Repurposing an “Old” Drug for Alzheimer’s Disease
Posted on by Dr. Francis Collins
Alzheimer’s disease research is among the many areas of biomedical science that Senator Barbara Mikulski has championed during her nearly 40 years on Capitol Hill. And it’s easy to understand why the Senator is concerned: an estimated 5 million Americans age 65 and older have Alzheimer’s disease, and those numbers are expected to rise exponentially as the U.S. population continues to age.
So, I was thrilled to have some encouraging progress to report last week when Senator Mikulski (D-MD) paid a visit to NIH’s National Center for Advancing Translational Sciences (NCATS) in Gaithersburg, MD. After a whirlwind tour of the cutting-edge robotics facility for high throughput screening of small molecules, she joined me and NCATS Director Dr. Chris Austin in announcing that, thanks to an innovative public-private partnership, an experimental drug originally developed to fight cancer is now showing promise against Alzheimer’s disease.
The compound, called saracatinib, is particularly exciting because it acts through a different mechanism than other experimental therapies now being tested for Alzheimer’s disease. The biopharmaceutical company AstraZeneca, which has agreed to supply the drug for the trials, first developed the compound to target a family of enzymes called src kinases, which are involved in the spread of cancer. Although the oral drug proved safe in human clinical trials, its performance was not impressive against cancer. So, the company shelved saracatinib, setting aside plans for further development.
That’s where the drug might have stayed had it not been for a basic research discovery made by a team led by Stephen Strittmatter of Yale University School of Medicine, New Haven, CT. Just a couple of years ago, in work involving a mouse model of Alzheimer’s disease , the neuroscientist and his colleagues discovered that a related kinase called Fyn may play a key role in the catastrophic changes in cellular architecture that take place in Alzheimer’s disease.
Specifically, Strittmatter’s group found that misfolded beta amyloid protein—a major component of the plaques seen in the brains of people with Alzheimer’s disease—interacts with another protein to activate Fyn excessively. This over-activation appears to spur the loss of neuronal synapses, which are essential for the communication of thoughts and formation of memories. The scientists reasoned that by blocking Fyn, they might be able to halt the destruction of synapses. But they needed a precisely targeted compound to do the job. They wondered whether saracatinib might do the trick, but that drug seemed out of reach because it was the exclusive property of AstraZeneca.
Enter the Discovering New Therapeutic Uses for Existing Molecules program, which was launched by NCATS less than two years ago. This pioneering partnership between NIH and industry provides an avenue for pharmaceutical companies to allow compounds that have failed along the way to be made available to the scientific community for other applications. The aim is to identify new uses for drugs already known to be safe in animals and humans, thereby reducing the time spent on safety testing and speeding the development of new therapies for patients in need.
By partnering with AstraZeneca through the New Therapeutic Uses program, the Yale team was able to obtain saracatinib at no cost and confirm that the compound does indeed block the Fyn kinase implicated in Alzheimer’s disease. In their recent study published in the Annals of Neurology , the researchers found that when they gave saracatinib to mice with Alzheimer’s-like symptoms for 4 weeks, they could turn off Fyn, get brain synapses firing again, and, most impressively, reverse memory loss in the animals. Because saracatinib had already passed human safety tests when it was evaluated for cancer, the researchers were able to assess its safety, tolerability, and dosing very quickly in a small number people with Alzheimer’s . Now, they are busy enrolling patients in a Phase 2a placebo-controlled clinical trial that will evaluate the effectiveness of saracatinib in about 150 people with mild Alzheimer’s disease .
What’s truly remarkable about this progress is that the Yale and AstraZeneca partners finished preclinical work, updated human safety studies, and began human efficacy studies, all within 18 months. That’s phenomenal when you consider that the average time for taking a compound from target discovery to human efficacy testing is currently about a decade!
Besides saracatinib, NIH-funded researchers are pursuing many other encouraging leads for treating and preventing Alzheimer’s disease. One that I’ve highlighted in the past is the Accelerating Medicines Partnership (AMP). The goal of this public-private effort, which involves NIH, industry, and nonprofit organizations, is to catalyze the identification of better biological targets and markers to enable the development of better drugs at a faster pace. AMP is starting with pilot projects in three disease areas, including Alzheimer’s.
NIH research is also vital to realizing the vision set forth in the National Plan to Address Alzheimer’s Disease. As part of this effort, we are supporting basic research in neuroscience, epidemiology studies to identify genes that raise or lower risk of developing the disease, and more than 25 clinical studies aimed at improving methods for early diagnosis and tracking disease progression.
 Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Um JW, Nygaard HB, Heiss JK, Kostylev MA, Stagi M, Vortmeyer A, Wisniewski T, Gunther EC, Strittmatter SM. Nat Neurosci. 2012 Sep;15(9):1227-35. doi: 10.1038/nn.3178.
 Fyn inhibition rescues established memory and synapse loss in Alzheimer mice. Kaufman AC, Salazar SV, Haas LT, Yang J, Kostylev MA, Jeng AT, Robinson SA, Gunther EC, van Dyck CH, Nygaard HB, Strittmatter SM. Ann Neurol. 2015 Feb 23. doi: 10.1002/ana/24393 [Epub ahead of print]
 Safety and tolerability of AZD0530 (saracatinib) in Alzheimer’s disease. ClinicalTrials.gov
Alzheimer’s Disease Education and Referral Center (National Institute on Aging/NIH)
Strittmatter Lab, Yale University
National Plan to Address Alzheimer’s Disease (U. S. Department of Health and Human Services)
NIH Support: National Center for Advancing Translational Sciences; National Institute on Aging; NIH Common Fund