For Alzheimer’s patients, a new era of treatment brings hope and risk

Jay Reinstein stood in the hospital hallway, gently bickering with his father about Larry David’s misanthropic character on “Curb Your Enthusiasm.”

“I don’t like him. He’s mean-spirited,” Max, 88, declared. An exasperated Jay replied, “Dad, it’s comedy!” Jay’s mother - Lois, 85 - rolled her eyes as the two men reached a truce based on their mutual love of Mel Brooks.

The friendly banter masked the wrenching reason for the family’s visit to MedStar Georgetown University Hospital. It wasn’t for Jay’s octogenarian parents; his father still works as a certified public accountant. It was for Jay, 62 years old and stricken with early-onset Alzheimer’s disease, which has driven him from a job he fiercely loved and recently forced him to stop driving. He’s here for tests that will show how quickly the illness is progressing.

Since being diagnosed five years ago with Alzheimer’s, Jay has felt desperate, sometimes panicky, about his fate. But now, he sees a sliver of hope: a new drug called Leqembi. It’s not a cure and does not restore memories destroyed by the fatal neurodegenerative disease. But the medication modestly slows progression of the condition, even as it raises significant safety and cost issues that are generating intense controversy.

The test Reinstein is undergoing on this day could help him get the drug. “I want more time to spend with my five grandchildren,” he said.

Leqembi, in a clinical trial, slowed cognitive decline by 27 percent over 18 months compared with a placebo. That represented a five-month delay in progression - dismissed as negligible by some but hailed as a milestone by others for a malady that has been largely untreatable. By Thursday, the Food and Drug Administration is expected to grant Leqembi full approval - the first time such a clearance has been granted to a therapy that changes the course of the disease. Other Alzheimer’s drugs treat symptoms, and often not very well.

“I am absolutely thrilled,” said Allan Levey, a neurologist at Emory University School of Medicine in Atlanta. Leqembi and other drugs in development for Alzheimer’s “bring hope to me as a specialist and to my patients.”

Reisa Sperling, an Alzheimer’s researcher at Brigham and Women’s Hospital in Boston, said Leqembi is not a home run but “a solid double . . . something to build on.” She added, “To me, it feels like the beginning of a new era.”

Skeptics note, however, that the drug’s effectiveness is limited - perhaps too subtle to be noticed by a patient - and that the medication can cause potentially dangerous brain swelling and bleeding. The drug is expensive - $26,500 per year. And Medicare, the federal health program for older Americans, intends to impose conditions on coverage, a move fueling a bitter battle between government officials and advocacy groups.

The raft of challenging issues means the new era of Alzheimer’s will dawn posing difficult questions for patients, doctors - and society.

Leqembi, an intravenous therapy by the pharmaceutical company Eisai in Tokyo and Biogen in Cambridge, Mass., belongs to a new class of Alzheimer’s drugs - monoclonal antibodies, or man-made proteins, that sharply reduce the toxic buildup of amyloid in the brain, a hallmark of the disease. A similar Eli Lilly drug, called donanemab, could be approved by the FDA by the end of this year or early next year.

Because of safety and logistical concerns, most Leqembi prescriptions appear likely to be handled initially at academic medical centers experienced in treating Alzheimer’s patients. They are best equipped to navigate the complex tasks of finding eligible patients and conducting follow-up tests. But even those centers are scrambling to establish safety procedures, find places for infusions and hire more specialists - amid a shortage of dementia experts.

As a result, many medical centers are unlikely to start using Leqembi until mid-autumn or later. If demand surges, patients could face substantial delays in getting the drug.

“Everyone admits we are not ready in terms of capacity to take on a lot more patients and create the bandwidth to get everyone in who might be interested,” University of Kansas neurologist Jeffrey M. Burns said. “There will be a lot of people trying to get into the memory clinics, and no one is ready.”

It’s far from clear whether there will be an immediate spike in demand. David S. Knopman, a neurologist at Mayo Clinic in Rochester, Minn., said when he tells older patients that Leqembi requires a trip to an infusion center every other week, “it’s a conversation stopper.” Most of his patients are in their 70s and 80s and often have other health problems. “Their spouses might have health issues,” he said. “They may not like to drive.”

Leqembi is for patients with mild cognitive impairment or early dementia caused by Alzheimer’s. Identifying those patients quickly, before they become too ill to benefit from the drug, will be challenging and time-intensive for physicians; many people with mild cognitive impairment are not diagnosed.

To get the medication, patients will need evidence of a buildup of amyloid in their brains. That is determined by amyloid PET scans - which can cost thousands of dollars and aren’t covered by Medicare except in a limited way in clinical trials - or lumbar punctures, also known as a spinal taps. Blood tests are on the horizon but not yet in mainstream use.

Once patients start receiving Leqembi, they will need several brain MRIs to check for side effects. Swelling and bleeding in the brain can usually be safely managed, according to doctors who have been involved in clinical trials of anti-amyloid drugs. They say the side effects are no worse than those for some cancer drugs.

But there were three deaths thought to be linked to Leqembi in an extended portion of its key study. And some patients - including those on blood thinners or with a condition that causes microscopic brain bleeds - could be especially vulnerable to dangerous side effects. If the drug is not handled correctly, some experts worry, more people could be injured and the drug itself could be imperiled.

One potential candidate for the drug at the University of Kansas is Steve Grant, a retired history teacher who still works as a substitute and assistant golf coach. Grant, 73, was diagnosed with mild cognitive impairment this year and is hoping to prolong the early stage of his illness. He’s not worried about side effects.

“Yeah, I understand (Leqembi) might be a temporary fix or just an extension of normality, and I’m fine with that,” said Grant, whose father died of Alzheimer’s at 69. “I’m ready to help myself out, selfishly, but also to help other people.”

Some other Alzheimer’s patients are adamant about rejecting Leqembi.

“This needs to go through much more research before they test-drive it on people,” said Joanna Fix, a 54-year-old Colorado Springs resident with early-onset Alzheimer’s.

A checkered history

Alzheimer’s drugs have had a long, difficult history. Tacrine, also known by its brand name, Cognex, was approved by the FDA in 1993, the first medication cleared for treatment of the disease. Like some drugs that followed, including Aricept, tacrine was designed to slow the breakdown of acetylcholine, a neurotransmitter involved in memory and learning.

But the drug, which did not change the course of the disease, fell out of use because of concerns about liver toxicity.

During the past several years, scientists have increasingly focused on biological markers of the disease, including amyloid clumps and tau tangles, also a signature characteristic of Alzheimer’s. But anti-amyloid medications failed repeatedly in clinical trials, or, in the case of a drug called Aduhelm, produced conflicting results. Until Leqembi.

In January, the FDA granted Leqembi accelerated approval based on data showing it sharply reduced brain amyloid. The approval required a larger study verifying that the drug provides a clinical benefit. In June, the agency’s outside experts, reviewing results from a confirmatory trial, unanimously agreed Leqembi helps patients, paving the way for traditional FDA approval.

Thomas M. Wisniewski, a neurologist at NYU Langone Health, called Leqembi a major breakthrough for the amyloid cascade hypothesis - the long-debated view that removing amyloid from the brain can slow Alzheimer’s - “but also for the field in general that therapies are possible for Alzheimer’s.”

Other doctors remain unconvinced. “The drug was incredibly effective at removing amyloid yet only minimally effective at improving cognition,” said Kenneth Covinsky, a geriatrician at the University of California at San Francisco.

Many experts agree that amyloid is just part of the Alzheimer’s story and that a cocktail of drugs - including anti-inflammatory and anti-tau agents - will be needed to effectively combat the disease. “Within five years, we will have combination therapies,” just like in cancer treatment, said Howard Fillit, co-founder and chief science officer of Alzheimer’s Drug Discovery Foundation, a nonprofit that promotes research into drugs for the disease.

A cautious approach

Fix had a PhD in psychology and was teaching at the University of the Pacific in Stockton, Calif., when her performance started to slip. She had “emerged from the womb ready to roll,” she said, but now was exhausted and dangerously absent-minded.

One day, when she stopped for gas on her way home, people came over to her car “screaming their heads off,” Fix said. She had forgotten to put the nozzle in the tank. Other times, she left her kitchen after turning on the stove, forgetting she was in the middle of cooking.

Nonplussed, Fix moved to Colorado to be near her family, thinking her problems were temporary. Seven years ago, at age 48, she was diagnosed with early-onset Alzheimer’s. When she told her boyfriend, he immediately called her father to ask for permission to marry her. “It was a pretty bad day and pretty good day at the same time,” she said.

Fix was prescribed Aricept, which treats symptoms such as memory loss and thinking problems but has side effects. She ended up hospitalized with atrial fibrillation.

Since then, Fix has become a vociferous critic of treating Alzheimer’s patients with drugs. “They are testing drugs on a population that is already at risk because we have really fragile stuff going on in our brains,” she said.

Fix said she would consider a drug only if it had obvious benefits and minor side effects like a rash or diarrhea. “Then it might be worth it for me, to be able to bathe myself or hang on to my short-term memory,” she said.

‘Safety first’

Gil Rabinovici is a neurologist in the memory and aging center at UCSF, which treats 6,500 patients per year and has 35 clinicians. The center has long been involved in testing anti-amyloid drugs. Even so, “it’s a big lift” to put in place all the steps to get ready for a drug he believes will transform the clinic’s care, he said.

“In my thinking, it’s safety first,” Rabinovici said.

Patients who might get Leqembi now will undergo genetic tests, he said. That’s because data showed that the medication could pose a higher risk for people with two copies of the APOE4 gene variant that increases the likelihood of Alzheimer’s. Some doctors also say they won’t prescribe the drug for people on blood thinners because of the increased chance of brain hemorrhage.

Still unresolved is one of the biggest questions involving Leqembi: How will patients get the drug if they don’t typically go to big medical centers? That includes rural patients and African Americans and Latinos, who typically receive less Alzheimer’s care than their White counterparts.

Medicare has said it plans to cover Leqembi and similar drugs that receive traditional FDA approval, but with a caveat: Physicians must participate in registries that collect evidence about how the drugs work in the real world. Collecting such information, Medicare officials say, won’t be a big burden because doctors will be gathering the data anyway, as they assess their patients. Some doctors agree, saying the requirement doesn’t appear onerous and will provide important information on unanswered questions about the drugs.

Other doctors and many advocates, including the Alzheimer’s Association, vigorously disagree, saying the restrictions will delay access. “I think it is going to be a big obstacle, not only because it will take more time and effort for clinicians to prescribe, but also because there will be a delay in setting up” the registries, said R. Scott Turner, a neurology professor at Georgetown University School of Medicine. He and others believe the restrictions also will worsen disparities in Alzheimer’s care.

Most people eligible for Leqembi are expected to be in Medicare - including those younger than 65. People with early-onset Alzheimer’s can enroll in the program after receiving Social Security disability payments for two years.

Even with Medicare coverage, patients could be responsible for more than $5,000 per year in out-of-pocket costs for the drug, according to KFF, a nonprofit health policy organization. And there could be additional costs for brain scans and other services. Private insurers tend to follow Medicare’s lead, so some kind of coverage seems likely once Leqembi gets full FDA approval.

In a statement, Aetna said its Medicare Advantage plans will continue to follow the guidelines set by Medicare. The company said its commercial plans will “assess any updated FDA labeling” for Leqembi when it is released.

The Medicare program could end up spending billions of dollars a year on the medication, depending on how many people opt to receive it. About 6.5 million people in the United States who are 65 and older have Alzheimer’s, according to the Centers for Disease Control and Prevention, but generally that does not include millions who might have mild cognitive dementia.

Covinsky, the UCSF geriatrician, said it was “absurd to pay all this money for a drug” when other steps - such as providing Medicare coverage for home health aides - would be more helpful to patients and families.

But proponents of Leqembi - and other drugs in the pipeline - say the expense will be worth it if the medications prevent the intense suffering and enormous costs imposed by the disease.

Stability, then fear

“It’s horrible” watching her son, Jay Reinstein, struggle against such an unforgiving foe, Lois Reinstein said. When she got sick as a little girl, her grandmother would murmur in Yiddish that she wished she could take the illness herself and spare the child. “That’s how I feel,” Lois said.

As a city official in Durham, N.C., and then as assistant city manager in Fayetteville, Reinstein prided himself on being hyper-organized and having a steel-trap memory. Then, he started forgetting details of city projects and couldn’t keep up even by working two extra hours a day. “He would say, ‘There is something wrong with me,’” his wife, Angela, said.

Diagnosed in 2018, Reinstein became extremely depressed. But after he began telling friends and family members, “I realized I was really loved,” he said. He retired in 2019.

Now, after a period of relative stability, Reinstein, who still lives in Durham, fears his illness may be accelerating. On a weekly talk radio show he co-hosts, he finds the off-the-cuff debates increasingly difficult. He recently failed a driving simulator test at the Memory Disorders Clinic of Duke University Health Systems in North Carolina, where he is being treated. The occupational therapist ordered him to take an Uber home.

Now getting Leqembi is an urgent priority. “If it gives me six or 12 or 24 more months at the current level, that’s a great thing,” Reinstein said.

That would be a benefit beyond what the drug provided in its key trial. Nevertheless, Reinstein, an outspoken advocate with a group called Voices of Alzheimer’s, remains undaunted in his efforts to prod Medicare to provide unrestricted coverage for Leqembi, as it does for most FDA-approved medications.

“Registries are a bunch of B.S.,” said Reinstein, who helped stage a “die-in” in Fayetteville to protest Medicare’s policy. Reinstein is on Medicare because he is receiving disability benefits.

At Georgetown hospital, Reinstein underwent tests as part of a study following the progression of Alzheimer’s in people with early-onset disease. Georgetown is taking part in the study, but Duke is not.

One of the tests was a PET scan designed to determine whether Reinstein has a buildup of amyloid in his brain. After being injected with a radioactive tracer that illuminates brain abnormalities, he stretched out on a long table, asking that the blaring music be changed from Ella Fitzgerald to Adele. Then, he was pushed into a huge, doughnut-shaped tube for 20 minutes.

When Reinstein gets the results, he said, he will forward them to Duke. Cindy Beam, his nurse there, said if the scan shows an accumulation of amyloid, Reinstein will be able to skip a lumbar puncture that Duke has scheduled to see if he qualifies for Leqembi.

As Reinstein was pulled from the PET scan, he grabbed his phone and did a quick video for “Jay’s Journal,” a series of videos documenting his experience that are posted online by an Alzheimer’s advocacy organization. Then, he went to find his parents and his wife, who were waiting to take him to dinner.