Abstract Details

Title First Human Dosing Experience with TRV130, a Biased Ligand at the Mu Opioid Receptor

Topic Ethics, Pain and Palliative Care

Presentation(s) P02 - (-)

Poster/Presentation
Number 013

Objective

Background BACKGROUND: TRV130 is a novel highly selective G-protein biased ligand of the mu opioid receptor; it stimulates canonical G protein coupling while simultaneously blocking [szlig]-arrestin-mediated signaling. In animals, TRV130 is a potent, efficacious analgesic with improved GI and respiratory side effects compared to morphine.

Design/Methods DESIGN/METHODS: A 3-part clinical study was conducted to evaluate the tolerability, PK and PD of TRV130 in healthy male subjects. The study was conducted under GCP principles.

Results RESULTS: In Part A eight cohorts of 8 subjects were enrolled. In each cohort, placebo (n=2) or TRV130 (n=6) was administered as a one-hour infusion. The TRV130 starting dose was selected based on the preclinical toxicology studies with subsequent doses determined by tolerability. TRV130 had a half-life of approximately 2 hours and produced a dose-related pupil constriction. TRV130 4 mg produced significant, near-maximal pupil constriction with no nausea or vomiting. In Part B, the PK of TRV130 was evaluated in 4 phenotypic CYP2D6 poor metabolizers (PMs). In PMs, TRV130 had similar maximal plasma concentrations and an approximately 50% reduction in clearance as non-PMs at the same dose. This suggests that tolerability will be similar in PMs and non-PMs, although PMs may require less frequent dosing. In Part C, the tolerability of bolus administration was studied. Six subjects received TRV130 1.5 mg administered over 30, 15, 5 and 1 minute on successive study days. TRV130 was well-tolerated at all rates. The effect of the 1.5 mg dose on pupil diameter was in line with the expected effect given the plasma concentrations observed.

Conclusions CONCLUSIONS: TRV130 is a novel mu opioid receptor G-biased ligand which exhibited excellent PK, PD and tolerability. Additional studies are planned to continue development of TRV130 for post-operative analgesia and to explore the feasibility of developing a transdermal formulation.

Authors/Disclosures
PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Gavin Giovannoni, MD (QMUL)	Dr. Giovannoni has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Giovannoni has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi. Dr. Giovannoni has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Merck KGaA. Dr. Giovannoni has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche-Genentech. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Moderna. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sandoz. Dr. Giovannoni has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Astoria Biologica. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Zenas. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Giovannoni has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Medscape.
	No disclosure on file

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