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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