New Alzheimer's disease treatment fails, then works, then fails again

 Alzheimer’s disease is one of the most devastating conditions of old age. By recent estimates, more than 5 million people in the U.S. have Alzheimer’s, and managing the disease will cost over $300 billion in 2020. As the population ages, this problem is growing worse, and yet we still have no effective treatment.

You might have seen rosy-looking ads for Alzheimer’s treatments, but nothing really works, not yet at least. That’s why many people were excited about the possibilities of a new drug, aducanumab, that showed early signs of being able to reduce the accumulations of “plaques” in the brain.

Background: in people with Alzheimer’s, a protein called beta-amyloid accumulates in the brain, forming plaques that seem to disrupt brain function. (This hypothesis is not fully proven, but it is widely considered credible.) Thus one way that we might treat Alzheimer’s would be to reduce or eliminate beta-amyloid plaques. That’s what Biogen’s new drug, aducanumab, is intended to do.

Biogen has run two separate trials, called “EMERGE” and “ENGAGE,” to test whether or not aducanumab (ADU for short) worked.

Here’s where things get murky. Back in March of 2019, both trials were halted due to “futility,” because ENGAGE was showing no benefits for the new drug. In EMERGE, the high-dose patients seemed to be getting some benefit, but Biogen had specified ahead of time that if either trial was failing, that would mean the drug wasn’t working. Thus they halted the trials, disappointing as it was.

Fast forward to October of 2019, though, and Biogen had a new story. They went back and looked at a subset of the patients in ENGAGE (the study that had failed), and said that there was a benefit after all, if they looked only at the high-dose patients. This past July, Biogen went to the FDA and applied for approval for ADU.

Just this past week, two very conflicting announcements about ADU appeared. First, on Wednesday, the FDA’s internal scientists released a very rosy report, saying that the data from one of the trials were “robust and exceptionally persuasive.” For the second trial, the scientists said that even though the drug initially seemed to fail, a closer review led them to conclude that overall, ADU did provide a benefit.

Biogen shares rose 45% that day, adding $17 billion to the company’s value.

Then on Friday, a panel of independent, external scientists released their conclusions, which resoundingly rejected the drug. The external panel said that the data from the two trials was unconvincing, and they pointed out “multiple red flags” in the analysis.

(Trading in Biogen stock was halted during the Friday meeting, but at the end of the day it was close to the high it reached on Wednesday.)

So what happened? It appears to be a classic case of cherry-picking: when the data from the ENGAGE study didn’t pan out, the company re-analyzed a subset of the data and found a more-positive picture.

That’s not really kosher, as explained by a separate group of scientists in a paper published just a few days ago in the journal Alzheimer’s & Dementia. In this paper, David Knopman and colleagues, from the Mayo Clinic and Stanford Medical School, analyzed data that Biogen has released from its two trials. (The trials haven’t been published, but some of the findings were released in a publicly-available slide presentation that the authors relied upon.)

Knopman and colleagues explained that after two conflicting trials, there simply isn’t enough evidence that ADU works, and they also offer alternative explanations for the positive findings. They argue that the best Biogen can do is to “perform another trial of high‐dose ADU of at least 78‐weeks duration,” which could determine whether or not the positive results were real or just coincidence.

It’s somewhat mysterious that the FDA’s internal panel released their rosy report about ADU on Wednesday, only to be slapped down just two days later by an independent outside panel of scientists. After reading the negative views of the external panel and the analysis in the paper by Knopman and colleagues, I’m very skeptical that ADU has any clinically significant effect. If it had a truly robust effect, it simply wouldn’t be so hard to tease it out.

So we still don’t have a good treatment for Alzheimer’s, but the world still needs one.