Aducanumab, the first Alzheimer’s-modifying therapy, submitted to the FDA. Can Biogen recover from their errors?
The summer of 2018 gave great news to Alzheimer’s disease researchers and physicians. A large trial was positive in delaying Alzheimer’s progression. The trial investigated a drug called BAN, which moved into a larger confirmatory trial. ANA was very proud to have contributed 12 subjects, and now three of them are receiving the drug as part of an extension trial. In March of 2019, however, Biogen’s aducanumab trial halted after an interim analysis judged the trial to be likely futile. This was a total surprise to most doctors in the field, like me. Biogen then looked at the full data set, and in the fall of 2019, declared the trial wasn’t futile at all!
They believe their error was hidden in two amendments of the protocol. One allowed the subjects who got brain swelling to get re-dosed. (The brain swelling is also called ARIA, and it happened to 35%, with 25% of those having symptoms, making the risk of symptomatic ARIA 9%). They also allowed people carrying a genetic risk for the disease, APOE4, to get the highest dose in the second amendment. These were both unfortunate decisions.
When a doctor uses the phrase “unfortunate decision,” it means that in retrospect it was idiotic. For one thing, the brain swelling, ARIA, is thought to be a one-time event. It VERY rarely affects another brain region. The amendment corrected the idiocy, but the decision stained the study and it was difficult to wash out. Failing to re-dose 1/3 of subjects with ARIA prevented them from getting the full treatment. By the time the futility analysis occurred, too few had been fully treated. The other decision, to limit the APOE4 carriers from the highest dose, now seems equally unfortunate and led to the same problem: too few had been fully treated.
The trial was halted without fully taking the amendments into account. At the time, one of the trials was trending positive! After the trial was judged to be futile, Biogen performed a last visit and the data set reduced from a planned 3285 patients (chosen carefully to power the trial enough to see a difference between treatment group and controls) to 2066.
Futility analyses try to predict an entire data set based on a limited data set. The decision not to continue may be akin to invading Russia in winter: it ranks among one of the worst decisions ever made. When subjects came in for their last visit, one trial showed a positive effect. The other trial was totally negative, which is concerning, but clearly stopped too early.
Now Biogen has submitted the drug to the FDA for approval. It is hard to guess at what the FDA will do. The ARIA is a concern. Most people I spoke to agree that it is unlikely to be approved, but no one can say for sure. The FDA’s language offers some help: “at least two adequate and well-controlled studies, each convincing on its own,” is their standard for effectiveness, meaning two trials showing positive effects. But the FDA allows itself “flexibility,” like one good phase 3 trial, “supported by data that provide strong mechanistic support.”
Biogen had shockingly limited biomarker data to provide such “mechanistic support” (about 3% of patients in the trial got spinal taps and very few got scans to look at another protein called tau), but they did show clearance of the protein that causes Alzheimer’s disease. If the FDA shows “flexibility,” then aducanumab will be approved. If approval, then Biogen will make many hundreds of billions of dollars until there’s another positive trial in this space.
The big news is that regardless of all this, we’re clearly seeing some positive effects from clinical research. Removing amyloid helps.
Regardless of the FDA decision later this year, we’ve just had the first + phase 3 trial in AD. This serves to establish a firm beachhead from which more trials will advance. For now, it the FDA asks Biogen to complete another trial and Biogen asks us to be a site, ANA stands ready to help. If the FDA approves the drug, then we will prescribe this to appropriate and interested patients, with full attention to risks and benefits.