Sometimes data just speaks for itself. But more often, its left to scientists and journalists to try and draw useful conclusions from complex observations. And so is the case with the latest data reported at the Alzheimer’s Association International Conference in Washington, D.C on two clinical-stage drug candidates. Predictably, there has been no shortage of comment (for example, here, here, here).
The first thing to remember is that the degree of anticipation, even hype, surrounding these data has much more to do with the undoubted importance of Alzheimer’s Disease as an unsolved clinical and societal crisis in the making. The data themselves were never going to make a difference, because one is a Phase 1/2 study and the other an extension study of a previously failed Phase 3. Neither could ever have provided an unequivocal positive outcome.
So the chattering revolves around whether the new data makes a future pivotal Phase 3 with an anti-amyloid antibody more or less likely to be positive. For bystanders, its fine to just wait and see since those trials are either running or have been committed to (although there is a very real risk that some of the coverage unreasonably raises hopes of helping current patients). It is for investors, and other residents of the global “biotech village”, that divining some scant thread of meaning from such data becomes a life-or-death activity.
But how you interpret this data probably depends on your original starting position.
For those who felt the anti-amyloid drug candidates were “promising”, the new data is broadly seen as slightly disappointing, though by no means a knock-out blow (although, as I have already noted its unclear what, if anything, could every convince the most ardent acolytes of the “amyloid hypothesis” that these drugs could never work). Judging by the decline in $BIIB share price (down 3-4% in immediate response to the data), many investors fell into this camp.
Ironically, for those who felt the previous extensive failures with anti-amyloid candidates in the clinic had already sealed the coffin for this approach (and I have very publicly put myself in that camp), this data seems somewhat more encouraging. For sure, the data have notched down expectations particularly for aducanumab (Biogen’s candidate), but the hype that surrounded the data released in March was entirely excessive given the size of the study set against the previous record of anti-amyloid agents in larger studies. So a degree of disappointment was necessary and expected.
However, the bottom-line is that the new data strengthens the belief that the groups treated with anti-amyloid had slower cognitive decline than the people treated with placebo in both the Biogen and Lilly studies.
Read that last sentence again. Its worded very carefully. Many main-stream journalists have translated that sentence to mean “the new data strengthen the belief that treating people with anti-amyloid slows cognitive decline”. But that is an extrapolation. It assumes that the difference between the groups is due to the drug treatment.
That assumption is no slam dunk. In the Biogen study, the number of people in each group is very small, so its perfectly possible that the people randomised to the placebo had a slightly greater intrinsic tendency to lose cognitive function. If that were so, the treatment and placebo groups would look different but the difference wouldn’t be due to the treatment.
The Lilly study was larger, but the patients in the extension study were not randomly selected – they were a sub-group of patients who seemed to have responded to anti-amyloid treatment with slower cognitive decline. But maybe they would have had slower cognitive decline anyway, even on placebo. This is called selection bias. And because the extension data is from these same patients it doesn’t eliminate the pernicious impact of bias in the selection of the study group.
In both cases, the new data strengthens the belief the groups are different, but not that the difference was due to the anti-amyloid drug candidates.
There are other reasons to be cautious about interpreting the data as further evidence for a treatment effect.
The arguably too-neat-to-be true dose-response curve with $BIIB’s aducanumab was indeed to too neat to be true. By 54 weeks the dose-response looks less like an example figure from stats text, and more like real-world data. The earlier disclosure was just clean and tidy by chance alone. The dose-response relationship made the “unequal randomisation” argument unlikely; now its gone away the real risk of unequal randomisation in such a small trial is back front and centre.
And then there is the toxicity. The $BIIB drug looks now rather like other anti-amyloid agents. Indeed, the biggest concern for $BIIB must be that any hope (pretense?) that aducanumab was “special” has largely gone away. Its “just” an anti-amyloid, and of course its well behind in the race to market. Presumably $LLY will be first-to-market with solaneuzumab if any of the class get approved.
And finally, we have to keep in perspective the likely maximum magnitude of any benefit. These changes in the slope of the cognitive decline curve are at best small. Miracle cures these are not. Thats unlikely to stop approval or multi-billion dollar sales, assuming that small improvement is eventually proven to be real, but it will make scoring a positive in a large Phase 3 all the more challenging (smaller effects are always harder to robustly ‘prove’).
Before today, I argued that there was little hope that an anti-amyloid would be clinically effective in Alzheimer’s Disease. With the new data there is still little to be positive about. Though, perhaps, it is one tiny step nearer to an approval line thats a million miles distant
Fortunately, though, opinion (be it mine or those of the anti-amyloid acolytes) means very little. Trials that everyone agrees will definitively answer the question are already under way (or committed to). The new data changes nothing in the real world: few minds will have changed, and no patients will be made better.
Read the original article here
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