Michael W. Lark, PhD, CSO and SVP, Research, Jonathan Violin, PhD, Head, Biology, David Soergel, M.D., VP and Head, Clinical Development, Trevena, Inc., King of Prussia, PA
Drug Discovery & Development - January 01, 2011
G-protein coupled receptors (GPCRs) are the most tractable drug discovery targets in the pharmaceutical industry. Classical GPCR drugs either activate or inhibit all of the intracellular signaling pathways at the receptor, which mediate both beneficial and adverse effects. Trevena is developing a pipeline of programs with enhanced therapeutic properties derived from selective activation of GPCR signaling. Trevena’s molecules are biased ligands, that selectively activate only those biological pathways at the receptor associated with beneficial effects.
There are significant opportunities to improve upon currently marketed GPCR drugs because many have limited efficacy and undesirable adverse effects. Trevena’s scientific founders discovered that both G-proteins and beta-arrestins activate unique intracellular pathways responsible for separable biological responses , and these responses can be independently modulated using biased ligands . Trevena has translated these findings into a proprietary drug discovery platform, and has identified biased ligands to multiple GPCRs. The company is currently testing its first novel biased ligand in humans. TRV120027 is being developed for the treatment of acute heart failure and Phase 1 clinical studies were successfully completed earlier this year, with a Phase 2 clinical trial expected to begin in 2011.
TRV120027 is a beta-arrestin-biased ligand that blocks angiotensin-mediated G-protein signaling at the AT1R receptor while simultaneously stimulating AT1R-specific beta-arrestin signaling . As presented at the 2010 Heart Failure Society of America meeting, TRV120027 possesses a unique set of properties in vivo, including cardiac performance enhancement, systemic blood pressure reduction, and a short half-life. TRV120027 has also shown cardiac unloading activity while preserving renal function, which is a key feature for a potential therapy for acute heart failure.
In addition to TRV120027, Trevena’s platform continues to deliver a portfolio of novel biased ligands, targeting receptors involved in CNS and inflammatory diseases. The two most advanced programs target receptors involved in pain control and novel biased ligands are currently being optimized to deliver transformational clinical candidates with improved therapeutic indices.
References
1. Lefkowitz RJ, Shenoy SK. Transduction of receptor signals by beta-arrestins. Science.2005;308:512-517.
2. DeWire SM, Ahn S, Lefkowitz RJ, Shenoy SK. Beta-arrestins and cell signaling. Annu Rev Physio. 2007;69:483-510.
3. Wei H, et al. Independent beta-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2. Proc Natl Acad Sci 2003;100:10782-10787.
4. Violin JD, DeWire, S.M., Yamashita, D., Rominger, D.H., Nguyen, L., Schiller, K., Whalen, E.J., Gowen, M. and Lark, M.W.t al. J. Pharm and Exp. Therap. 2010;335:1-8.
There are significant opportunities to improve upon currently marketed GPCR drugs because many have limited efficacy and undesirable adverse effects. Trevena’s scientific founders discovered that both G-proteins and beta-arrestins activate unique intracellular pathways responsible for separable biological responses , and these responses can be independently modulated using biased ligands . Trevena has translated these findings into a proprietary drug discovery platform, and has identified biased ligands to multiple GPCRs. The company is currently testing its first novel biased ligand in humans. TRV120027 is being developed for the treatment of acute heart failure and Phase 1 clinical studies were successfully completed earlier this year, with a Phase 2 clinical trial expected to begin in 2011.
TRV120027 is a beta-arrestin-biased ligand that blocks angiotensin-mediated G-protein signaling at the AT1R receptor while simultaneously stimulating AT1R-specific beta-arrestin signaling . As presented at the 2010 Heart Failure Society of America meeting, TRV120027 possesses a unique set of properties in vivo, including cardiac performance enhancement, systemic blood pressure reduction, and a short half-life. TRV120027 has also shown cardiac unloading activity while preserving renal function, which is a key feature for a potential therapy for acute heart failure.
In addition to TRV120027, Trevena’s platform continues to deliver a portfolio of novel biased ligands, targeting receptors involved in CNS and inflammatory diseases. The two most advanced programs target receptors involved in pain control and novel biased ligands are currently being optimized to deliver transformational clinical candidates with improved therapeutic indices.
References
1. Lefkowitz RJ, Shenoy SK. Transduction of receptor signals by beta-arrestins. Science.2005;308:512-517.
2. DeWire SM, Ahn S, Lefkowitz RJ, Shenoy SK. Beta-arrestins and cell signaling. Annu Rev Physio. 2007;69:483-510.
3. Wei H, et al. Independent beta-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2. Proc Natl Acad Sci 2003;100:10782-10787.
4. Violin JD, DeWire, S.M., Yamashita, D., Rominger, D.H., Nguyen, L., Schiller, K., Whalen, E.J., Gowen, M. and Lark, M.W.t al. J. Pharm and Exp. Therap. 2010;335:1-8.
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