The amyloid theory just won’t die. In fact, by approving Biogen's new Alzheimer's disease drug, the FDA has just resurrected it for a long and healthy future.
This is great news for Biogen, but it will decimate Alzheimer’s research, faith in the agency and the healthcare budget for decades to come.
In an approval based on amyloid clearance, the FDA gave Biogen the benefit of the doubt in allowing it to market aducanumab, now Aduhelm, in Alzheimer’s, saying it doesn’t need actual proof that it can help patients for many, many years.
Instead, the FDA said a surrogate endpoint, which substitutes a biomarker that might indicate efficacy for an actual clinical endpoint that demonstrates it directly, was good enough for a drug that could make Biogen $17 billion a year.
For the company, this endpoint was clearing amyloid, the sticky plaques that can accumulate in the brain that pharma has spent years studying as the cause of Alzheimer's.
What all these tests have shown—and this includes most of Biogen’s trials—is that clearing amyloid in Alzheimer's patients does not necessarily improve cognitive function nor lead to meaningful endpoints for patients or their families. Many drugs have cleared amyloid but failed to produce any statistically significant clinical benefit and were then tossed into the trash.
This is, in fact, exactly what happened to aducanumab a few years back; after much hype, the drug failed to help Alzheimer's patients, and Biogen gave up, only to come back in 2019 after some data mining to find glimmers in a subpopulation.
Cognitive decline slowed in a statistically significant way in the subset of patients who received the highest dose of aducanumab, according to the pharma's re-analysis. But aducanumab did not show the same benefit when used at a lower dose in this trial—and it didn’t show a benefit at any dose in the other trial.
This was, Biogen reckoned, good enough, and it ran with this analysis to the FDA, which is under pressure to approve drugs in general—and especially in Alzheimer's after a 20-year drought.
The agency's own documents assessing the drug, released late last year ahead of an expert advisory panel meeting, read like a press release from Biogen itself. But when the advisory committee met, it eviscerated the FDA documents and Biogen’s data.
The whole picture of the data are murky at best: Scott Emerson, M.D., Ph.D., a biostatistician at the University of Washington and an advisory committee panelist, said Biogen’s approach was akin to “firing a shotgun at a barn and then painting a target around the bullet holes.”
The FDA, however, went against its advisory committee, which is highly unusual, to approve the med this week. And not just for a subpopulation, either, but pretty much for all Alzheimer's patients, and without the need for specific biomarkers.
There are more than 6 million Alzheimer's patients in the U.S. At a list price of $56,000 for an average patient per year, before discounts, prescribing the infusion even to a quarter of these would cost more than $100 billion.
Biogen’s drug can cause serious side effects, which will need to be monitored. Around 40% of treated patients in Biogen’s late-stage trials developed brain swelling. Most didn’t suffer symptoms, but they need regular brain scans to avoid complications.
Biogen will also have to do a new trial to prove its drug actually works, but that will take years, perhaps as many as nine. (Though the FDA has said it expects it more rapidly than that.)
We have already seen this situation with Sarepta Therapeutics and its equally controversial approval in 2016 for a new Duchenne muscular dystrophy drug. It used a surrogate endpoint—in this case, dystrophin increase—to win Exondys 51 approval. A clinical benefit, however, was not found, as the FDA admitted.
Under the FDA's accelerated approval system, Sarepta got away with the surrogate endpoint, but the FDA required a follow-up trial. Five years down the line, and we’re still waiting for it. We could see history repeat itself for Biogen.
Both of my maternal grandparents died of Alzheimer's in their mid-80s after years of a slow decline. It is one of the most devastating diseases to watch, as it robs them of who they were, changes their personality and behavior and makes them forget who you are, erasing years of memories you thought were set in stone until it eventually kills them.
The care for Alzheimer's patients is frankly pathetic: There is one main drug, Aricept, which doesn’t really work for most patients, with medical intervention focused on social care, or with home visits, and diagnosis done via a paper test.
The mainstays of my experience with the disease were trying to remind them who they are, keeping things consistent and not getting upset when they ask who you are. It felt like using a broom to sweep back the coming tide.
If they were alive today, Aduhelm would not have helped them nor saved their lives. It would have added an extra financial burden on an already over-stretched system and possibly given them side effects that would have made things worse.
The FDA is, with this approval, peddling false hope, helping only Biogen’s C-suite and its investors, while opening the door for more amyloid drugs to be brushed off and put out anew, where the FDA via precedent would almost have to approve them if they clear amyloid well enough.
It's like arresting an innocent person on flimsy evidence they may have been involved in several murders, and then managing to get them convicted and thrown in jail; the local community are relieved that a serial killer is caught, and the police can notch up a success. The real murderer, however, remains at large, but no-one is looking for them anymore.
We don’t understand the mechanics of Alzheimer's or how to stop it: Amyloid theory is one of the most tested areas in neuroscience, and it has come up snake eyes again and again and again. Yet, this decision opens the floodgates for more bad science.
Everyone is desperate for a working Alzheimer's drug, but this is not it. Now, instead of forcing companies to look elsewhere in their research and, hopefully, find better targets and curative approaches, we are stuck in the amyloid slow lane.