The Food and Drug Administration yanked the fight against Alzheimer’s out of the mire with its approval of the first disease-modifying therapy. Although it’s a modest first step, it paves the way for more momentous breakthroughs.
The drug — aducanumab by Biogen and Eisai — is a monoclonal antibody that clears a toxic protein called beta-amyloid from the brain. The drug can’t reverse Alzheimer’s-related damage once amyloid has seized a beachhead and symptoms of the disease emerge. Its promise lies in battling amyloid before it does irreversible harm.
Opponents of approval wanted to see stronger data showing that the drug could slow the progression of Alzheimer’s. But the FDA decided not to make perfect be the enemy of the good. It approved the drug, which will be sold as Aduhelm, under narrow clinical circumstances: It’s currently for people with early-stage Alzheimer’s who have had a PET scan confirming the presence of beta-amyloid in their brains.
While aducanumab is no panacea, it offers a disease-modifying treatment for people who have not had one so far. The FDA’s approval signals a way forward for other therapies and a willingness to use real-word data to determine aducanumab’s long-term effectiveness against Alzheimer’s.
Clinicians can now look to the possibility of combining aducanumab with other therapies for maximum effect. Even more exciting is the possibility of using the drug to attack amyloid buildup in people with no symptoms of Alzheimer’s identified through novel blood tests and genetic markers currently under development.
The course of Alzheimer’s averages 25 years, including many early years when the disease is gathering steam but causes no symptoms. When it finally emerges, though, it is brutal, stripping away memory, personality, speech, and the ability to do basic activities like feed yourself. Many with Alzheimer’s die of the disease; the rest dwindle away. It traumatizes and impoverishes patients and families.
The numbers are bleak: Alzheimer’s has contributed to the deaths of as many as 1 million Americans over the last decade, affecting more Black and Hispanic Americans than white Americans. Six million Americans are currently living with the disease, which is expected to rise to 13 million by 2050.
Every week symptoms are delayed is a psychic and financial blessing. That’s a leading reason that two large patient advocacy groups, the Alzheimer’s Association and UsAgainstAlzheimer’s, have both endorsed the approval of aducanumab.
We have served as a scientific adviser (D.G.) and as a consultant (D.L.) to Biogen, and we have seen what the drug can do. In clinical trials, participants with early Alzheimer’s symptoms taking aducanumab at first seemed to show no significant benefit compared to those taking placebo. But after analyzing a larger dataset from the studies, which was done in concert with the FDA, the company found a slower decline in patients who received higher doses of aducanumab. In other words, the drug was helping people who had not yet been felled by full-blown Alzheimer’s.
The approval of aducanumab also lays the groundwork for new research into polypharmacy. There is a growing belief that a successful Alzheimer’s treatment will require a combination of treatments that can address multiple targets. Similar multidrug approaches have proven successful in HIV, cancer, heart disease, hepatitis C, and other diseases. In these, the initial combinations were of drugs previously approved as single drug treatments. For example, the drugs now used in combination to create the highly active antiretroviral therapy that revolutionized the treatment of HIV were initially approved as marginally effective monotherapies.
To start down that path, one drug must come first. Some commentators have warned that the approval of aducanumab will slow progress toward better drugs by crowding out subsequent discoveries. We disagree: Aducanumab approval is a green flag for more innovation.
The FDA rejected six high-profile amyloid-based drugs between 2016 and 2019, arguably causing companies to scale back research and development in this area. FDA approval sends a signal to the marketplace that there is a compelling need among patients and the market will sort it out. Any drug that modifies the trajectory of the disease will also encourage patients to seek earlier diagnosis, further expanding the market and the rewards for future innovators. If future drugs — and there are some in the pipeline — work better, they will supplant the drugs that came before.
The evidence gathered from initial real-world use of a novel drug class often proves invaluable. The FDA approved the use of statins to combat cholesterol before there was hard evidence that the drugs could reduce heart disease. It took several years of real-world use to show a reduction in deaths, but in the meantime many lives were saved. Similarly, the FDA has granted access to cancer therapies that showed some period of added survival before clinical evidence was amassed on overall survival rates.
Approval of aducanumab may trigger thorny debate over reimbursement for the drug, but there is a way forward on that as well. Medicare could count the number of people whose condition matches the approved use and give the company a lump sum based on that number. That would prevent runaway costs if demand soared while underlining the narrow basis for issuing prescriptions.
Today’s decision marks a point of departure from a long stretch of failure and frustration to new days of hope. With its approval of aducanumab, the FDA is fueling the chances of even more breakthroughs.
This article was originally published in STAT.