Will Biogen’s Alzheimer’s Drug – Aduhelm Help with Dementia Treatment?

FDA endorsement of Biogen’s Alzheimer’s drug Aduhelm has triggered a major debate in dementia treatment.
More than 6 million Americans are affected by Alzheimer’s or other dementias, the sixth-leading cause of death in the U.S.. By some professional estimates, the number of sufferers could, unfortunately, double in the decades ahead.

Several high-profile FDA panel advisors quit after the controversial Biogen drug approval, which could generate billions of dollars in sales. Still, other advisors and dementia experts say it may be a more hopeful brain disease pipeline.

The FDA’s approval of Biogen’s Alzheimer’s drug Aduhelm was a milestone moment in the life of Dr. Paul Aisen. The Alzheimer’s Therapeutic Research Institute director at USC has invested the past three decades centered on treating neurodegenerative disease. In recent years helped guide this particular drug through the various phases of clinical trials.

During approvals, Dr. Aisen has felt slightly perplexed through how the Food and Drug Administration early its use on an “accelerated” basis in early June, usually requested for cancer medications. This meant its clinical benefits were regarded as likely, but approval for long-term use would be subject to more intensive study in the fourth phase of trials.

Showcasing the “unusual nature” of the regulator’s green light, given that an advisory board of experts had firmly, and openly, opposed the approval, Aisen, who operates as a paid consultant to Biogen, insists there were still “many questions that I have — that do not yet have answers.”

Three FDA panelist overseeing the research have resigned due to the approval this week, including Dr. Aaron Kesselheim, a professor of medicine at Harvard health School, who said in a letter, the agency’s choice on Biogen “was probably the medication approval decision that is worst in present U.S. history.”

Last November, in an 8-1 vote, that panel said Biogen’s late-stage study didn’t provide “strong evidence” exhibiting that aducanumab efficiently treated Alzheimer’s; two other panelists said the data was “uncertain.”

While Aisen views Aduhelm as an “effective treatment” for a disease that affects millions of Americans, he also worries about the FDA ruling’s ramifications for the panoply of other potential treatment possibilities in late-stage development.

One immediate challenge other teams working on a wider Alzheimer’s drug pipeline are encountering, he said in a recent video call, would be to retain participants in ongoing trials, let alone attract new ones.

“In the majority cases,” he discussed, many Alzheimer’s patients 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 may one day prove safer, more reliable, or more effective 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 leading drug companies deserted efforts to study brain diseases, including Pfizer and Boehringer Ingelheim in 2018 — in fact, Biogen quit funding R&D on Aduhelm at one point during the clinical trials in 2019 before reversing its decision— after many years of failure in search of a breakthrough.

The controversy concerning the Biogen drug, including its potential cost, comes against an environment of massive, unmet need for dementia therapeutic medications and a disease that costs the U.S. as much as $259 billion annually. More than 6 million Americans have Alzheimer’s or other forms of dementia, based on estimates from the Alzheimer’s Association, and by 2050 that number could get to over 12 million people at the cost of $1 trillion annually.

That is why some dementia drug industry experts are paying attention to the renewed attention and renewed funding rather than the potential drawbacks from the Biogen approval, according to Dr. Jeffrey Cummings, a neurologist at the University of Nevada, Las Vegas. He writes 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 five cancer drugs (20%) that are successful.

Cummings says any downside effects 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 means to get an approval as well as acceptance for a particular disease.”

In the past, 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 stunted progress.

Next in the dementia drug pipeline
For the select few other developmental Alzheimer’s drugs trying to clear the same types of regulatory hurdles and prove their effectiveness — Eli Lilly’s donanemab, Roche’s gantenerumab, and Eisai’s lecanemab them — there may be a silver lining to relinquishing the first-mover advantage to Aduhelm.

After decades of expensive but thus far mostly ineffective research trials, the CEO of pharma giant Eli Lilly, David Ricks, said his firm was “getting closer and closer to the goal” after a favorable set of Phase Two results for its offering, donanemab.

According to CNBC’s Healthy Returns Summit in May, which took place before the FDA’s approval for rival Biogen’s Aduhelm, David Rick said his team felt “good about the probability of success,” and said he wanted to explore an “accelerated” approach 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.”

Nevertheless, he recognized that enlisting patients for the next phase of trials required a significantly larger cohort of individuals, bearing in mind that it would last 18 months; he did not anticipate a new authorized product before late 2023 at the earliest.

Transforming healthcare – Healthy Returns Summit with Eli Lilly CEO David Ricks
Several experts told CNBC the Biogen drug’s distinctive tolerance for regulatory approval, with treatment potential appearing to trump unknown real-world benefits, could reinvigorate efforts by challengers like Lilly. The latter are focused on creating drugs that rely on fairly similar techniques.

Aduhelm’s clinical trial statistics had shown the drug adequately targets. It cleared out clusters of a specific type of protein that are thought by many researchers to be responsible for Alzheimer’s. But it supplied insufficient evidence to prove the drug offers patients with cognitive benefits.

Disagreement over-targeting beta-amyloid formations
Identified among scientists as aducanumab, it operates by promoting an array of identical antibodies replicated from white blood cells. These antibodies are selected for their targeting abilities since they can recognize specific proteins, called beta amyloids, that have developed particular formations in the body.

There is considerable evidence indicating that these beta-amyloid formations, also known as “pathological aggregates” or “plaques,” are a significant driver of Alzheimer’s disease, though the precise causal mechanisms are still not fully comprehended, according to Christian Pike of USC’s Leonard Davis School of Gerontology. Nonetheless, he says the antibodies can assist in the prevention of these plaques forming before directing other particles to {break|split} them apart, a process that’s demonstrably acknowledgeable 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 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 assemble, 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 dispersed.

“If you say ‘Well hey, the FDA is buying into this general concept,'” said Pike in a phone call, “if we can eliminate 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 proposes the continued trialing of Biogen’s drug will establish useful to that confirmatory work.

“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.”