This week, Pfizer and J&J finally discontinued development of iv bapineuzumab for Alzheimer’s Disease (AD) after a second spectacular failure in Phase 3. That they discontinued the programme surprised almost no-one. Everyone, it seems, is smart after the event, but the potential for anti-amyloid therapies was not always viewed with such negativity.
Once upon a time, almost the entire Alzheimer’s research community believed that deposition of amyloid into neurofibrillar tangles to form plaques was the causative event underpinning AD. Dissenters were viewed with the same skepticism as ‘flat-earthers’. All the evidence stacked up – if you could just reduce amyloid deposition you would prevent or even cure the disease.
Unfortunately, obtaining proof of this hypothesis required vast Phase 3 studies – early clinical studies in AD are a classical example of a ‘low validity environment’ – in other words, early (cheap and quick) results are notoriously poor predictors of late (slow and expensive) studies such as the Phase 3 studies now reporting. As a result, it was the strength of the amyloid hypothesis (and the weight of its large number of acolytes) that drove global pharma execs to back these trials – despite Phase 2 data that was at best equivocal.
And because the amyloid hypothesis is wrong, and the Phase 2 studies poorly predictive, the whole house comes crashing down spectacularly, with billions of dollars wasted.
If the theoretical underpinning for new trials in these indications are always at risk of “inflation”, how can we play in these areas and still stay “safe”?
There are parallels with another unfolding disaster – the CETP inhibitors. Here, in another low-validity environment, the HDL hypothesis had gained almost religious support (just like the amyloid hypothesis), and again the flawed hypothesis will result in a dramatic and expensive failure in Phase 3. The only difference is that the LDL-cholesterol lowering effects of the CETP inhibitors may rescue some value even though the HDL hypothesis was completely off-target.
These late stage failures in indications that demand vast Phase 3 studies are killing the pharmaceutical industry. What are their origins? And how do we avoid them in the future? DrugBaron sees it as more than coincidence that powerful theories grow up specifically in these low validity environments – and the lesson for the pharma industry is to stay pragmatic and recognize that ideas, as well as economic assets, can show bubble behaviour – and the crash that follows an “ideas bubble” is every bit as painful as the conventional financial post-bubble crash.
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 …