Biased agonism of the μ-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: A randomized, double-blind, placebo-controlled, crossover study in healthy volunteers

Abstract

Opioids provide powerful analgesia but also efficacy-limiting adverse effects, including severe nausea, vomiting, and respiratory depression, by activating μ-opioid receptors. Preclinical models suggest that differential activation of signaling pathways downstream of these receptors dissociates analgesia from adverse effects; however, this has not yet translated to a treatment with an improved therapeutic index. Thirty healthy men received single intravenous injections of the biased ligand TRV130 (1.5, 3, or 4.5mg), placebo, or morphine (10mg) in a randomized, double-blind, crossover study. Primary objectives were to measure safety and tolerability (adverse events, vital signs, electrocardiography, clinical laboratory values), and analgesia (cold pain test) versus placebo. Other measures included respiratory drive (minute volume after induced hypercapnia), subjective drug effects, and pharmacokinetics. Compared to morphine, TRV130 (3, 4.5mg) elicited higher peak analgesia (105, 116 seconds latency vs 75 seconds for morphine, P<.02), with faster onset and similar duration of action. More subjects doubled latency or achieved maximum latency (180 seconds) with TRV130 (3, 4.5mg). Respiratory drive reduction was greater after morphine than any TRV130 dose (-15.9 for morphine versus -7.3, -7.6, and -9.4 h*L/min, P<.05). More subjects experienced severe nausea after morphine (n=7) than TRV130 1.5 or 3mg (n=0, 1), but not 4.5mg (n=9). TRV130 was generally well tolerated, and exposure was dose proportional. Thus, in this study, TRV130 produced greater analgesia than morphine at doses with less reduction in respiratory drive and less severe nausea. This demonstrates early clinical translation of ligand bias as an important new concept in receptor-targeted pharmacotherapy.

Fulfilling the Promise of "Biased" G Protein–Coupled Receptor Agonism

“…This compound, factor of 3-fold for G protein over arrestin signaling), yet the authors reported a favorable separation between analgesic efficacy and gastrointestinal and respiratory side effects when tested in rodent models (Dewire et al, 2013). Currently in clinical trials, TRV-130 has proven to be a very potent analgesic in humans (Soergel et al, 2014). However, the results of the phase II clinical trial have not revealed a significant reduction in side effects, raising the question of whether biased agonists at MOR can dissociate analgesia from respiratory depression/constipation or if a greater degree of bias is necessary to translate into human therapeutic responses.…”

Opioid-induced constipation: advances and clinical guidance

“…TRV-130 has also shown central opioid action, as demonstrated by marked pupillary constriction [Soergel et al 2014a]. Currently, TRV-130 is being evaluated in patients undergoing abdominoplasty and bunionectomy [ClinicalTrials.gov identifiers: NCT02100748, NCT02335294].…”

Biased Agonism of Endogenous Opioid Peptides at theμ-Opioid Receptor

“…Indeed, enhanced morphine analgesia with reduced respiratory and gastrointestinal side effects was reported in b-arr2 knockout mice (Bohn et al, 1999;Raehal et al, 2005;Maguma et al, 2012). Recently, ligands with impaired b-arr2 recruitment have been reported to provide potent analgesia with less severe side effects (Groer et al, 2007;DeWire et al, 2013;Soergel et al, 2014). However, the improved pharmacological profiles of these ligands may still be due to their partial agonism, with lower overall efficacy than morphine, rather than true "bias" away from b-arr2 recruitment (Thompson et al, 2015).…”