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Preclinical data indicate TetraLogicís Birinapant's broad activity in models of infectious disease
by Lloyd Dunlap  |  Email the author


MALVERN, Pa.—TetraLogic Pharmaceuticals Corporation has announced results from its collaboration with the Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia, indicating that SMAC mimetics, including TetraLogic's lead compound birinapant, may have broad applicability in the treatment of infectious disease.
SMACs (small mitochondria-derived activator of caspases) are released into the cytosol following an increase in permeability. These mitochondrial proteins bind to inhibitor of apoptosis proteins (IAPs) and deactivate them, preventing the IAPs from arresting the apoptotic process and therefore allowing apoptosis to proceed.
Previous preclinical studies performed at the Walter and Eliza Hall Institute have demonstrated that birinapant decreases the viral burden in mice infected with human hepatitis B virus (HBV) by inducing apoptosis of virally infected liver cells resulting in the reduction of circulating HBV and surface antigen (HBsAg). Recent studies have extended these findings and indicate that other novel SMAC mimetics from TetraLogic's library share this activity in HBV.
Birinapant has also indicated activity in other models of infectious disease; specifically, it induces cell death in human blood cells infected with human immunodeficiency virus, decreases the bacterial burden in the lungs of mice infected with tuberculosis and in mice infected with Legionella.
TetraLogic has entered into a license agreement with the Walter and Eliza Hall Institute for worldwide exclusive rights to a patent application relating to a method of treating intracellular infections with administration of an inhibitor of the Inhibitor of Apoptosis (IAP) proteins.
"We are delighted with the progress of this research collaboration," said institute director Professor Doug Hilton, "and we are looking forward to the initiation of clinical studies based on this work."
"These results further support the fundamental mechanism by which SMAC mimetics are operating, and provide additional rationale for the study of birinapant in infectious disease," said Dr. Glenn Begley, TetraLogic's chief scientific officer.
The Walter and Eliza Hall Institute is Australia's oldest medical research institute. It is home to almost 750 researchers who are working to understand, prevent and treat diseases including infectious diseases, cancers and immune disorders. It is located in Parkville, Melbourne, and is closely associated with The University of Melbourne and The Royal Melbourne Hospital.
Birinapant (TL32711) is a potent, bivalent SMAC mimetic that binds with differential affinity to multiple members of the IAP family including cIAP1, cIAP2, XIAP, and ML-IAP. Birinapant is differentiated from other SMAC mimetics in that it results in the selective degradation of cIAP1 bound to TRAF-2 in the TNF receptor complex, sparing non-TRAF-2 bound cIAP1. This unique IAP antagonism profile of birinapant may result in the improved tolerability and therapeutic index observed with this agent.
TetraLogic is a clinical-stage biopharmaceutical company focused on discovering and developing novel small molecule therapeutics in oncology and infectious diseases. TetraLogic has two clinical-stage product candidates in development: birinapant and suberohydroxamic acid phenyl ester (SHAPE). Birinapant is currently being tested in Phase 1 and Phase 2 clinical trials for hematological malignancies and solid tumors. SHAPE is entering Phase 2 trials for early-stage CTCL.
Code: E06091401



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