title: 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.
authors: Trevena, Inc, King of Prussia, PA, USA Hambel Statistical Consulting LLC, Wayne, PA, USA ICON plc, Hanover, MD, USA CRI Lifetree Inc, Salt Lake City, UT, USA.
authors: David G
authors: DG
authors: Soergel
authors: Ruth Ann
authors: RA
authors: Subach
authors: Nancy
authors: N
authors: Burnham
authors: Michael W
authors: MW
authors: Lark
authors: Ian E
authors: IE
authors: James
authors: Brian M
authors: BM
authors: Sadler
authors: Franck
authors: F
authors: Skobieranda
authors: Jonathan D
authors: JD
authors: Violin
authors: Lynn R
authors: LR
authors: Webster
mesh_terms: D000293:Adolescent; D000328:Adult; D000698:Analgesia; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D018592:Cross-Over Studies; D004244:Dizziness / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006261:Headache / Q000139:chemically induced; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy*; D013141:Spiro Compounds / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D013876:Thiophenes / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D014839:Vomiting / Q000139:chemically induced; D055815:Young Adult
chemical_list: C586842:((3-methoxythiophen-2-yl)methyl)((2-(9-(pyridin-2-yl)-6-oxaspiro(4.5)decan-9-yl)ethyl))amine; D000701:Analgesics, Opioid; D013141:Spiro Compounds; D013876:Thiophenes; D009020:Morphine
keywords: Biased ligand; Clinical trial; Morphine; Postoperative pain; mu-Opioid receptor