The FDA's approval of Biogen's Alzheimer's drug Aduhelm was a landmark moment in the life of Dr. Paul Aisen. The director of the Alzheimer's Therapeutic Research Institute at USC has spent the past three decades focused on treating the neurodegenerative disease, and in recent years helped shepherd this particular drug through the various phases of clinical trials.
But sitting in his sun-drenched office in San Diego in early June, he felt slightly confounded by the manner in which the Food and Drug Administration early June approved its use on an "accelerated" basis, which is usually reserved for cancer medications. This meant its clinical benefits were considered likely, but approval for long-term use would be subject to more extensive study in a fourth phase of trials.
Highlighting the "unusual nature" of the regulator's green light, given that an advisory board of experts had strongly, and publicly, opposed the approval, Aisen, who works as a paid consultant to Biogen, insists there were still "a lot of questions that I have — that do not yet have answers."
Three members of the FDA panel overseeing research have resigned since the approval this week, including Dr. Aaron Kesselheim, a professor of medicine at Harvard Medical School, who said in a letter the agency's decision on Biogen "was probably the worst drug approval decision in recent U.S. history."
Last November, in an 8-1 vote, that panel said Biogen's late-stage study didn't provide "strong evidence" showing that aducanumab effectively treated Alzheimer's; two other panelists said it the data was "uncertain."
While Aisen considers Aduhelm an "effective treatment" for a disease that affects millions of Americans, he also has concerns about the FDA ruling's implications for the panoply of other potential treatment options that are in late-stage development.
One immediate challenge facing other teams working on a wider Alzheimer's drug pipeline, he said in a recent video call, would be to retain participants in ongoing trials, let alone attract new ones.
"In most cases," he explained, many Alzheimer's sufferers will drop out of other drug studies to pursue treatment with the newly approved Aduhelm. Their departures would make trial data for those alternative drugs less useful, even though the drugs in question might one day prove safer, more effective, or more appropriate for different stages of the disease's progression. But perhaps perversely, he still considers Aduhelm's approval "a boost towards those efforts — a strong boost."
Over 6 million Americans suffer from Alzheimer's
In recent years, some major drug companies abandoned efforts to research brain diseases, including Pfizer and Boehringer Ingelheim in 2018 — in fact, Biogen had given up on Aduhelm at one point during the clinical trials in 2019 before reversing its decision— after decades of failure in search of a breakthrough.
The controversy surrounding the Biogen drug, including its potential cost, comes against a landscape of massive, unmet need for dementia treatment and a disease that costs the U.S. as much as $259 billion annually. More than 6 million Americans have Alzheimer's or another form of dementia, according to estimates from the Alzheimer's Association, and by 2050 that number could reach over 12 million people at a cost of $1 trillion annually.
That is why some dementia drug experts are focusing on the renewed attention and fresh financing rather than the potential negatives from the Biogen approval, according to Dr. Jeffrey Cummings, a neurologist at the University of Nevada, Las Vegas, who publishes an annual review of the Alzheimer's drug development pipeline. His research consistently showed the drug-failure rate at 99.6 percent before the Biogen approval, a stark contrast to the 1 out of every 5 cancer drugs (20%) that are successful.
Cummings says any negative side effect for other drug trials in the short term would be "overcome, if anything, by the increased interest that companies and venture capital and biotech has, once they see that there is a way to get an approval for a particular disease."
In recent history, The National Institutes of Health spent two to three times more on heart disease and cancer research than on dementia, while a lack of qualified participants for clinical trials also slowed progress.
Next in the dementia drug pipeline
For the handful of other developmental Alzheimer's drugs hoping to clear those same regulatory hurdles and prove their efficacy — Eli Lilly's donanemab, Roche's gantenerumab and Eisei's lecanemab among them — there may be a silver lining to ceding first-mover advantage to Aduhelm.
After decades of expensive but thus far largely fruitless research trials, the CEO of pharma giant Eli Lilly, David Ricks, said his firm was "getting closer and closer to the goal" after a positive set of Phase Two results for its offering, donanemab.
Speaking at CNBC's Healthy Returns Summit in May, a month before the FDA's approval for rival Biogen's Aduhelm, he said his team felt "good about the probability of success," and said he wanted to explore an "accelerated" route too, using what he called "adaptative pathways at the FDA to consider looking at data sooner" that "should be applied in a serious and widespread condition like Alzheimer's."
However, he acknowledged that recruitment for the next phase of trials required a significantly larger cohort of participants, and given that it would last 18 months, he did not expect a new approved product before late 2023 at the earliest.
Several experts told CNBC the Biogen drug's unique threshold for regulatory approval, with treatment potential seeming to trump uncertain real-world benefits, could reinvigorate efforts by competitors like Lilly, who are focused on developing drugs that rely on relatively similar techniques.
Aduhelm's own clinical trial data had shown the drug successfully targets and clears out clusters of a specific type of protein that are believed by many researchers to be responsible for Alzheimer's. But it offered insufficient evidence to prove the drug provides patients with cognitive benefits.
Debate over targeting beta amyloid formations
Known among scientists as aducanumab, it works by offering an array of identical antibodies that are cloned from white blood cells. These antibodies are chosen for their targeting abilities, since they can identify specific proteins, called beta amyloids, that have constructed particular formations in the body.
There is extensive evidence suggesting that these beta amyloid formations, also known as "pathological aggregates" or "plaques," are a major driver of Alzheimer's disease, though the exact causal mechanisms are still not fully understood, according to Christian Pike of USC's Leonard Davis School of Gerontology. Nonetheless, he says the antibodies can help prevent these plaques from forming, before directing other particles to break them apart, a process that's clearly identifiable in before-and-after neural imaging.
For an analogy, it may be helpful to think of the beta amyloid proteins as young people walking around a city over the course of the day, where the city is the human body, and the day is a human lifespan. In certain cities, as afternoon turns into evening, individual young people start to congregate, and some of those congregations can turn toxic, and begin to cause problems. The antibodies delivered by Aduhelm act like law enforcement officers, arriving on the scene, identifying troublesome gatherings, surrounding them, separating them, then ordering bystanders to make the young people disperse.
"If you say 'Well hey, the FDA is buying into this general concept,'" said Pike in a phone call, "if we can remove beta amyloid from the brains of persons that are affected by the disease, even with limited evidence of cognitive benefits," he continued, "there might be a variety of different therapies that would qualify under these types of criteria."
The long line of past failures from within the Alzheimer's pipeline that targeted beta amyloid will continue to weigh on optimism, until conclusive proof is generated — something this week's controversy over the first new Alzheimer's drug approved in decades indicates has not been done yet.
"What we're going to find out from the use of this drug one way or the other is whether or not the amyloid clearing hypothesis is correct," says USC health economist Darius Lakdawalla, who argues the continued trialing of Biogen's drug will prove useful to that confirmatory effort.
"If it is correct, then I think it opens the door for a lot of innovation, a lot of drug candidates that are going to try to clear amyloid in the future pursuit of that hypothesis."
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