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Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington’s Disease Patients—A Randomized Phase 2 Clinical Trial

Azevan Pharmaceuticals, Inc., Bethlehem, PA 18015, USA
Department of Biological Sciences, Lehigh University, Bethlehem, PA 18015, USA
Department of Biostatistics, University of Iowa, Iowa City, IA 52242, USA
Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA
National Institutes of Health, NINDS, Bethesda, MD 20852, USA
Department of Neurology, Medstar Georgetown University Hospital, Washington, DC 20007, USA
Voyager Therapeutics Inc., Cambridge, MA 02139, USA
Barrow Neurological Institute, Phoenix, AZ 85013, USA
Department of Neurology, College of Medicine, The University of Arizona, Phoenix, AZ 85004, USA
Department of Neurology, College of Medicine, Creighton University, Phoenix, AZ 85013, USA
Department of Neurology, Cooper University Hospital, Camden, NJ 08103, USA
Department of Neurology, UT Southwestern Medical Center, Dallas, TX 75390, USA
Department of Neurology, University of Rochester Medical Center, Rochester, NY 14618, USA
Department of Neurology, Vanderbilt University, Nashville, TN 37212, USA
Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA
Department of Neurology, University of Cincinnati, Cincinnati, OH 45219, USA
Department of Neurology, Emory University, Atlanta, GA 30322, USA
Department of Neurology, Northwestern University, Chicago, IL 60611, USA
Department of Neurology, University of Colorado Denver, Aurora, CO 80045, USA
Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL 35233, USA
Department of Neurology, Ohio State University, Columbus, OH 43210, USA
Department of Neurology, University of California Los Angeles, Los Angeles, CA 90095, USA
Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA
Department of Neurology, Washington University, Saint Louis, MO 63110, USA
Department of Neurosciences, University of California San Diego, La Jolla, CA 92121, USA
Department of Neurology, Stony Brook University Hospital, Stony Brook, NY 11794, USA
Department of Neurology, Swedish Medical Center, Seattle, WA 98122, USA
Department of Neurology, University of Miami, Miami, FL 33136, USA
Department of Neurology, Columbia University, New York, NY 10032, USA
Clinical Neurosciences Center, University of Utah, Salt Lake City, UT 84132, USA
Department of Neurology, University of Kansas Medical Center, Kansas City, KS 66160, USA
Department of Clinical Sciences, Florida State University, Tallahassee, FL 32306, USA
Author to whom correspondence should be addressed.
J. Clin. Med. 2020, 9(11), 3682;
Received: 22 September 2020 / Revised: 6 November 2020 / Accepted: 9 November 2020 / Published: 16 November 2020
(This article belongs to the Section Clinical Neurology)
SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington’s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington’s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression. View Full-Text
Keywords: Huntington’s disease; safety; tolerability; vasopressin 1a receptor antagonist Huntington’s disease; safety; tolerability; vasopressin 1a receptor antagonist
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Figure 1

MDPI and ACS Style

Brownstein, M.J.; Simon, N.G.; Long, J.D.; Yankey, J.; Maibach, H.T.; Cudkowicz, M.; Coffey, C.; Conwit, R.A.; Lungu, C.; Anderson, K.E.; Hersch, S.M.; Ecklund, D.J.; Damiano, E.M.; Itzkowitz, D.E.; Lu, S.; Chase, M.K.; Shefner, J.M.; McGarry, A.; Thornell, B.; Gladden, C.; Costigan, M.; O'Suilleabhain, P.; Marshall, F.J.; Chesire, A.M.; Deritis, P.; Adams, J.L.; Hedera, P.; Lowen, K.; Rosas, H.D.; Hiller, A.L.; Quinn, J.; Keith, K.; Duker, A.P.; Gruenwald, C.; Molloy, A.; Jacob, C.; Factor, S.; Sperin, E.; Bega, D.; Brown, Z.R.; Seeberger, L.C.; Sung, V.W.; Benge, M.; Kostyk, S.K.; Daley, A.M.; Perlman, S.; Suski, V.; Conlon, P.; Barrett, M.J.; Lowenhaupt, S.; Quigg, M.; Perlmutter, J.S.; Wright, B.A.; Most, E.; Schwartz, G.J.; Lamb, J.; Chuang, R.S.; Singer, C.; Marder, K.; Moran, J.A.; Singleton, J.R.; Zorn, M.; Wall, P.V.; Dubinsky, R.M.; Gray, C.; Drazinic, C. Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington’s Disease Patients—A Randomized Phase 2 Clinical Trial. J. Clin. Med. 2020, 9, 3682.

AMA Style

Brownstein MJ, Simon NG, Long JD, Yankey J, Maibach HT, Cudkowicz M, Coffey C, Conwit RA, Lungu C, Anderson KE, Hersch SM, Ecklund DJ, Damiano EM, Itzkowitz DE, Lu S, Chase MK, Shefner JM, McGarry A, Thornell B, Gladden C, Costigan M, O'Suilleabhain P, Marshall FJ, Chesire AM, Deritis P, Adams JL, Hedera P, Lowen K, Rosas HD, Hiller AL, Quinn J, Keith K, Duker AP, Gruenwald C, Molloy A, Jacob C, Factor S, Sperin E, Bega D, Brown ZR, Seeberger LC, Sung VW, Benge M, Kostyk SK, Daley AM, Perlman S, Suski V, Conlon P, Barrett MJ, Lowenhaupt S, Quigg M, Perlmutter JS, Wright BA, Most E, Schwartz GJ, Lamb J, Chuang RS, Singer C, Marder K, Moran JA, Singleton JR, Zorn M, Wall PV, Dubinsky RM, Gray C, Drazinic C. Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington’s Disease Patients—A Randomized Phase 2 Clinical Trial. Journal of Clinical Medicine. 2020; 9(11):3682.

Chicago/Turabian Style

Brownstein, Michael J., Neal G. Simon, Jeffrey D. Long, Jon Yankey, Hilda T. Maibach, Merit Cudkowicz, Christopher Coffey, Robin A. Conwit, Codrin Lungu, Karen E. Anderson, Steven M. Hersch, Dixie J. Ecklund, Eve M. Damiano, Debra E. Itzkowitz, Shifang Lu, Marianne K. Chase, Jeremy M. Shefner, Andrew McGarry, Brenda Thornell, Catherine Gladden, Michele Costigan, Padraig O'Suilleabhain, Frederick J. Marshall, Amy M. Chesire, Paul Deritis, Jamie L. Adams, Peter Hedera, Kelly Lowen, H. D. Rosas, Amie L. Hiller, Joseph Quinn, Kellie Keith, Andrew P. Duker, Christina Gruenwald, Angela Molloy, Cara Jacob, Stewart Factor, Elaine Sperin, Danny Bega, Zsazsa R. Brown, Lauren C. Seeberger, Victor W. Sung, Melanie Benge, Sandra K. Kostyk, Allison M. Daley, Susan Perlman, Valerie Suski, Patricia Conlon, Matthew J. Barrett, Stephanie Lowenhaupt, Mark Quigg, Joel S. Perlmutter, Brenton A. Wright, Elaine Most, Guy J. Schwartz, Jessica Lamb, Rosalind S. Chuang, Carlos Singer, Karen Marder, Joyce A. Moran, John R. Singleton, Meghan Zorn, Paola V. Wall, Richard M. Dubinsky, Carolyn Gray, and Carolyn Drazinic. 2020. "Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington’s Disease Patients—A Randomized Phase 2 Clinical Trial" Journal of Clinical Medicine 9, no. 11: 3682.

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