Yesterday, Roche (OTCQX:RHHBY) announced its decision to discontinue its Phase 3 study of gantenerumab, its experimental anti-amyloid antibody, in early Alzheimer’s Disease. The study failed a futility analysis – the clearest possible evidence of a lack of signal.
This marks the latest nadir for the amyloid hypothesis – the dominant collective understanding of the molecular pathogenesis of Alzheimer’s Disease for more than two decades. A hypothesis that has remained the mainstream opinion in the face of the most extraordinary amount of negative data. Proof, if proof were needed, that some hypotheses have a status beyond disproval.
There are lots of good, if circumstantial, reasons to believe in the importance of beta-amyloid in dementia – not least because the brains of sufferers are stuffed full of it. It was, therefore, a very reasonable proposition that antibodies capable of clearing beta-amyloid from the brain would be a breakthrough therapy for what is certain to be the global epidemic of the 21st Century.
The pharmaceutical industry responded by generating the necessary antibodies, and demonstrated some impressive effects: Both Lilly’s (NYSE:LLY) solanezumab and bapineuzumab from Pfizer (NYSE:PFE) and J&J (NYSE:JNJ) substantially reduced beta-amyloid in phase 2 trials. That anti-amyloid antibodies clear beta-amyloid is not in doubt (although that simple statement itself belies a layer of complexity: beta-amyloid is not one substance but a family of related substances, some of which are cleared with certain antibodies and others, most likely, are not).
Thus emboldened, a number of these anti-amyloid antibodies were advanced into large, lengthy and eye-wateringly expensive Phase 3 clinical trials. The goal was to demonstrate an improvement in cognition (functions such as memory, which are progressively lost in dementia). The omens were surely excellent: after all, it was clear the agents did what it said on the tin (cleared amyloid) and the hypothesis itself was gold-plated.
But then the trials started to read out, and the picture was uniformly negative. By 2012 we had several huge Phase 3 trials with a couple of different anti-amyloid antibodies from different companies – and a slew of negative data.
What happened next was very interesting.
Instead of drawing the obvious conclusion (that the amyloid hypothesis was false), the assembled masses began casting around for a different explanation for the surprising failure. Some pointed at the affinity of the antibodies that had failed in Phase 3 and argued that a “better” antibody would have yielded a different outcome (even though even the lowest affinity antibody had been …
On Friday, Novartis announced that its anti-IL17A antibody secukinumab …
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