Aduhelm from Biogen
The FDA approval of Biogen’s Alzheimer’s drug Aduhelm marked a milestone in Dr. Paul Aisen. The director of the Alzheimer’s Therapeutic Research Institute at USC has focused on the treatment of neurodegenerative disease for the past three decades and in recent years has helped guide this particular drug through the various phases of clinical trials.
But as he sat in his sun-drenched San Diego office in early June, he felt slightly puzzled by the way the Food and Drug Administration approved their use in early June on an “accelerated” basis, normally reserved for cancer drugs. This meant that the clinical benefit was considered likely, but approval for long-term use would be the subject of a larger study in a fourth phase of studies.
Aisen, who works as a paid advisor to Biogen, emphasizes the “unusual nature” of the regulator’s green light, as an advisory board of experts voted and publicly opposed the approval, and insists that there were still “many questions the “I have – they still have no answers.”
Three members of the FDA’s panel that oversees the research have resigned since it was approved this week, including Dr. Aaron Kesselheim, a medicine professor at Harvard Medical School, who said in a letter the agency’s decision on Biogen was “probably the worst drug approval decision in history.” recent US history. “
Last November, that panel said in an 8-1 vote that Biogen’s late-stage phase did not provide “strong evidence” showing that aducanumab is effective in treating Alzheimer’s; two other panellists said the data was “uncertain”.
While Aisen sees Aduhelm as an “effective treatment” for a disease that affects millions of Americans, he also has concerns about the impact of the FDA’s decision on the range of other potential treatment options that are in the late stages of development.
An immediate challenge facing other teams working on a broader Alzheimer’s drug pipeline, he said in a recent video call, would be to keep participants in ongoing studies, let alone attract new ones.
“In most cases,” he said, many people with Alzheimer’s disease would drop out of other drug trials to begin treatment with the newly approved Aduhelm. Leaving them would make the study data for these alternative drugs less useful, even if the drugs in question might one day prove to be safer, more effective, or more suitable for different stages of the disease. But perhaps pervertedly, he still regards Aduhelm’s approval as “a boost to these efforts – a powerful boost”.
Over 6 million Americans suffer from Alzheimer’s
In the past few years, some large pharmaceutical companies have abandoned brain disease research efforts, including Pfizer and Boehringer Ingelheim in 2018 – in fact, Biogen Aduhelm had given up 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 Biogen drug, including its potential cost, is hitting a massive, unmet need for dementia treatment and a disease that costs the US up to $ 259 billion annually. The Alzheimer’s Association estimates that more than 6 million Americans have Alzheimer’s or some other form of dementia, and by 2050 that number could reach over 12 million people, which costs a trillion dollars a year.
Because of this, some dementia drug experts are focusing on the new attention and funding, rather than the potential downsides of Biogen approval, said Dr. Jeffrey Cummings, a neurologist at the University of Nevada, Las Vegas, who does an annual review of. publishes Alzheimer’s drug development pipeline. His research consistently showed that drug failure rates prior to Biogen’s approval were 99.6 percent, a stark contrast to 1 in 5 successful cancer drugs (20%).
Cummings says that any short-term adverse side effect for other drug trials “will be overcome, if at all, by increased interest from companies, venture capital, and biotechnology once they see that there is a way to get approval for a particular drug”. Illness.”
In recent history, the National Institutes of Health spent two to three times more research on heart disease and cancer than on dementia, while the lack of qualified participants for clinical trials also slowed progress.
Next in the dementia drug pipeline
For the handful of other Alzheimer’s drugs in development hoping to overcome the same regulatory hurdles and prove their effectiveness – including Eli Lillys Donanemab, Roches Gantenerumab, and Eiseis Lecanemab – there could be a silver lining, the first mover advantage to cede to Aduhelm.
After decades of expensive but largely unsuccessful research attempts, pharmaceutical giant Eli Lilly’s CEO David Ricks said that after a series of positive phase two results for its Donanemab offering, his company is “getting closer and closer to the goal”.
Speaking at CNBC’s Healthy Returns Summit in May, a month before the FDA approved Aduhelm’s rival Biogen, he said his team felt “good about the probability of success” and said he wanted an “accelerated” route too explore what he called “adaptative avenues for the FDA to consider earlier study of data” that “should be used in a serious and widespread disease like Alzheimer’s”.
However, he conceded that recruiting for the next phase of the studies would require a significantly larger cohort of participants, and since it would take 18 months, he did not expect a new approved product until late 2023 at the earliest.
Several experts told CNBC that the Biogen drug’s unique threshold for regulatory approval, with the treatment potential appearing to trump uncertain real-world benefits, efforts of competitors like Lilly, who are focused on drug development on relatively based on similar techniques.
Aduhelm’s own clinical study data had shown that the drug successfully attacked and cleared clusters of a certain type of protein that many researchers believe may be responsible for Alzheimer’s disease. But it didn’t offer enough evidence to prove that the drug provided cognitive benefits to patients.
Debate on targeting amyloid beta formations
Known by scientists as aducanumab, it works by offering a set of identical antibodies that are cloned from white blood cells. These antibodies are chosen for their targeting abilities, as they can identify specific proteins called beta-amyloids that have built up certain formations in the body.
There is ample evidence that these beta-amyloid formations, also known as “pathological aggregates” or “plaques,” are a major cause of Alzheimer’s disease, although the exact causal mechanisms are not yet fully understood, according to Christian Pike von USC’s Leonard Davis School of Gerontology. Nonetheless, he says the antibodies can help prevent these plaques from forming before other particles are caused to break them apart, a process that is clearly identifiable in before and after neural imaging.
As an analogy, it may be helpful to think of the amyloid beta proteins as young people walking through a city during the day, where the city is the human body and the day is a human lifespan. In certain cities, when afternoon turns into evening, individual young people gather, and some of these gatherings can become toxic and begin to cause problems. The antibodies supplied by Aduhelm act like police officers arriving at the scene, identifying disruptive gatherings, surrounding them, separating them, and then instructing bystanders to disperse the young people.
“When you say, ‘Well, hey, the FDA is buying in that general concept,'” Pike said on a phone call, “if we can remove beta-amyloid from the brains of people with the disease, even if we can there is limited evidence of cognitive benefits, “he continued,” there could be a variety of different therapies that would qualify under these criteria.
The long string of past failures within the Alzheimer’s pipeline that targeted beta-amyloid will continue to weigh on optimism until conclusive evidence is produced – something this week’s controversy over the first new approved Alzheimer’s drug in decades shows has not yet been done.
“What we’re going to find out by using this drug one way or another is whether or not the amyloid clearing hypothesis is correct,” says USC health economist Darius Lakdawalla, who argues that Biogens will continue to test it Drug will prove useful to this confirmatory experiment.
“If it’s right, then I think it opens the door to a lot of innovation, a lot of drug candidates that will try to remove amyloid in the pursuit of that hypothesis in the future.”