OK, we have kind of a complicated situation today. Biogen (NASDAQ:BIIB) and Eisai (EASLF) (EASLY) have press-released what appear to be positive results for an anti-amyloid antibody therapy for Alzheimer's. Since every single other attempt in this area has failed, often at great expense, what are we to make of this?
Well, the first thing to say is that antibodies are all different. That's why they exist. So you can't draw a direct line from the failure of previous agents to a possible success here. But that's about the most positive thing I have to say, because those earlier failures are not meaningless either, not by a long shot. Previous agents have demonstrated binding to amyloid, brain penetration, and even reduction of brain amyloid in vivo in human subjects - all without having any useful clinical effects. So if this one (BAN2401, developed earlier by Eisai in collaboration with a Swedish company, BioArctic) is showing some, then there is explaining to be done. As I understand it, it's targeted at soluble amyloid protofibers, but I am unaware of any direct comparisons of its binding profile with previous antibodies in the field. Biogen and Eisai must have had reason to believe that this one might be different (positive), but lots of people have thought that in Alzheimer's research and landed hard anyway (negative).
One complication is that the companies have not announced all that much. They say that the highest dose of the antibody demonstrated statistically significant slowing of the disease as determined by ADCOMS scores and that PET imaging also showed positive results. But we have no numbers whatsoever, making it completely impossible to evaluate these claims. There's no way to have an informed opinion on the matter without seeing the data, which will surely be shown at some future conference. Until then, all one can say is that Biogen and Eisai believe that what they have is sufficient to make a public announcement about it and will be backing up their claims at a later date.
And when the data do come out, it's going to be complicated to evaluate. That's because this is a Bayesian trial, as opposed to one run under the more typical "frequentist" statistical framework. Adaptive/Bayesian trial designs have been talked about for years in the business, because they have possible advantages versus the traditional trials, but they've been talked about a lot more than they've actually been run. Oversimplifying, a Bayesian trial has the possibility of changing the patient population being evaluated while the trial is being still being run, thus the "adaptive" part. If you do that in a traditional trial without having stated up front everything you're going to do and exactly when and why (as in a crossover design), you will have blown your chance to say anything statistically meaningful about its outcome, but not so with Bayesian statistics, if set up properly.
Now come the headaches. That's because (as Matthew Herper notes here), the Bayesian trial design, when run for 12 months, said that the drug failed to show meaningful effects. But the companies said earlier that it was always their plan to continue out to at least 18 months and do a more conventional statistical analysis at that point, and that's the basis of this new announcement about the high-dose group. I am absolutely not competent to evaluate how you'd do that sort of statistical-regime crossover, and I very much look forward to people who know their stuff getting a chance to look over the trial design, the data, and the results. Did the Bayesian design allow patients to move into the high-dose group if it showed more effect? In that case, why didn't it show an overall positive result at 12 months? How many patients, then, are in the cohort that showed significance in the later conventional evaluation? Who knows? We don't have any of the key details yet, and there are definitely more details to go over this time than usual. Until then...?
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