Benefit and Risk Evaluation of Biased μ-Receptor Agonist Oliceridine versus Morphine.

Benefit and Risk Evaluation of Biased μ-Receptor Agonist Oliceridine versus Morphine.

Albert Dahan, C. Jan van Dam, Marieke Niesters, Monique van Velzen, Michael J. Fossler, Mark A. Demitrack, Erik Olofsen. Anesthesiology 2020. doi:

Incidence of Opioid-Induced Respiratory Depression Associated with Oliceridine and Morphine as Measured by the Frequency and Average Cumulative Duration of Dosing Interruption in Patients Treated for Acute Postoperative Pain: Findings indicate improved safety with oliceridine.

Evaluating the Incidence of Opioid-Induced Respiratory Depression Associated with Oliceridine and Morphine as Measured by the Frequency and Average Cumulative Duration of Dosing Interruption in Patients Treated for Acute Postoperative Pain.

Sabry Ayad, Mark A. Demitrack, David A. Burt, Cathy Michalsky, Linda Wase, Michael J. Fossler & Ashish K. Khanna. Clin Drug Investig (2020).

Oliceridine Monograph

Oliceridine, a G protein-selective ligand at the μ-opioid receptor, for the management of moderate to severe acute pain

Gan TJ & Wase L. Drugs Today (Barc). 2020 Apr;56(4):269-286. doi: 10.1358/dot.2020.56.4.3107707.

Phase 3 “Real World” Safety Study for Oliceridine

ATHENA: A Phase 3, Open-Label Study Of The Safety And Effectiveness Of Oliceridine (TRV130), A G-Protein Selective Agonist At The μ-Opioid Receptor, In Patients With Moderate To Severe Acute Pain Requiring Parenteral Opioid Therapy

Bergese SD, Brzezinski M, Hammer GB, Beard TL, Pan PH, Mace SE, Berkowitz RD, Cochrane K, Wase L, Minkowitz HS, Habib AS. J Pain Research. 2019, 12: 3113-3126.

DOI: 10.2147/JPR.S217563 [open access]

Pharmacokinetics of IV oliceridine in patients with renal impairment or patients with mild/moderate hepatic impairment- No dose adjustments required

The Influence of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Oliceridine

Nafziger AN, Arscott KA, Cochrane K, Skobieranda F, Burt DA, Fossler MJ. Clin Pharmacol Drug Dev. 2019 Nov 7. doi:10.1002/cpdd.750.[open access]

Oliceridine (TRV130) Phase-3 Pivotal trial in soft-tissue (abdominoplasty) acute pain

APOLLO-2: A Randomized, Placebo and Active-Controlled Phase III Study Investigating Oliceridine (TRV130), a G Protein-Biased Ligand at the μ-Opioid Receptor, for Management of Moderate to Severe Acute Pain Following Abdominoplasty

Neil K. Singla, Franck Skobieranda, David G. Soergel, Monica Salamea, David A. Burt, Mark A. Demitrack, Eugene R. Viscusi Pain Pract. 2019 Sep;19(7):715-731

Oliceridine (TRV130) Phase-3 Pivotal trial in hard-tissue (bunionectomy) acute pain

APOLLO-1: a randomized placebo and active-controlled phase III study investigating oliceridine (TRV130), a G protein-biased ligand at the µ-opioid receptor, for management of moderate-to-severe acute pain following bunionectomy

Eugene R Viscusi, Franck Skobieranda, David G Soergel,Emily Cook, David A Burt, and Neil Singla. J Pain Res. 2019; 12: 927–943.

Oliceridine (TRV130) Phase 2b trial in soft-tissue (abdominoplasty) acute pain

A randomized, Phase IIb study investigating oliceridine (TRV130), a novel µ-receptor G-protein pathway selective (μ-GPS) modulator, for the management of moderate to severe acute pain following abdominoplasty

Neil Singla, Harold S Minkowitz, David G Soergel, David A Burt, Ruth Ann Subach, Monica Y Salamea, Michael J Fossler, and Franck Skobieranda. J Pain Res. 2017; 10: 2413–2424

Oliceridine (TRV130) Phase 2 trial in hard-tissue (bunionectomy) acute pain

A randomized, phase 2 study investigating TRV130, a biased ligand of the μ-opioid receptor, for the intravenous treatment of acute pain.

Viscusi ER, Webster L, Kuss M, Daniels S, Bolognese JA, Zuckerman S, Soergel DG, Subach RA, Cook E, Skobieranda F. Pain. 2016 Jan;157(1):264-72.

TRV130- phase I study in healthy volunteers

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

Soergel D, Subach RA, Burnham N, Lark MW, James IE, Sadler BM, Skobieranda F, Violin JD, Webster LR. Pain. 2014 Sep;155(9):1829-35

TRV130 – analgesia and ventilatory response to hypercapnia vs. morphine in healthy volunteers

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

Soergel DG, Subach RA, Burnham N, et al. Pain. 2014;155(9):1829-1835. doi:10.1016/j.pain.2014.06.011

TRV130- First clinical experience, pharmacokinetics and pharmacodynamics

First clinical experience with TRV130: pharmacokinetics and pharmacodynamics in healthy volunteers

Soergel DG, Subach RA, Sadler B, Connell J, Marion AS, Cowan CL, Violin JD, Lark MW. J Clin Pharmacol. 2014 Mar;54(3):351-7.

TRV130-Concept of biased ligand

Structure-activity relationships and discovery of a G protein biased μ opioid receptor ligand, [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro-[4.5]decan-9-yl]ethyl})amine (TRV130), for the treatment of acute severe pain

Chen XT, Pitis P, Liu G, Yuan C, Gotchev D, Cowan CL, Rominger DH, Koblish M, Dewire SM, Crombie AL, Violin JD, Yamashita DS. J Med Chem. 2013 Oct 24;56(20):8019-31.

TRV-130 preclinical safety results

A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine

DeWire SM, Yamashita DS, Rominger DH, Liu G, Cowan CL, Graczyk TM, Chen XT, Pitis PM, Gotchev D, Yuan C, Koblish M, Lark MW, Violin JD. J Pharmacol Exp Ther. 2013 Mar;344(3):708-17.

Improved Safety of Opioid Analgesic Oliceridine Compared to Morphine Assessed by Utility Function Analysis

Albert Dahan, Marieke Niesters, Michael J. Fossler, Mark A. Demitrack, Erik Olofsen.

Annual Meeting of the American Society of Anesthesiologists (ASA); 2019

Biased ligands at G-protein-coupled receptors: promise and progress

Violin JD, Crombie AL, Soergel DG, Lark MW. Trends Pharmacol Sci. 2014 Jul;35(7):308-16.

Signalling bias in new drug discovery: detection, quantification and therapeutic impact

Kenakin T, Christopoulos A. Nat Rev Drug Discov. 2013 Mar;12(3):205-16.

Discovery of β-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy

Allen JA, Yost JM, Setola V, Chen X, Sassano MF, Chen M, Peterson S, Yadav PN, Huang XP, Feng B, Jensen NH, Che X, Bai X, Frye SV, Wetsel WC, Caron MG, Javitch JA, Roth BL, Jin J. Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18488-93.

Structural features for functional selectivity at serotonin receptors

Wacker D, Wang C, Katritch V, Han GW, Huang XP, Vardy E, McCorvy JD, Jiang Y, Chu M, Siu FY, Liu W, Xu HE, Cherezov V, Roth BL, Stevens RC. Science. 2013 May 3;340(6132):615-9.

Quantifying ligand bias at seven-transmembrane receptors

Rajagopal S, Ahn S, Rominger DH, Gowen-MacDonald W, Lam CM, Dewire SM, Violin JD, Lefkowitz RJ. Mol Pharmacol. 2011 Sep;80(3):367-77.

Beta-arrestin-biased ligands at seven-transmembrane receptors

Violin JD, Lefkowitz RJ. Trends Pharmacol Sci. 2007 Aug;28(8):416-22.

Beta-arrestins and cell signaling

DeWire SM, Ahn S, Lefkowitz RJ, Shenoy SK. Annu Rev Physiol. 2007;69:483-510.

Biased ligands: pathway validation for novel GPCR therapeutics

Rominger DH, Cowan CL, Gowen-MacDonald W, Violin JD. Curr Opin Pharmacol. 2014 Jun;16:108-15

TRV250 – Phase 1 Study in Healthy Volunteers

A Phase I, Randomized, Single Blind, Placebo Controlled, Single Ascending Dose Study of the Safety, Tolerability, and Pharmacokinetics of Subcutaneous and Oral TRV250, a G Protein-Selective Delta Receptor Agonist, in Healthy Subjects.

Fossler MJ, Schmith V, Greene SA, et al. CNS Drugs. 2020;34(8):853-865. doi:10.1007/s40263-020-00738-0

A Phase 1 Healthy Volunteer Study of the Safety, Tolerability and Pharmacokinetics of TRV250, a G Protein-Selective Delta Receptor Agonist

Mark A. Demitrack, Michael S. Kramer, Kelly Arscott, Ian E. James, Michael J.Fossler.

A First-in-Human Clinical Study With TRV734, an Orally Bioavailable G-Protein-Biased Ligand at the μ-Opioid Receptor

James IE, Skobieranda F, Soergel DG, Ramos KA, Ruff D, Fossler MJ. Clin Pharmacol Drug Dev. 2019 Jul 8.

Formulation and Food Effect Studies of TRV734, an Oral, G Protein-biased Ligand of the μ-opioid Receptor

Franck Skobieranda, Ian E. James, Michael J. Fossler, Gregory Alcorn, David G. Soergel.

An orally available µ-opioid receptor biased ligand is analgesic with reduced constipation in rodents

Jonathan D. Violin, Scott M. DeWire, Mike Koblish, Daniel Chen, Aimee L. Crombie, Dennis Yamashita, Ruth Ann Subach, David G. Soergel, Michael W. Lark.

β-Arrestin-Biased Angiotensin II Receptor Agonists for COVID-19

Manglik A, Wingler LM, Rockman HA, Lefkowitz RJ. Circulation. 15 May 2020.