Lilly Drug Slows Alzheimer’s by 35%, Bolstering Treatment Approach

Julie Steenhuysen and Deena Beasley wrote . . . . . . . . .

An experimental Alzheimer’s drug developed by Eli Lilly and Co slowed cognitive decline by 35% in a late-stage trial, the company said on Wednesday, providing what experts say is the strongest evidence yet that removing sticky amyloid plaques from the brain benefits patients with the fatal disease.

Lilly’s drug, donanemab, met all goals of the trial, the company said. It slowed progression of Alzheimer’s by 35% compared to a placebo in 1,182 people with early-stage disease whose brains had deposits of two key Alzheimer’s proteins, beta amyloid as well as intermediate levels of tau, a protein linked with disease progression and brain cell death.

The study also evaluated the drug in 552 patients with high levels of tau and found that when both groups were combined, donanemab slowed progression by 29% based on a commonly used scale of dementia progression known as the Clinical Dementia Rating Scale (CDR-SB).

Using that scale, experts said Lilly’s findings were roughly on par with Eisai Co Ltd and Biogen Inc’s lecanemab, sold under the brand name Leqembi, which reduced cognitive decline by 27% in patients with early Alzheimer’s in a study published last year.

The results drove Lilly’s shares to a record high, up more than 6% at $429.85.

Dr. Ronald Petersen, an Alzheimer’s researcher at Mayo Clinic, said Lilly’s trial is the third to show removing amyloid from the brain slows progression of the disease, which could put to rest some lingering doubts about the benefits of drugs in the class and the amyloid-lowering theory.

“It’s modest, but I think it’s real,” he said of the benefit, “and I think it’s clinically meaningful.”

Dr. Erik Musiek, a Washington University neurologist at Barnes-Jewish Hospital, said the efficacy looks as good or better than lecanemab.

“The evidence is really starting to build up that these drugs do work,” he said.

Musiek said the findings also offer some of the first evidence for the benefit of earlier treatment. “It really does suggest that you need to remove these plaques early, before the tau really gets going,” he said.

In the donanemab treatment group, Lilly said brain swelling, a known side effect of drugs of this type, occurred in 24% of participants, with 6.1% experiencing symptoms. Brain bleeding occurred in 31.4% of the donanemab group and 13.6% of the placebo group.

In the Leqembi Phase 3 trial, the drug was associated with brain swelling in nearly 13% of its study participants.

Lilly said the incidence of serious brain swelling in the donanemab study was 1.6%, including two deaths attributed to the condition, and a third, after an incident of serious brain swelling.

A research note by SVB Securities analyst David Risinger was headlined: “Donanemab Succeeds, But Safety Remains a Concern”.

“Clearly, one saw benefits here, but there is some risk that needs to be considered,” said Dr. Eric Reiman, executive director of the Banner Alzheimer’s Institute, which is running a study of donanemab in presymptomatic patients.

Lilly said it plans to file for traditional U.S. approval by the end of June, and with regulators from other countries shortly thereafter. A company spokesman said a U.S. approval decision should come by year-end or early 2024.

Alzheimer’s experts said they were eager to see full results of the study, including data on how the drug performs in people who carry an Alzheimer’s risk gene known as APOE4, who have been prone to increased risk of side effects in prior trials.

Those results are set to be presented at an Alzheimer’s meeting in Amsterdam this summer.

Study participants received a monthly intravenous infusion of donanemab. At 12 months, half had no evidence of amyloid plaques, the company said.

It also said 47% of donanemab patients in the 18-month trial had no disease progression at 12 months, compared with 29% of the placebo group.

Lilly’s drug is poised to become the third in its class on the market following U.S. approval of two similar medicines developed by partners Eisai and Biogen – Leqembi as well as Aduhelm, which failed to gain traction with doctors or insurers after showing little evidence that it slowed cognitive decline.

Both were approved under the FDA’s accelerated review program, based on their ability to remove amyloid plaques.

Leqembi is currently undergoing the FDA’s standard review process, with a decision due by July 6.

Lilly is still working on finalizing the price for donanemab, and plans for it to be in the same range as other similar therapies, CEO David Ricks told CNBC.

More than 6 million Americans are living with Alzheimer’s, and that number is projected to rise to nearly 13 million by 2050, according to the Alzheimer’s Association.

Source: Reuters






Two Healthy Diets May Reduce Brain ‘Plaques’ Tied to Alzheimer’s Risk

Elderly adults who eat plenty of leafy green vegetables, fish and other healthy fare may take years off their “brain age,” a new study suggests.

Researchers found that seniors with either of two healthy eating patterns — the Mediterranean and MIND diets — showed fewer brain “plaques,” abnormal protein clumps that are a hallmark of Alzheimer’s disease.

In fact, people with the highest Mediterranean or MIND scores had brains that were up to 18 years younger than their counterparts with more of a burger-and-fries diet.

Experts said the findings do not prove that spinach and fish will ward off dementia. But they do add to a growing body of evidence linking healthy eating to slower brain aging.

Lead researcher Puja Agarwal called the results “exciting,” because they suggest that even a simple dietary change could make a substantial difference.

Based on the findings, older people who eat, say, a cup of leafy greens a day could have a brain that’s four years younger, versus their peers who shun the likes of kale and spinach.

The study, published in Neurology, builds on past research into diet and dementia.

Both the Mediterranean and MIND diets have already been linked to slower mental decline and a lower risk of Alzheimer’s disease, the researchers said in background notes. Now the new findings connect the diets to fewer objective signs of Alzheimer’s — the plaques that begin to form in the brain years before dementia symptoms appear.

That strengthens the case that the eating patterns are truly associated with lower Alzheimer’s risk, according to Agarwal, an assistant professor at Rush University Medical College in Chicago.

“It also gives us a first view into the mechanisms,” she said.

That is, less accumulation of brain plaques may be one way the diets protect against Alzheimer’s — though, Agarwal said, it’s not yet clear how they might accomplish that.

The traditional Mediterranean diet — famously linked to lower risks of heart disease and stroke — is generally high in fish, olive oil, vegetables, beans, nuts and fiber-rich grains.

The MIND diet is very similar, but emphasizes leafy green vegetables and berries over other vegetables and fruit. That’s based on research tying those foods to better brain health.

Both diets, according to the Rush University researchers, are high in plant foods that have various nutrients and chemicals that can ease inflammation in the body and protect cells from damage.

Both diets are also notable for what they leave out: red meat, sugar and heavily processed foods.

The new findings are based on autopsied brain tissue from 581 participants in a long-running Rush study on memory and aging. When they entered the study, typically in their early 80s, they gave consent to donate their brains after death.

Each year, study participants complete detailed dietary questionnaires. Agarwal’s team used that information to give each of the 581 deceased participants a Mediterranean and a MIND diet “score.” The more their eating habits looked like those diets, the higher the scores.

Overall, the researchers found, participants who’d scored highest in Mediterranean-style eating had brains that, based on plaque buildup, were 18 years younger than those of participants with the lowest Mediterranean scores. The differences were similar, though somewhat smaller, when it came to MIND scores.

Certain foods stood out, too, Agarwal said. People who ate the most leafy greens — at least seven servings a week — spared themselves about 19 years of brain aging, versus their peers who ate no more than one serving a week.

Of course, people who eat healthfully may have advantages, like a higher income or more education. They may also have fewer chronic medical conditions, or do other things to support their health, like exercising and refraining from smoking.

Agarwal’s team accounted for as many of those factors as they could, and healthy eating was still strongly linked to a younger-looking brain.

The findings are “intriguing,” said Heather Snyder, vice president of medical and scientific relations at the Alzheimer’s Association.

“This study takes what we know about the link between nutrition and risk for cognitive decline a step further by looking at the specific brain changes that occur in Alzheimer’s disease,” said Snyder, who had no role in the study.

She noted that the Alzheimer’s Association is leading a two-year clinical trial that is testing whether a combination of lifestyle changes can slow cognitive decline in older adults. The MIND diet is part of that combo.

It’s not yet clear what the best lifestyle “recipe” is, according to Snyder. What is clear, she said, is that people should strive for a “heart-healthy diet that incorporates nutrients that our bodies and brains need to be at their best.”

The participants in the Rush study were asked about their eating habits in the past year. It’s not known, Agarwal said, if they’d eaten that way their whole lives, or made changes at some point.

Still, she said, “it’s never too late” to revamp your diet for the better.

Source: HealthDay





Initial Symptoms Could Predict How Fast Alzheimer’s Progresses

Dennis Thompson wrote . . . . . . . . .

Memory loss is the most common symptom associated with Alzheimer’s disease — the terrifying prospect of slowly forgetting yourself and everything around you.

But people who exhibit memory loss early on in their dementia actually have a slower rate of decline than those who develop other symptoms earlier, a new study reports.

Difficulty forming sentences, making plans, solving problems or judging space and distance — these symptoms all herald a steeper and faster decline for Alzheimer’s and dementia patients than do early memory problems, researchers found.

“People with memory changes in fact have a slightly slower rate of disease progression than people who have other symptoms, like language or judgment issues, in terms of their ability to function independently and take care of themselves,” said lead researcher Dr. Jagan Pillai, a neurologist with the Cleveland Clinic Center for Brain Health, in Ohio.

If these early symptoms prove to be a reliable clue, they could help patients and their families better prepare for what’s ahead, he said.

Future Alzheimer’s drug trials could also avoid potential bias by making note of people’s early symptoms and sorting out those expected to have a more rapid decline, Pillai added.

“In clinical trials, everyone with Alzheimer’s disease is lumped together,” Pillai said. “You can imagine bias occurring if the medication arm of the trial has more people with non-memory problems than the placebo arm. That could bias the results.”

For the study, his team analyzed data on more than 2,400 people with dementia, drawn from a database maintained by the National Alzheimer’s Coordinating Center.

Many Alzheimer’s treatment centers in the United States regularly feed information into the federal database, which since its start in 1984 has grown into a large repository of patient data for research.

Memory problems are the most common early symptom of Alzheimer’s and dementia. Nearly 80% of the time, memory loss serves as the first sign that something is wrong, results show.

“When anyone thinks about Alzheimer’s disease, they think about someone having memory loss and how it progressed over time to affect other areas of their function or their thinking,” Pillai said. “It’s less well-known to the general public that Alzheimer’s can present with other symptoms initially.”

But nearly 10% of dementia patients initially have symptoms related to their executive function, the researchers found.

“They might have problems making judgments,” Pillai said. “They cannot plan their day or perform a task like signing on to a computer.”

Another 10% first present with symptoms related to language.

“They’re just not able to speak in full sentences, and struggle with expressing themselves,” Pillai said.

People with those rarer early symptoms had a faster rate of decline in their brain function and their ability to maintain their quality of life, study results showed.

“That really means that a good clinician actually has a lot of opportunity to have insight into what’s going to happen to a patient over time,” said Mary Sano, director of the Alzheimer’s Disease Research Center at Mount Sinai, in New York City.

“I think that’s really important because there’s always some hesitancy about whether or not to diagnose Alzheimer’s disease,” Sano said. “And what you can see is that it is important to get the evaluation. It will tell you a little bit about your prognosis and what you might expect over time.”

There’s no way to know why these differences in decline exist, but it could be based on how Alzheimer’s or dementia affects specific regions of the brain, Pillai said.

A brain region affected by dementia might produce specific early symptoms, and that region might also be prone to rapid decline.

Another potential explanation might involve how these early symptoms affect a person’s everyday life, Pillai said.

“Let’s say someone has a memory problem, but they can still function independently in their daily routine, because their routine has been pretty consistent over a period of time for them, so they’re able to function within that specific limitation,” he said.

“Whereas if you have changes like language problems, that limits your ability to go out and make things happen in society. Your social life changes pretty significantly. Or if you have a spatial problem, it’s difficult to navigate outside of home, outside of your comfort zone. If you have judgment issues, you cannot take on any new projects pretty early,” Pillai continued.

So those things start affecting daily functioning much earlier than memory issues, which people can likely compensate for longer, he suggested.

Claire Sexton, the Alzheimer’s Association senior director of scientific programs and outreach, agreed with Pillai.

“If language abilities and executive functioning are somewhat preserved, this may limit the rate of decline in overall cognition and functioning,” she said.

Researchers said the difference in the speed of decline is enough that it could have biased the clinical trials that led to the approval of the Alzheimer’s drugs Aduhelm (aducanumab) and Leqembi (lecanemab).

“Future clinical trials might have to be more careful in making sure that people with memory or non-memory problems are equally balanced in both the drug and the placebo arms, so there’s no bias in terms of measuring effectiveness,” Pillai said.

He doubts that these symptoms could be used to determine who might benefit from the new Alzheimer’s drugs.

“If future studies show that the disease itself is very different for memory problems versus other non-memory changes, then it might have future implications for therapies,” Pillai said. “But we’re not there yet.

But Sano said the symptoms might give doctors an idea of what to expect from the drug in specific patients.

“If you knew that a person’s first symptom was one of these other ones and you might expect that they were going to deteriorate more rapidly, then your expectation of the treatment might be that it could still have an effect but it might not be as effective as it is if someone didn’t have those additional symptoms,” Sano said.

The findings were recently published online in the journal Alzheimer’s & Dementia.

Source: HealthDay





FDA Approves 2nd Alzheimer’s Drug, Despite Safety Concerns

Ernie Mundell wrote . . . . . . . . .

The U.S. Food and Drug Administration on Friday approved a second Alzheimer’s drug, lecanemab, despite reports of rare brain bleeds linked to use of the drug in some patients.

However, the FDA pointed to the drug’s benefits, as well.

“Alzheimer’s disease immeasurably incapacitates the lives of those who suffer from it and has devastating effects on their loved ones,” Dr. Billy Dunn, director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, said in an agency news release. “This treatment option is the latest therapy to target and affect the underlying disease process of Alzheimer’s, instead of only treating the symptoms of the disease.”

Lecanemab, made by Eisai and marketed by Biogen as Leqembi, will be only the second Alzheimer’s drug to receive the FDA’s blessing in the past 18 months; the agency’s speedy approval of the drug Aduhelm in June 2021 generated controversy in the medical community over its lack of effectiveness, brain bleed concerns and hefty price tag.

But Alzheimer’s experts said the story is somewhat different with Leqembi.

“Unlike Aduhelm, which had an incomplete data set and where clinical trial data failed to demonstrate a definitive slowing in cognitive decline, lecanemab showed statistically significant slowing in cognitive and functional decline, as well as reduction of brain amyloid levels, and downstream beneficial effects on other markers of neurodegeneration,” Dr. Sarah Kremen, who leads the Alzheimer’s Disease Clinical Trials Program at Cedars-Sinai in Los Angeles, said in a statement.

“We need — and are on the way to having — multiple drugs we can combine to personalize treatments to match each patient’s Alzheimer’s pathology, which will have a much greater impact on slowing the disease,” Dr. Howard Fillit, co-founder and chief science officer of the Alzheimer’s Drug Discovery Foundation, said in a statement.

“Today’s news is incredibly important and a source of optimism not only for patients, but also for the medical and research community,” said Fillit. “It shows us that our years of research into what is arguably the most complex disease humans face is paying off.”

Still, Leqembi has been linked to two deaths from brain bleeds among people who used it in trials.

And not every patient would stand to benefit from Leqembi, stressed the Cleveland Clinic’s Dr. Babak Tousi. He led the portion of the clinical trial that was conducted at the Cleveland Clinic, in Ohio.

“The trial was designed for patients in the earlier stage of Alzheimer’s disease, people with mild cognitive impairment or early stage of dementia,” Tousi noted. “It will probably be for people who have early stage of disease, with no to minimal assistance needed for activities of daily living.”

The results of the 18-month trial, which involved about 1,800 patients, gained wide attention when they were published Dec. 1 in theNew England Journal of Medicine, Tousi noted.

In the trial, early-stage Alzheimer’s patients who took Leqembi showed a 27% reduction in their mental decline compared to patients in the placebo arm of the trial. The drug’s users also showed less evidence of amyloid protein plaques in their brain compared to non-users.

“Lecanemab clearly did what it was designed to do — it removed amyloid plaque,” said Tousi, who heads the Clinical Trials Program at the Cleveland Clinic Center for Brain Health. “The results demonstrated all the downstream effects we hoped would happen in terms of reduction of biomarkers and less clinical decline on several functional and cognitive measures. So, this difference will likely translate to a longer period of independent living for patients.”

Two patient deaths raise questions

Still, the deaths of two patients enrolled in the trial cast a cloud on these hopeful findings. Both died from brain hemorrhages that seem linked to the use of Leqembi.

In one case, a 65-year-old woman with early-stage Alzheimer’s died from a massive brain bleed that some researchers link to Leqembi, according to a report published Nov. 27 in Science Insider.

The woman suffered a stroke, as well as a type of brain swelling and bleeding that’s been previously seen with such antibodies, the report noted.

ER doctors at Northwestern University Medical Center in Chicago treated the woman with a common but powerful clot-busting drug, tissue-plasminogen activator (t-PA). She immediately had substantial bleeding throughout her brain’s outer layer.

“As soon as they put it in her, it was like her body was on fire,” her husband told Science Insider. “She was screaming, and it took like eight people to hold her down. It was horrific.”

The woman died a few days later, the case report said.

The death follows that of an 80-year-old man who was taking part in Leqembi’s phase 3 clinical trial. His death was linked to a possible interaction between the experimental drug and a blood thinner called apixaban (Eliquis).

Rudolph Castellani, a Northwestern neuropathologist who autopsied the woman, determined that she had amyloid deposits surrounding many of her brain’s blood vessels.

The woman had been receiving biweekly infusions of Leqembi, which appears to have inflamed and weakened her blood vessels, Castellani said. These vessels then burst when exposed to the clot-buster, something that can happen even in conventional stroke cases.

“It was a one-two punch,” Castellani told Science Insider. “There’s zero doubt in my mind that this is a treatment-caused illness and death. If the patient hadn’t been on lecanemab, she would be alive today.”

While Eisai declined to comment on the woman’s case, the company did issue a statement saying that “All the available safety information indicates that lecanemab therapy is not associated with an increased risk of death overall or from any specific cause.”

The woman might have received either Leqembi or a placebo during the 18-month trial, but she was definitely given the drug during the month preceding her death. She’d opted to receive it as part of an open-label extension of the clinical trial.

Weakened blood vessels

The woman and the man both had widespread cerebral amyloid angiopathy (CAA), a condition in which amyloid deposits gradually replace the smooth muscle of blood vessel walls.

Nearly half of Alzheimer’s patients have CAA, and many also suffer from heart ailments that are normally treated with blood thinners, the report noted.

Experts explained to Science Insider that in these types of patients, stripping the amyloid away — as drugs like Leqembi are meant to do — could weaken the blood vessels and make them vulnerable to bleeds if exposed to blood thinners or clot busters.

More details on the woman’s case — including autopsy results — were released Wednesday in the New England Journal of Medicine by doctors at Northwestern Medicine in Chicago. The autopsy confirmed extensive brain bleeding and amyloid deposits within many blood vessels.

The Northwestern team believes that exposure to t-PA triggered burst blood vessels throughout the patient’s brain, causing death.

“The extensive number and variation in sizes of the cerebral hemorrhages in this patient would be unusual as a complication of t-PA solely related to cerebrovascular amyloid,” they wrote, but prior use of Leqembi may have tipped the balance, triggering the hemorrhages.

In a journal response to the article Drs. Marwan Sabbagh and Christopher H. van Dyck said they “agree that this case raises important management issues for patients with Alzheimer’s disease.”

But factors other than the patients’ use of Leqembi could have been at play, they pointed out. In the woman’s case, an extended period of very high blood pressure could have been a contributing factor. In the man’s case, a drug he was taking to counter atrial fibrillation might have played a role in the hemorrhaging.

Besides the two fatal cases, the clinical trial also showed that 2.8% of participants who took the drug had a symptomatic side effect called ARIA-E, which involves swelling in the brain. ARIA-E was not seen among any participants who got the placebo.

Risks versus benefits

However, for the millions of Americans affected by Alzheimer’s, any beneficial drug could be welcome.

After Medicare limited its coverage of Aduhelm, citing risks and unclear benefit, the expensive drug was essentially sidelined.

In a statement, Eisai said that it planned to price Leqembi at $26,500 per year. According to The New York Times, that’s somewhat higher than the price range the Institute for Clinical and Economic Review has said would be cost-effective for patients: between $8,500 and $20,600 a year.

Like Aduhelm, Leqembi — given via infusion every two weeks — is a monoclonal antibody that targets amyloid proteins, which tend to clump in the brains of people with Alzheimer’s. Years of research have uncovered precious little evidence that clearing these plaques actually helps with memory and thinking problems. Earlier this month, another anti-amyloid monoclonal antibody, gantenerumab, failed to show any benefit.

For his part, Tousi stressed that Leqembi will not produce a dramatic turnaround in the cognitive health of people with Alzheimer’s disease.

“It is not that you take this medication and your memory gets better,” he said. “It is a newer concept for many patients. It is not treating the symptoms, but it slows down the decline. … It is a small benefit but is still a benefit. The findings are promising when we don’t have any other treatments available.”

Source: HealthDay





Blood Test that Diagnoses Alzheimer’s YEARS Before Symptoms Develop Could be on Horizon

Mark Waghorn wrote . . . . . . . . .

A blood test that diagnoses Alzheimer’s years before symptoms develop could be on the horizon.

Scientists have identified chemicals linked to mild cognitive impairment (MCI) – an early sign of the disease.

It could lead to drugs or lifestyle changes being prescribed when they are most likely to be effective.

Corresponding author Professor Bin Xu, of North Carolina Central University, said: “Our work provides a new avenue for developing diagnosis and differentiation tools for Alzheimer’s.”

The discovery offers hope of national screening programs. It is based on post mortem brain tissue from patients who died with and without the disease.

Specific forms of a rogue protein, known as p-tau198 and p-tau217, differentiated those with MCI from older subjects without the impairment.

They show up in plasma, a yellowish liquid that carries red and white blood cells around the body.

Currently, PET (positron emission tomography) scans are required for clinical diagnosis of dementia (ADRD) or spinal lumbar punctures. Both are costly.

Identifying biomarkers for the development of non-invasive or minimally invasive and inexpensive tests is thus an urgent and unmet need.

Significant progress has been made in the last few years, such as the development of tests for tau biomarkers with blood samples.

Prof Xu said: “However, so far there are no well-established biomarkers that are capable of robustly discriminating MCI or the first stage of Alzheimer’s from cognitively normal samples.”

The study found several potential candidates. In particular, p-tau198 also discriminated Alzheimer’s from two other neurodegenerative diseases where tau is known to clump.

Prof Xu said: “Importantly, both p-tau 198 and p-tau217 also could differentiate brain tissue of patients with MCI – an early sign of Alzheimer’s.

“They could help clinicians intervene early, as new treatments become available, before significant neurological damage occurs.”

Mild cognitive impairment is a transitional stage between normal ageing and dementia, leading to minor memory lapses that sometimes become more serious.

The number of dementia cases worldwide will triple to more than 150 million by 2050. There is no cure.

One of the reasons drugs have failed to date is they are given to trial participants once the memory robbing disease has already taken hold.

Prof Xu said: “Identification of p-tau198 or other promising candidates for general MCI diagnosis may have significant impact on clinical practice for much needed early Alzheimer’s biomarker development.”

Source: Mirror