumab (brand name: Aduhelm). As with people who took lecanemab, those taking aducanumab showed improvements in cognitive tests compared to people taking a placebo. But the benefits of aducanumab—unlike with lecanemab—were reported in an earlier phase 1 study that involved a smaller number of patients and that was designed to test the safety, not the efficacy, of the therapy. These benefits were not robustly and consistently repeated in phase 3 studies of the drug. Still, the FDA approved the medication in a controversial decision based on the assumption that lowering levels of amyloid in the brain, which aducanumab did, would translate into meaningful clinical benefits. But given the uncertainty of the data, the Centers for Medicare and Medicaid Services decided not to cover the high cost of the drug, which runs $56,000 a year, and required additional trials to confirm the treatment’s effectiveness. The Alzheimer’s community of patients and physicians have been reluctant to take the risk of trying the therapy—and despite being the first disease-modifying drug approved by the FDA, aducanumab has remained under-utilized.

Eisai, which had partnered with the U.S. biotech company Biogen to develop and test aducanumab, now has stronger results with lecanemab to support the connection between lowering amyloid and measurable brain benefits for Alzheimer’s patients. That will likely boost so-called anti-amyloid strategies, which focus on shrinking or ridding the brain of the protein plaques that build up in order to slow the neurodegeneration that’s the hallmark of the disease. But the scientific ride isn’t over yet; even with the encouraging results, the amyloid strategy still has a lot to prove. At the same conference at which the lecanemab data were presented, Roche is reporting on its anti-amyloid treatment, but with more disappointing results. Roche found that its compound, gantenerumab, did not lower amyloid significantly and did not help patients improve their scores on cognitive tests.

What are patients and the doctors who care for them to make of these reports? To start, “not all anti-amyloid drugs are the same,” says Dr. Pierre Tariot, director of the Banner Alzheimer’s Institute. “We are still learning what it means to mitigate amyloid dysregulation in terms of longer term benefit. But we now have an array of results with some encouraging signals that look like some of these drugs bully the disease process, and that is associated with some measurable clinical benefit for people with mild symptoms.”

The keys to lecanemab’s success

Eisai’s positive results were a long time coming. Research on lecanemab began in the mid-1990s, as the company’s scientists continued their hunt for a drug to treat Alzheimer’s. In 1996, the company had successfully brought the second medication ever for the disease, donepezil (brand name: Aricept), to the market after the FDA approved it for people with mild-to-moderate Alzheimer’s. The drug does not change the progression of the disease but can improve some of its cognitive symptoms.

Encouraged by that success, while at the same time realizing that donepezil fell short of treating the disease, Eisai’s scientists focused on tackling the amyloid buildup in the brain that contributed to memory loss and other cognitive symptoms of Alzheimer’s. They decided to find and target one of amyloid’s more noxious forms: protofibrils, which are particularly toxic to nerve cells in the brain.

But isolating just the right form of amyloid, and finding ways to remove it without causing other side effects, was a long and arduous process. Researchers trying to develop Alzheimer’s treatments reported many false starts, and patients and families became more desperate. “When we met with patient advocacy groups, most of the time the first thing I said to them was, ‘Sorry,’” says Ivan Cheung, chairman and CEO of Eisai Inc. “They wanted to know why it was taking so long, and were we not trying hard enough, or were we not intelligent enough? We disappointed a lot of families.”

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Amyloid, a protein made in the brain and other parts of the body, only becomes problematic when it sticks together and form plaques that strangle neurons and their delicate connections. One form, amyloid beta, can become especially molecularly clingy, sticking together to first form oligomers and protofibrils—and eventually clump together into plaques. After painstaking work testing compound after compound, Eisai’s scientists found that lecanemab binds to protofibrils with a 1,000-fold greater affinity than it does to amyloid beta, which means it can drastically reduce the most dangerous forms of the protein.

While Eisai was collaborating with Biogen on both aducanumab and lecanemab, each of the two companies called dibs on one compound and took on the responsibility for developing and testing it. Biogen claimed aducanumab, and Eisai took responsibility for lecanemab.

Biogen notched the first victory, when its phase 1 study of aducanumab stunned the Alzheimer’s community in 2014 with its tantalizingly positive results. Based on those findings, the company decided to leapfrog over phase 2 trials by conducting a more comprehensive phase 3 study, since they already had a strong signal that the drug could reduce amyloid and slow cognitive decline. An early readout of the drug in 2019, however, showed no significant improvements in brain function among people taking the drug, and the company decided to end the trial. Upon further analysis of the data, however, its scientists found glimmers of hope and restarted the study among people with mild-to-moderate Alzheimer’s. Ultimately, Biogen conducted two studies of the drug: one which turned out positive, showing drops in amyloid, and one that showed little difference between the treated and placebo patients. Because there were no treatments for Alzheimer’s, and a dire unmet need for one, the FDA decided, in an unusual and controversial move, that the reduction in amyloid, and the earlier promising phase 1 findings of improvements in cognitive function, were sufficient to approve the drug on the condition that Biogen conduct an additional study to prove its effectiveness. Many in the scientific community disagreed, and insurers sensed that skepticism and declined to cover the treatment except for people enrolled in research studies.

Eisai took a different approach with lecanemab. After promising phase 1 results, which showed that homing in on protofibrils was safe for patients, it embarked in 2012 on a lengthy phase 2 study that would take 18 months. Led by the company’s senior vice president of clinical research Dr. Michael Irizarry, Eisai’s team designed a novel and complicated trial that adjusted which doses people received based on early readouts and modeling of results from the first patients. The idea was to ensure that time and resources weren’t wasted; scientists tested each of five doses at a time and waited months to see if the drug had any effect or caused any adverse reactions. The patients enrolling later in the trial benefited from what the team was learning from the participants who had come before them. “During the study, a computer algorithm looked at cognitive outcomes and predicted which dose was effective, and started to weight future randomization of the volunteers to doses that were most likely to be effective, and reducing the sample sizes of the doses that were less effective,” says Irizarry.

The approach was tedious and raised questions among some experts who thought the trial was more complex than it needed to be. “We received a lot of questions about why we were doing that,” says Cheung of the phase 2 study design. “They thought we were being irrational.”

It didn’t help that the drawn-out phase 2 trial occurred while the explosive news about aducanumab’s success was dominating headlines, and the trial concluded after Biogen announced that its drug didn’t appear to work after all. Eisai announced the launch of its phase 3 trail of lecanemab just weeks after Biogen closed down its trial of aducanumab. Cheung argues that the rather than making the emotional decision to give up on lecanemab after aducanumab’s troubles—even though both targeted amyloid—it was rational to forge ahead based on the strong data from the phase 2 portion that showed signs that the drug would be effective.

What these results mean for Alzheimer’s patients

Eisai continued to complete its phase 3 trial, in a much simpler format this time, with the confidence gained from the detailed phase 2 study that the results would likely show that lecanemab improved patients’ cognitive function.

In a way, the circumstances surrounding aducanumab’s failure relieved some of the pressure for Eisai and lecanemab, as the Alzheimer’s community now set lower expectations for what to expect from an anti-amyloid drug. Complicating the study, COVID-19 created challenges for the participants, who had to visit clinics or hospitals to receive the drug as an IV infusion over about an hour twice a month. “We set up home infusions, remote safety assessments, and remote cognitive assessments,” says Irizarry. “We tried a whole lot of things to make it easier for people to participate.”

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Fortunately, the unmet need for a treatment for Alzheimer’s ensured that less than 20% of volunteers dropped out of the trial; previous studies of drug candidates often saw 20% to 25% of participants leave the study.

In September 2022, Eisai’s long game paid off, when the company announced that lecanemab was the first anti-amyloid drug to help patients slow their cognitive decline in a phase 3 study. “The phase 2 results ended up being quite predictive of the phase 3 results, and we expected that,” says Irizarry.

The study followed the participants over 18 months, but Cheung speculates that the improvements will only continue the longer people take the drug. While it won’t mean that patients can expect to be cured of Alzheimer’s, it could mean several more years of functioning at a level that allows them to live independently, or attend a child’s wedding or a grandchild’s graduation. “Based on our phase 2 results, our projection is that lecanemab can delay the time from early Alzheimer’s to moderate Alzheimer’s by about three years,” says Cheung.

A drug that produces 27% improvement in performance on cognitive tests is not a slam-dunk therapy. But experts see it as a wedge into a new era of Alzheimer’s treatments: those that can chip away at the buildup of amyloid in the brain, and then eventually slow or prevent the damage to nerve cells that comes later in the disease course.

So far, lecanemab appears to have fewer side effects than aducanumab. Eisai reports that 12.6% of people experienced brain inflammation known as ARIA-E that can be potentially lethal, but which is treatable if the medication is stopped or the dose reduced. Most of these were detected on brain scans and the patients did not report symptoms of the side effect. (By comparison, about a third of people taking aducanumab developed ARIA-E in the drug’s phase 3 study.) Because of this more favorable side-effect profile, lecanemab does not have to be titrated, or started at a lower dose and gradually brought up to the optimal dose with each infusion depending on whether the patient develops signs of ARIA-E. That’s critical to preserve brain function, said Dr. Sharon Cohen, medical director of the Toronto Memory Program, who oversaw the study at her site, during a briefing at the conference. “If time is brain, and other [therapies] are taking eight to nine months to reach the optimal dose, patients are losing brain during that process. With lecanemab, patients are starting from day one at the optimal therapeutic dose, and that is time-saving and brain-saving.” The data found that lecanemab is safe at the tested dose of 10mg/kg every two weeks for 18 months; while 13 people died during the trial, they were almost equally distributed among the treatment and placebo groups, with seven deaths among those taking the drug, and six in the placebo group.

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The FDA will likely consider those deaths, as well as data from the trial showing that people taking anti-coagulant drugs may have a slightly higher risk of bleeding events, before determining whether lecanemab is safe to prescribe as it stands, or if an additional warning on the label about hemorrhage risk is warranted. The agency will also compare the risk of ARIA-E among people taking lecanumab with the risk associated with other amyloid-lowering drugs.

But based on the positive results, the door is now open to investigating how these anti-amyloid therapies can best be used to slow cognitive decline. Irizarry is already studying how lecanemab might be combined with other promising therapies, for example. Experts believe that the deposition of amyloid plaques leads to the disorganized structure of another protein, tau, which creates tangles that disrupt the critical connections neurons have to each other. Combining an anti-amyloid drug such as lecanemab with an anti-tau compound could help to put the brakes of the neurodegeneration associated with Alzheimer’s.

“With my patients, I start with the analogy of a life raft that has a leak,” says Tariot. “Any medication will be a patch that slows down the leak, but doesn’t prevent it altogether. For some of my patients, it’s helpful to think of drugs like these as a disease-slower-downer.”

But the picture may not be as clear as patients might hope. While lecanemab seems to be an encouraging way to reduce amyloid in the brain and slow cognitive decline, other anti-amyloid drugs may not perform as well. Roche recently announced that its amyloid therapy, gantenerumab, failed to shrink amyloid plaques and show significant improvement on cognitive tests. But gantenerumab is given as an injection—not as an IV infusion—and that may lead to inadequate levels of the drug in the brain to make a difference. In addition, says Dr. Eric Reiman, executive director of the Banner Alzheimer’s Institute, the drug was reformulated slightly between the phase 2 and phase 3 studies, and that may have affected its performance as well. And while the compound did not dramatically reduce amyloid plaque, it did produce some drop in amyloid. “It’s not inconsistent with the idea that reduction in amyloid and reductions in amyloid in the blood, and cerebrospinal fluid is associated with clinical benefit,” Reiman says.

Eli Lilly has reported promising early results with its anti-amyloid compound, donanemab, and plans to complete its phase 3 study in 2024. Anticipating that those results will be positive, the company filed a request in August for accelerated approval of the drug with the FDA. Eisai began an accelerated approval process as well with lecanemab based on the positive phase 2 results, and the FDA is expected to make a decision by January 6. After the agency makes that decision, Cheung says the company plans to file the phase 3 data to seek full approval. Taken together, “the picture that is emerging is that substantial [amyloid] plaque lowering seems to be associated with clinical benefit,” says Dr. Michael Weiner, professor of radiology medicine, neurology, and psychiatry at University of California, San Francisco. “At least we seem to finally be in the era of disease-modifying treatments.”

Weiner says the next challenge for the scientific community will be to find ways to prevent Alzheimer’s from damaging brain neurons to begin with, and ongoing trials of other compounds, as well as planned trials using lecanemab and donanemab even earlier in high-risk patients, will reveal how feasible that may be. Blood tests for Alzheimer’s will be critical to accomplish that, and researchers are actively working to develop tests to pick up amyloid in the blood. Since 2021, doctors have been able to order the first such test in the U.S., called PreclivityAD, from C2N Diagnostics, which was approved for use by certain laboratories. “Blood testing for Alzheimer’s will be coming into the clinical arena very quickly,” says Weiner, “and that will be accelerated if lecanemab is approved, which everybody is hoping for, and if Eisai can show that a blood test is sufficient for treatment. We are just at the beginning of the beginning. We are now in the treatment era, in the blood test era for Alzheimer’s disease. The field of Alzheimer’s disease research right now is one of the most interesting in all of medicine.”