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Open AccessArticle

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

by
Michael J. Brownstein
1,*,
Neal G. Simon
1,2,
Jeffrey D. Long
3,
Jon Yankey
3,
Hilda T. Maibach
1,
Merit Cudkowicz
4,
Christopher Coffey
3,
Robin A. Conwit
5,
Codrin Lungu
5,
Karen E. Anderson
6,
Steven M. Hersch
4,7,
Dixie J. Ecklund
3,
Eve M. Damiano
1,
Debra E. Itzkowitz
1,
Shifang Lu
1,2,
Marianne K. Chase
4,
Jeremy M. Shefner
8,9,10,
Andrew McGarry
11,
Brenda Thornell
4,
Catherine Gladden
4,
Michele Costigan
3,
Padraig O'Suilleabhain
12,
Frederick J. Marshall
13,
Amy M. Chesire
13,
Paul Deritis
13,
Jamie L. Adams
13,
Peter Hedera
14,
Kelly Lowen
14,
H. Diana Rosas
4,
Amie L. Hiller
15,
Joseph Quinn
15,
Kellie Keith
15,
Andrew P. Duker
16,
Christina Gruenwald
16,
Angela Molloy
16,
Cara Jacob
16,
Stewart Factor
17,
Elaine Sperin
17,
Danny Bega
18,
Zsazsa R. Brown
18,
Lauren C. Seeberger
19,
Victor W. Sung
20,
Melanie Benge
20,
Sandra K. Kostyk
21,
Allison M. Daley
21,
Susan Perlman
22,
Valerie Suski
23,
Patricia Conlon
23,
Matthew J. Barrett
24,
Stephanie Lowenhaupt
24,
Mark Quigg
24,
Joel S. Perlmutter
25,
Brenton A. Wright
26,
Elaine Most
25,
Guy J. Schwartz
27,
Jessica Lamb
27,
Rosalind S. Chuang
28,
Carlos Singer
29,
Karen Marder
30,
Joyce A. Moran
30,
John R. Singleton
31,
Meghan Zorn
31,
Paola V. Wall
31,
Richard M. Dubinsky
32,
Carolyn Gray
32 and
Carolyn Drazinic
33
1
Azevan Pharmaceuticals, Inc., Bethlehem, PA 18015, USA
2
Department of Biological Sciences, Lehigh University, Bethlehem, PA 18015, USA
3
Department of Biostatistics, University of Iowa, Iowa City, IA 52242, USA
4
Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA
5
National Institutes of Health, NINDS, Bethesda, MD 20852, USA
6
Department of Neurology, Medstar Georgetown University Hospital, Washington, DC 20007, USA
7
Voyager Therapeutics Inc., Cambridge, MA 02139, USA
8
Barrow Neurological Institute, Phoenix, AZ 85013, USA
9
Department of Neurology, College of Medicine, The University of Arizona, Phoenix, AZ 85004, USA
10
Department of Neurology, College of Medicine, Creighton University, Phoenix, AZ 85013, USA
11
Department of Neurology, Cooper University Hospital, Camden, NJ 08103, USA
12
Department of Neurology, UT Southwestern Medical Center, Dallas, TX 75390, USA
13
Department of Neurology, University of Rochester Medical Center, Rochester, NY 14618, USA
14
Department of Neurology, Vanderbilt University, Nashville, TN 37212, USA
15
Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA
16
Department of Neurology, University of Cincinnati, Cincinnati, OH 45219, USA
17
Department of Neurology, Emory University, Atlanta, GA 30322, USA
18
Department of Neurology, Northwestern University, Chicago, IL 60611, USA
19
Department of Neurology, University of Colorado Denver, Aurora, CO 80045, USA
20
Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL 35233, USA
21
Department of Neurology, Ohio State University, Columbus, OH 43210, USA
22
Department of Neurology, University of California Los Angeles, Los Angeles, CA 90095, USA
23
Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
24
Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA
25
Department of Neurology, Washington University, Saint Louis, MO 63110, USA
26
Department of Neurosciences, University of California San Diego, La Jolla, CA 92121, USA
27
Department of Neurology, Stony Brook University Hospital, Stony Brook, NY 11794, USA
28
Department of Neurology, Swedish Medical Center, Seattle, WA 98122, USA
29
Department of Neurology, University of Miami, Miami, FL 33136, USA
30
Department of Neurology, Columbia University, New York, NY 10032, USA
31
Clinical Neurosciences Center, University of Utah, Salt Lake City, UT 84132, USA
32
Department of Neurology, University of Kansas Medical Center, Kansas City, KS 66160, USA
33
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; https://doi.org/10.3390/jcm9113682
Received: 22 September 2020 / Revised: 6 November 2020 / Accepted: 9 November 2020 / Published: 16 November 2020
(This article belongs to the Section Clinical Neurology)
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Abstract

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

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