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Opioid Receptor Blocker Shows Promise in Phase II Depression Trial

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Opioid Receptor Blocker Shows Promise in Phase II Depression Trial NEWS & ANALYSIS BIOBUSINESS BRIEFS acetylcholine receptor α4β2 subtype TRIAL WATCH modulator developed by Targacept and AstraZeneca, failed despite showing promising results in Phase II trials. Opioid receptor blocker Such failures highlight the challenges in designing and implementing Phase III trials for depression. “These include the need to shows promise in Phase II identify and recruit the most appropriate patient population, using the right depression trial assessment tools, and conducting high-quality objective assessments of the patients,” says Trivedi. Preliminary results from a Phase II trial of addiction. So combining buprenorphine Non-monoaminergic antidepressants Alkermes’s ALKS 5461, a therapeutic that with a μ-opioid receptor antagonist may also offer a more rapid onset of action acts as a κ-opioid receptor antagonist, gives the formulation greater functional than current drugs. Trivedi notes that indicate that it improves symptoms in selectivity and makes pharmacological although it is of high interest to see whether patients with major depressive disorder sense,” says Chavkin. patients who do respond to current who do not respond to current therapies. The Phase II trial assessed the efficacy treatments could benefit from faster-acting Current antidepressants — selective and safety of ALKS 5461 administered antidepressants, determining this would serotonin reuptake inhibitors, serotonin once daily for 4 weeks as an adjunctive require a very specific study design. “I am noradrenaline reuptake inhibitors and tricyclic treatment in 142 patients. The study not aware of studies that have successfully antidepressants — all modulate monoamine met its primary end point of a significant randomized treatment responders to levels and have limitations that include a lack improvement (p = 0.026) in depressive rapidly acting antidepressants to answer of effectiveness in a substantial proportion of symptoms, as measured by the Hamilton this important question,” he says. patients. “About 25–50% of patients have Depression Rating Scale (HAM-D17). Indeed, several drugs that have non- depression that is difficult to treat and Detailed data were due to be presented at monoamine-based targets are progressing probably need drugs or devices that have a the Annual New Clinical Drug Evaluation in the clinic (TABLE 1). “The availability new mechanism of action,” says Madhukar Unit Meeting in Hollywood, Florida, USA, of new antidepressants that do not target Trivedi, Professor of Psychiatry and Director of at the end of May. the monoaminergic system would be very the Comprehensive Center for Depression, Based on these data and earlier positive exciting,” enthuses Trivedi. “They would aid University of Texas Southwestern Medical Phase I/II trial results, Alkermes plans to translational research by allowing us to Centre, USA (who has consulted for Alkermes). advance ALKS 5461 into Phase III trials, assess the influence of novel molecular targets According to Charles Chavkin, Professor a stage at which there have been several on neural circuitry, and would enable us to in the Department of Pharmacology at the costly failures for novel antidepressants. determine how best to match patients with the University of Washington, Seattle, USA, new For example, all trials in the recent Phase III most appropriate treatment,” he concludes. antidepressants that target the κ-opioid programme for TC-5214, a nicotinic Charlotte Harrison receptor (like ALKS 5461) could be of particular value for patients who have a stress-induced component in their illness. Table 1 | Non-monoaminergic agents in clinical trials for depression “Individuals with depression and anxiety have heightened sensitivities to stress Compound Company Targets Phase exposure, and the endogenous dynorphin Mifepristone Corcept Androgen receptors, III opioid peptides that are released following Therapeutics glucocorticoid receptors, exposure to stress act at κ-opioid receptors,” progesterone receptors he explains. “In preclinical models, κ-opioid AZD6765 AstraZeneca NMDA receptors IIb receptor antagonists effectively reduce the ABT-436 AbbVie Vasopressin receptors II anxiety-like and depression-like behaviours ALKS 5461 Alkermes Opioid receptors II caused by stress exposure.” ALKS 5461 is a combination therapy Esketamine Janssen NMDA receptors II composed of buprenorphine (a κ-opioid GLYX-13 Naurex NMDA receptors (glycine site) II receptor antagonist and a μ-opioid receptor ADX-71149 Janssen mGluR2 II agonist that is already approved to treat pain and opioid addiction) and samidorphan, LY2940094 Eli Lilly Nociceptin (also known II as orphanin FQ) receptor (an investigational μ-opioid receptor antagonist). MK-6096 Merck & Co. Hypocretin (also known as II orexin) receptor “There is a good history of patient exposure to buprenorphine, but because it RG1578 Roche mGluR2 II has weak agonist activity at the μ-opioid RG7090 Roche mGluR5 II receptors (where morphine and oxycodone mGluR; metabotropic glutamate receptor; NMDA, N-methyl-d-aspartate. Data were taken from the act), there are risks of sedation and BioMedTracker database from Sagient Research and the Cortellis database from Thomson Reuters. NATURE REVIEWS | DRUG DISCOVERY VOLUME 12 | JUNE 2013 | 415 © 2013 Macmillan Publishers Limited. All rights reserved.
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