|Phase||Target||Indication||Preclinical Phase 1 Phase 2 Phase 3 NDA|
|NDA||Mu-receptor||Moderate to Severe Acute Pain||intravenous|
|TRV734||Phase 1||Mu-receptor||Moderate to Severe Pain||oral|
Acute and chronic pain represents a serious and costly public health issue. Opioid analgesics are used to treat pain that is not adequately managed by weaker analgesics. However, these drugs are limited in their safety and tolerability by respiratory depression, constipation, nausea and vomiting. The constipating effects in particular are common with chronic opioid use and can be dose-limiting, resulting in inadequate pain control(2). Numerous approaches have been attempted to mitgate constipation. Laxatives, peripherally restricted opioid antagonists, such as methylnaltrexone and alvimopan, and multimodal analgesia, such as the opioid/SNRI tapentadol, are only partially effective, increase cost and can cause problematic new side effects in an attempt to mitgate the adverse effects of opioid analgesics. Based on the very large market and substantial limitations confronting current analgesics, we believe a new opioid with a more precisely targeted mechanism of action could provide a significant product opportunity in the acute and chronic pain markets.
TRV734 is an oral new chemical entity, distinct from oliceridine, that targets the μ-opioid receptor, and selectively stimulates G protein coupling at the receptor, the mechanism by which opioid drugs confer analgesia. Unlike morphine, oxycodone, and other currently prescribed opioids, TRV734 has very weak β-arrestin recruitment. Published scientific data suggest that β-arrestin-2 inhibits morphine pain relief and promotes morphine-induced respiratory depression, constipation, and analgesic tolerance(2, 3). Animal studies at Trevena demonstrated less gastrointestinal dysfunction with TRV734 than equianalgesic doses of oxycodone or morphine. This profile is consistent with the published data for OLINVO(4, 5), and suggests that TRV734 may be able to deliver better pain relief than current opioid analgesics like oxycodone, or equivalent pain relief to these drugs with improved safety and/or tolerability.
This study was completed in June 2014, and was a two-part study to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of TRV734 including single ascending dose, relative bioavailability, and food effect evaluations in 76 healthy adult males. TRV734 was orally available with dose-related increases in plasma concentrations, with peak plasma concentrations reached approximately one hour after dosing and a terminal half life consistent with use for treating acute pain. Pupil constriction indicative of analgesia was observed at doses of 80 mg and higher, and mild-to-moderate adverse effects were reported at the maximum explored dose of 250 mg. This suggests that the analgesic efficacy of TRV734 may be separable from opioid-related adverse effects. There were no clinically significant changes in vital signs, laboratory values or ECG parameters, and no severe or serious adverse events reported.
In February 2015 we reported results of this two-part trial, which evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of oral TRV734 in healthy males and females. In part A of the study, 125 mg TRV734 was given to 13 males following a high fat meal, a standard meal, and in three split portions following a fast. TRV734 in each dosing paradigm was associated with pupil constriction, a marker of CNS opioid activity, lasting approximately 4-6 hours, consistent with previous data. In part B of the study, 62 male and female subjects fed standard meals were given placebo, 10 mg immediate-release oxycodone, or 60, 80, 125, or 175 mg of TRV734 every 6 hours for 24 hours. Trends in pupil constriction and increased tolerability of cold-induced pain after the first and last dose were noted for all doses of TRV734, with duration of approximately 4-6 hours. These effects were similar to those seen with 10 mg oxycodone.
TRV734 was generally safe and well tolerated, and there were no serious or severe adverse events in either part of the study. Adverse events were generally opioid-related; the most common were somnolence, nausea, headache, dizziness, and vomiting, and were observed for both TRV734 and oxycodone. The Bowel Function Index (BFI), a validated tool to evaluate clinical constipation, was used to explore the potential for TRV734 to cause opioid-induced constipation and in this study showed encouraging trends compared to oxycodone.
Trevena is seeking a worldwide partner to develop and commercialize TRV734.
1. Raehal KM et al, Morphine side effects in β-arrestin 2 knockout mice. J Pharmacol Exp Ther. 2005 Sep;314(3):1195‑201. View PDF.
2. Bohn LM et al, Mu opioid receptor desensitization by β-arrestin-2 determines morphine tolerance but not dependence. Nature. 2000 Dec 7;408(6813):720‑3. View on PubMed.
3. DeWire SM et al. A G protein-biased ligand at the Mu opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J Pharmacol Exp Ther. 2013 Mar;344(3):708‑17. View PDF.
4. Soergel DG et al. Biased agonism of the mu-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. PAIN 2014 Sep; 155(9): 1829-35. View on PubMed.
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