Preclinical Research Validates Role of BMP Pathway in Treating Progressive Kidney Disease and Potential for Thrasos’ Compounds to Selectively Target the Pathway
MONTREAL--(BUSINESS WIRE)-- Thrasos today announced that the journal Nature Medicine has published the results of a collaborative research program detailing the role of the bone morphogenic protein (BMP) pathway in the development of kidney disease. This research was led by Dr. Raghu Kalluri, Professor of Medicine at Harvard Medical School, Beth Israel Deaconess Medical Center, in collaboration with the Thrasos research team and Dr. Mary Rusckowski, Associate Professor at the University of Massachusetts Medical School. Dr. Kalluri is a world-recognized expert in understanding of the process of renal fibrosis and the role of BMPs in controlling that process. The research describes the potential for Thrasos’ compounds to specifically target receptors in this pathway, potentially leading to the control of fibrosis and induction of kidney regeneration.
BMPs are key regulators of inflammation, fibrosis and apoptosis. High-affinity receptors for specific BMPs are present in kidney epithelial cells and are thought to mediate BMP actions in the kidney. One such receptor is activin-like kinase 3 (Alk3). The comprehensive set of preclinical studies detailed in the Nature Medicine article demonstrate that Alk3 is elevated early in diseased kidneys following injury and also suggest that Alk3-mediated signaling can protect kidneys by inhibiting fibrosis. This research shows that the process through which this occurs involves the control of inflammation, apoptosis and inhibition of an epithelial-to-mesenchymal (EMT) shift.
Thrasos has designed and produced an extensive library of small peptide agonists that bind selectively to the BMP receptors, including Alk3. A representative peptide agonist from this portfolio, THR-123, was used in these studies and was shown to control and reverse fibrosis and induce kidney regeneration in five well established preclinical models of chronic renal injury. Importantly, THR-123 was delivered orally in all studies and achieved its effects without inducing bone formation. The scientific team also verified that THR-123 operates through Alk3 signaling by studying an Alk3 conditional knock-out model, which did not respond to THR-123 therapy.
"These are really interesting results,” said John Moran, MD, FRACP, FACP, Vice President of Clinical Affairs - Home Modalities, DaVita, Inc. “Preventing kidney damage from progressing to end-stage disease, where the patient needs a transplant or dialysis, is the ultimate research goal. The researchers used multiple well established models of human kidney disease and showed that in these models, such progression can not only be halted, it can even be reversed. And, importantly, this was accomplished with very focused targeting of what appears to be a key pathway by which kidney scarring occurs."
Richard Andrews, President and Chief Executive Officer of Thrasos, commented, “The results detailed in this paper support and extend our ongoing work with our extensive portfolio of compounds acting on this pathway. The Thrasos portfolio includes both THR-184, targeted at Acute Kidney Injury, and THR-123, focused on Chronic Kidney Disease. The Thrasos team is delighted to see this important research published and we believe this pathway offers great promise in the treatment of Acute Kidney Injury and Chronic Kidney Disease. The Company is advancing both THR-184 and THR-123 and has successfully completed Phase 1 studies with THR-184. We expect to begin Phase 2 clinical testing in Acute Kidney Injury before the end of the year with this compound.”
The article, “Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis,” was published in the February 5, 2012 online version of Nature Medicine. Authors on the paper were: Hikaru Sugimoto1, Valerie LeBleu1, Dattatreyamurty Bosukonda2, Peter Keck2, Gangadhar Taduri1, Wibke Bechtel1, Hirokazu Okada1, William Carlson2,3, Philippe Bey3, Mary Rusckowski4, Björn Tampe5, Desiree Tampe5, Keizo Kanasaki1, Michael Zeisberg1,5, and Raghu Kalluri1,5,6 of 1Beth Israel Deaconess Medical Center and Harvard Medical School, 2Thrasos Innovation Inc., 3Massachusetts General Hospital/Harvard Medical School, 4University of Massachusetts Medical School, 5Goettingen University Medical Center, Georg August University, and 6Harvard–Massachusetts Institute of Technology.
Thrasos is a private, clinical stage, bio-therapeutics company focused on the discovery and development of targeted therapies for the prevention and treatment of kidney disease. The Company has advanced two compounds, THR-184 and THR-123, into development for Acute Kidney Injury (AKI) and Chronic Kidney Injury (CKD), respectively. The Company’s drug candidates were selected from an extensive inventory of active peptide compounds generated by the Company’s technology platform. Thrasos pioneered the design of compounds based on the structure of the bone morphogenic protein (BMP) family of proteins to activate the Smad transduction pathway. The resulting peptides have been shown to be orally active and protect, repair and restore cell and tissue function in the kidney and other organs.
Richard Andrews, 514-940-2714
MacDougall Biomedical Communications
Sarah Cavanaugh or Jennifer Conrad, 781-235-3060
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