Three times, Eli Lilly has tried to demonstrate the efficacy of the drug solanezumab in the treatment of Alzheimer’s disease. And three times, the drug failed. What does this mean?
Solanezumab is a monoclonal antibody that selectively attaches to a form of amyloid-beta, widely thought to be the key agent that causes Alzheimer’s disease. The first two studies were phase three, double-blind studies of patients with mild to moderate Alzheimer’s disease. That means earlier studies had found the drug reasonably safe and had identified a dose that had the desired effect on brain amyloid. The results of EXPEDITION1 and EXPEDITION 2 were both published in the New England Journal of Medicine in January, 2014. The authors found that after 18 months of treatment with intravenous solanezumab, there was no improvement in either tests of cognitive function (the Alzheimer’s Disease Assessment Scale) or daily activities (the Alzheimer’s Disease Cooperative Study Activities of Daily Living scale). There was a hint in subgroup analysis that maybe the patients with milder disease might benefit; hence the new study, EXPEDITION3, which evaluated the drug in patients with clinical evidence of mild dementia and abnormalities on PET scan suggestive of amyloid deposition. But alas, the results of this trial are no more encouraging than those of its predecessors.
Solanezumab is not the only anti-amyloid monoclonal antibody that has been tested and found wanting. Two other double blind randomized, placebo-controlled phase 3 trials were conducted with Bapineuzumab in patients with mild to moderate Alzheimer’s, One trial involved carriers of the APOE-4 allele, a gene for a cholesterol carrying protein that has been associated with an increased risk of dementia; the other involved non-carriers. Once again, there was no difference between patients receiving active drug and those getting placebo, whether on tests of cognition or on measures of overall daily functioning.
So now solanezumab has failed three times. Not because it caused terrible side effects, as was the case with earlier attempts to “vaccinate” against Alzheimer’s disease, that were in some instances effective but that caused a debilitating and/or lethal inflammatory response in the central nervous system. Solanezumab failed because it didn’t work. What does this tell us about the use of monoclonal antibodies in Alzheimer’s disease?
An article in Scientific American two years ago on “Why Alzheimer’s Drugs Keep Failing” makes clear that it’s not just a handful of drugs that have fallen short of their promise. According to the article, “dementia has become a graveyard for a large number of promising drugs.” In fact, the failure rate for Alzheimer’s disease “drug candidates” is 99.6 percent (compared to 81 percent for cancer drugs). The problem, in large measure, is that symptoms begin a decade or more after the disease actually starts, by which time intervention may be too late. It’s as though we didn’t treat coronary artery disease until after a patient developed cardiomyopathy, until after so much heart muscle had died that the heart scarcely pumped at all. One strategy for drug development is therefore to identify markers for disease long before there are clinical manifestations, in principle allowing for treatment at a much earlier stage than occurred with any of the solanezumab trials. Another is to target other suspects besides amyloid—abnormal proteins such as tau that also contribute to the development of dementia. Still another strategy is to focus on “disease-modifying treatment,” an approach that slows the progression of the disease rather than one that focuses on cure.
Perhaps another reason that Alzheimer’s disease is such a hard nut to crack is that the brain is an extraordinarily complicated organ, arguably far more complex than the heart. The heart, after all, is basically a pump. An ingenious pump fed by a system of blood vessels and operated by an electrical mechanism, and one that has proved far more complicated than was initially assumed, but nonetheless simple by comparison with the brain. Because the brain is such a remarkable organ and because Alzheimer’s disease strikes its most elusive function, cognition, it is not entirely surprising that treating this disorder has proved so challenging.
The message is not that we should give up. But it is that there’s no cure around the corner. The most effective strategy to date is to decrease the likelihood of developing Alzheimer’s through a combination of smoking cessation, treatment of high blood pressure, and treatment (or prevention) of diabetes—a strategy developed for the prevention of cardiac disease and incidentally found to help stave off dementia. And in the mean time, as scientists continue to struggle to understand the pathogenesis of Alzheimer’s and devise new strategies for intervening in the relentless progression of this dread disease, we must continue to find better ways to support people who are afflicted, allowing them to find as much meaning and satisfaction as possible in their lives.
This is the last post on “Life in the End Zone” in 2016. See you next year!
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