studies

1308A AASLD ABSTRACTS HEPATOLOGY, October, 2015
EDP-239 plasma PK parameters following oral dosing in HCV
patients
Disclosures:
Lijuan Jiang - Employment: Enanta Pharmaceuticals, Inc
Xuemin Jiang - Employment: Novartis
Eric Lawitz - Advisory Committees or Review Panels: AbbVie, Achillion Pharmaceuticals,
Regulus, Theravance, Enanta, Idenix Pharmaceuticals, Janssen, Merck
& Co, Novartis, Gilead; Grant/Research Support: AbbVie, Achillion Pharmaceuticals,
Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmith-
Kline, Idenix Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Merck & Co,
Novartis, Nitto Denko, Theravance, Salix, Enanta; Speaking and Teaching: Gilead,
Janssen, AbbVie, Bristol Meyers Squibb
Fred Poordad - Advisory Committees or Review Panels: Abbott/Abbvie, Achillion,
BMS, Inhibitex, Boeheringer Ingelheim, Pfizer, Genentech, Idenix, Gilead,
Merck, Vertex, Salix, Janssen, Novartis; Grant/Research Support: Abbvie,
Anadys, Achillion, BMS, Boehringer Ingelheim, Genentech, Idenix, Gilead,
Merck, Pharmassett, Vertex, Salix, Tibotec/Janssen, Novartis
Stefan Zeuzem - Consulting: Abbvie, Bristol-Myers Squibb Co., Gilead, Merck
& Co., Janssen
Kenneth Tack - Consulting: Enanta Pharmaceuticals, Inc
Richard Colvin - Employment: Novartis Institute for Biomedical Research
Yat Sun Or - Employment: Enanta Pharmaceuticals, Inc, Enanta Pharmaceuticals,
Inc
The following authors have nothing to disclose: Kiran Dole, Kimberley Caliri
2261
Short-term safety and pharmacokinetics of co-administration
of EDP239, an HCV NS5A inhibitor, and alisporivir
(ALV), a cyclophilin inhibitor, in healthy subjects
Xuemin Jiang 1,2 , Richard Colvin 1,2 , June Ke 1,2 , Sachin Desai 1,2 ,
Surendra Machineni 1,2 , Jie Zhang 1,2 , Wei Zhou 1,2 , Sun Haiying
1,2 , Steven J. Kovacs 1,2 ; 1 Novartis, East Hanover, NJ; 2 Institutes
for Biomedical Research, East Hanover, NJ
Introduction: Cyclophilin A plays essential roles in HCV replication
and assembly, including modulating the function of NS5A.
Combined cyclophilin and NS5A inhibition is a clinically
untested therapeutic approach despite in vitro studies suggesting
additive-to-synergistic effects of the two mechanisms, acting
at functionally dependent sites of the HCV replication complex.
An EDP239 C 24h
of 317 ng/mL reduced viral load by >3
log10 after a single 100 mg dose in GT1-infected patients. ALV
is a cyclophilin inhibitor that has pan-genotypic anti-HCV activity
with demonstrated clinical efficacy. It is a time-dependent
CYP3A4 inhibitor and inhibitor of multiple uptake and efflux
transporters, including P-gp. EDP239 is a substrate of CYP3A4
and P-gp in vitro. Methods: Open-label; fixed sequence design
(n=26). Subjects received multiple doses of EDP239 30 mg BID
for 21 days with co-administration of ALV 400 mg BID days 8
through 21. Both drugs administered with food. Blood samples
were collected up to 12 hours after dose administration on
days 7, 15 and 21 to measure plasma concentrations by LC/
MS/MS. Non-compartmental PK analysis using WinNonlin;
ANOVA for statistical comparisons; routine safety assessments
with safety data descriptively summarized. Results: 22 subjects
completed the study. Study treatments were well tolerated
with no safety-related discontinuations. Adverse effects were
consistent with the known effects of either EDP239 (gastrointestinal
complaints) or ALV (gastrointestinal complaints, headache,
laboratory abnormalities, increases in blood pressure).
Median EDP239 T max
was 3, 4.5, and 4 h on days 7, 14,
and 21, respectively. The EDP239 C 12h
was 2180 ng/mL
when administered with ALV. EDP 100 mg was comparable
to C12h of EDP 30 mg when combined with a alisporivir.
EDP239 had no apparent effect on ALV exposure (compared
with historical data). Conclusion Short term co-administration
of EDP239 and ALV was safe and well tolerated. The data
suggest that therapeutic combination of ALV and EDP239 is
feasible. The observed EDP239 exposures can be expected
to have clinical activity against GT1 and GT3 HCV. The time
course of exposure to EDP239 was relatively flat with minimal
difference between peak and trough. Exploiting the interaction
may allow EDP239 to treat patients with G3 HCV infection
without increasing overall exposure beyond exposures previously
safely investigated in humans.
Disclosures:
Xuemin Jiang - Employment: Novartis
Richard Colvin - Employment: Novartis Institute for Biomedical Research
Surendra Machineni - Employment: Novartis Healthcare Private Limited
Steven J. Kovacs - Employment: Novartis
The following authors have nothing to disclose: June Ke, Sachin Desai, Jie Zhang,
Wei Zhou, Sun Haiying
2262
SB 9200 Shows Antiviral Activity Against HCV-RNA
by Targeting Host Cytosolic Sensor Proteins RIG-I and
NOD-2 to activate IFN signaling pathways
Kumar Visvanathan 2,1 , Rosemary M. Millen 2,1 , Stuart K. Roberts 4,5 ,
Peter W. Angus 6,2 , Wendy Cheng 8 , Nada Farhat 9 , My My Trinh 9 ,
Radhakrishnan P. Iyer 10 , Murray L. Barclay 7 , Alex J. Thompson 3,2 ;
1 Innate Immunity Laboratory, St Vincent’s Hospital Melbourne, Melbourne,
VIC, Australia; 2 Medicine, Univeristy of Melbourne, Melbourne,
VIC, Australia; 3 Gastroenterology, St. Vincents Hospital,
Melbourne, Fitzroy, VIC, Australia; 4 Gastroenterology, Alfred Hospital,
Melbourne, VIC, Australia; 5 Medicine, Monash University,
Melbourne, VIC, Australia; 6 Liver Transplant Unit, Austin Hospital,
Melbourne, VIC, Australia; 7 Gastroenterology & Clinical Pharmacology,
Christchurch Hospital and University of Otago, Christchurch,
New Zealand; 8 Gastroenterology, Royal Perth Hospital,
Perth, WA, Australia; 9 Pharsight Consulting Services, Princeton,
NJ; 10 Spring Bank Pharmaceuticals, Milford, MA
Introduction. SB9200 activates RIG-I and NOD-2 pathways in
virally infected cells and has been shown to maximally reduce
HCV RNA by 1.9 log10 in HCV patients (Thompson EASL
2015). We aimed to evaluate the relationship between the
pharmacokinetics of SB 9200, and the induction of innate
immunity and antiviral response. Methods. HCV patients, GT 1
and 3, received 200-900 mg of SB9200 PO daily for 7 days.
Early antiviral kinetics were measured from baseline through
7 days after the first dose of SB 9200. Patients were divided
into null responders at day 7 (NR, < 0.5 log10 reduction in
HCV RNA, n=11) or responders (R, >0.9 log10, n=6). Clinical
characteristics at baseline for NR vs. R were similar for
median HCV RNA, BMI, ALT, AST, platelets and Fibroscan.
50% of R were IL28b CC compared to 18% of NR. Plasma
interferon alpha (IFNa) was measured on day 1, 7 and 14
by ELISA. Interferon stimulating genes ISG15 and OAS1 were
measured on Day 1, 2, 3, 7 and 14 in peripheral blood via
RT-PCR. GAPDH was used as an internal control. Data are represented
as ratios from baseline for IFNa, ISG15, and OAS1.
For pharmacokinetic analysis, blood samples were collected on