New Alzheimer’s Drug Brings Hope—and Tough Choices for Patients, Caregivers

New Alzheimer’s Drug Brings Hope—and Tough Choices for Patients, Caregivers

After many a long time of little or no progress in treating the dementia associated with Alzheimer’s, a brand new drug now offers desire to patients and caregivers. Lecanemab, announced late last month, became observed in medical trials to sluggish cognitive decline in early-degree Alzheimer’s sufferers. “It’s a very encouraging end result,” says Dr. David Wolk, co-director of the University of Pennsylvania’s Penn Memory Center.

The arrival of lecanemab comes with a few massive caveats, however. The drug has sizable fitness risks, consisting of bleeding and mind swelling. It’s luxurious—drug producer Eisai estimates the yearly charge of remedy could be somewhere among $nine,249 and $35,605, and it’s unclear what insurance will cover. And the drug has handiest a modest impact on the debilitating progress of Alzheimer’s.

Some scientists also are having 2d thoughts approximately the method that brought about lecanemab—particularly, looking to sluggish Alzheimer’s entirely by means of inhibiting the accumulation of beta-amyloid, a protein that accumulates in the mind cells to shape plaques. After 3 decades of chasing one failed remedy after every other and burning thru billions of greenbacks in studies funding, lecanemab is the primary unequivocally successful plaque-inhibiting remedy for Alzheimer’s. (A comparable drug, Aduhelm, become accredited ultimate yr by the U.S. Food and Drug Administration to a few controversy.) Many scientists now suppose amyloid plaque is handiest one in all many factors in inflicting the ailment’s debilitating outcomes and speak to for brand new procedures.

The FDA is anticipated to decide on an elevated approval status for lecanemab on January 6, which might join additional sufferers in new trials. If the ones are a hit, complete approval could probably arrive overdue next year.

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Lecanemab is a monoclonal antibody, a man-made protein that acts like natural antibodies to target particular disease-causing retailers. In this example, that concentrate on is beta-amyloid. Researchers have targeted on anti-amyloid drugs due to a long-dominant principle that plaques are the primary reason of the ailment. The idea turned into, break the plaques, remedy Alzheimer’s.

The outcomes were disappointing. Each amyloid drug charges pharmaceutical groups $five.6 billion on common and thirteen years from preclinical study to FDA approval. Between 1998 and 2017, 146 new capsules, maximum focused on amyloid, failed. Four tablets were located to alleviate signs and symptoms, in preference to alter the ailment pathology, and these have been not amyloid pills—they came from a one of a kind elegance of medicine entirely.

In 2016, the amyloid drug aducanumab offered a glimmer of desire. Marketed beneath the logo name Aduhelm, it become located to efficaciously clean amyloid and sluggish cognitive decline. That September, the magazine Nature ran a cowl that study: “TARGETING AMYLOID.”

The outcomes turned out to be ambiguous. The FDA drew criticism for approving the drug without compelling proof of efficacy. In specific, Biogen (which additionally makes lecanemab) in no way completed phase 2 research, the “learn and verify” phase of checking out that determines dosing that balances protection and gain. The loss of phase 2 information later called into query the validity of the effects of the segment three studies, the big-scale trials that the FDA relies directly to determine a remedy’s protection and efficacy. .

Ten of the FDA’s 11 advisory-panel participants voted that there has been insufficient evidence that Aduhelm labored to grant the drug approval; the eleventh member became unsure. 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 remedy [Aduhelm], I may not prescribe it.”

“There have been some of issues with the design of the take a look at,” Karlawish told Newsweek.

Despite these issues, the FDA greenlighted the drug. Several health care structures chose not to administer it, and Medicare restrained coverage to patients in clinical studies. Then, in every other blow to the amyloid approach, examine consequences released in November showed that some other surprisingly anticipated drug, gantenerumab, didn’t slow cognitive decline.

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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 extensively utilized scales apart from the CDR-SM to assess “secondary quit factors.” “What I observed specially thrilling were the outcomes on caregiver burden and sufferers’ self-pronounced exceptional of existence,” says Karlawish, which are measured in part with a affected person questionnaire. The results confirmed greater benefits for caregivers and sufferers when the usage of the drug as opposed to placebo. “All the measures display a common tale,” Karlawish says, “that is that the disease system changed into slowed.”

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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.”

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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.

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