URB937 is in development for treatment of acute, post-operative pain, a market that has been estimated at $5.9 billion (GBI Research). Exxel Pharma is positioning the drug as a safe, non-addictive alternative to opiate type drugs, and the company is exploring additional clinical indications for commercialization.
The URB937 drug is a small molecule, peripheral inhibitor of the enzyme fatty acid amide hydrolase (FAAH; IC50=26.8 nM). The FAAH enzyme breaks down the naturally occurring endocannabinoid anandamide, and inhibition of FAAH by URB937 results in elevated anandamide levels and increased cannabinoid receptor signaling. The drug has profound analgesic effects in a variety of animal models of nociceptive, inflammatory and neurogenic pain, indicating it will have broad clinical application and commercial potential. Importantly, the drug does not penetrate the blood-brain barrier and therefore exerts its action only in peripheral tissues. This feature differentiates URB937 from any other FAAH inhibitors currently in development, and significantly enhances the analgesic effects of the drug compared to global FAAH inhibitors.
In animal models of postoperative pain, oral administration of URB937 suppresses pain in a dose-dependent manner, with ED50 values of 1.8-3.4 mg/kg. Importantly, URB937 is more efficacious and longer lasting than
The URB937 drug is excluded from the brain by a transporter with a pharmacology resembling BCRP, but is free to act on peripheral FAAH. The site of analgesic action is most likely peripheral pain-sensing nerve endings (red circle). Expanded red circle shows the predicted molecular mechanism of drug action, inhibition of FAAH-catalyzed metabolism of anandamide (AEA), which allows for persistent AEA activation of peripheral CB1 receptors on peripheral nerve endings. Activation of CB1 receptors ultimately reduces transmission of pain signals to the spinal cord, preventing pain sensation (Modified from Nature Neuroscience).
Based on preclinical efficacy data, mechanism of action and a significant unmet medical need, Exxel Pharma is developing URB937 as a transformative therapy for non-addictive management of chronic and acute pain. The clinical lead indication is post-surgical pain, representing a market that has been estimated to $5.9 billion (GBI Research), and which is ripe for disruption by novel, safe, non-addictive therapies such as URB937.
| Animal model | Species | Gender | Comparative analgesic efficacy | Reference |
| Inflammatory Pain | ||||
| Carrageenan | Mouse | Male | Superior to URB597 | Clapper et al., 2010 |
| Mouse | Male | Superior to Indomethacin and Gabapentin | Sasso et al., 2012 | |
| Synergistic with Indomethacin | ||||
| Rat | Female | Superior to Indomethacin | Moreno-Sanz et al., 2012 | |
| Formalin model | Rat | Male | Clapper et al., 2010 | |
| Complete Freud’s adjuvant (CFA) | Mouse | Male | Superior to URB597, PF-04457845 and | Sasso et al., 2012 |
| Dexamethasone | ||||
| Neuropathic Pain | ||||
| Chronic constriction injury (CCI) | Mouse | Male | Comparable to URB597 | Clapper et al., 2010 |
| Mouse | Male | Superior to Indomethacin and Gabapentin | Sasso et al., 2012 | |
| Synergistic with Indomethacin | ||||
| Chemotherapy-induced neuropathy | Rat | Male | Comparable to URB597 and Morphine | Guindon et al., 2013 |
| Superior to Gabapentin | ||||
| Postoperative Pain | ||||
| Brennan model | Mouse | Male | Synergistic with Ankle Joint Mobilization (AJM) | Martins et al., 2013 |
| Mouse | Male | Superior to URB597, PF-04457845, Indomethacin, | Sasso et al., Unpublished | |
| Gabapentic and Morphine | ||||
| Accelerates wound healing | ||||
| Visceral Pain | ||||
| Acetic acid-induced writhing | Mouse | Male | Comparable to URB597 and Indomethacin | Clapper et al., 2010 |
| Mouse | Female | Comparable to Indomethacin | Moreno-Sanz et al., 2012 |
A list of published URB937 data, including work from international, academic research laboratories, can be found here.
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