Alzheimer’s drug sparks emotional battle as FDA nears deadline on whether to approve

When Phil Gutis was diagnosed with early-stage Alzheimer’s disease at 54, he immediately enrolled in a clinical trial for an experimental drug but had little hope of being helped. Over time, though, he started feeling better, his brain less cloudy.

"There was just a fogginess I remember having a couple of years ago that I don't really feel I have now," said Gutis, who has received monthly infusions of a medication called aducanumab for five years, except for a short interruption.

Now, he is hoping others with the disease will have a chance to try the drug. But he is worried that the Food and Drug Administration, which is weighing whether to approve the drug, will reject it, derailing the medication and jeopardizing his ability to get the treatment.

"Would my world become fuzzy again?" said Gutis, who lives in New Hope, Pa., with his husband and is a former reporter. "I don't want to go backward."

By June 7, the FDA is expected to make one of its most important decisions in years: whether to approve the drug for mild cognitive impairment or early-stage dementia caused by Alzheimer's. It would be the first treatment ever sold to slow the deterioration in brain function caused by the disease, not just to ease symptoms. And it would be the first new Alzheimer's treatment since 2003.

The medication is a monoclonal antibody, a protein made in the laboratory that can bind to substances — in this case, clumps of amyloid beta, a sticky plaque compound that many scientists believe damages communication between brain cells and eventually kills them. The treatment is designed to trigger an immune response that removes the plaques.

Approval is far from assured. While everyone agrees there is an enormous need for new treatments — about 6.2 million Americans have Alzheimer's, a number expected to more than double by 2050 — the drug's messy, complicated history is sparking a battle among researchers, doctors, patients and advocates about whether the medication works and what regulators should do.

Supporters, including some doctors who treat Alzheimer's and advocacy groups such as the Alzheimer's Association and UsAgainstAlzheimer's, acknowledge the drug's clinical trial data is far from perfect. But they say it would help some patients, and argue that approval would launch an era of increased research and investment into therapies for a progressive, terminal illness that causes incalculable misery and costs society billions of dollars a year.

"This will give us a new biological foothold to build on," said Stephen Salloway, director of neurology and the Memory and Aging Program at Butler Hospital in Providence, R.I., and a professor at Brown University. "To get the best in class, you have to have the first in class."

But critics argue the drug's trial data falls far short of proving the drug works. They note that one of the late-stage trials was positive and the other was negative — hardly convincing evidence. In an acrimonious meeting last fall, an FDA advisory committee recommended against approval and harshly rebuked FDA staff for what it called an overly positive view.

"The worst thing for people with Alzheimer's would be to put out a product that doesn't work," Aaron S. Kesselheim, a professor of medicine at Harvard Medical School and a member of the panel, said in a recent interview. "It will be sold at an extremely high price and waste resources that could go to other things."

The drug — likely to earn its maker billions of dollars — is the latest example of a controversial treatment that is passionately supported by patients and advocacy groups but has been rejected by the FDA's outside advisers and is viewed skeptically in some quarters of the agency.

In 2016, the FDA approved a drug for Duchenne muscular dystrophy after outside experts recommended against approval and internal reviewers raised doubts about the drug's efficacy. The decision caused an uproar, leading to questions about the impact of pressure from advocates. The official who approved the drug — Janet Woodcock, now acting FDA commissioner — has said that while the trial was flawed, the drug might still help patients with the fatal muscle-wasting disease.

The intense disagreement on aducanumab puts the FDA in a difficult position, said Howard Fillit, founding executive director and chief science officer of the Alzheimer's Drug Discovery Foundation, which works to accelerate the discovery of drugs for the disease.

"There is tremendous pressure on the FDA from the Alzheimer's community, but in this case," Fillit said, "I think the science is unfortunately somewhat ambiguous."

The drug's maker, the giant biotech company Biogen, says the medication, by slowing the disease, gives patients valuable time to be with their families and to perform everyday tasks such as cleaning and shopping.

But the intravenous treatment does not cure Alzheimer's or reverse it. It could carry a price tag as high as $50,000-a-year per patient, according to drug analysts, adding billions of dollars to the nation's health tab. And, depending on how the FDA writes the label, millions of people could be eligible for the drug, or at least for an assessment of whether they should take it, experts say.

That has some experts wondering if demand would overwhelm a system that does not have enough Alzheimer's specialists. Massachusetts-based Biogen has said it has 600 sites across the country ready to administer the drug if it gets the FDA nod.

The drug's path has been full of twists and turns. After aducanumab showed promise in 2016, Biogen launched two late-stage trials — then stopped them halfway through, in March 2019, when an analysis concluded the studies would not reach their goal of slowing cognitive and functional impairment in participants.

Seven months later, in a stunning reversal, the company unveiled an analysis that included updated data and told a different story. In one study, people given the drug had declined 22 percent more slowly than those who had received a placebo. The other trial failed to reach its goal, though the company was encouraged by data from a subset of study participants who got more of the drug. Biogen concluded the key to effectiveness was giving patients a high-enough dose, but critics howled, with one calling the analysis "a post hoc dumpster dive operation."

What most outraged Biogen's detractors was the FDA's strong support for the drug. The agency's medical reviewers in November told the advisory committee the single successful trial was "exceptionally persuasive," while the FDA's own statistical review found the data conflicting and said only a third trial could show whether the drug worked.

Scott Emerson, professor emeritus of biostatistics at the University of Washington and a member of the advisory panel, suggested at the session that the analysis fit "the Texas sharpshooter fallacy," in which someone fires a shotgun at a barn and then paints "a target around the bullet holes."

Since then, the argument has escalated.

Butler Hospital's Salloway, who has treated dozens of patients with aducanumab during eight years as a clinical trial investigator, said "a substantial number of people do better with this drug than expected." He said he treated 17 patients for four years and that 10 of them did not decline while they were taking the medication. "That is not typical of Alzheimer's," he said, adding the data was not published.

He and others highlight the desperate situation of patients who don't have any treatments that change the course of the disease — aducanumab would be the first. If he told patients there was a new Alzheimer's drug with mixed data on effectiveness and asked whether they would like to try it, "they'd say, 'Are you nuts? Of course I would,' " Salloway said. While he said he hopes the FDA approves the drug, he also would like the agency to require a post-approval study to collect more efficacy data.

"We don't think this is the end all or be all," Harry Johns, president and chief executive of the Alzheimer's Association, said of aducanumab. "It will take more advances, but it does appear from the science that people, especially at early stages, could be real beneficiaries and that the benefits accumulate over time."

Critics say Biogen should conduct a third trial — but before, not after, the drug is approved.

"When you have one study that is positive and one that is negative, it seems to lead to an inability to draw a conclusion and therefore to a need for a third trial," said David S. Knopman, a Mayo Clinic neurologist who treats Alzheimer's patients and is a member of the FDA advisory committee. He had recused from the November meeting because he has been a site investigator for aducanumab.

Critics also point out the drug has potential side effects — brain swelling and tiny bleeds in the brain, although they were managed well in the trial.

The Institute for Clinical and Economic Review, a Boston-based nonprofit organization that assesses the value of new treatments, said in a preliminary report there was "insufficient" data to determine whether the drug helps patients and said the price should be set at $2,500- to $8,000-a-year per patient.

Johns, of the Alzheimer's Association, said a third trial would simply take too long — four to six years — during which more and more patients would slide deeper into dementia.

The wrangling over aducanumab is the latest chapter in the long-running debate about the "amyloid hypothesis," a theory proposed in the early 1990s that amyloid plaques are the cause, or at least an important hallmark, of Alzheimer's and should be targeted.

Detractors argue the dominance of the approach has yielded a string of failed drugs — including ones that clear amyloid but don't improve cognition — and squeezed out other approaches such as targeting a protein called tau or examining the role of inflammation.

But supporters say using higher doses of anti-amyloid treatments and administering them much earlier will make them effective. Earlier this year, data on an Eli Lilly drug also showed it slowed declines in early-stage patients. In both camps, there is broad agreement that other approaches also need to be explored and that it probably will require combinations of drugs to effectively treat the disease. Lifestyle factors such as diet, exercise and sleep also are getting attention.

The trials show the Biogen drug eliminates amyloid plaque — the debate is whether that improves patients’ cognitive abilities.

Peter Bristol, a 77-year-old horticulturist who lives in Wakefield, R.I., and whose mother and brother died of Alzheimer's, hasn't taken aducanumab but is hoping it will be available if he needs it. He has mild cognitive impairment, a precursor to Alzheimer's. "Lots of people out there are looking for hope," he said.

Gutis, who once worked as a reporter for the New York Times and as a communications director for nonprofit groups, began worrying about memory losses several years ago, when he got lost driving familiar routes and couldn't remember a friend from his college newspaper.

In 2016, he responded to an advertisement for a clinical trial and was diagnosed with early-onset Alzheimer's. When the Biogen trial was halted halfway through, he went several months without the drug, then enrolled in a longer-term study by the company.

If the FDA does not approve the drug, it is not clear what Biogen will do: Will it conduct another trial and reapply to the FDA, or drop the drug? Biogen declined to comment on its plans. If he is unable to get aducanumab, said Gutis, who is 59 and on disability, he would probably look for another trial.

He doesn’t want to give up. “Alzheimer’s is a very, very lonely disease,” he said. “It’s very isolating. Your friends disappear. It really does box you into a quiet place.”