Elisabeth Rosenthal: Why we may never know if Biogen’s Alzheimer’s drug works

A normal brain on the left and a late-stage Alzheimer's brain on the right.

From Kaiser Health News

The Food and Drug Administration’s approval in June of a drug purporting to slow the progression of Alzheimer’s disease was widely celebrated, but it also touched off alarms. There were worries in the scientific community about the drug, developed by Cambridge, Mass.-based Biogen, mixed results in studies — the FDA’s own expert advisory panel was nearly unanimous in opposing its approval. And the annual $56,000 price tag of the infusion drug, Aduhelm, was decried for potentially adding costs in the tens of billions of dollars to Medicare and Medicaid.

But lost in this discussion is the underlying problem with using the FDA’s “accelerated” pathway to approve drugs for conditions such as Alzheimer’s, a slow, degenerative disease. Though patients will start taking it, if the past is any guide, the world may have to wait many years to find out whether Aduhelm is actually effective — and may never know for sure.

The accelerated approval process, begun in 1992, is an outgrowth of the HIV/AIDS crisis. The process was designed to approve for sale — temporarily — drugs that studies had shown might be promising but that had not yet met the agency’s gold standard of “safe and effective,” in situations where the drug offered potential benefit and where there was no other option.

Unfortunately, the process has too often amounted to a commercial end run around the agency.

The FDA explained its controversial decision to greenlight the Biogen pharmaceutical company’s latest product: Families are desperate, and there is no other Alzheimer’s treatment. Also, importantly, when drugs receive this type of fast-track approval, manufacturers are required to do further controlled studies “to verify the drug’s clinical benefit.” If those studies fail “to verify clinical benefit, the FDA may” — may — withdraw them.

But those subsequent studies have often taken years to complete, if they are finished at all. That’s in part because of the FDA’s notoriously lax follow-up and in part because drugmakers tend to drag their feet. When the drug is in use and profits are good, why would a manufacturer want to find out that a lucrative blockbuster is a failure?

Historically, so far, most of the new drugs that have received accelerated approval treat serious malignancies.

And follow-up studies are far easier to complete when the disease is cancer, not a neurodegenerative disease such as Alzheimer’s. In cancer, “no benefit” means tumor progression and death. The mental decline of Alzheimer’s often takes years and is much harder to measure. So years, possibly decades, later, Aduhelm studies might not yield a clear answer, even if Biogen manages to enroll a significant number of patients in follow-up trials.

Now that Aduhelm is shipping into the marketplace, enrollment in the required follow-up trials is likely to be difficult, if not impossible. If your loved one has Alzheimer’s, with its relentless diminution of mental function, you would want the drug treatment to start right now. How likely would you be to enroll and risk placement in a placebo group?

The FDA gave Biogen nine years for follow-up studies but acknowledged that the timeline was “conservative.”

Even when the required additional studies are performed, the FDA historically has been slow to respond to disappointing results.

In a 2015 study of 36 cancer drugs approved by the FDA, only five ultimately showed evidence of extending life. But making that determination took more than four years, and over that time the drugs had been sold, at a handsome profit, to treat countless patients. Few drugs are removed.

It took 17 years after initial approval via the accelerated process for Mylotarg, a drug to treat a form of leukemia, to be removed from the market after subsequent trials failed to show clinical benefit and suggested possible harm. (The FDA permitted the drug to be sold at a lower dose, with less toxicity.)

Avastin received fast-track approval as a breast cancer treatment in 2008, but three years later the FDA revoked the approval after studies showed the drug did more harm than good in that use. (It is still approved for other, generally less common cancers.)

In April, the FDA said it would be a better policeman of cancer drugs that had come to markets via accelerated approval. But time — as in delays — means money to drug manufacturers.

A few years ago, when I was writing a book about the business of U.S. medicine, a consultant who had worked with pharmaceutical companies on marketing drug treatments for hemophilia told me the industry referred to that serious bleeding disorder as a “high-value disease state,” since the medicines to treat it can top $1 million a year for a single patient.

Aduhelm, at $56,000 a year, is a relative bargain — but hemophilia is a rare disease, and Alzheimer’s is terrifyingly common. Drugs to combat it will be sold and taken. The crucial studies that will define their true benefit will take many years or may never be successfully completed. And from a business perspective, that doesn’t really matter.

Elisabeth Rosenthal, M.D., is editor of Kaiser Health News.

 erosenthal@kff.org, @rosenthalhealth

Harris Meyer: Amidst intense controversy, FDA approves Biogen’s Alzheimer's drug

Drawing comparing a normal aged brain (left) and the brain of a person with Alzheimer's (right). Characteristics that separate the two are pointed out.

From Kaiser Health News

The Food and Drug Administration has approved the first treatment for Alzheimer’s disease, a drug developed by Biogen, which is based in Cambridge’s Kendall Square neighborhood. But the approval highlights a deep division over the drug’s benefits as well as criticism about the integrity of the FDA approval process.

The approval of aducanumab came despite a near-unanimous rejection of the product by an FDA advisory committee of outside experts in November. Doubts were raised when, in 2019, Biogen halted two large clinical trials of the drug after determining it wouldn’t reach its targets for efficacy. But the drugmaker later revised that assessment, stating that one trial showed that the drug reduced the decline in patients’ cognitive and functional ability by 22 percent.

Some FDA scientists in November joined with the company to present a document praising the intravenous drug. But other FDA officials and many outside experts say the evidence for the drug is shaky at best and that another large clinical trial is needed. A consumer advocacy group has called for a federal investigation into the FDA’s handling of the approval process for the product.

A lot is riding on the drug for Biogen. It is projected to carry a $50,000-a-year price tag and would be worth billions of dollars in revenue to the Cambridge company.

The FDA is under pressure because an estimated 6 million Americans are diagnosed with Alzheimer’s, a debilitating and ultimately fatal form of dementia, and there are no drugs on the market to treat the underlying disease. Although some drugs slightly mitigate symptoms, patients and their families are desperate for a medication that even modestly slows its progression.

Aducanumab helps the body produce antibodies that remove amyloid plaques from the brain, which has been associated with Alzheimer’s. It’s designed for patients with mild-to-moderate cognitive decline from Alzheimer’s, of which there are an estimated 2 million Americans. But it’s not clear whether eliminating the plaque improves brain function in Alzheimer’s patients. So far, nearly two dozen drugs based on the so-called amyloid hypothesis have failed in clinical trials.

Besides questions about whether the drug works, there also are safety issues. More than one-third of patients in one of the trials experienced brain swelling and nearly 20 percenty had brain bleeding, though those symptoms generally were mild and controllable. Because of those risks, patients receiving aducanumab have to undergo regular brain monitoring through expensive PET scans and MRI tests.

Some physicians who treat Alzheimer’s patients say they won’t prescribe the drug even if it’s approved.

“There’s a lot of hope among my patients that this is going to be a game changer,” said Dr. Matthew Schrag, an assistant professor of neurology at Vanderbilt University. “But the cognitive benefits of this drug are quite small, we don’t know the long-term safety risks, and there will be a lot of practical issues in deploying this therapy. We have to wait until we’re certain we’re doing the right thing for patients.”

Many aspects of aducanumab’s journey through the FDA approval process have been unusual. It’s “vanishingly rare” for a drug to continue on toward approval after its clinical trial was halted because unfavorable results showed that further testing was futile, said Dr. Peter Lurie, president of the Center for Science in the Public Interest and a former FDA associate commissioner. And it’s “mind-boggling,” he added, for the FDA to collaborate with a drugmaker in presenting a joint briefing document to an FDA advisory committee.

“A joint briefing document strikes me as completely inappropriate and an abdication of the FDA’s claim to being the best regulatory agency in the world,” Lurie said.

Three FDA advisory committee members who voted in November against approving the drug wrote in a recent JAMA commentary that the FDA’s “unusual degree of collaboration” with Biogen led to criticism that it “potentially compromised the FDA’s objectivity.” They cast doubt on both the drug’s safety and the revised efficacy data.

The FDA and Biogen declined to comment for this article.

Despite the uncertainties, the Alzheimer’s Association, the nation’s largest Alzheimer’s patient advocacy group, has pushed hard for FDA approval of aducanumab, mounting a major print and online ad campaign last month. The “More Time” campaign featured personal stories from patients and family members. In one ad, actor Samuel L. Jackson posted on Twitter, “If a drug could slow Alzheimer’s, giving me more time with my mom, I would have read to her more.”

But the association has drawn criticism for having its representatives testify before the FDA in support of the drug without disclosing that it received $525,000 in contributions last year from Biogen and its partner company, Eisai, and hundreds of thousands of dollars more in previous years. Other people who testified stated upfront whether or not they had financial conflicts.

Dr. Leslie Norins, founder of a group called Alzheimer’s Germ Quest that supports research, said the lack of disclosure hurts the Alzheimer’s Association’s credibility. “When the association asks the FDA to approve a drug, shouldn’t it have to reveal that it received millions of dollars from the drug company?” he asked.

But Joanne Pike, the Alzheimer’s Association’s chief strategy officer, who testified before the FDA advisory committee about aducanumab without disclosing the contributions, denied that the association was hiding anything or that it supported the drug’s approval because of the drugmakers’ money. Anyone can search the association’s website to find all corporate contributions, she said in an interview.

Pike said her association backs the drug’s approval because its potential to slow patients’ cognitive and functional decline offers substantial benefits to patients and their caregivers, its side effects are “manageable,” and it will spur the development of other, more effective Alzheimer’s treatments.

“History has shown that approvals of first drugs in a category benefit people because they invigorate the pipeline,” she said. “The first drug is a start, and the second and third and fourth treatment could do even better.”

Lurie disputed that. He said lowering the FDA’s standards and approving an ineffective or marginally effective drug merely encourages other manufacturers to develop similar, “me too” drugs that also don’t work well.

Anne Saint says she wouldn’t have risked putting her husband, Mike Saint, on the new Alzheimer’s drug aducanumab because of safety issues. Mike died in September at age 71. (MOLLY SAINT)

The Public Citizen Health Research Group, which opposes approval of aducanumab, has called for an investigation of the FDA’s “unprecedented and inappropriate close collaboration” with Biogen. It asked the inspector general of the Department of Health and Human Services to probe the approval process, which that office said it would consider.

The group also urged the acting FDA commissioner, Dr. Janet Woodcock, to remove Dr. Billy Dunn, an aducanumab advocate who testified about it to the advisory committee, from his position as director of the FDA’s Office of Neuroscience and hand over review of the drug to staffers who weren’t involved in the Biogen collaboration.

Woodcock refused, saying in a letter that FDA “interactions” with drugmakers make drug development “more efficient and more effective” and “do not interfere with the FDA’s independent perspective.”

Although it would be unusual for the FDA to approve a drug after rejection by an FDA advisory committee, it’s not unprecedented, Lurie said. Alternatively, the agency could approve it on a restricted basis, limiting it to a segment of the Alzheimer’s patient population and/or requiring Biogen to monitor patients.

“That will be tempting but shouldn’t be the way the problem is solved,” he said. “If the product doesn’t work, it doesn’t work. Once it’s on the market, it’s very difficult to get it off.”

If the drug is approved, Alzheimer’s patients and their families will have to make a difficult calculation, balancing the limited potential benefits with proven safety issues.

Anne Saint, whose husband, Mike, had Alzheimer’s for a decade and died in September at age 71, said that based on what she’s read about aducanumab, she wouldn’t have put him on the drug.

“Mike was having brain bleeds anyway, and I wouldn’t have risked him having any more side effects, with no sure positive outcome,” said Saint, who lives in Franklin, Tenn. “It sounds like maybe that drug’s not going to work, for a lot of money.”

Their adult daughter, Sarah Riley Saint, feels differently. “If this is the only hope, why not try it and see if it helps?” she said.

Harris Meyer is a Kaiser Health News reporter.

Judith Graham: The education of a doctor caring for his wife

Dr. Alois Alzheimer's patient Auguste Deter in 1902. Hers was the first described case of what became known as Alzheimer's disease.

From Kaiser Health News

Dr. Arthur Kleinman, a professor of psychiatry and anthropology at Harvard University, calls this “enduring the unendurable” in his recently published book, The Soul of Care: The Moral Education of a Husband and a Doctor.

The book describes Kleinman’s awakening to the realities of caregiving when his beloved wife, Joan, was diagnosed with a rare form of early Alzheimer’s disease that causes blindness as well as cognitive deterioration.

Although Kleinman’s specialty is studying how patients experience illness, he wasn’t prepared for the roller coaster of family caregiving. Each time he adapted to Joan’s changing condition, another setback would occur, setting off new crises and fueling uncertainty and stress.

During 11 years of caregiving until Joan’s death, in 2011, Kleinman learned that no one who goes through this emerges unchanged. He became less self-centered, more compassionate and more aware of how the health-care system fails to support family caregivers ― the backbone of the nation’s long-term care system.

I spoke with Kleinman in mid-November at a caregiving panel. His remarks below are edited for length and clarity.

About his book. “I wrote it for a specific reason. I had spent my whole career as an expert on care. I myself was a psychiatrist who worked with patients with chronic medical disorders, [such as] chronic pain, diabetes, heart disease, cancer. I thought I knew it all. A veil of ignorance was raised from my eyes by my experience as a primary family caregiver.

“What is that veil of ignorance about? It’s about recognizing just how difficult family care is for [people with] dementia and, not just dementia, but many other problems.”

Daily responsibilities. “Let’s say in the fifth year, what was it like? I would get Joan up around 6 a.m. and take her to the bathroom. I have to handle the toilet paper, wash her hands, dress her to work out, take her to the bath and bathe her.

“I would shampoo her hair, dry her, pick out her clothes [for the day]. After that, I would prepare breakfast. As she got increasingly agitated, [that] became difficult because I had to sometimes hold her hands [to] keep her from throwing things or getting up and hurting herself. Because she was blind, she couldn’t see where she was. And then I would help her eat ― usually, at the end, feeding her ― and then take her to a room where we would sit and listen quietly to music.

“Maybe six, seven years into this, I would just sit there and hold her hands. And even that became difficult. So, I would tell her stories of the past … our stories. [Editorial note: This is just the beginning of a day full of similar tasks.]

“I discovered early on that the ritualization of acts of caring ― the dressing, bathing, all these things ― is a way of habit formation that keeps you going.”

Challenging masculinity. “We had a great relationship, but it was asymmetrical. For 36 years, my wife took care of me. I was raised as a classical male in the 1940s. When I showed an interest in cooking, my grandmother said to me, ‘What are you, a sissy?’ I was a tough kid on New York [City] streets. I had the most unpromising beginnings to be a caregiver. And my wife slowly socialized me to a different kind of masculinity, to be able to care.

“[Pay family members for caregiving] and you’ll see more men do it. Go to Australia, for example, where there’s very good compensation for care, and you’re astonished at the number of men who are caring for children, who are caring for elderly, and the like.”

Asking for help. “I have a wide circle of friends and colleagues, and [after the book] many of them said they had never realized what was involved. Part of that was my fault. I had a lot of trouble asking for help. Actually, at one point, I so exhausted myself that my kids, who are great, said, ‘You really need assistance.’ And they stepped in, as did my mother. My mother, who at the time was in her 90s.

“So, I had a great system of care around me, but I [also] needed a home health aide to [help with Joan and] keep myself going. I found an Irish woman … and she was fabulous.”

Maintaining presence. “In spite of that, I found it extraordinarily difficult in terms of other elements of care, one of which is presence. To keep your liveliness, your love, the presence of who you are going while you’re doing all this work of caregiving ― it is extremely difficult and demanding, but it’s crucial.

“When people ask ‘Why do you do [this]?’ the answer of most family caregivers I’ve spoken to is ‘Well, it was there to do. It’s got to be done, [so] you do it.’”

Learning about failure. “I was fortunate in life; I had a golden career. I have a personality that is like a bulldog, and when I start something I finish it. But there’s no finishing care. Every one of us [family caregivers], if we’re honest, you fail at a certain point. The frustrations build, anger mounts, you control your anger so you don’t injure the person you’re caring for. But you’ve got to somehow handle it inside you.”\

The soul of care. “I think what lies at the soul of care is a form of love. You will do everything you can for another because they mean so much to you. [But] it is also problematic, because we all have complex relationships and we’ve got other things going on in our lives.

“We endure, we learn how to endure, how to keep going. We’re marked, we’re injured, we’re wounded. We’re changed … [in] my case, for the better. If you had known me before my 11 years of care, you wouldn’t recognize me today. I was your classical hard-driving Harvard professor … as tough as any other professor at Harvard Medical School.

“I’ve redeemed myself through this experience, in a way.”

A call for change. “How do we strengthen caregiving? How do we do those things that will make it recognized as important as it is? It’s going to take a radical rethinking. Our health-care system [is focused on] entirely the wrong issues. Economics is not the most central aspect of care; it’s caregiving

“Do you know not a single one of the senior neurologists I went to with Joan who wanted to do everything diagnostically made the recommendation ‘You want to think about a home health aide now, even though you don’t need it right now. You have to look into how you’re going to reconfigure your house [for] someone who’s both blind and with dementia. [Or] a social worker is a great navigator of what the health-care system is about. You want to take advantage of that.’

“So, this is where I believe that our whole health care system has got to be rethought, from the bottom up with attention to care at its core.”

We’re eager to hear from readers about questions you’d like answered, problems you’ve been having with your care and advice you need in dealing with the health-care system. Visit khn.org/columnists to submit your requests or tips.

Judith Graham is a Kaiser Health News journalist.

Film about the arts vs. Alzheimer's to be on PBS

 

Watercolor by HILDA GORENSTEIN (aka Hilgos), part of a series she did after developing Alzheimer's disease.

Note to  southeastern New England readers: This movie  discussed below will be shown at 10 p.m., Friday, Nov. 7, on Rhode Island PBS. 

I Remember Better When I Paint shows how the creative arts can enhance the quality of life for people with Alzheimer’s. The film will be shown  on public television stations nationwide during November, which is National Alzheimer’s Awareness Month in the U.S.

Narrated by Academy award-winning actress Olivia de Havilland, this international documentary includes visits to a variety of care facilities, as well as leading art museums in North America and Europe, to demonstrate how creative activities such as drawing, painting and museum visits can reawaken a sense of identity, dignity and engagement among those with severe memory impairment.

Leading doctors and neurologists explain how parts of the brain can be spared and discuss the life-enriching benefits of these new approaches. Among these experts are Dr. Robert Butler, M.D.,  founding director of the National Institutes on Aging (NIH) and a Pulitzer Prize-winning author; Dr. Samuel Gandy, M.D., of Mt. Sinai School of Medicine; Dr. Robert Green, M.D., of Brigham and Women’s Hospital and Harvard Medical School,  and Dr. Robert Stern, M.D. professor of neurology at Boston University.

Inspiring personal stories are featured, including that of Rita Hayworth, as told by her daughter, Yasmin Aga Khan, to highlight the transformative impact of art and other creative therapies and how they are changing the way we look at Alzheimer’s.

The inspiration for the film came from the artist Hilgos, who had severe memory loss. When her daughter, Berna Huebner, asked: “Mom, do you want to paint?” She unexpectedly responded, “Yes, I remember better when I paint.” Art students helped her regain a capacity for exchange and communication through painting.

The movie was written and directed by Eric Ellena and Berna Huebner, and is a French Connection Films and Hilgos Foundation production. The program is a presentation of WTTW National Productions in Chicago, and is distributed nationally by American Public Television (APT).

I have been following  the saga  of this movie for years, even before I wrote about it in an article  in a fine magazine then called Miller-McCune and now called Pacific Standard.

-- Robert Whitcomb

Of factories, Florida and Alzheimer's

By Robert Whitcomb

rwhitcomb51@gmail.com

Many citizens wonder what to do with 19 acres of Providence land that have been made available for development by moving Route 195. What a huge opportunity!

The property is in the middle of New England’s second-largest city; alongside the East Coast’s “Main Street” — Route 95 — whose intersection with 195 created one of the East's big crossroads; next to internationally known academic institutions; spectacularly situated at the head of a great bay, and near a large hospital complex. And just down the road is Green Airport, which is being expanded to allow nonstop flights to the West Coast and Western Europe.

What to put on the property? Offices and academic facilities, especially those connected with medically related activities; design businesses (Rhode Island School of Design spinoffs?), restaurants, hotels and stores. But let’s not ignore manufacturing.

This would not be the “dark satanic mills” of yore, emitting thick pollutants into the air and water. Most American manufacturing is much, much cleaner these days. It also employs fewer people, as foreign factories and robotic systems here have taken over much of the work, though the factory workers we have are generally well paid. To make such high-end stuff as pharmaceuticals in plants on the 195 land is just common sense. Consider that the proximity of Routes 195 and 95 and Narragansett Bay’s ports makes shipping manufacturing materials into and finished products out of this part of Providence remarkably easy. And there’s lots of engineering expertise in the region.

And if you think that a factory can’t co-exist attractively with a thickly settled area, consider Genzyme’s plant in the Allston section of Boston.

But the area needs more and better mass transit to serve the neighborhood, whose warren of confusing streets could scare away car-based people. Eventually a couple of trolley lines (real ones, with rails) should run through the newly developed area to connect the old downtown, the medical complex to the south and College Hill. But let development be dense; sociological and other studies associate density with lower crime and higher urban energy. Planners for the land should keep out windswept parking lots.

All in all, the 195 land offers the biggest opportunity to raise the profile and thus the prosperity of Providence since the rivers were moved.

***

We just got back from Naples, Fla., where I worked and we saw relatives in one of the most demure parts of the peninsula. The overloaded airline system makes travel to and from the Sunshine State increasingly difficult. And the urbanization and suburbanization of much of Florida have tattered much of its semi-tropical beauty. Still, the warmth, the greenery and the ease of strolling compared with walking on New England’s icy streets, narrowed by inadequate snowplowing, made it seem paradisiacal. And the quiet was addictive; the sound of wind through the palms and the surf were the main background sounds as I typed in my brother-in-law’s office.

It brought back memories of a quiet, lush Florida from my childhood. I remember the smell of the orange groves, the roadside juice stands and the long stretches of unbuilt-on beach backed only with palmettos and dune grass. My first memory is of an old man throwing bread to pelicans on the beach in Siesta Key, near Sarasota. Later ones include discovering Key lime pie and stone crab, drinking from a coconut and enjoying the best roadside kitsch in America.

Parts of my family had been going to Florida for part of the winter since around World War I. Naturally they complained about its over-development. Of course, they helped start the problem. (However, they never took part in the sort of crazy land speculation immortalized in the Marx Brothers’ 1929 film “The Cocoanuts,” in which Groucho’s character keeps trying to unload swampland on unsuspecting investors. Not much has changed since then!)

When there’s something nice, we overuse it, which is what happened to Florida, especially after air-conditioning, interstate highways and jet travel made getting and staying there so much easier. The Florida that I briefly revisited the other week, just before its high season, evoked in me balmy nostalgia for a time before Florida became a mega-state.

***

Kudos to Cape Cod-based writer/editor/publisher Greg O’Brien, 64, who has been writing (as self-therapy) about Alzheimer’s disease since he was diagnosed with it, in 2009. One of his projects is his book “On Pluto: Inside the Mind of Alzheimer’s.” Then there’s my friend Berna Huebner, whose movie and book, “I Remember Better When I Paint,” describe how her mother, a successful Chicago-based painter, regained some of her skills and energy after she was persuaded to return to painting after Alzheimer’s seemed to doom her to a life of, by turns, agitation and depressed passivity. We’d better be looking for many routes for relief for dementia victims — and their families -- as the number of victims swells in the next two decades.

(In 2010, I wrote a magazine piece about this.)

Robert Whitcomb (rwhitcomb51@gmail.com), a former editor of The Providence Journal's Commentary pages,  is a Providence-based writer and editor and the overseer of  www.newenglanddiary.com. He is also a director of Cambridge Management Group (cmg625.com).