The decadeslong search for effective ways to treat or prevent Alzheimer’s disease is littered with failures, leaving 5.7 million Americans already living with this form of dementia without a lifeline. The rest of us are left to hope we won’t be among the 1 in 10 older than 65 who gets the devastating diagnosis.
But precision medicine — an approach that is changing the treatment of cancer and spawning targeted therapies for a wide range of diseases — may open new avenues for the treatment of Alzheimer’s disease. And new ways to test experimental treatments show promise to more quickly identify treatments that work, and perhaps the patients in whom they will work best.
These approaches raised expectations that at least two experimental drugs — BAN2401 and Anavex 2-73 — might successfully treat some with Alzheimer’s. In BAN2401, the successful preliminary finding of a trial that enrolled 856 patients with early Alzheimer’s disease has breathed new life into a hypothesis that persists despite withering failures: that reducing clumps of proteins called amyloid plaques that accumulate in the brains of those with Alzheimer’s might slow or reverse their symptoms of memory loss and cognitive confusion.
Using an innovative clinical trial design, the U.S. and Japanese companies developing BAN2401 found that over 18 months of treatment, patients who got the highest doses of the medication had dramatic reductions in amyloid plaque deposits in their brains. And compared with subjects who got a placebo, those who got the highest dose showed a 26 percent slowing of clinical decline after 18 months.
As the trial progressed, its “adaptive design” — considered controversial by some researchers — ensured that when new subjects were recruited, they were more likely to be assigned to arms of the trial that showed the greatest promise.
“Alzheimer’s disease trials need to evolve,” said James A. Hendrix, director of global science initiatives at the Alzheimer’s Association. “We need to try new things and learn from other diseases” such as cancer, he said, where for select subsets of patients, new targeted therapies are delivering cures. He said, “Maybe one-size-fits-all is not the best approach.”
In a first-ever bid to apply the principles of precision medicine to Alzheimer’s disease, researchers also reported on a small study of patients who bear a few “actionable genetic variants.” In these patients, they found, Anavex 2-73 appeared to slow and perhaps even reverse early cognitive decline.
Researchers built an extra step into their safety trial: sequencing the subjects’ genomes. In doing so, they hoped to find genomic signatures in some patients that would make them more likely to respond positively to the drug.
Researchers knew what they were looking for: gene variations that were likely to interfere with the actions of Anavex 2-73 and make treatment unsuccessful. They found two such genetic variants, present in about one-fifth of humans.
When they narrowed the subject pool to just those patients whose genetic makeup was compatible with its mode of action, they found that subjects who got the medication for 57 weeks experienced “clinically meaningful” improvements in their ability to reason, remember and carry on daily activities.
It is far too early to tout the success of the drug and a larger trial is to begin in Australia and North America. The experimental medication is also being tested as a possible treatment for dementia associated with Parkinson’s disease, Rett syndrome and Fragile X syndrome.
The idea that a medication to treat Alzheimer’s disease might work in some patients and not as well in others is consistent with a growing sense that Alzheimer’s may be many different diseases. And it also fits with the notion that genetic factors — acting alone or collectively — predispose some to Alzheimer’s while protecting others.
In precision medicine, researchers work to identify the genetic factors that drive or contribute to a disease and build medicine that targets the effects of those miscreant genes. Then, they use genomic sequencing to identify just those patients who bear the genetic signatures their drug works on. More often than not, these drugs are costly. But when the right patients get the right medicine at the right time, treatments will be more effective and have fewer side effects.
Such new approaches could turn the tide in the discouraging search for Alzheimer’s treatments, said Dr. Deepak Bhatt, an expert on adaptive trial designs and precision medicine. He said, “Identifying which patients might benefit from a novel therapy using biomarkers or genetics will likely be a big part of how medicine is individualized in the future.”