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Biogen Alzheimer's Case Shows Danger of Trials Killing Good Drugs

Biogen (NASDAQ:BIIB) shocked the biotechnology world last week with a surprise announcement that its Alzheimer's drug aducanumab may be efficacious after all. While it is most definitely great news, coverage has been nevertheless one-sided.

Almost all of the emphasis has been how it will change the Alzheimer's community (and Biogen) for the better. However, there is another, more worrying side to this story: what would have happened had Biogen simply killed the trial entirely after the futility analysis that suspended it?


Perhaps an efficacious drug for a disease that the medical community has been tackling for decades with near complete failure, would have been thrown in the dustbin of history along with nearly every other attempt ever made. Any future advance that could have been based off of aducanumab would have been aborted, and the estimated 44 million worldwide who suffer from Alzheimer's would have been back at square one.

This goes beyond the consideration of whether aducanumab will be approved in the end by the FDA. Even if it isn't, the positive data here cannot be denied, and so further progress against Alzheimer's can still be made regardless.

So how close was the drug from being scrapped entirely, and how can such a potential danger be prevented in the future?

It's hard to know exactly, but we do have at least some general idea of how close Biogen came to completely throwing out aducanumab right as it was about to succeed. The two phase III trials testing the drug were initiated in August and September of 2015, but a key protocol amendment to both trials was made in March 2017. That ammendment saw carriers of the APOE4 gene have their dosage increased from 6mg/kg from 10mg/kg.

For background, the APOE gene helps break down amyloid plaques in the brain before they form into big clumps. These clumps are theorized to play a part in causing Alzheimer's. APOE has variants that differ by one or two base pairs, and one of those variants, APOE4, is not as efficient at clearing those plaques as the other variants. Researchers speculate that this may be what leads to carriers of the APOE4 gene variant to be more susceptible to Alzheimer's.

Anyway, what caused the futility analysis to be off base was that the two studies did not enroll patients at the same rate; just by luck of the draw, more APOE4 patients in one trial ended up getting the higher dose for a longer period of time than the other trial. The futility analysis that ultimately stopped the trials in their tracks last March came just as one trial was trending positive, while the other was not. Researchers weren't sure why at the time, but they later figured out that the relative rates of enrollment were responsible.

Had APOE4 carriers not had their dosages increased back in 2017, it is unlikely that aducanumab would have been brought back to life at all, and it probably would have been forgotten.

So how can something like this be prevented? In a recent report about the emergency suspension of the trials back in March, Bloomberg wrote about what happened to Dr. Catherine Mummery, a principal investigator in the trial:


"Word came down so abruptly that three patients were in the middle of getting infusions at the time," said Catherine Mummery, a consulting neurologist there and a principal investigator for one of the trials. Mummery had to rush down to the clinic to tell the patients their treatments needed to be stopped immediately.



Futility analyses are designed to prevent the needless trial of unproven medications on humans, which seems reasonable. However, these analyses are based on statistical modeling and are thus prone to errors of human assumption, especially in diseases that are as poorly understood as Alzheimer's. This is all the more true when protocol amendments are made mid-trial, such as was the case here. All things considered, rushing down to a clinic to tell patients in the middle of getting infusions that their treatments must be stopped seems a bit extreme.

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This article first appeared on GuruFocus.