En español | It's been nearly two years since Biogen announced it would seek federal approval for its drug, aducanumab, to treat some people in the early stages of Alzheimer's disease. And by June 7, the U.S. Food and Drug Administration (FDA) will decide whether it plans to bring the medication to market.
The process hasn’t been free from controversy, though. The fate of the drug suffered a serious blow back in November, when an FDA-convened panel of outside experts expressed concern over the data backing aducanumab’s effectiveness. The FDA does not have to follow the recommendations of the advisory panel, but it typically does.
If approved, aducanumab would be the first new Alzheimer's treatment in 17 years and the only one that reduces cognitive decline by tackling an underlying cause of the disease, not just its symptoms. It works by targeting the buildup of toxic amyloid plaques, which disrupt cell function in the brain and are a hallmark of Alzheimer's disease. Several other drugs have attempted to target amyloid, but none have succeeded yet.
"We've been waiting for a disease-modifying therapy; I've been waiting for it for decades,” says Richard Isaacson, M.D., director of the Alzheimer's Prevention Clinic at Weill Cornell Medicine and New York-Presbyterian.
Aducanumab is not a cure for Alzheimer's, experts stress, and if it's approved, it won't be available to everyone who has the disease. But its authorization would signify progress in a long pursuit to bring help to the more than 6 million older Americans suffering from the debilitating condition.
"[It] would be a victory for all of those individuals living with Alzheimer's and their families,” says Joanne Pike, chief strategy officer of the Alzheimer's Association.
The bumpy, winding road toward approval
Aducanumab's development has been fraught with concerns and setbacks. Months before Biogen made the decision to seek FDA approval, the company went so far as to scrap its late-stage testing of the drug. Aducanumab's two identically designed clinical trials were both stopped in March 2019 because an early analysis showed the drug was unlikely to be effective.
However, hopes were resurrected when a subsequent analysis of a larger set of data from the trials, conducted after testing ended, found that in one study, participants who received high doses of aducanumab actually experienced improvements in memory, cognition and activities of daily living. Results from the other trial were less convincing, although Biogen says an analysis of a narrower set of data from that trial also found evidence of improvement among participants. The discrepancies in the data from the two trials are what the FDA advisory panel homed in on and expressed concern over in its Nov. 6, 2020, meeting.
Some experts suggest that since the two clinical trials showed divergent outcomes, a third trial is needed to prove that aducanumab would, in fact, improve the lives of patients suffering from the debilitating disease. The Alzheimer’s Association released a statement after the FDA’s advisory committee meeting pointing out that an additional phase 3 trial would deny access to the drug for up to four years. “A four-year delay is too long for too many — those who have the disease and their caregivers,” Harry Johns, the organization’s CEO said.
Safety is also top of mind. The drug, a monoclonal antibody, has been shown to cause small bleeds and swelling in the brain, which means if it's approved and used by patients, periodic MRI scans may be needed to monitor these side effects, explains Ronald Petersen, M.D., director of the Mayo Clinic's Alzheimer's Disease Research Center, who also consults for Biogen.
"We have huge hope that it could work, and people need hope,” says Sarah Lenz Lock, senior vice president for policy at AARP and executive director of the AARP-founded Global Council on Brain Health (GCBH). “But it's really important for the FDA to play this very scientifically accurate. We're relying on the FDA to make a wise decision.”
Questions on access and availability emerge
Beyond efficacy and safety, there are questions surrounding how easily patients will be able to access the drug if it is approved. Biogen's clinical trial population was made up of people who had mild cognitive impairment and people with mild dementia due to Alzheimer's disease. So if aducanumab gets the green light from the FDA, the drug will presumably be limited to patients who are in the beginning stages of Alzheimer's disease and who have evidence of amyloid in the brain.
But early diagnosis is tricky. For starters, there is no single test to determine whether someone has Alzheimer's disease. And most people aren't diagnosed by doctors until after signs of mental decline set in and brain damage has already occurred, which may be too late. Expensive brain scans and spinal taps can identify amyloid in the brain before severe symptoms start, but “not everybody has access to amyloid scans,” Isaacson points out. “They're FDA-approved, but they're oftentimes hard to get” and insurance may not cover the costs.
Less invasive blood tests that physicians can use to detect amyloid and other signs of Alzheimer's disease have proved promising in studies but are still at least a couple of years away from being widely available in doctors’ offices.
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"I'm not sure that our health care system and practitioners with boots on the ground are truly ready for this drug's approval,” Isaacson adds. “These logistical and operational challenges are real.”
Another thing to consider: Aducanumab is an infusion therapy, not a pill that can be popped at home. This means patients have to receive the medicine intravenously, and, as Isaacson points out, memory clinics may not be equipped to deliver infusion drugs.
Travel to these regular appointments will also need to be arranged, although this will likely be less of a burden for people with early Alzheimer's, compared to individuals in later stages of the disease, says Sharon Cohen, M.D., medical director of the Toronto Memory Program, who also served on the steering committee for aducanumab during its clinical trials.
"In these early stages, people are very aware and very eager to hang on to their abilities,” she explains. Many still work and are still able to carry out everyday activities. “Having been involved in the aducanumab program, the burden to patients and families coming in for monthly infusions has been surprisingly well tolerated,” Cohen adds.
Finally, there's the question of how much the drug will cost and whether insurers will pay for it. “All that needs to be sorted out after the [FDA review process],” says Petersen, who also serves on AARP's GCBH governance committee.
Aducanumab won't ‘stamp out’ Alzheimer's disease
One thing is for sure: If aducanumab receives FDA approval, it won't be the end-all-be-all for Alzheimer's disease treatments. Research into various causes of the disease and therapies to treat it is ongoing. And many experts predict that, similar to cancer, overcoming Alzheimer's will require a combination approach, perhaps involving multiple drugs that tackle different processes and problems in the brain.
Nonpharmacological prescriptions are also likely to play a role. Blood pressure control, exercise, diet and sleep have all been shown to reduce risk of cognitive decline in adults.
"This is not going to stamp out Alzheimer's disease; it's going to treat one component of a complex process,” Petersen says.
And even though the drug is not expected to be available to everyone with Alzheimer's, Pike, from the Alzheimer's Association, says aducanumab's pending approval will benefit the masses by “invigorating the field” and ushering in a new era of possibilities.
“Companies now potentially can see a pathway to approvability,” she says. And as more drugs are approved, researchers can begin to test combination therapies.
"I'm very excited and I'm hopeful,” Isaacson says about the FDA's forthcoming decision. “This drug may be one part of the war” in the fight against Alzheimer's disease. But “we still need more drugs that hopefully will come out along the way."
Editor’s Note: This story, originally published Nov. 5, 2020, has been updated to include new information.