The Food and Drug Administration is about to announce one of its most controversial decisions in years: the fate of an Alzheimer's drug that could become the first approved treatment in nearly two decades of failed efforts to find ways to contain the debilitating disease.
On Monday, the agency will decide on the drug aducanumab, which aims to slow the progression of memory and thinking problems at the onset of the disease. If approved, it would be the first new Alzheimer's drug since 2003 and the first drug on the market to attack the disease process, not just relieve symptoms.
Analysts predict that within a few years it would become a blockbuster drug, costing tens of thousands of dollars per patient annually, and giving its maker Biogen a godsend.
Patient groups desperate for treatment are pushing for approval. But the green light for the drug would meet the objections of several prominent Alzheimer's experts and the F.D.A independent advisory body.
In November, the committee overwhelmingly voted against a marketing authorization recommendation, saying the data was inconclusive with evidence that aducanumab slows cognitive decline. Three members of the advisory committee later wrote point-by-point criticisms of the evidence. Other scientists and an independent think tank say aducanumab has shown no convincing benefit to outweigh its safety risks.
"This should not be approved as there has been no substantial evidence of effectiveness," said Dr. Lon Schneider, director of the California Alzheimer's Disease Center at the University of Southern California and one of many investigators involved in conducting one of the aducanumab studies. "There is very little potential for this to address patient needs."
Aside from the status of this particular drug, some experts fear that approval could lower the standards for future drugs – a particularly important issue at a time when public confidence in science is wavering.
“I just don't see a path for approval as there is no evidence yet that this product works, and I think it would set a remarkably dangerous precedent – not just for Alzheimer's research, but for wider regulation of prescription drugs as well in our country, ”said Dr. G. Caleb Alexander, an FDA advisory committee member and internist, epidemiologist, and expert on drug safety and efficacy at the Johns Hopkins Bloomberg School of Public Health.
About six million people in the United States and about 30 million worldwide have Alzheimer's, a number that is expected to double by 2050. Currently, five drugs approved in the United States can delay cognitive decline in various stages of Alzheimer's disease by several months. About two million Americans have mild Alzheimer's disease, suitable criteria for aducanumab, a monthly intravenous infusion that requires regular imaging to detect potential brain swelling.
Biogen officials declined to comment on the article, but on phone calls, medical meetings, and F.D.A. Presentations, they said, the evidence shows a cognitive benefit. Several Alzheimer's experts, whose experience includes advising Biogen, recently wrote that aducanumab "reaches the standard of reasonable efficacy with sufficient safety."
The debate centers around two contradicting Phase 3 studies that were never fully completed. One suggested that a high dose could slightly slow cognitive decline; the other showed no benefit. Biogen says that given the need for Alzheimer's drugs, the only positive study, as well as the results of a small safety study and aducanumab's ability to reduce an important protein, should warrant approval.
The F.D.A. usually follows the recommendations of the advisory committee and usually requires two convincing studies for approval, but it has made exceptions, especially for serious illnesses that do not require treatment.
Two other drugs currently in trials seem more promising than aducanumab, experts say, but it could be three or four years before the data shows whether they deserve approval. Many families say it is too long to wait.
"There are many problems with the data," affirmed Maria Carrillo, chief science officer of the Alzheimer's Association, a group of patients who are vigorously advocating approval. But she said her organization needs to "weigh the overwhelming reality of what people are living with today" and help give patients something to try instead of waiting several years for more conclusive positive results.
The F.D.A. itself seems divided. In presentations to the Advisory Committee, a clinical analyst cited "substantial evidence of effectiveness to support approval". But an F.D.A. The statistician wrote that another study was needed because "there is no compelling, substantial evidence of a treatment effect or slowing down the disease".
And some experts, like Dr. Ronald Petersen, director of the Mayo Clinic's Alzheimer's Research Center in Rochester, Minnesota, say they are "on the fence". He said he would like to offer patients a new option soon, but "the data are in doubt".
Aducanumab, a monoclonal antibody, targets a protein, amyloid, that clumps into plaques in the brains of Alzheimer's patients. Many amyloid-lowering drugs have failed to slow symptoms in studies, a history that some experts say makes it particularly important that the aducanumab data be convincing. If effective, it would support a long-held, unproven theory that an attack on amyloid can help if done early enough.
Excitement over aducanumab grew after a small early study evaluating safety showed amyloid reduction, suggesting that it could slow cognitive decline. The F.D.A. allowed Biogen to skip the phase 2 studies and conduct two phase 3 studies with approximately 1,640 patients each.
Both studies were stopped prematurely in March 2019 when an independent data monitoring committee said aducanumab did not appear to be working. As a result, 37 percent of participants never completed the 78-week study.
However, in October, Biogen announced it was of benefit in a study after evaluating data from 318 participants who were assessed by the monitoring committee before the studies stopped but after the cutoff point for results.
In that study, Biogen said the highest dose slowed cognitive decline by 22 percent, or about four months over 18 months. A lower dose in this study and high and low doses in the other showed no statistically significant advantage over a placebo.
"One study was positive and one study conducted identically was negative," said Dr. David Knopman, clinical neurologist at Mayo Clinic and lead investigator for a study. “I don't think there's a Ph.D. in statistics to see that this is inconclusive. "
Dr. Alexander added that Biogen's post-analytical interpretation of the data was "like the sniper fallacy in Texas – the idea that the sniper shoots up a barn and then hits the bull's eye on the group of holes he likes." . "
In contrast, Dr. Stephen Selloway, who received research and consulting fees from Biogen but was not paid to be a lead investigator for the aducanumab study, a "passionate" advocate of approval. He thinks the evidence is sufficient because Alzheimer's is so disabling.
"I understand people's concerns – the dataset has problems, of course," said Dr. Selloway, Director of Neurology and the Memory and Aging Program at Butler Hospital in Providence, R.I. "F.D.A. is obviously in a difficult position. "
But he prefers to give the patient the opportunity. Of his 17 participants in both the safety study and Phase 3, he said 10 had remained relatively cognitively stable for several years, while seven had declined at typical rates.
"It didn't work for everyone," he said, but "there just seemed to be more people who were stable longer than I'm used to."
One challenge in assessing the effects is that many early-stage patients are slowly declining anyway, said Dr. Cutter.
Proponents and many patients say it makes sense to delay the deterioration even slightly. However, some experts say that slowing each study by 0.39 on an 18-point scale to memory, problem-solving skills, and function may not be noticeable to the patient's experience and not justify approval of a drug that does failed in another study and poses a risk of damage.
"This product would not be very effective at all, even in the best of circumstances, with significant safety risks," said Dr. Alexander.
The potential damage includes brain swelling or bleeding, which occurs in approximately 40 percent of the Phase 3 study participants who receive the high dose. Most were either asymptomatic or had headache, dizziness, or nausea. But such effects caused 6 percent of high-dose recipients to stop. No Phase 3 participant died from the effects, but one participant in the safety study did.
The views of some study participants reflect the complexity of the situation.
Dewayne Nash, 71, of Santa Barbara, Calif., Learned after the study that he was given a placebo for 18 months during which his cognitive levels improved – in part, he believes, because he lowered his cholesterol. Dr. Nash, a retired family doctor, then took aducanumab for seven months and went up to the high dose in hopes that the decline would slow down, but "I didn't notice any difference."
Dr. Nash, whose mother and brother died of Alzheimer's disease, will soon resume aducanumab for previous participants through Biogen's study. He said he would have liked to approve it for his situation because he expects them to decline before other therapies become available and is willing to risk "brain hemorrhage and such."
But scientifically, "I don't like it when they rush drugs," he said.
"You really should be doing the studies that need to be done," before they are approved, he added. Otherwise, "you are giving people a drug that can help, but maybe not".
Dr. Selloway said one study patient whose dementia remained mild for significantly longer than expected was Henry Magendantz, a retired obstetrician and gynecologist in Providence, RI Dr. Magendantz, 84, began the safety study after his wife, Kathy Jellison, noticed he was having trouble following the furniture-assembling steps.
He was given placebo for one year, then lower-dose aducanumab for one year, then the high dose for two years before the 2019 stop. During that time, Ms. Jellison said he “slipped a bit,” but she believes that aducanumab is causing the decrease slowed down enough to allow him to participate in tasks like selecting an assisted living facility, which he moved to in October 2018.
"That bought us some time," she said.
Another problem with rating treatments is that some rating scales, including the aducanumab studies, include reports from relatives or caregivers who may miss subtle symptom progression.
"It's mushy stuff," said Susan Woskie, a retired professor of public health at the University of Massachusetts Lowell, whose wife Debby Rosenkrantz, 68, attended the trial. "This stuff is really difficult, I think, to compile into metrics that have any validity."
Ms. Rosenkrantz, a former social worker in Cambridge, Massachusetts, said that I was on low-dose aducanumab for about eight months during the study: "I was really optimistic that there was a drug and to me it was like, yes". , it works."
However, since the resumption of infusions in Biogen's study for previous participants last September, "I haven't noticed any change," she said.
She suffers from short-term memory loss and cannot follow prescriptions. "It just feels like there's a void in places where there shouldn't be a void in my brain," she said.
Dr. Woskie said the couple crave treatment, but when the F.D.A. Biogen said, "‘ No, we're not speeding up your approval; come back when you have more data, "that wouldn't surprise me, and it might make sense."
Some doctors who think the evidence on aducanumab is weak, including Dr. Knopman, say that if approved, they would share their reservations with patients but feel ethically committed to offering them.
Still, Dr. Jason Karlawish, co-director of the University of Pennsylvania's Penn Memory Center and investigator for Biogen-sponsored studies: “Doctors like me who would prescribe say, 'I want an effective drug.' To prescribe my patients – but it is not the drug. "