TY - JOUR
T1 - Safety and antiviral activity of the HCV entry inhibitor ITX5061 in treatment-naive HCV-infected adults
T2 - A randomized, double-blind, phase 1b study
AU - Sulkowski, Mark S.
AU - Kang, Minhee
AU - Matining, Roy
AU - Wyles, David
AU - Johnson, Victoria A.
AU - Morse, Gene D.
AU - Amorosa, Valerianna
AU - Bhattacharya, Debika
AU - Coughlin, Kristine
AU - Wong-Staal, Flossie
AU - Glesby, Marshall J.
N1 - Funding Information:
The A5277 study team also acknowledges the expert guidance of the study by Katharine Bergstrom, MS, CCRP, and active participation of site principal investigators and research coordinators: Pablo Tebas, MD, Principal Investigator; Deborah Kim, RPh, Site Pharmacist; and Kathryn Maffei, BSN, Study Nurse/Coordinator—University of Pennsylvania (Site 6201), ACTG CTU grant AI-069467-07; CFAR grant 5-P30-AI-045008-15. Andi Weiss, B Pharm, and Ilene Wiggins, RN—Johns Hopkins University AIDS Clinical Trials Unit (Site 201), ACTG CTU grant AI69465; CTSA grant NIH UL1 RR025005 awarded to Johns Hopkins University. Dr Kara Chew and Maria Palmer PA—UCLA CARE Center (Site 601), ACTG CTU grant UM1 AI069424; CTSI grant UL1TR000124 citation for Publications. Amneris Luque, MD, and Mary Adams, RN—University of Rochester (Site 1101), ACTG CTU grant UMI AI069511; CRC grant UL1 RR024160. Susanna Naggie, MD, and Cara Johnson, RN—Duke University Medical Center CRS (Site 1601), ACTG CTU grant 5UM1-AI069484-07.Kerry Upton and Dana Green, Alabama Therapeutics CRS (Site 5801), ACTG CTU grant U01 AI069452; grant UL1TR00165. Julie Hoffman, RN, and Linda Mexiner, RN —University of California, San Diego (Site 0701), ACTG CTU grant AI69432. Annie Luetkemeyer, MD, and Anna Smith, RN—UCSF AIDS CRS (Site 801), ACTG CTU grant 5UO1 AI069502. Kenneth Sherman, MD, PhD, and Michelle Saemann, RN—University of Cincinnati (Site 2401), ACTG CTU grant AI-069513. Jorge L. Santana Bagur, MD, and Santiago Marrero de León, MD—Puerto Rico-AIDS Clinical Trials Unit (Site 5401), ACTG CTU grant 5UM1AI069415-07. The technical support for HCV RNA and HCV genotyping efforts by J. Darren Hazelwood, UAB Virology Specialty Laboratory 54 (Dr Victoria Johnson) is greatly appreciated. Birmingham Veterans Affairs Medical Center core laboratory facilities, UAB VSL (NIH/NIAID 7UM1AI068636), and UAB Center for AIDS Research laboratory facilities (UAB CFAR P30AI27767-24) are acknowledged. The technical support of the ACTG Pharmacology Specialty Laboratory and the Translational Pharmacology Research Core, School of Pharmacy and Pharmaceutical Sciences at the University at Buffalo, NYS Center of Excellence in Bioinformatics and Life Sciences is greatly appreciated. ITX5061 and internal standard were obtained by the University at Buffalo through a material transfer agreement with iTherX Pharmaceuticals, Inc, San Diego, California.
Funding Information:
Financial support. This work was supported by award number U01AI068636 from the National Institute of Allergy and Infectious Diseases (NIAID) and supported by National Institute of Mental Health (NIMH), National Institute of Dental and Craniofacial Research (NIDCR). Additional financial support for this study came from UM1 AI068634 and K24 AI078884 (M. J. G.) from the National Institute of Allergy and Infectious Diseases with additional support from K24DA00432 (M. S. S.) from the National Institute on Drug Abuse and by grant number UL1 RR 025005 from the National Center for Research Resources (N. C. R. R.), a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.
PY - 2014/3
Y1 - 2014/3
N2 - 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.
AB - 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.
KW - HCV
KW - SRB1
KW - entry inhibitors
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U2 - 10.1093/infdis/jit503
DO - 10.1093/infdis/jit503
M3 - Article
C2 - 24041792
AN - SCOPUS:84894235263
SN - 0022-1899
VL - 209
SP - 658
EP - 667
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
IS - 5
ER -