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Research at Pacific paves way for Eidos Therapeutics

May 5, 2017

Palo Alto-based BridgeBio Pharma has announced it has committed $27 million to advance Eidos Therapeutics' development of AG10. Co-founded by Mamoun M. Alhamadsheh, PhD, associate professor of pharmaceutics and medicinal chemistry, and Isabella Graef, MD, assistant professor of pathology at Stanford University, Eidos' mission is to develop a therapeutic treatment that addresses the root cause of transthyretin (TTR) amyloidosis. Currently there is no FDA-approved treatment for the rare, fatal disease that affects more than 250,000 people worldwide.

TTR is a relatively abundant protein found in the blood. It is normally a four-part molecule, but genetic mutations or environmental factors can cause it to become unstable. If the protein destabilizes, it can misfold, which creates amyloid fibrils which are the cause of the disease. AG10 is a small molecule developed by Alhamadsheh's lab collaboration with Stanford University. AG10 binds to the TTR molecules, stabilizing the structure and preventing the disease-causing amyloid fibrils from forming.

Unstable TTR can result in TTR cardiomyopathy or TTR polyneuropathy, both of which are progressive, fatal diseases. TTR cardiomyopathy can be caused by a genetic mutation, the most common mutation, V122I TTR, is found in approximately 4 percent of African-Americans. The only disease-modifying treatment currently available is a liver and heart transplant.   

For patients with TTR polyneuropathy, misfolded TTR amyloid fibrils accumulate in the peripheral nervous system, which affects movement and sense of touch, as well as digestive and cardiovascular functions. There are no FDA-approved treatments for this form of the disease.

Pacific faculty and students have been instrumental in demonstrating the potential of AG10.

"They helped with characterizing the chemical and biological properties that determined the suitability of AG10 as a drug candidate," Alhamadsheh said. Assisting in this research are William K. Chan, PharmD, PhD, professor and chair of the Department of Pharmaceutics and Medicinal Chemistry; Miki Susanto Park, PhD, professor of pharmaceutics and medicinal chemistry; Sravan C. Penchala '16, PhD; and students Mark Miller '17, Wabel Albusairi '17 and Arindom Pal '19.

The potential for a broader application of this research inspired Alhamadsheh and his colleagues.

"We were interested in finding stabilizers for proteins involved in Alzheimer's disease," Alhamadsheh said. "There are some genetic correlations between TTR and Alzheimer's. We hope that the knowledge and insight gained from studying TTR can help us develop a treatment for Alzheimer's." 

Alhamadsheh's lab at Pacific continues to research TTR. Currently, his focus is on the native, stable form of TTR with the goal of extending the half-life of therapeutic agents, which would result in decreasing the frequency of doses for a variety of medications. His research was initially funded by an American Association of Colleges of Pharmacy New Investigator Award and now is funded by a National Institutes of Health grant.

"It was a great experience for students to work on something fruitful. They worked with seasoned professionals in both academics and industry," Alhamadsheh said. "When students have the opportunity to research alongside faculty members it broadens their knowledge and increases career opportunities."  

He shares that the TTR research at Pacific led to opportunities for Penchala, the lead author of a study on AG10 published in the Proceedings of the National Academy of Sciences. After earning his doctorate at Pacific, Penchala went on to accept a position at Merck Research Labs.

Alhamadsheh continues to be involved in Eidos as scientific advisor. Eidos plans to start the first phase of clinical trials this year.

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about the author

Anne Marie H. Bergthold  

Anne Marie H. Bergthold is the Marketing Coordinator at the Thomas J. Long School of Pharmacy and Health Sciences at Pacific.