Journal of Clinical Medicine (Nov 2020)
Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington’s Disease Patients—A Randomized Phase 2 Clinical Trial
- Michael J. Brownstein,
- 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. Diana 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,
- Carolyn Drazinic
Affiliations
- Michael J. Brownstein
- Azevan Pharmaceuticals, Inc., Bethlehem, PA 18015, USA
- Neal G. Simon
- Azevan Pharmaceuticals, Inc., Bethlehem, PA 18015, USA
- Jeffrey D. Long
- Department of Biostatistics, University of Iowa, Iowa City, IA 52242, USA
- Jon Yankey
- Department of Biostatistics, University of Iowa, Iowa City, IA 52242, USA
- Hilda T. Maibach
- Azevan Pharmaceuticals, Inc., Bethlehem, PA 18015, USA
- Merit Cudkowicz
- Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA
- Christopher Coffey
- Department of Biostatistics, University of Iowa, Iowa City, IA 52242, USA
- Robin A. Conwit
- National Institutes of Health, NINDS, Bethesda, MD 20852, USA
- Codrin Lungu
- National Institutes of Health, NINDS, Bethesda, MD 20852, USA
- Karen E. Anderson
- Department of Neurology, Medstar Georgetown University Hospital, Washington, DC 20007, USA
- Steven M. Hersch
- Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA
- Dixie J. Ecklund
- Department of Biostatistics, University of Iowa, Iowa City, IA 52242, USA
- Eve M. Damiano
- Azevan Pharmaceuticals, Inc., Bethlehem, PA 18015, USA
- Debra E. Itzkowitz
- Azevan Pharmaceuticals, Inc., Bethlehem, PA 18015, USA
- Shifang Lu
- Azevan Pharmaceuticals, Inc., Bethlehem, PA 18015, USA
- Marianne K. Chase
- Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA
- Jeremy M. Shefner
- Barrow Neurological Institute, Phoenix, AZ 85013, USA
- Andrew McGarry
- Department of Neurology, Cooper University Hospital, Camden, NJ 08103, USA
- Brenda Thornell
- Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA
- Catherine Gladden
- Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA
- Michele Costigan
- Department of Biostatistics, University of Iowa, Iowa City, IA 52242, USA
- Padraig O'Suilleabhain
- Department of Neurology, UT Southwestern Medical Center, Dallas, TX 75390, USA
- Frederick J. Marshall
- Department of Neurology, University of Rochester Medical Center, Rochester, NY 14618, USA
- Amy M. Chesire
- Department of Neurology, University of Rochester Medical Center, Rochester, NY 14618, USA
- Paul Deritis
- Department of Neurology, University of Rochester Medical Center, Rochester, NY 14618, USA
- Jamie L. Adams
- Department of Neurology, University of Rochester Medical Center, Rochester, NY 14618, USA
- Peter Hedera
- Department of Neurology, Vanderbilt University, Nashville, TN 37212, USA
- Kelly Lowen
- Department of Neurology, Vanderbilt University, Nashville, TN 37212, USA
- H. Diana Rosas
- Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA
- Amie L. Hiller
- Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA
- Joseph Quinn
- Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA
- Kellie Keith
- Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA
- Andrew P. Duker
- Department of Neurology, University of Cincinnati, Cincinnati, OH 45219, USA
- Christina Gruenwald
- Department of Neurology, University of Cincinnati, Cincinnati, OH 45219, USA
- Angela Molloy
- Department of Neurology, University of Cincinnati, Cincinnati, OH 45219, USA
- Cara Jacob
- Department of Neurology, University of Cincinnati, Cincinnati, OH 45219, USA
- Stewart Factor
- Department of Neurology, Emory University, Atlanta, GA 30322, USA
- Elaine Sperin
- Department of Neurology, Emory University, Atlanta, GA 30322, USA
- Danny Bega
- Department of Neurology, Northwestern University, Chicago, IL 60611, USA
- Zsazsa R. Brown
- Department of Neurology, Northwestern University, Chicago, IL 60611, USA
- Lauren C. Seeberger
- Department of Neurology, University of Colorado Denver, Aurora, CO 80045, USA
- Victor W. Sung
- Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL 35233, USA
- Melanie Benge
- Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL 35233, USA
- Sandra K. Kostyk
- Department of Neurology, Ohio State University, Columbus, OH 43210, USA
- Allison M. Daley
- Department of Neurology, Ohio State University, Columbus, OH 43210, USA
- Susan Perlman
- Department of Neurology, University of California Los Angeles, Los Angeles, CA 90095, USA
- Valerie Suski
- Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
- Patricia Conlon
- Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
- Matthew J. Barrett
- Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA
- Stephanie Lowenhaupt
- Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA
- Mark Quigg
- Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA
- Joel S. Perlmutter
- Department of Neurology, Washington University, Saint Louis, MO 63110, USA
- Brenton A. Wright
- Department of Neurosciences, University of California San Diego, La Jolla, CA 92121, USA
- Elaine Most
- Department of Neurology, Washington University, Saint Louis, MO 63110, USA
- Guy J. Schwartz
- Department of Neurology, Stony Brook University Hospital, Stony Brook, NY 11794, USA
- Jessica Lamb
- Department of Neurology, Stony Brook University Hospital, Stony Brook, NY 11794, USA
- Rosalind S. Chuang
- Department of Neurology, Swedish Medical Center, Seattle, WA 98122, USA
- Carlos Singer
- Department of Neurology, University of Miami, Miami, FL 33136, USA
- Karen Marder
- Department of Neurology, Columbia University, New York, NY 10032, USA
- Joyce A. Moran
- Department of Neurology, Columbia University, New York, NY 10032, USA
- John R. Singleton
- Clinical Neurosciences Center, University of Utah, Salt Lake City, UT 84132, USA
- Meghan Zorn
- Clinical Neurosciences Center, University of Utah, Salt Lake City, UT 84132, USA
- Paola V. Wall
- Clinical Neurosciences Center, University of Utah, Salt Lake City, UT 84132, USA
- Richard M. Dubinsky
- Department of Neurology, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Carolyn Gray
- Department of Neurology, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Carolyn Drazinic
- Department of Clinical Sciences, Florida State University, Tallahassee, FL 32306, USA
- DOI
- https://doi.org/10.3390/jcm9113682
- Journal volume & issue
-
Vol. 9,
no. 11
p. 3682
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.
Keywords