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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RxCelerate Ltd is an outsourced drug development platform based near Cambridge, UK. We specialize in delivering an entire road map of drug development services from discovery and medicinal chemistry through to formal preclinical development and clinical up to Phase IIa. In the last five years, we have witnessed dramatic changes in the drug development …
