This study will test the safety and tolerability of HCV Entry Inhibitor ITX 5061 in Liver Transplant Recipients with Hepatitis C infection. The investigators hypothesize that ITX 5061 oral monotherapy will be safe in adults during and after liver transplantation and that therapy will also inhibit HCV infection of newly transplanted livers in adults with prior HCV infection.

Start Date01 Mar 2012

Sponsor / Collaborator

iTherX Pharmaceuticals, Inc.

100 Clinical Results associated with iTherX Pharmaceuticals, Inc.

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01 Mar 2016·Liver TransplantationQ1 · MEDICINE

Effect of scavenger receptor class B type I antagonist ITX5061 in patients with hepatitis C virus infection undergoing liver transplantation

Q1 · MEDICINE

Article

Author: Venuto, Charles S ; Rowe, Ian A ; Mutimer, David J ; Morse, Gene D ; Balfe, Peter ; Allen, Todd M ; Parker, Richard ; Guo, Kathy ; Barton, Darren ; Wong-Staal, Flossie ; Ogilvie, Colin B ; Tully, Damien C ; Hedegaard, Ditte L ; McKelvy, Jeffrey F ; McKeating, Jane A ; Armstrong, Matthew J

Hepatitis C virus (HCV) entry inhibitors have been hypothesized to prevent infection of the liver after transplantation. ITX5061 is a scavenger receptor class B type I antagonist that blocks HCV entry and infection in vitro. We assessed the safety and efficacy of ITX5061 to limit HCV infection of the graft. The study included 23 HCV‐infected patients undergoing liver transplantation. The first 13 “control” patients did not receive drug. The subsequent 10 patients received 150 mg of ITX5061 immediately before and after transplant and daily for 1 week thereafter. ITX5061 pharmacokinetics and plasma HCV RNA were quantified. Viral genetic diversity was measured by ultradeep pyrosequencing (UDPS). ITX5061 was well tolerated with measurable plasma concentrations during therapy. Although the median HCV RNA reduction was greater in ITX‐treated patients at all time points in the first week after transplantation, there was no difference in the overall change in the area over the HCV RNA curve in the 7‐day treatment period. However, in genotype (GT) 1–infected patients, treatment was associated with a sustained reduction in HCV RNA levels compared to the control group (area over the HCV RNA curve analysis, P = 0.004). UDPS revealed a complex and evolving pattern of HCV variants infecting the graft during the first week. ITX5061 significantly limited viral evolution where the median divergence between day 0 and day 7 was 3.5% in the control group compared to 0.1% in the treated group. In conclusion, ITX5061 reduces plasma HCV RNA after transplant notably in GT 1–infected patients and slows viral evolution. Following liver transplantation, the likely contribution of extrahepatic reservoirs of HCV necessitates combining entry inhibitors such as ITX5061 with inhibitors of replication in future studies. Liver Transpl 22:287‐297, 2016. © 2015 AASLD.

01 Nov 2014·HepatologyQ1 · MEDICINE

Successful anti-scavenger receptor class B type I (SR-BI) monoclonal antibody therapy in humanized mice after challenge with HCV variants within vitroresistance to SR-BI-targeting agents

Q1 · MEDICINE

Article

Author: Dubuisson, Jean ; Belouzard, Sandrine ; Bankwitz, Dorothea ; Rice, Charles M. ; Nicosia, Alfredo ; Pietschmann, Thomas ; Wong-Staal, Flossie ; Catanese, Maria Teresa ; Vercauteren, Koen ; Meuleman, Philip ; Cortese, Riccardo ; Leroux-Roels, Geert ; Mesalam, Ahmed Atef ; Van Den Eede, Naomi

Hepatitis C virus (HCV)-induced endstage liver disease is currently a major indication for liver transplantation. After transplantation the donor liver inevitably becomes infected with the circulating virus. Monoclonal antibodies (mAbs) against the HCV coreceptor scavenger receptor class B type I (SR-BI) inhibit HCV infection of different genotypes, both in cell culture and in humanized mice. Anti-SR-BI mAb therapy is successful even when initiated several days after HCV exposure, supporting its potential applicability to prevent HCV reinfection of liver allografts. However, HCV variants with reduced SR-BI dependency have been described in the literature, which could potentially limit the use of SR-BI targeting therapy. In this study we show, both in a preventative and postexposure setting, that humanized mice infected with HCV variants exhibiting increased in vitro resistance to SR-BI-targeting molecules remain responsive to anti-SR-BI mAb therapy in vivo. A 2-week antibody therapy readily cleared HCV RNA from the circulation of infected humanized mice. We found no evidence supporting increased SR-BI-receptor dependency of viral particles isolated from humanized mice compared to cell culture-produced virus. However, we observed that, unlike wild-type virus, the in vitro infectivity of the resistant variants was inhibited by both human high density lipoprotein (HDL) and very low density lipoprotein (VLDL). The combination of mAb1671 with these lipoproteins further increased the antiviral effect.CONCLUSIONHCV variants that are less dependent on SR-BI in vitro can still be efficiently blocked by an anti-SR-BI mAb in humanized mice. Since these variants are also more susceptible to neutralization by anti-HCV envelope antibodies, their chance of emerging during anti-SR-BI therapy is severely reduced. Our data indicate that anti-SR-BI receptor therapy could be an effective way to prevent HCV infection in a liver transplant setting.

01 Apr 2013·Antiviral TherapyQ4 · MEDICINE

Itx 5061 Quantitation in Human Plasma with Reverse Phase Liquid Chromatography and Mass Spectrometry Detection

Q4 · MEDICINE

Article

Author: McKelvy, Jeffrey ; Lapham, Jill ; Morse, Gene D ; Hochreiter, Jill ; Johnson, Victoria A ; Wong-Staal, Flossie ; Glesby, Marshall J ; Sulkowski, Mark

Background ITX 5061 is a highly potent small molecule inhibitor of scavenger receptor-B1, an integral transmembrane protein that is found in liver cells and is actively involved in the transport of HCV into hepatocytes. Currently, ITX 5061 is being investigated in monoinfected hepatitis C patients in a proof-of-concept clinical trial carried out by the AIDS Clinical Trial Group (ACTG). Methods To provide quantitative results in human plasma for pharmacokinetic analysis, an assay for ITX 5061 was validated. ITX 5061 and the internal standard, a deuterated analogue, were separated by isocratic reverse phase chromatography using a Polar RP column (Phenomenex Synergi™; 2.0 mmx50 mm, 4 μm) and detected via electrospray coupled to a triple quadrupole mass spectrometer with a run time of 5 min. Multiple reaction monitoring in positive mode was used with ITX 5061 at 585/114 m/z and the internal standard at 592/122 m/z with a linear range of 2.50–5,000 ng/ml. Human plasma was extracted using a protein precipitation combing 400 μl of acetonitrile with 100 μl of EDTA plasma. Results The interassay variation ranged from 1.19 to 13.2%, while the intraassay variation ranged from 0.394 to 12.9% over 6 days of testing. The method was successfully applied to the samples collected for the ACTG Protocol A5277. Plasma concentrations at 1 h and 24 h following 150 mg ITX 5061 daily in HCV monoinfected patients ( n=3) ranged from 138 to 518 ng/ml and 33 to 111 ng/ml, respectively. Conclusions The ITX 5061 assay is accurate and reproducible with a wide linear range and will be used for pharmacokinetic analysis and dose-finding studies in HCV-monoinfected patients.

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