This research was supported by BrightFocus
A BrightFocus grant to Stephen Strittmatter of Yale, combined with an innovative NIH research program, has led to a clinical trial of saracatinib, an experimental cancer drug, to treat early Alzheimer’s. Above, in a mouse brain that models Alzheimer’s disease, you can see how the growth of amyloid beta clusters, shown in red, starts to interfere with the function of neurons, shown in green.
Good news from Yale—researchers there report early success using a still-experimental cancer drug known as saracatinib (AZD0530) to treat Alzheimer’s disease in mice. Testing in humans with early Alzheimer’s disease is now underway.
The work leading to clinical trials was partially funded by BrightFocus. A current BrightFocus grantee (2013-16), Stephen Strittmatter, MD, PhD, is chief investigator and senior author of the report that is newly published online in the Annals of Neurology (Kaufman et al, 2015).
In addition to receiving BrightFocus support, Strittmatter and colleagues also received support from NIH to conduct the experiments, and their accomplishment represents one of the successes of the federal New Therapeutic Uses program launched in 2012 by the National Center for Advancing Translational Sciences (NCATS) at NIH. That program matches scientists with pharmaceutical compounds that have undergone significant research and development by industry, including safety testing in humans, to test potential ideas for new therapeutic uses.
With his BrightFocus grant, Strittmatter is investigating prion proteins and the spread of Alzheimer’s plaques in the brain. From theirs and related studies, the team knew that a protein called Fyn kinase plays a central role in how amyloid beta clusters damage brain cells.
Saracatinib targets the same Fyn protein, and in cancer trials run by AstraZeneca, its manufacturer, had cleared several key steps in the drug development process. This gave Strittmatter and colleagues a head start in their Alzheimer’s research.
First they administered saracatinib to mice with Alzheimer’s-like symptoms, such as memory loss and age-related buildup of abnormal amyloid beta clusters. After four weeks, the Alzheimer’s mice showed complete reversal of spatial learning and memory loss. Furthermore, when the scientists examined the brains of the treated mice, they found that the characteristic Alzheimer’s-related loss of synapses (i.e., junctures where signals pass from one neuron to another) had been fully restored. This physical finding provided a biological explanation for the memory improvement. The treatment also reduced several other Alzheimer’s-related biochemical changes in the mice and did not appear to be toxic.
Once they had animal evidence of saracatinib’s potential usefulness in Alzheimer’s, the Yale scientists completed a successful Phase 1b safety trial in humans with Alzheimer’s disease (NCT01864655).
Now they are enrolling more participants in a larger, multisite Phase 2a trial to assess safety, tolerability and effectiveness of the experimental compound. A total of 152 participants will receive saracatinib or placebo for one year, and the researchers expect to have final results within two years.
Typically, it can take a decade or longer from the discovery of a therapeutic target (in this case, fyn until drug discovery techniques pan out and an experimental compound is ready to enter a Phase 2a human clinical trial to establish dosing levels and test its effectiveness. In the case of saracatinib, thanks to the NCATS’ New Therapeutic Uses program and AstraZeneca’s willingness to share its new compound, these researchers were able to hasten the process and complete animal and preclinical safety studies in less than two years.
“The investigational drug already had been developed, optimized and studied in animals as well as tested for safety in humans, so our ability to obtain this asset through NCATS and AstraZeneca gave us an incredible shortcut in the drug development process,” Strittmatter said in an NIH press release.
In a Connecticut public radio program that aired in February, he talked about the early research funded by BrightFocus and others that led down this path to a potentially useful therapy in humans. A partial transcript of that program appears below.
Clinical Trial Information
A total of 152 men and women aged 55-85 with mild Alzheimer’s (MMSE score 18-26) will be recruited for the upcoming Phase 2 treatment trial of saracatinib in Alzheimer’s disease (NCT02167256). The trial is being sponsored by Yale University and the Alzheimer's Disease Cooperative Study (ADCS). There are 19 planned sites in the United States and Vancouver, BC, Canada. View this web page for more information, or go to the federal website, www.clinicaltrials.gov.
From Bench to Bedside
In a talk show on Connecticut public radio station WNPR last February, Strittmatter (pictured above) talked about the link between early discoveries made using a grant from BrightFocus and clinical investigation of saracatinib.
“Our focus in the laboratory, at the bench, has been on understanding how amyloid peptide makes neurons dysfunctional. We screened through all the genes that the mouse has, and we found a particular gene, called prion protein, that would capture the amyloid beta from the extracellular space and trigger bad events in the neuron.
“When we studied that process, we found that it went from prion protein to a protein called MUR5 and then to a protein inside the neuron, at the synapse, called fyn. Each of these three steps is a potential place to intervene with a drug. Fortunately, the third step, fin kinase, is one for which there had already been drugs developed, because this group of proteins plays a role in cancer.
“And so we made this connection from the bench to the bedside. The drugs have already been developed, and they’re safe.”
Click here for a link to that WNPR program, “Unlocking the Mysteries of Alzheimer’s Disease.”
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