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Randomized Proof of Concept Trial of GLYX-13, an N-Methyl-D-Aspartate Receptor Glycine Site Partial Agonist, in Major Depressive Disorder Nonresponsive to a Previous Antidepressant Agent

PRESKORN, SHELDON MD; MACALUSO, MATTHEW; MEHRA, DO VISHAAL MD; ZAMMIT, GARY MD; MOSKAL, JOSEPH R. PhD; BURCH, RONALD M MD, PhD the GLYX-13 Clinical Study Group

Journal of Psychiatric Practice®: March 2015 - Volume 21 - Issue 2 - p 140–149
doi: 10.1097/01.pra.0000462606.17725.93
COLUMNS: Psychopharmacology
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Background. Approximately 45% of patients with major depressive disorder (MDD) do not remit when treated with biogenic amine antidepressants. Consequently, there is a significant need for antidepressant agents with different mechanisms of action. Early proof of concept (POC) studies with such novel agents play a significant role in helping drug developers identify agents and mechanisms of action that merit more intensive research. Studies have demonstrated that high affinity N-methyl-Daspartate (NMDA) receptor blockers (eg, ketamine) can produce rapid antidepressant effects in patients who have not responded to currently available agents, but treatment with these agents is accompanied by psychotomimetic effects that make their use problematic. This column describes a POC study involving GLYX-13, an N-methyl-D-aspartate receptor glycine site functional partial agonist. Method. In this double-blind, randomized, placebo-controlled study, a single intravenous (IV) dose of GLYX-13 (1, 5, 10, or 30 mg/kg) or placebo was administered to 116 subjects with MDD who had not benefitted from a trial of at least one biogenic amine antidepressant during the current episode. The primary outcome measure was score on the Hamilton Depression Rating Scale-17 (Ham-D17), which was used to rate overall depressive symptoms at baseline and at 24 hours and days 3, 7, 14, and, in some arms, days 21 and 28 after administration. Results. GLYX-13, 5 or 10 mg/kg IV, reduced depressive symptoms as assessed by the Ham-D17 at days 1 through 7. Onset of action as assessed using the Bech-6 occurred within 2 hours. GLYX-13 did not elicit psychotomimetic or other significant side effects. Conclusion. In this early POC study, GLYX-13 reduced depressive symptoms within 2 hours and this effect was maintained for 7 days on average in subjects with MDD who had not responded to another antidepressant agent during the current depressive episode. The findings of this study support the hypothesis that modulation of the NMDA receptor is a valid target for the development of antidepressant drugs and the need for additional studies to further evaluate the effects of GLYX-13. POC studies such as the one described here play a pivotal role in allowing drug researchers to decide whether to move forward with larger and more expensive studies, and they enable them to focus available resources on those molecules that appear to have the most therapeutic promise. Based on the POC study described here, a multiple dose study has been completed which showed sustained therapeutic benefit with repeated dosing of GLYX-13 for more than 6 weeks. Phase 3 studies are now being planned. (Journal of Psychiatric Practice 2015;21:140–149)

PRESKORN and MACALUSO: University of Kansas School of Medicine, Wichita, KS; MEHRA: Artemis Institute for Clinical Research, San Diego, CA; ZAMMIT: CliniLabs, New York, NY; MOSKAL: Dept Biomedical Engineering, Falk Center for Molecular Therapeutics, McCormick School of Engineering and Applied Sciences, Northwestern University, and Naurex Inc, Evanston, IL; BURCH: Naurex Inc, Evanston, IL

Acknowledgements. The GLYX-13 Clinical Study Group Principal Investigators were Misha Backonja, MD, Lifetree Clinical Research, Salt Lake City, UT; Daniel Greuner, MD, Lifetree Clinical Research, Philadelphia, PA; Paul Gross, MD, Lehigh Center for Clinical Research, Allentown, PA; David Krefetz, DO, Lifetree Clinical Research, Willingboro, NJ; Benji Kurian, MD, University of Texas Southwestern Medical Center, Dallas, TX; Michael Lesem, MD, Claghorn-Lesem Clinical Research Ltd, Houston, TX; Matthew Macaluso, DO, and Sheldon Preskorn, MD, University of Kansas School of Medicine, Wichita, KS; Raymond Manning, MD, CNRI-LA, Pico Rivera, CA; Vishaal Mehra, MD, Artemis Institute for Clinical Research, San Diego, CA; Rick Mofsen, MD, CRI Worldwide LLC, St Louis, MO; and Gary Zammit, PhD, Clinilabs, New York, NY.

Funding for this study was provided in its entirety by Naurex, Inc, 1801 Maple Avenue, Suite 4300, Evanston IL 60201, which owns patents, patent applications, and commercialization rights to GLYX-13. Dr. Burch is an employee of Naurex and has received financial compensation and stock. Drs. Macaluso, Mehra, Preskorn, and Zammit were paid clinical investigators for Naurex. During the past 12 months, Dr. Preskorn has been a consultant for AssureX, Delphor, Eisai, Johnson & Johnson, Merck, Naurex, Sunovion, and Tashio. Dr. Moskal is the founder of Naurex, Inc. He has founders' shares of stock in the company and receives financial compensation as a consultant.

Clinical trial registration. Single IV Dose of GLYX-13 in Patients With Treatment-Resistant Depression, http://www.clinicaltrials.gov/ct2/show/NCT01234558?term=Naurex&rank=2,NCT01234558; Single Ascending Dose Safety, Tolerability and Pharmacokinetics Study of GLYX-13 in Normal Volunteers, http://www.clinicaltrials.gov/ct2/show/NCT01014650?term=Naurex&rank=3,NCT01014650.

Note: Portions of this column are adapted with permission from Moskal et al. 2014.9

Please send correspondence to: Ronald M Burch, MD, PhD, Naurex, Inc, 1801 Maple Avenue, Suite 4300, Evanston IL, 60201ronburch@naurex.com

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