The biotech company Trevena recently released top-line data from a Phase IIb trial of a ‘biased’ligand that is designed to cherry-pick the beneficial rather than the deleterious signalling pathways activated by the μ-opioid receptor. The small molecule TRV130 matched morphine for pain relief after surgery while showing a reduced liability for hypoventilation, nausea and vomiting.“Classically we thought that on-target adverse effects were unavoidable, that you could not dissect them from whatever benefits that receptor could mediate,” says Jonathan Violin, scientific co-founder of Trevena. This Phase II success proves that such biochemical dissection is possible with biased ligands, he adds, offering new hope for drug classes that have burdensome on-target side effect profiles.

So far, Trevena is the only company to advance biased ligands into clinical trials, but a 2012 collaboration between the company and Merck & Co. to identify novel biased ligands shows that big pharma companies are also interested. And although G protein-coupled receptors (GPCRs) are the first focus of choice for these compounds, the potential for ligand bias transcends drug classes and targets.