It should be obvious, given previous posts here, that I think that the FDA approval of Biogen’s aducanumab for Alzheimer’s was a mistake. It is a mistake for a whole list of reasons, and we’re about to see another one of those in action.
Eli Lilly has been attacking Alzheimer’s for decades now, in what can be seen simultaneously as admirable persistence and as a very expensive exercise in futility. Several years ago, the company spent a great deal of time and money trying to prove efficacy with an anti-amyloid antibody, solanezumab, and eventually got nowhere. But that was in the distant, far-off days of 2016. Things are different now: Biogen’s anti-amyloid antibody doesn’t really seem to work, either (which is why they stopped the Phase III for futility), but the FDA approved it anyway, because it lowers amyloid, even though no amyloid-lowering therapy has ever shown efficacy.
Lilly, experienced brick-wall-impacters that they are, has been working on yet another anti-amyloid antibody (donanemab). Phase II results came out on this one in March, and it was really more of the same. There was a new rating scale endpoint, the iARDS, in which the therapy did show a statistically significant improvement at the 76-week mark. But a whole list of other endpoints whiffed, coming out no different than placebo. It was hard to generate much enthusiasm – you’d think that any Alzheimer’s therapy that actually worked, that actually had a chance of making a difference out in the real world, would be able to show more than that.
You see where we’re going here. Back in the solanezumab days (which I never thought I’d end up nostalgic for) the company would be trying to come up with another trial to show efficacy. But the heck with that. They’ve instead asked the FDA for “breakthrough” designation to try to speed regulatory approval, and the agency has granted it. After the aducanumab approval, what choice did they really have? For that matter, Biogen and Eisai applied for breakthrough status for their follow-up antibody, lecanemab, and the agency granted that yesterday. Why not?
Biocentury‘s Steve Usdin had an interview with the FDA’s Janet Woodcock recently, and she has vigorously defended this approval (as she defended the eteplirsen approval for Duchenne muscular dystrophy, which was another drug that showed no real evidence of efficacy and whose approval was accomplished by her over-ruling the rest of the agency). The follow-up compound to that one was suddenly approved last year as well, despite no convincing efficacy data, I should add, and despite the company not having (at the time) gotten around to doing any of the post-approval studies that they committed to with eteplirsen, either. We’ll see how Biogen does with its post-approval study of aducanumab in Alzheimer’s patients, which was also mandated by the FDA. They have nine years to do it, and my prediction, unfortunately, is that they will take every single day of it.
At any rate, the Woodcock interview is very interesting, but often odd. For example, there’s this statement:
“. . .What we’re seeing now is this blend of empiricism and extremely advanced mechanism-based drug development. It’s hard for everybody to adapt. It’s like “What party are we at today?”
In some areas we’re seeing very close working together to chart the path forward and extremely mechanistically based interventions. At the same time, we’re still seeing standard drug development. You don’t hear too many people talking about high-throughput screening anymore, though, for example, which is the height of empiricism.”
I think she’s confusing HTS with phenotypic screening there. A lot of target-driven mechanism-based drug discovery efforts start with high-throughput screens against those targets, while a target-agnostic phenotypic approach is what I would call the “height of empiricism”. But if that’s what she meant, it’s odd to say that you don’t hear many people talking about it any more.
Woodcock points out in the interview that she herself was not involved in the aducanumab decision. In response to a direct question on the matter, I would call this a sidestep:
Biocentury: . . .Where people are questioning it is whether there’s a connection between that and clinical benefit. Are we going to see FDA’s thinking about that, about why you’re confident that it’s reasonably likely to predict clinical benefit?
Woodcock: Yes, that’s definitely part of an accelerated approval, of course, because there’s long been skepticism about the amyloid hypothesis. I think they are acutely aware of that.
She also said that the approval was “was based on much more solid data than many of the other approvals that we do for serious and life-threatening diseases like cancer“, but to me that evades the question as well. These cancer trials do not take place against a backdrop of repeated failures against the exact same hypothesis, do they? That, and the relatively quick and fatal course of the underlying disease, is what makes accelerated approval in that area more appropriate (and more feasible, in my eyes), and I just can’t make the same case for yet another whack at the amyloid hypothesis in Alzheimer’s.
These antibodies (and who knows what else) will be up for approval well before the Biogen post-approval data are ready. And even if aducanumab doesn’t turn out to work, how much difference will the FDA then allow that to make? That one didn’t do much, but maybe the next amyloid-clearing agent will? How will you know unless you approve it and find out? Oh, I know, you could make the companies run those trials, but desperate patients are waiting, money in hand, and you wouldn’t want to deny them (and their insurance companies) a chance to spend it on something that you’re not sure does any good. Right?
So if you look at the disease landscape not knowing the back story, things look great: the FDA just approved a new Alzheimer’s drug and now there are two more Breakthroughs right behind it! But if you do know what’s going on, it’s downright depressing: the agency approved a drug that shows no solid evidence of helping anyone (and more believable evidence of its ability to cause harm), and this mistake is allowing everyone else to jump on the same damn bandwagon with data that are no better. Put out more flags.
The post Open the Floodgates first appeared on In the Pipeline.
