Well, the tease is over: Biogen and Eisai have released data on their Alzheimer’s antibody, BAN2401. And the situation is messy, as many had feared. The top-line results are mostly positive, but there are several confounding factors that make them a matter of argument (see below).
The companies were scheduled to go public with the information at 4:30 EST yesterday afternoon at a meeting in Chicago, and trading in Biogen shares was pretty lively during the day (of course, it had been pretty lively ever since the announcement a few weeks ago). In mid-morning the shares suddenly leapt like a trout, ramping up steeply over the next hour or so, and then falling back just as rapidly. Some folks were moving an awful lot of a rather expensive stock on both sides of that trade, that’s for sure. For the rest of the day, the stock generally moved up in anticipation of the results, closing at a three-year high.
And that’s how we know that the news didn’t leak, actually. Because while the initial impression was favorable (as the cognitive assay percentage changes were released), further inspection as the slides went on raised several questions. One of the cognitive measures, for example, did not reach significance. The 10mg dose of the antibody did look favorable – but lower doses were, if anything, worse than the placebo group, which is a bit odd. The actual scores on these cognitive scales were not available, just the percentage changes, leading some to think that if those scores had been clear winners that someone might have been willing to recall them. Most worryingly, it turns out that there was a clear difference between the placebo group and the treatment group in APOE4 status.
APOE4, a lipoprotein, has been recognized as a risk factor for Alzheimer’s since back in the 1990s, although the mechanism behind that has been the subject of debate. But there was a regulatory-mandated change in enrollment of APOE4 patients during the (Bayesian) trial, for fear of a brain-swelling side effect that these patients are also prone to, and there ended up being far more APOE4-positive patients in the placebo group compared to the high-dose group (70% versus 30%). Which might well make that group show faster deterioration during the period of the study. Which might well blow your statistical proof that your drug substance is an improvement.
This issue, more than any other, seems to be the cloud hanging over these results today. But there are other thing to think about – for example, Lilly’s failed antibody solenuzemab was able to put up similar cognitive score changes in Phase II but ultimately failed (and more than once) in Phase III. And in general, drugs just don’t get better in Phase III – it can happen, but it’s not the way to bet. Moving to a larger, more diverse population (which is one of the things that Phase III is supposed to represent) tends to flatten things out as compared to often-more-carefully-chosen Phase II population. So the optimistic case would be that BAN2401 could continue to be mildly positive later in the clinic, and “mildly positive” would likely be enough for approval, given the state of Alzheimer’s therapy. But how likely is that compared to the other possibility, that the antibody has just managed to show the best possible numbers that it could manage to produce, and that they might be artifactual.
Well, one thing seems clear: the stock-market-bull case for this drug is in ruins. You had people running around thinking “Big win! Fast track! Early approval!”, which is why the stock (below $290/share in late June) had run up to almost $384 at the close yesterday. You can forget about all that early approval stuff (although Biogen and Eisai aren’t saying what they’ll do yet). My own opinion is that there will have to be a large, lengthy, expensive Phase III effort on this one, just like there’s a large, lengthy, expensive Phase III effort on every Alzheimer’s drug. And both investors and patients will have to hope that this one doesn’t end up like the rest of those Phase III trials did. It’s anyone’s guess. But the historical track record for Alzheimer’s drugs, anti-amyloid therapies, and anti-amyloid antibodies in particular is there for anyone to see. While I’m offering opinions, I think that any sort of early approval for BAN2401 would be a mistake. I completely understand the huge medical need for such a therapy, but what we equally don’t need (I exclude Biogen and Eisai shareholders from that “we”) is a rush by millions of patients, and their insurance companies, and the US government’s reimbursement system, into a drug that doesn’t actually do anything.
That would be both wasteful and cruel. I wish that I had better news for people looking for some therapeutic option for Alzheimer’s, but all I can see is “Maybe, and maybe not, and not for some time”.
Full disclosure: I went short Biogen stock during the morning yesterday, just in time to watch up immediately go up ten dollars a share. I covered my position this morning at the open, and I’ve timed this blog post to appear afterwards, not that think that I can move Biogen’s stock price. Other things being equal, I will tend to be short pretty much anyone who’s about to announce a big, important Alzheimer’s result, at least so long as the field is in the state it’s in today.