Aduhelm from Biogen
The FDA approval of Biogen’s drug Aduhelm for Alzheimer’s disease marked a turning point in the life of Dr. Paul Aisen. The director of the Alzheimer’s Therapeutic Research Institute at USC has spent the past three decades focusing on treating neurodegenerative disease and in recent years has helped 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 baffled by how the Food and Drug Administration in early June approved its use on an “fast-track” basis, which is typically reserved for anti-drug drugs. the cancer. This meant that its clinical benefits were considered probable, but approval for long-term use would be subject to further study in a fourth phase of trials.
Emphasizing the “unusualness” of the regulator’s green light, given that an expert advisory board had strongly and publicly opposed the approval, Aisen, who works as a paid consultant for Biogen, insists that there were still “a lot of questions that I got – that haven’t yet answered.”
Three members of the FDA panel overseeing the research have resigned since approval this week, including Dr. Aaron Kesselheim, professor of medicine at Harvard Medical School, who said in a letter that the agency’s decision on Biogen ” was possibly the worst drug approval decision in recent US history. “
Last November, in an 8-1 vote, that panel said Biogen’s late stage study failed to provide “strong evidence” that aducanumab was effective in treating Alzheimer’s disease; two other panelists said the data was “uncertain”.
While Aisen sees Aduhelm as an “effective treatment” for a disease that affects millions of Americans, he is also concerned about the implications of the FDA decision for the panoply of other potential treatment options under development. .
An immediate challenge facing other teams working on a larger Alzheimer’s drug pipeline, he said on a recent video call, would be to retain participants in ongoing trials, let alone attract new ones.
“In most cases,” he explained, many people with Alzheimer’s disease will drop out of further drug studies to continue treatment with the newly approved Aduhelm. Their departures would make trial data for these alternative drugs less useful, although the drugs in question may one day prove to be safer, more effective, or more suited to different stages of disease progression. But perhaps perversely, he still considers Aduhelm’s endorsement “a boost to these efforts – a big boost”.
More than 6 million Americans suffer from Alzheimer’s
In recent years, some large pharmaceutical companies abandoned research efforts on diseases of the brain, including Pfizer and Boehringer Ingelheim in 2018 – in fact, Biogen ditched Aduhelm at one point during clinical trials in 2019 before reversing its decision – after decades of failure in search of a breakthrough.
The controversy surrounding the drug Biogen, including its potential cost, faces a landscape of massive and unmet dementia treatment needs and a disease that costs the United States up to $ 259 billion a year. More than 6 million Americans have Alzheimer’s disease or another form of dementia, according to Alzheimer’s Association estimates, and by 2050, that number could grow to over 12 million people at a cost of $ 1,000 billion per year.
That’s why some dementia drug experts are focusing on renewed attention and fresh funding rather than the potential downsides of Biogen approval, according to Dr. Jeffrey Cummings, a neurologist at the University of Nevada, Las Vegas, which publishes an annual review of the Alzheimer’s disease drug development pipeline. His research has consistently shown that the drug failure rate was 99.6% before Biogen’s approval, a stark contrast to 1 in 5 (20%) cancer drugs that are successful.
Cummings says any negative side effects for further short-term drug trials would be “overcome, if at all, by increased interest in business, venture capital and biotechnology, once they see that ‘there is a way to get approval for a disease. “
In recent history, the National Institutes of Health spent two to three times as much on heart disease and cancer research than on dementia, while the lack of qualified participants for clinical trials has also slowed progress.
Next in the dementia drug pipeline
For the handful of other drugs for the development of Alzheimer’s disease in the hope of overcoming those same regulatory hurdles and proving their effectiveness – Eli Lilly’s donanemab, Roche’s gantenerumab and Eisei’s lecanemab among them – there may be a silver lining to ceding the first-mover advantage to Aduhelm.
After decades of costly but so far largely unsuccessful research trials, pharmaceutical giant Eli Lilly CEO David Ricks said his company was “getting closer and closer to the target” after a positive set of phase two results for its offering, donanemab.
Speaking at CNBC’s Healthy Returns Summit in May, a month before FDA approval for rival Biogen’s Aduhelm, he said his team felt “good about the likelihood of success” and said he also wanted to explore a “fast-track” path, using what he called “FDA adaptation pathways to consider reviewing data earlier” that “should be applied in severe and widespread disease. like Alzheimer’s disease ”.
However, he acknowledged that recruiting for the next phase of trials required a much larger cohort of participants, and given that it would last 18 months, he did not expect a new product approved until the end of 2023. as soon as possible.
Several experts told CNBC that the single threshold for regulatory approval for the drug Biogen, with treatment potential appearing to outweigh uncertain real-world benefits, could re-energize the efforts of competitors like Lilly, which focus on the drug. drug development based on relatively similar techniques.
Aduhelm’s own clinical trial data has shown that the drug successfully targets and eliminates groups of a specific type of protein that many researchers believe is responsible for Alzheimer’s disease. But he offered insufficient evidence to prove that the drug offers patients cognitive benefits.
Known among scientists as aducanumab, it works by offering a range of identical antibodies that are cloned from white blood cells. These antibodies are chosen for their targeting abilities because they can identify specific proteins, called beta-amyloids, that have built up particular formations in the body.
There is ample evidence to suggest that these beta-amyloid formations, also known as “pathological aggregates” or “plaques,” are a major contributor to Alzheimer’s disease, although the exact causal mechanisms are still not fully understood, according to USC’s Leonard Davis Christian Pike. School of Gerontology. Nonetheless, he says antibodies can help prevent these plaques from forming, before directing other particles to separate them, a process clearly identifiable in neural imaging before and after.
By analogy, it may be helpful to think of beta-amyloid proteins as young people walking around a city during the day, where the city is the human body and the day is a human lifespan. In some cities, as the afternoon turns into the evening, young people start to gather, and some of these congregations can turn poisonous and start causing problems. The antibodies delivered by Aduhelm act as law enforcement agents, arriving at the scene, identifying bothersome gatherings, surrounding them, separating them, then ordering passers-by to disperse the young people.
“If you say, ‘Well the FDA is going with that general concept,'” Pike said on a phone call, “if we can remove beta-amyloid from the brains of people with the disease, even with some evidence. limited cognitive benefits, ”he continued,“ there could be a variety of different therapies that would qualify under these types of criteria. ”
The long line of past failures in the Alzheimer’s pipeline targeting beta-amyloid will continue to weigh on optimism, until conclusive evidence is generated – what this week’s controversy over the first new drug for Alzheimer’s disease approved for decades indicates has yet to be done.
“What we’re going to find out from using this drug one way or another is whether the amyloid elimination hypothesis is correct,” says the health economist at the USC Darius Lakdawalla, who says further testing of Biogen’s drug will prove helpful. to this confirmation effort.
“If that’s correct, then I think it opens the door for a lot of innovation, a lot of drug candidates who will try to eliminate amyloid in the future pursuit of this hypothesis.”