After many decades of little or no progress in treating the dementia associated with Alzheimer's, a new drug now offers hope to patients and caregivers. Lecanemab, announced late last month, was found in clinical trials to slow cognitive decline in early-stage Alzheimer's patients. "It's an extremely encouraging result," says Dr. David Wolk, co-director of the University of Pennsylvania's Penn Memory Center.
The arrival of lecanemab comes with some big caveats, however. The drug has significant health risks, including bleeding and brain swelling. It's expensive—drug manufacturer Eisai estimates the annual price of treatment would be somewhere between $9,249 and $35,605, and it's unclear what insurance will cover. And the drug has only a modest effect on the debilitating progress of Alzheimer's.
Some scientists are also having second thoughts about the strategy that led to lecanemab—namely, trying to slow Alzheimer's solely by inhibiting the buildup of beta-amyloid, a protein that accumulates in the brain cells to form plaques. After three decades of chasing one failed treatment after another and burning through billions of dollars in research funding, lecanemab is the first unequivocally successful plaque-inhibiting treatment for Alzheimer's. (A similar drug, Aduhelm, was approved last year by the U.S. Food and Drug Administration to some controversy.) Many scientists now think amyloid plaque is only one of many factors in causing the disease's debilitating effects and call for new approaches.
The FDA is expected to decide on an accelerated approval status for lecanemab on January 6, which would enroll additional patients in new trials. If those are successful, full approval would likely arrive late next year.
Reality Is Complicated
Lecanemab is a monoclonal antibody, a man-made protein that acts like natural antibodies to target specific disease-causing agents. In this case, that target is beta-amyloid. Researchers have focused on anti-amyloid drugs due to a long-dominant theory that plaques are the primary cause of the disease. The idea was, destroy the plaques, cure Alzheimer's.
The results were disappointing. Each amyloid drug costs pharmaceutical companies $5.6 billion on average and 13 years from preclinical study to FDA approval. Between 1998 and 2017, 146 new drugs, most targeting amyloid, failed. Four drugs were found to alleviate symptoms, rather than alter the disease pathology, and these were not amyloid drugs—they came from a different class of drugs entirely.
In 2016, the amyloid drug aducanumab offered a glimmer of hope. Marketed under the brand name Aduhelm, it was found to effectively clear amyloid and slow cognitive decline. That September, the journal Nature ran a cover that read: "TARGETING AMYLOID."
The results turned out to be ambiguous. The FDA drew criticism for approving the drug without compelling evidence of efficacy. In particular, Biogen (which also makes lecanemab) never completed phase 2 studies, the "learn and confirm" phase of testing that determines dosing that balances safety and benefit. The lack of phase 2 data later called into question the validity of the results of the phase 3 studies, the large-scale trials that the FDA relies on to determine a treatment's safety and efficacy. .
Ten of the FDA's 11 advisory-panel members voted that there was insufficient evidence that Aduhelm worked to grant the drug approval; the 11th member was uncertain. In May 2021, Dr. Jason Karlawish, Wolk's co-director of the Penn Memory Center, wrote in an essay for STAT News with the headline: "If the FDA approves Biogen's Alzheimer's treatment [Aduhelm], I won't prescribe it."
"There were a number of issues with the design of the study," Karlawish told Newsweek.
Despite these concerns, the FDA greenlighted the drug. Several health care systems chose not to administer it, and Medicare limited coverage to patients in clinical studies. Then, in another blow to the amyloid approach, study results released in November showed that another highly anticipated drug, gantenerumab, failed to slow cognitive decline.
Glass Half Full
On the heels of anti-amyloid controversy and failures, lecanemab had a lot to prove. But when it comes to its predecessor, Aduhelm, "they're really not comparable," says Karlawish. "It's comparing apples and kumquats." The "most compelling difference" between the two drugs, says Wolk, is that the lecanemab trial completed its phase 3 study, with results that suggested "real change" to the course of the disease.
The lecanemab trial took place over 18 months and included 1,795 people between the ages of 50 and 90. The report of the findings, published in The New England Journal of Medicine, showed that participants who received the drug experienced 27 percent less decline in cognitive health than those who received placebo. This was measured using a scale, called CDR-SB, which scores the severity of dementias from 0 to 18. The lecanemab patient group scored 0.45 points better compared to placebo at the end of the trial.
Medical researchers differ on what those numbers mean in terms of a patient's well-being. Interpreting a patient's test results has "as much art as science behind it," says Karlawish.
Some experts are skeptical that lecanemab confers much of a benefit at all. "A less than half a point difference on an 18-point scale after 18 months of treatment is a rather small effect," Dr. Madhav Thambisetty, a neurologist and a senior investigator at the National Institute on Aging, told Newsweek.
Others say the glass is half full. According to Wolk, the findings represent "real differences" in the progress of the disease. Because the study focused on people at the early stages, 18 months is a relatively short amount of time to measure the magnitude of beneficial effects. In a disease that advances slowly, even a small benefit can make a big difference over time. For example, on the CDR-SB scale, a 0.5 score in memory signifies "benign forgetfulness," while a 1.0 reflects "moderate memory loss" that "interferes with everyday activities."
Investigators also used scales other than the CDR-SM to assess "secondary end points." "What I found particularly interesting were the results on caregiver burden and patients' self-reported quality of life," says Karlawish, which are measured in part with a patient questionnaire. The results showed greater benefits for caregivers and patients when using the drug versus placebo. "All the measures show a common story," Karlawish says, "which is that the disease process was slowed."
Judging the Risks
Since no drug is risk free, it's important to
consider the benefits in relation to the side effects. According to the report, "serious adverse events" occurred in 14 percent of participants in the lecanemab group and 11 percent of those in the placebo group. Wolk says this isn't surprising, given that the study followed older adults and reflects data like hospitalizations for other medical conditions. The most commonly reported adverse events were infusion-related reactions.
MRI scans showed brain swelling in 12.6 percent of patients who received lecanemab, compared to 1.7 percent in the control group. Most of these cases resolved themselves within months. Another 14 percent of patients who received the drug experienced small hemorrhages, compared to 7.7 percent in the placebo group. The most common symptom was dizziness.
Two participants died after the 18-month trial was completed, so it's not known if those deaths were linked to the treatments, or even if they received the drug or a placebo. In a statement, Eisai denied the deaths were linked to lecanemab.
Karlawish hopes that if the FDA approves the drug, it will require a Risk Evaluation and Mitigation Strategy, a specialized safety protocol that ensures providers of a new drug demonstrate certain knowledge and skills to correctly diagnose, treat and monitor a patient for side effects. Because the U.S. doesn't have a well-defined specialty of Alzheimer's physicians, the protocol would also train general neurologists and geriatricians to use the drug, allowing for safer and more widespread access.
"While we would like a grand slam, a drug that is cheap, super safe and completely halts or reverses the disease, it is simply not realistic for an extremely heterogeneous and complicated neurodegenerative condition," says Wolk.
If the drug is approved, physicians will make decisions about prescribing it on a case-by-case basis. Given the bleeding side effects, Wolk is concerned that the drug may be too risky for patients on blood thinners. Another concern is that lecanemab, like other anti-amyloid drugs, can cause the brain to shrink. If so, says Thambisetty, "these drugs might be worsening the degenerative process."
Alzheimer's patients, though, don't have a lot of good options. Considering the severity of the disease, says Dr. Babak Tousi of the Cleveland Clinic, "for the appropriate patient, this is the appropriate treatment."
Future Treatments
Lecanemab's trial results have brought renewed hope to scientists developing anti-amyloid drugs, and some in the pipeline may turn out to improve the prospects for patients. For instance, donanemab, another monoclonal antibody, has shown promise in early studies; results from its phase 3 trials are expected to be released in spring 2023.
After decades of amyloid taking center stage (and most of the research funding), scientists pursuing non-amyloid-specific approaches are starting to get more attention. "There are some valid points to amyloid hypothesis at this point," says Tousi. "But it's not the whole story."
A theory quickly gaining traction among researchers is that multiple factors contribute to
onset of the disease. One of these is thought to be the accumulation of a protein called tau. While tau also exists in healthy brains, in people with Alzheimer's, the proteins are abnormally shaped and misfolded. Tau dysfunction has previously been linked to serious brain disorders, including chronic traumatic encephalopathy and a variety of dementias. New studies are targeting tau, in the hope that eradicating the toxic protein might help Alzheimer's patients gain improved cognition.
Other factors researchers are considering include impaired glucose or sugar metabolism and chronic inflammation caused by overactive immune system cells in the brain. It's worth noting that several of the risk factors for Alzheimer's—including depression, air pollution and sleep disorders—have been shown to cause neuroinflammation.
Although it's unclear exactly how Alzheimer's takes hold in the brain, it seems to be activated by a variety of interconnected processes. That means treatments may require a combination of approaches—and that amyloid may be only one piece of a larger Alzheimer's puzzle.
Thambisetty's team at the NIA is looking into whether medicines that are already FDA-approved to treat other conditions could address some of the contributing factors of Alzheimer's. For instance, drugs called TNF-inhibitors, which are used for patients with rheumatoid arthritis, might help stop inflammation. So far, they appear to lower the risk of Alzheimer's disease in patients with heart disease.
Dr. Ralph Nixon, Professor of Psychiatry and Cell Biology at NYU Grossman School of Medicine, began researching alternative pathways 30 years ago, even as the amyloid theory took off.
Looking deeper into the neurons affected by early stages of the disease, Nixon suspected that the trouble begins long before the emergence of plaque. In a study published in June in Nature Neuroscience, his team found that in mice, tiny organelles inside brain cells, called lysosomes, which remove metabolic waste, start to malfunction—the enzymes they emit weren't acidic enough to break down the waste. As a result, toxins built up until the cells burst.
Nixon thinks something similar may be happening in the brain cells of Alzheimer's patients. In recent months, they found that human neurons malfunction in a similar way, most likely due to an overproduction of a protein called beta-CTF. That protein, which so far has been largely ignored, could be a productive target for new drugs.
The results come as something of a vindication to Nixon and his colleagues, who have seen their non-amyloid-centric approaches ignored and marginalized. As biotech companies start to pay attention to alternative approaches, other researchers may come to embrace the disease's complexity and not be afraid of challenging old assumptions. "They can say, 'okay there's more to the disease, and I'm not going to be blackballed; I'm not going to be ignored.'"
Patients might soon be better for it.
