The aducan'tumab crisis

[Aimless]

Interesting developments at FDA after controversial approval of purported Alzheimers treatment:

Twitter Link

Very interesting issue in many different respects, but I thought this signal from expert advisors was especially interesting.

[BalticSailor]

It's good to see at least some sort of backlash. "FDA is not presently capable of adequately integrating the Committee's scientific recommendations into its approval decisions" is just about the mildest way of commenting on the situation.

[wiggin]

It's good to see at least some sort of backlash. "FDA is not presently capable of adequately integrating the Committee's scientific recommendations into its approval decisions" is just about the mildest way of commenting on the situation.

It was pretty stunning how bad the committee's review was... In November everyone wrote it off even though there was some enthusiasm at the FDA for the drug. The accelerated approval process isn't intended to be a backup plan if your phase 3 data is crap. Honestly people need to rethink beta amyloid as a good target, it's been such a bust and relying on the surrogate endpoints based on an unproven hypothesis is irresponsible.

[BalticSailor]

Honestly people need to rethink beta amyloid as a good target, it's been such a bust and relying on the surrogate endpoints based on an unproven hypothesis is irresponsible.

Yeah, at this point it seems abundantly clear that from all the lead compounds that show some promising results in the amyloid plaque area, the proportion that actually improves any clinically significant outcome comes out to zilch. I'm afraid that it will remain the low hanging fruit for anti-Alzheimer's drug trials for some time, though - in no small part directly as a result from this fuck-up of a decision.

[wiggin]

Yeah, at this point it seems abundantly clear that from all the lead compounds that show some promising results in the amyloid plaque area, the proportion that actually improves any clinically significant outcome comes out to zilch. I'm afraid that it will remain the low hanging fruit for anti-Alzheimer's drug trials for some time, though - in no small part directly as a result from this fuck-up of a decision.

You know, I've actually had a pretty positive view of the FDA based on my interactions with them - most of the time their staff ask good, salient questions, and can be persuaded by solid scientific arguments and data. They're strict without being unreasonable (though there are certainly a few things that they have PTSD about and will ask for even if it's not relevant). Obviously I wasn't interacting with this group, but this is such a momentous decision (we're talking about a multi-billion dollar drug to address a massive unmet need - and it doesn't appear to have evidence supporting efficacy!), I'm pretty disappointed that this has gotten through.

The risk, as you note, is that it'll take a long time to prove that aducanumab doesn't work all that well and in the meantime billions of dollars of R&D money will go to an approach that has failed, consistently. I get that we don't have a lot of good options on Alzheimer's - frankly it's one of the biggest clinical problems that we don't really even have a vague idea how to address - but approving something with such thin and contradictory data seems irresponsible.

I should note that I'm not an expert on neurodegenerative diseases, beta amyloids, or these specific trials. But the November committee meeting was so negative that I can't help but conclude the FDA is wrong on this one.

[BalticSailor]

Well, I've had no interaction with FDA whatsoever, but I had this belief that it exists, at least partially, for the purpose of not letting this sort of thing through. Approval for a drug that had its trials terminated as a result of futility analysis - that's not a thing that should have happened, regardless of any amount of later massaging of data to eke out a fleeting illusion of efficacy. The unmet need you accurately describe as massive, should have been the additional motivation, if any was ever needed, to tread carefully in this case; it's not like the "Evil Big Pharma" meme needs any reinforcement, but it sure is going to get some if this treatment turns out to be an expensive piece of false hope - and it seems extremely likely that it will.

The risk, as you note, is that it'll take a long time to prove that aducanumab doesn't work all that well and in the meantime billions of dollars of R&D money will go to an approach that has failed, consistently. I get that we don't have a lot of good options on Alzheimer's - frankly it's one of the biggest clinical problems that we don't really even have a vague idea how to address - but approving something with such thin and contradictory data seems irresponsible.

My concern goes a bit beyond that. I really dislike the idea that Biogen gets 9 years of time for "confirmatory trial" - first of all, it seems that they can make quite a bit of profit during that time, and secondly, it may be possible to artificially delay that deadline (lengthy design negotiations, restrictive participation criteria, etc.) and make more money, should they wish to follow that disingenuous path - and nothing about the whole ordeal so far says "they would never", IMO. They deserve none of that. And yes, additional R&D spending on the amyloid hypothesis fueled by this nominal success is something I'd rather not see - but the major issue I see here is the inevitable relaxation of standards. After all, if this "treatment" was approved on the basis of the questionable secondary endpoint of removing amyloid plaques, why not others? There are many compounds that have seemed hopeful in the Alzheimer's field on that basis alone, yet they bailed out when they couldn't produce any results in cognitive decline tests. Now that the bar is lowered, why not re-apply? Sure, none of the previous compounds met any clinically significant threshold, but dealing with the amyloid plaques? That they can do, with all the evidence you'd need. On what grounds can the FDA turn those compounds down now? I sincerely hope I'm wrong here, but this whole deal has the air of the Pandora's box being opened.

[Aimless]

There's a reasonably plausible timeline on which not offering this—eg. in Medicare—will be regarded as unacceptable. So yeah, potentially a massive cash cow. Enough to criticize about the process and actual data without getting into the amyloid debate.

[BalticSailor]

Aaaaand here we go:

https://blogs.sciencemag.org/pipelin...the-floodgates

"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."

"...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?"

[wiggin]

This surrogate endpoint is so shitty, it's not even funny. I mean, at least tau seems to be correlated with cognitive decline a bit better.