|Phase 3||Mu-receptor||Moderate to Severe Pain||intravenous|
|TRV734||Phase 1||Mu-receptor||Moderate to Severe Pain||oral|
Migraine is a common and sometimes debilitating brain disorder that remains poorly treated for many patients. 610 million headaches are treated annually in the United States, including the acute treatment of episodic migraine headaches (440 million in 2014) as well as chronic migraine headaches (170 million in 2014)(1). We estimate that approximately 20% to 30% of these patients either do not respond to or cannot tolerate the market-leading triptan drug class, and an additional 25% would benefit from improved efficacy compared to these drugs.
Activation of the delta receptor has recently emerged as a potentially valuable new mechanism of action for treating migraine(2). In addition, delta opioid receptor agonists also have shown therapeutic potential in preclinical models for additional indications including Parkinson's disease(3) and neuropathic pain(4,5). These discoveries have attracted substantial research interest, in part because the delta receptor is not associated with the addiction liability of mu opioid drugs like morphine or oxycodone(6). However, delta receptor activation has caused seizures in preclinical studies, limiting the utility of many known delta receptor agonists(7). Several approaches to separating these delta receptor effects have been attempted, but none has yet achieved human proof of concept, and no selective delta receptor agonists have been approved for human use.
Trevena scientists discovered that delta receptor-mediated seizures are reduced in β-arrestin2 knockout mice, while effects linked to therapeutic benefit are preserved. This suggests that a G protein-biased ligand may be able to avoid delta receptor-mediated seizures while preserving the proposed CNS benefits of previous delta receptor agonists. Other preclinical work has showed that delta receptor biased ligands may offer improved efficacy over unbiased ligands in mood disorders(8).
Trevena scientists leveraged these discoveries and Trevena’s ABLE™ platform to design TRV250, a small molecule G protein biased ligand targeting the delta-receptor. Based on the initial profile of TRV250, we anticipate focusing our initial development efforts on the acute treatment of episodic and chronic migraine headaches, with a goal of providing a new option to migraine patients who are not adequately treated by currently approved medications.
1. Migraine Pharmacor Report © 2014 Decision Resources, LLC
2. Pradhan AA, et al, Delta opioid receptor agonists inhibit migraine-related hyperalgesia, aversive state and cortical spreading depression in mice. Br J Pharmacol. 2014 May;171(9):2375-84
3. Mabrouk OS, et al, New insights into the role of delta receptors in parkinsonism. J Neurochem. 2008 Dec;107(6):1647-59. View PDF.
4. Gaveriaux-Ruff C, et al, Genetic ablation of delta opioid receptors in nociceptive sensory neurons increases chronic pain and abolishes opioid analgesia. Pain. 2011 Jun;152(6):1238-48. Epub 2011 Feb 3. View on PubMed.
5. Scherrer G et al, Dissociation of the opioid receptor mechanisms that control mechanical and heat pain. Cell. 2009 Jun 12;137(6):1148-59. View PDF.
6. Hudzik TJ et al, Effects of the delta opioid agonist AZD2327 upon operant behaviors and assessment of its potential for abuse. Pharmacol Biochem Behav. 2014 Sep;124:48-57 View on PubMed.
7. Broom DC, et al, Comparison of receptor mechanisms and efficacy requirements for delta agonist-induced convulsive activity and antinociception in mice. J Pharmacol Exp Ther. 2002 Nov;303(2):723-9. View PDF.
8. Pradhan AA et al, The delta opioid receptor: an evolving target for the treatment of brain disorders. Trends Pharmacol Sci. 2011 Oct;32(10):581-90. View Free PMC Article.
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