title: Safety and antiviral activity of the HCV entry inhibitor ITX5061 in treatment-naive HCV-infected adults: a randomized, double-blind, phase 1b study.
abstract: BACKGROUND
  Hepatitis C virus (HCV) entry involves scavenger receptor B1 (SRB1). In vitro, SRB1 inhibition by ITX5061 impedes HCV replication.
  
  
  METHODS
  Multicenter study to assess safety/activity of ITX5061 in previously untreated, noncirrhotic, HCV genotype 1 infected adults. Design included sequential cohorts of 10 subjects with ITX5061 (n = 8) or placebo (n = 2) to escalate duration (3 to 14 to 28 days) or deescalate dose (150 to 75 to 25 mg) based on predefined criteria for safety and activity (≥ 4 of 8 subjects with HCV RNA decline ≥ 1 log10 IU/mL).
  
  
  RESULTS
  Thirty subjects enrolled in 3 cohorts: ITX5061 150 mg/day by mouth for 3 (A150), 14 (B150), and 28 (C150) days. Six subjects had grade ≥ 3 adverse events (one in placebo); none were treatment related. One of the 7 C150 subjects (14.3%, 95% confidence interval [CI], .7%-55.4%) had ≥ 1 log10 IU/mL decline in HCV RNA (1.49 log10 IU/mL), whereas none of the 6 placebo, 8 A150 or 8 B150 subjects showed such decline.
  
  
  CONCLUSIONS
  Oral ITX5061 150 mg/day for up to 28 days was safe and well tolerated. In the 28-day cohort, 1 of 7 subjects showed antiviral activity; however, predefined criteria for antiviral activity were not met at the doses and durations studied.
authors.affiliation: Johns Hopkins University, Baltimore, Maryland.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sulkowski
authors.forename: Minhee
authors.initials: M
authors.lastname: Kang
authors.forename: Roy
authors.initials: R
authors.lastname: Matining
authors.forename: David
authors.initials: D
authors.lastname: Wyles
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Johnson
authors.forename: Gene D
authors.initials: GD
authors.lastname: Morse
authors.forename: Valerianna
authors.initials: V
authors.lastname: Amorosa
authors.forename: Debika
authors.initials: D
authors.lastname: Bhattacharya
authors.forename: Kristine
authors.initials: K
authors.lastname: Coughlin
authors.forename: Flossie
authors.initials: F
authors.lastname: Wong-Staal
authors.forename: Marshall J
authors.initials: MJ
authors.lastname: Glesby
mesh_terms: D000998:Antiviral Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D016174:Hepacivirus / Q000187:drug effects*; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010655:Phenylenediamines / Q000009:adverse effects* / Q000627:therapeutic use*; D013449:Sulfonamides / Q000009:adverse effects* / Q000627:therapeutic use*
chemical_list: D000998:Antiviral Agents; C583499:ITX-5061; D010655:Phenylenediamines; D013449:Sulfonamides
keywords: HCV; SRB1; entry inhibitors
references.citation: Antivir Ther. 2013;18(3):329-36
references.pmid: 22954720
references.citation: Antivir Ther. 2012;17(6 Pt B):1133-46
references.pmid: 23188760
references.citation: Ann Intern Med. 2012 Feb 21;156(4):271-8
references.pmid: 22351712
references.citation: J Biol Chem. 2010 Jul 2;285(27):21092-102
references.pmid: 20375010
references.citation: Nature. 2007 Apr 12;446(7137):801-5
references.pmid: 17325668
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15422-7
references.pmid: 12438696
references.citation: J Virol. 2010 Jun;84(11):5494-507
references.pmid: 20237087
references.citation: J Virol. 2013 Aug;87(15):8282-93
references.pmid: 23698298
references.citation: Nature. 2011 Jun 08;474(7350):208-11
references.pmid: 21654804
references.citation: Nature. 2009 Feb 12;457(7231):882-6
references.pmid: 19182773
references.citation: N Engl J Med. 2011 Jun 23;364(25):2405-16
references.pmid: 21696307
references.citation: J Virol. 2006 Nov;80(22):11082-93
references.pmid: 16956932
references.citation: J Biol Chem. 2003 Oct 24;278(43):41624-30
references.pmid: 12913001
references.citation: J Clin Invest. 2001 Sep;108(6):793-7
references.pmid: 11560945
references.citation: Science. 1996 Jan 26;271(5248):518-20
references.pmid: 8560269
references.citation: Hepatology. 2011 Oct;54(4):1433-44
references.pmid: 21898493
references.citation: N Engl J Med. 2011 Mar 31;364(13):1195-206
references.pmid: 21449783
references.citation: Lancet. 2001 Apr 7;357(9262):1069-75
references.pmid: 11297957
references.citation: J Infect Dis. 2012 Feb 15;205(4):656-62
references.pmid: 22279172
references.citation: Arterioscler Thromb Vasc Biol. 2009 Dec;29(12):2054-60
references.pmid: 19815817
references.citation: J Hepatol. 2011 Jan;54(1):48-55
references.pmid: 20932595
references.citation: J Hepatol. 2011 Mar;54(3):566-76
references.pmid: 21146244
references.citation: J Virol. 2008 Dec;82(24):12020-9
references.pmid: 18829747