FDA approves first GPCR biased agonist

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The FDA has approved Trevena’s μ-opioid agonist oliceridine for moderate to severe acute pain in adults. Oliceridine was once heralded as an exemplar of the possibilities of biased GPCR agonists, drugs that can preferentially activate only a subset of a receptor’s signalling pathways. Even with the approval, however, the purported clinical benefits of these agents remain to be demonstrated.

“I don't think this is going to move the field [of biased agonism] in one direction or another,” says Bryan Roth, a pharmacologist at the University of North Carolina who discovered another biased opioid agonist called PZM21. “It is a big win for Trevena,” he adds.

Traditional opioid agonists are associated with adverse events including respiratory depression and gastrointestinal complications. Some evidence suggests, however, that the analgesic effects of these GPCR agonists may be a result of associated G-protein signalling whereas the adverse events are a result of associated β-arrestin 2 signalling. With oliceridine, Trevena sought to preferentially stimulate the G-protein signalling, in the hope of developing a next-generation opioid with a cleaner safety profile.

The company first submitted the drug for approval in 2017. An FDA advisory committee voted against approving the drug in 2018, after the agency noted concerns with the drug’s safety and benefit–risk profile. Months later, the FDA rejected the drug. Now, even as the agency approved the drug, it noted that the safety profile of the drug “is similar to other opioids”.

Earlier this year, three laboratories reported on their efforts to collaboratively evaluate whether the side effects of opioids are due to β-arrestin 2 signalling. Writing in the British Journal of Pharmacology, they concluded that their results “call into question the concept of developing G protein-biased μ-opioid receptor agonists as a strategy for the development of safer opioid analgesic drugs”.

Nature Reviews Drug Discovery 19, 659 (2020)

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