About Trevena
Trevena is focused on the identification of novel GPCR drugs with unique biology designed to deliver high levels of efficacy and/or low side effect potential.
In the past, drugs that target GPCRs were developed based on a limited signaling paradigm in which stimulation of the receptor (e.g. the beta-adrenergic receptor) by an agonist (e.g. epinephrine) leads to activation of all intracellular signaling pathways emanating from the receptor via a heterotrimeric G-protein. This G-protein activates a primary intracellular signal transduction cascade, leading to second messenger stimulated signaling (e.g. via cAMP) and resulting in changes in physiological function (e.g. heart rate).
However, GPCRs do not only signal in this simplistic fashion, but rather activate a network of downstream effects comprised of parallel signal transduction pathways. Two families of such pathways appear to be ubiquitous across nearly all GPCRs: G-proteins, as described above, and beta-arrestins, which desensitize G-protein signals, promote receptor internalization, and initiate distinct signals in their own right. Like G-proteins, the two beta-arrestin isoforms (beta-arrestin1 and beta-arrestin2) can activate a range of downstream effectors, including MAPK and PI3K pathways.
Classical pharmacology assumes that ligands will turn all of these various signals on (in the case of agonists) or off (in the case of antagonists) to an equivalent extent. However, it is now clear that this is not always the case. Some intrinsically biased ligands stabilize discrete receptor states, engaging only a subset of a receptor’s downstream pathways
The efficacy and side effect profile associated with any drug molecule is a function of all the signaling pathways that it activates (or inhibits) when it binds to its target(s). In the case of GPCRs, certain pharmacologic effects are strongly linked with specific subsets of their signaling pathways, while some side effects can result from activation of distinct pathways emanating from the same receptor. Trevena is focused on developing GPCR ligands that are biased towards induction or blockade of specific signaling pathways to selectively engage the desired signal cascade to deliver optimal therapeutic effects.
Trevena's drug discovery platform is licensed from Duke University Medical Center and is is based on extensive research from the laboratories of Robert J Lefkowitz, M.D., James B. Duke Professor of Medicine and Biochemistry and Howard A. Rockman, M. D., Chief of Cardiovascular Medicine and Edward Orgain Professor of Cardiology. The platform translates into a fully integrated collection of tools for finding and characterizing biased GPCR ligands, the Advanced Biased Ligand Explorer (ABLE). The platform includes customized assays, proprietary software, animal models and unique biological signaling information across multiple GPCRs as illustrated below:
Trevena has already applied this platform to a number of receptors delivering a pipeline of differentiated GPCR targeted medicines.