SBIR-STTR Award

Pain management remains a significant unmet medical need. Anandamide is an endogenous marijuana-like ('endocannabinoid') molecule that plays important roles in the regulation of pain. Previous work has shown that endocannabinoid receptors located outside the central nervous system (CNS) exert a powerful regulatory control over pain initiation. Moreover, there is evidence that clinical conditions associated with chronic pain are accompanied by abnormal elevations in the peripheral levels of anandamide. The biological actions of anandamide are stopped by the intracellular enzyme, fatty acid amide hydrolase (FAAH), which catalyzes the deactivating hydrolysis of anandamide. To explore the role of peripheral anandamide in pain regulation, the lab of Daniele Piomelli at the University of California, Irvine, has developed a novel class of FAAH inhibitors that do not enter the CNS and therefore suppress anandamide deactivation only in the periphery of the body. The prototype member of this class is called URB937. URB937 is potent at attenuating pain-related behaviors in animal models, suggesting that it might offer a radically innovative approach to pain therapy. Our proposal has three primary goals aimed at testing this hypothesis: (1) Further characterize the analgesic properties of URB937. We will profile the effects of oral URB937 in industry-appropriate preclinical models of post-operative pain and visceral pain/referred hyperalgesia. (2) Compare the analgesic efficacy of URB937 with that of other analgesics. We will compare the efficacy of URB937 with that of clinically used analgesics, including opiates (morphine), non- steroidal anti-inflammatory drugs (indomethacin) and gabapentin. (3) Determine whether URB937 produces side effects similar to those caused by other analgesics. Clinically used analgesics cause a series of common side effects that include gastric irritation, constipation and sedation. Previous work in our lab has shown that URB937 produces no gastric irritation after oral dosing. We will test now whether URB937 causes constipation or sedation, using morphine and gabapentin as comparators. If the results of these studies show that URB937 is equal or superior to its comparators, we will apply for STTR Phase 2 funding to move forward the preclinical development of URB937.

Public Health Relevance Statement:


Public Health Relevance:
Current analgesic drugs are effective in only 25% of patients and can cause a variety of adverse events by acting on brain cells. We recently discovered a new class of medications, called 'peripheral FAAH inhibitors', which alleviate pain in experimental animals without entering the brain. Here, we propose to lay the groundwork needed to translate this research finding into a safe and effective treatment for human pain conditions.

Project Terms:
Absence of pain sensation; Acute; Adverse effects; Adverse event; afferent nerve; Analgesics; anandamide; Animal Model; Animals; Anti-inflammatory; Anti-Inflammatory Agents; Anticonvulsants; Arachidonic Acids; Attenuated; Behavior; Biological; Biology; Brain; brain cell; California; Chemical Stimulation; chronic pain; Clinical; Colon; comparative efficacy; Complex Regional Pain Syndromes; Constipation; Data; Development; Dose; effective therapy; Endocannabinoids; Enzymes; Ethanolamines; experience; fatty acid amide hydrolase; Fiber; Funding; gabapentin; Genetic; Goals; Grant; Human; Hydrolysis; Hyperalgesia; Indomethacin; Industry; inhibitor/antagonist; innovation; irritation; Knowledge; Marihuana; Mediating; Medical; Medicine; member; Modeling; Morphine; mouse model; Mus; Nerve Fibers; Neuraxis; Neurons; Neurotransmitters; Nociception; novel; novel therapeutics; Operative Surgical Procedures; Opiates; Oral; Pain; pain inhibition; Pain management; Patients; Peripheral; Pharmaceutical Preparations; Phase; Play; Positioning Attribute; Postoperative Pain; pre-clinical; Pre-Clinical Model; Preclinical Drug Development; Process; Property; prototype; public health relevance; receptor; receptor expression; Receptor, Cannabinoid, CB1; Regulation; Research; Role; Safety; Sedation procedure; Series; Signal Transduction; Small Business Technology Transfer Research; Spinal Cord; Spinal cord posterior horn; Stomach; Testing; Tissues; Translating; transmission process; Universities; Visceral pain; Work

Pain management is a significant unmet medical need. Anandamide is an endocannabinoid mediator that plays important roles in the regulation of pain. Previous work has shown that endocannabinoid receptors located outside the central nervous system (CNS) exert a powerful regulatory control over pain initiation. The biological actions of anandamide are stopped by the enzyme, fatty acid amide hydrolase (FAAH). To explore the role of anandamide in the peripheral regulation of pain, our lab has developed a novel class of FAAH inhibitors that do not enter the CNS. The lead compound in this class, called URB937, exerts profound analgesic effects in animal models, suggesting that peripheral FAAH blockade may offer an innovative approach to pain therapy. Work done during the Phase 1 of the present application has demonstrated that URB937 (a) suppresses postoperative pain in mice more effectively than do currently used analgesics; (b) does not cause side effects typical of those drugs (i.e., sedation, constipation, gastric damage); (c) shows a high degree of target selectivity; (d) has excellent oral bioavailability in rats; and (e) exerts no genotoxic effcts in the Ames' test and does not inhibit the human potassium hERG channel. These results identify URB937 as a suitable candidate for preclinical development in postoperative pain, an extremely common but still underserved pain condition. The objective of present proposal is to complete all key activities needed to enable the filing of an Investigational New Drug (IND) for URB937 in postoperative pain. Our specific aims are: Aim 1. Synthesis and physicochemical characterization of URB937. We will produce a large-scale lot of URB937 for use in nonclinical pharmacokinetics and toxicology studies. Aim 2. Drug metabolism (DM) and pharmacokinetic (PK) properties of URB937. We will collect the DM-PK data necessary to support the IND filing of URB937. Aim 3. Nonclinical toxicology properties of URB937. We will collect the toxicology data necessary to support the IND filing of URB937. Aim 4. Nonclinical pharmacodynamics of URB937. We will develop a circulating biomarker for peripheral FAAH inhibition, which will be of great value during the clinical development of URB937. The proposed studies will be coordinated by an experienced team of scientists and pharmaceutical professionals, which include Anteana's cofounders, Professor Daniele Piomelli and Dr. Miguel Garcia-Guzman, Professor Andrew Rice (Imperial College, London), a world-recognized leader in pain therapy; along with and independent consultants Dr. Edward Monaghan (Soar Pharmaceutical Development Services: preclinical development); Dr. Fred Reno (toxicology); Dr. William Schmidt (NorthStar Consulting, health economics); Dr. Jason Brittain (JNG Pharmaceutical Consulting, Chemistry, Manufacturing, and Controls); and Dr. Richard Lowenthal (Pacific Link Consulting, regulatory affairs). We expect that the successful completion of our studies will provide the data needed to file an IND for URB937 and allow us to raise the private capital necessary to bring this compound to clinical proof of concept.

Public Health Relevance Statement:


Public Health Relevance:
Current painkillers work well in only about one quarter of the patients who take them, and can cause a variety of negative effects - for example, sedation and addiction - by acting on cells of the brain. Our lab has recently discovered a new class of medications, called `peripheral FAAH inhibitors', which cannot enter the brain yet produce powerful pain suppression in experimental models. Here, we propose a series of studies that will enable the clinical testing of the lead compound in this class for the treatment of acute pain after surgery.

Project Terms:
Acute Pain; addiction; Adverse effects; Ames Assay; Analgesics; anandamide; Animal Model; Biological; Biological Assay; Biological Availability; Biology; Brain; brain cell; Capital; Chemistry; circulating biomarkers; Clinic; Clinical; clinical development; Collection; college; commercialization; Constipation; Consult; Data; Development; Drug Kinetics; drug metabolism; Endocannabinoids; Enteral; Enzymes; experience; Experimental Models; FAAH inhibitor; fatty acid amide hydrolase; Generations; genotoxicity; Goals; health economics; Human; Industry; innovation; Investigational Drugs; Investments; Ion Channel; Knowledge; Lead; Link; London; Long-Term Effects; Marijuana; Mediator of activation protein; Medical; Membrane Transport Proteins; Mus; Neuraxis; Neurotransmitters; Non-Steroidal Anti-Inflammatory Agents; novel; novel therapeutics; Operative Surgical Procedures; Opiates; Oral; Pain; Pain management; Patients; Peripheral; peripheral pain; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Play; Postoperative Pain; Potassium; preclinical development; Privatization; professor; programs; Property; public health relevance; Rattus; receptor; Regulation; Regulatory Affairs; research clinical testing; Rice; Role; Safety; Scientist; Sedation procedure; Series; Services; Spinal Cord; Stomach; Toxicology; Translating; United States Food and Drug Administration; Work