Approval of groundbreaking Alzheimer’s drug confuses the research community

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Amyloid-β plaques in the brain are a target of Alzheimer’s treatments.Photo credit: Thomas Deerinck, NCMIR / SPL

Yesterday’s Food and Drug Administration (FDA) approval for the first new drug for Alzheimer’s in 18 years was welcomed by some people looking for hope for an intractable disease. For many researchers, however, it was a surprise – and a disappointment.

Aducanumab – developed by biotechnology company Biogen in Cambridge, Massachusetts – is the first approved drug that attempts to treat a possible cause of the neurodegenerative disease, not just the symptoms. But approval has sparked a heated debate over whether the drug is effective. Many experts, including an independent panel of neurologists and biostatisticians, told the FDA that clinical trial data inconclusive evidence that aducanumab could slow cognitive decline.

The FDA relied on an alternative activity measurement instead, which sets a dangerous precedent, some researchers warn.

Current Alzheimer’s drugs only treat symptoms of the disease, for example by delaying memory loss by a few months. Aducanumab removes clumps of a protein in the brain called amyloid-β that some researchers believe is the leading cause of Alzheimer’s disease. This theory is known as the amyloid hypothesis. The FDA approved the drug for its ability to reduce the levels of these plaques in the brain.

“This is a very slim tube to hang a regulatory decision on,” said Jason Karlawish, geriatrician and co-director of the Penn Memory Center in Philadelphia, Pennsylvania. Despite the dominance of the amyloid hypothesis over the past few decades, the evidence that a decrease in plaque levels is linked to an improvement in cognition is “thin at best,” says Karlawish.

“Desperation should drive the funding of science, not the way we interpret science,” he says.

Desperate need

But some patient populations are desperately looking for anything that could counterbalance the effects of the incurable, progressive disease. It is estimated that 35 million people worldwide have Alzheimer’s.

“History has shown us that approvals for the first drug in a new category are stimulating the field, increasing investment in new treatments, and driving greater innovation,” said Maria Carrillo, chief science officer of the Alzheimer’s Association patient advocacy in Chicago, Illinois. in a statement. “We are hopeful, and this is the beginning – both for this drug and for better treatments for Alzheimer’s.”

Others fear that approval will have the opposite effect, namely hampering research efforts. Karlawish suggests that people with Alzheimer’s disease may start stopping ongoing clinical trials of aducanumab. Others fear that drug developers may abandon other goals. If evidence that the amyloid-lowering activity is sufficient to gain regulatory approval, it could deter developers from focusing on treatments with the great cognitive benefits patients need, some scientists say.

“This will set the research community back by 10 to 20 years,” says George Perry, a neurobiologist at the University of Texas at San Antonio and a skeptic of the amyloid hypothesis.

‘Problem data set’

Aducanumab, an intravenously infused antibody, is the latest in a long line of therapeutic candidates aimed at fighting amyloid plaques. Although not every drug of this type has improved cognition so far, the questions remain whether amyloid-β is the right drug target and whether researchers are testing the optimal therapeutic candidates, the right doses, and the right patients.

“The problem with most amyloid studies is that they didn’t refute anything,” says Bart De Strooper, director of the UK Dementia Research Institute in London. “You just proved that a drug doesn’t work the way it was used.”

Researchers’ concerns are now focused on aducanumab’s turbulent passage through clinical trials and the resulting dataset, which is incomplete and unpublished.

The FDA approval is based on data from two Phase III studies. In March 2019, researchers looked at preliminary data while these studies – which were being conducted in people with early-stage Alzheimer’s – were ongoing. They concluded that these would not be successful, and Biogen stopped both studies prematurely.

But months later the biotech company brought the antibody back from the abyss, after a closer examination of the data. The slowdown in cognitive decline was statistically significant in the subset of participants who received the highest dose of aducanumab, as shown by Biogen’s re-analysis. Aducanumab did not have the same benefit when used at a lower dose in this study, and it did not show any benefit at any dose in the other study.

For Paul Aisen, director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California at San Diego, the entirety of the data speaks in favor of approval. “My personal opinion is that aducanumab is an effective therapy,” says Aisen, a consultant for Biogen. “But that was a problematic dataset. It was a very tense situation, ”he admits.

Those tensions were seen at an FDA meeting last November to discuss the study data. An independent panel of experts advising the FDA evaluated the data and argued strongly against Biogen’s claim that the partially positive study results weighed more heavily than the negative ones. Scott Emerson, a biostatistician at the University of Washington at Seattle who was on the panel, described the approach as “firing a shotgun at a barn and then painting a target around the bullet holes.”

The data also showed that aducanumab had non-negligible side effects. About 40% of the treated participants in the two studies developed brain swelling. Most people wouldn’t have symptoms related to the swelling, but they would need regular brain scans to avoid dangerous complications – a burden for patients, neurologists, and healthcare systems.

At the November meeting, 10 out of 11 panelists ultimately voted that the data presented cannot be taken as evidence of the effectiveness of aducanumab; the remaining panelist was unsure. This week the FDA came to the opposite conclusion.

Examination after admission

As a condition of FDA approval – which was based on the agency’s “accelerated approval program” – Biogen must now conduct a “post-marketing” study to confirm that the drug can improve perceptions. Details on when and how this process will take place are not yet known. Biogen has up to nine years to complete the study.

This worries industry observers. “Experience shows that relying on expedited approval to get timely, high-quality post-approval evidence isn’t always a given,” said Aaron Kesselheim, who studies pharmacoeconomics at Harvard Medical School in Boston, Massachusetts and a member of the FDA panel is the discussed aducanumab.

The FDA’s decision to accelerate aducanumab approval – after a roller coaster ride through a clinical trial program – could also have wider implications. “This opens the door for pharmaceutical companies looking to use the accelerated approval program to bring drugs to market based on extremely low-quality evidence or post-hoc data fishing,” says Kesselheim.

Ripple effects

Biogen is now a great godsend with aducanumab; the share price rose 40% after approval.

Some experts expected the FDA to only approve the antibody for people with early-stage disease, but regulators haven’t restricted its use – anyone with Alzheimer’s can take it. Biogen will charge around $ 56,000 per person per year for the drug. If 5% of 6 million people with Alzheimer’s disease in the United States received treatment, the drug’s revenue would reach nearly $ 17 billion a year. This would make it the second most powerful drug after current revenues.

The Institute for Clinical and Economic Review, a nonprofit based in Boston, Massachusetts, estimates the cost-effective price at $ 2,500 to $ 8,300 per year.

The approval is also likely to shake up the development of future Alzheimer’s drugs, researchers say.

With an established path of approval, drug developers are likely to duplicate their anti-amyloid drugs. The pharmaceutical companies Eli Lilly, Roche and Eisai already have anti-amyloid antibodies in phase III studies. They, too, could now potentially receive approvals with evidence of amyloid-lowering effects regardless of the compounds’ effects on cognition.

Prior to approval, the research community had started focusing on other drug targets related to Alzheimer’s disease. For example, more than ten drug candidates currently in clinical trials are designed to remove another toxic protein called tau from the brain.

David Knopman, a neurologist at the Mayo Clinic in Rochester, Minnesota, hopes this and previous efforts will not stall due to the success of aducanumab due to its amyloid-lowering activity. “We have to look at other goals,” he says.

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