With the news that Pfizer and Johnson & Johnson are scrapping further study of the drug bapineuzumab (bapi) after its second failure in a major clinical trial, and expectations no better for solanezumab, a similar drug under development by Eli Lilly, it now appears conclusive that the amyloid vaccine approach fails to provide any significant benefit for patients who have dementia.
The amyloid cascade hypothesis has been the dominant (though hardly exclusive) theory of the pathogenesis of Alzheimer’s for twenty years,and the idea of a vaccine targeting amyloid in the brain has been highly hyped for a decade. It’s worth recalling the sort of enthusiasm surrounding bapi in a typical news story when clinical trials were just getting started in 2009:
It’s not yet clear what such a high profile failure will mean for the AD field. Not surprisingly, pharma leaders continue to defend the amyloid vaccine approach that they have bet so heavily on. The New York Times story on the bapi failure quotes a scientific spokesman from Johnson & Johnson reiterating the company’s belief “that targeting and clearing beta amyloid remains a promising path to potential clinical benefits for people suffering from this disease.”
Meanwhile, other academic and industry leaders are spinning out modification of the amyloid hypothesis that refine the drug target. In 2010, as prospects for drugs like bapi that target amyloid plaques began to look increasingly poor, some researchers began to argue that the problem was free floating amyloid, and that the formation of plaques might be the body’s attempt to limit the damage by sequestering amyloid.
Many others have argued that the problem is not that the drugs are ineffective, but that treatment must begin much earlier in the disease, perhaps even before patients show any clinical signs of dementia. To investigate this, the National Institute on Aging has funded the Dominantly Inherited Alzheimer Network project, which will try to capitalize on the fact that the very rare early onset form of Alzheimer’s is caused by a known gene mutation, which will allow researchers to identify and test drugs on people who will develop dementia before any symptoms have appeared. But even if positive results are found in trials with early onset cases, it is not clear that these will be relevant to the much more common late-onset form of dementia since a different set of genetic factors are involved. More importantly, nothing is known about the potential risks of long-term treatment with anti-amyloid drugs. In the best case scenario, an Alzheimer’s drug would work less like a magic bullet, and more like the anti-cholesterol drugs — with all of the costs and controversies included.
Given these costs and barriers, and the fact that it clearly established by repeated studies that maintaining good overall health through exercise, mental stimulation and social engagement can significantly lower the risk of dementia as we age, I am inclined to join Peter Whitehouse in hoping that the failure of the anti-amyloid drugs will result in a fundamental re-orientation of our approach to Alzheimer’s that emphasizes more positive and realistic attitudes about aging and focuses on maintaining a rich life world.
But, to paraphrase Winston Churchill’s famous aphorism, given the great economic, intellectual and cultural investment that has been made in finding a medical solution to dementia, we are not likely to pursue such a simple, sensible course until we have exhausted all other possibilities.
For now, the amyloid hypothesis and the broader pharmacological approach to dementia may seem to many people like one more thing in our society that is just too big to fail.