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

Michael J Brownstein¹, Neal G Simon^{1

2}, Jeffrey D Long³, Jon Yankey³, Hilda T Maibach¹, Merit Cudkowicz⁴, Christopher Coffey³, Robin A Conwit⁵, Codrin Lungu⁵, Karen E Anderson⁶, Steven M Hersch^{4

7}, Dixie J Ecklund³, Eve M Damiano¹, Debra E Itzkowitz¹, Shifang Lu^{1

2}, Marianne K Chase⁴, Jeremy M Shefner^{8

9

10}, Andrew McGarry¹¹, Brenda Thornell⁴, Catherine Gladden⁴, Michele Costigan³, Padraig O'Suilleabhain¹², Frederick J Marshall¹³, Amy M Chesire¹³, Paul Deritis¹³, Jamie L Adams¹³, Peter Hedera¹⁴, Kelly Lowen¹⁴, H Diana Rosas⁴, Amie L Hiller¹⁵, Joseph Quinn¹⁵, Kellie Keith¹⁵, Andrew P Duker¹⁶, Christina Gruenwald¹⁶, Angela Molloy¹⁶, Cara Jacob¹⁶, Stewart Factor¹⁷, Elaine Sperin¹⁷, Danny Bega¹⁸, Zsazsa R Brown¹⁸, Lauren C Seeberger¹⁹, Victor W Sung²⁰, Melanie Benge²⁰, Sandra K Kostyk²¹, Allison M Daley²¹, Susan Perlman²², Valerie Suski²³, Patricia Conlon²³, Matthew J Barrett²⁴, Stephanie Lowenhaupt²⁴, Mark Quigg²⁴, Joel S Perlmutter²⁵, Brenton A Wright²⁶, Elaine Most²⁵, Guy J Schwartz²⁷, Jessica Lamb²⁷, Rosalind S Chuang²⁸, Carlos Singer²⁹, Karen Marder³⁰, Joyce A Moran³⁰, John R Singleton³¹, Meghan Zorn³¹, Paola V Wall³¹, Richard M Dubinsky³², Carolyn Gray³², Carolyn Drazinic³³

Affiliations

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.

PMID: 33207828
PMCID: PMC7696926
DOI: 10.3390/jcm9113682

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

Michael J Brownstein et al. J Clin Med. 2020.

. 2020 Nov 16;9(11):3682.

doi: 10.3390/jcm9113682.

Authors

Affiliations

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.

PMID: 33207828
PMCID: PMC7696926
DOI: 10.3390/jcm9113682

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: Huntington’s disease; safety; tolerability; vasopressin 1a receptor antagonist.

PubMed Disclaimer

Conflict of interest statement

Funding: National Institute of Neurological Diseases and Stroke SBIR Fast-track award to Azevan Pharmaceuticals, Inc (U44NS090616), NINDS grants supporting the NeuroNext Network (Clinical Coordinating Center U01NS077179; Data Coordinating Center U01NS077352), the CHDI Foundation (grant to NGS) and Azevan Pharmaceuticals, Inc. The STAIR trial was sponsored by Azevan Pharmaceuticals, Inc. and was conducted through the NINDS NeuroNEXT Network (22 sites).

Figures

**Figure 1**
The STAIR trial (Safety, Tolerability, and Activity of SRX246 in Irritable Subjects with Huntington’s Disease) graphic illustrates the dosing and dose escalation schedule in the study. The treatment for each subject was assigned by a randomized code. A block randomization scheme was used to ensure approximately even distribution of subjects in treatment groups at each site (1:1:1 allocation). All subjects in the active arms were given 80 mg BID SRX246 for two weeks to provide an initial assessment of safety risks. Active arm subjects all escalated to 120 mg BID at week 2 and at week 6, half were escalated to 160 mg BID. The final sample size (N) randomized to each dose group is shown.

See this image and copyright information in PMC

References

1. Ghosh R., Tabrizi S.J. Clinical Features of Huntington’s Disease. In: Nóbrega C., Pereira de Almeida L., editors. Polyglutamine Disorders. Advances in Experimental Medicine and Biology. Volume 1049. Springer; Cham, Switzerland: 2018. - DOI - PubMed
1. FDA The Voice of the Patient: Huntington’s Disease. 2016 Available online: https://www.fda.gov/media/96196.
1. Fabio K., Guillon C., Lu S., Heindel N., Miller M., Ferris C., Brownstein M.J., Garripa C., Steiner M., Coccaro E., et al. Vasopressin antagonists as anxiolytics and antidepressants: Recent developments. Front. CNS Drug Discov. 2010;1:156–183. - PubMed
1. Guillon C.D., Koppel G.A., Brownstein M.J., Chaney M.O., Ferris C.F., Lu S.F., Fabio K.M., Miller M.J., Heindel N.D., Hunden D.C., et al. Azetidinones as vasopressin V1a antagonists. Bioorg. Med. Chem. 2007;15:2054–2080. doi: 10.1016/j.bmc.2006.12.031. - DOI - PMC - PubMed
1. Ferris C., Stolberg T., Kulkarni P., Murugavel M., Blanchard R., Blanchard D.C., Febo M., Brevard M., Simon N.G. Imaging the neural circuitry and chemical control of aggressive motivation. BMC Neurosci. 2008;9:111. doi: 10.1186/1471-2202-9-111. - DOI - PMC - PubMed

Grants and funding

LinkOut - more resources

Full Text Sources
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous