SEARCH

SEARCH BY CITATION

1081

  1. Top of page

Daclatasvir Pharmacokinetics in Healthy Subjects: No Clinically-Relevant Drug-Drug Interactions with Either Cyclosporine or Tacrolimus

Marc Bifano1, Robert Adamczyk1, Carey Hwang1, Hamza Kan-doussi2, Alan S. Marion3, Richard J. Bertz1; 1Research and Development, Bristol-Myers Squibb, Hopewell, NJ; 2Research and Development, Bristol-Myers Squibb, Lawrenceville, NJ; 3ICON Development Solutions, Omaha, NE

Background Chronic HCV infection is the main cause of liver transplantation (LT). HCV recurrence, seen in = 50% of HCV-infected LT patients during the first postoperative year, is the main cause of graft failure (despite long-term treatment with immunosuppressants eg cyclosporine [CSP] or tacrolimus [TAC]) and death in HCV-infected LT patients. Drug-drug interactions (DDIs) with CSP and TAC hinder the use of boceprevir and telaprevir in LT patients. Daclatasvir (DCV) —a first-in-class HCV NS5A inhibitor with pan-genotypic activity in vitro and demonstrated clinical efficacy as part of multiple (including all-oral) regimens — has a pharmacokinetic (PK) profile supportive of QD dosing and a low probability of DDIs as a perpetrator and manageable DDIs as a victim. It is anticipated that DCV will be co-administered with CSP and TAC in the clinical setting. Methods Healthy fasted subjects (age 18-49 years; BMI 18-32 kg/m2) received a single oral dose of CSP 400 mg on Days 1 and 9 and DCV 60 mg QD on Days 4-11 (Group 1), or received a single oral dose of TAC 5 mg on Days 1 and 13 and DCV 60 mg QD on Days 8-19 (Group 2). Blood samples for PK analysis were collected on Days 1 and 9 for CSP (72h), 1 and 13 for TAC (168h), and 8 and 9 (Group 1) or 12 and 13 (Group 2) for DCV (24h). Statistical analyses (geometric mean ratios [GMR] and 90% confidence intervals [CI]) on the PK parameters of CSP, TAC and DCV (max. plasma conc. [Cmax], AUC from time zero until the time of last quantifiable concentration [AUC0_τ,end of the dosing interval [AUC0_TAU] or extrapolated to infinity [AUC0_∞ and plasma conc. 24h post-dose [C24]) were performed. Results Evaluable data from 14 subjects in each group were collected. DCV did not affect the PK parameters of either CSP or TAC, and TAC did not affect the PK parameters of DCV; all GMRs were close to 1 and the 90% CIs were contained within the accepted no-effect boundary (0.80-1.25). Co-administration of CSP resulted in modest increases in DCV AUC0_TAU (40%) and C24 (56%); Cmax was unaffected. Conclusions No clinically-relevant DDIs were observed when DCV was co-administered with CSP or TAC; CSP caused a modest increase in DCV exposure. Dose adjustments for DCV, TAC, or CSP during co-administration of DCV with CSP or TAC are unlikely to be required.

Table 1. 
 CMR (90% CI
Treatment comparisonCmaxAUC0-τAUC0-TAUAUC0-∞C24
CSP + DCV vs CSP alone0.96(0.91, 1.02)1.02(0.96, 1.08)NA1.03(0.97, 1.09)NA
CSP + DCV vs DCV alone1.04 (0.94, 1.15)NA1.40 (1.29, 1.53)NA1.56(1.41, 1.71)
TAC + DCV vs TAC alone1.05 (0.90, 1.23)1.00(0.87, 1.15)NA1.00(0.88, 1.13)NA
TAC + DCV vs DCV alone1.07(1.02, 1.12)NA1.05(1.03, 1.07)NA1.10(1.03, 1.19)
Disclosures

Marc Bifano - Employment: Bristol-Myers Squibb Pharmaceutical

Robert Adamczyk-Employment: Bristol-Myers Squibb; Stock Shareholder: Bristol-Myers Squibb

Carey Hwang - Employment: Bristol-Myers Squibb; Stock Shareholder: Bristol-Myers Squibb

Richard J. Bertz - Employment: Bristol-Myers Squibb

The following people have nothing to disclose: Hamza Kandoussi, Alan S. Marion

1082

  1. Top of page

GS-5816, a Once-Daily NS5A Inhibitor, Demonstrates Potent Antiviral Activity in Patients with Genotype 1, 2, 3, or 4 HCV Infection in a 3-Day Monotherapy Study

Eric Lawitz1, Steven J. Glass2, Daniel Gruener3, Bradley Freilich4, John M. Hill5, John O. Link6, Polina German6, Christy Hebner6, Lingling Han6, Diana M. Brainard6, John McNally6, William B. Smith7, Suzanne Kim8, Thomas C. Marbury9, Jon Ruckle10, Maribel Rodriguez-Torres11; 1Texas Liver Institute, University of Texas Health Sciences Center, San Antonio, TX; 2CRI Worldwide, LLC, Marlton, NJ; 3CRI Worldwide, LLC, Philadelphia, PA; 4Kansas City Gas-troenterology and Hepatology, Kansas, MO; 5Avail Clinical Research, LLC, Avail, FL; 6Gilead Sciences, Inc., Foster City, CA; 7New Orleans Center for Clinical Research, Knoxsville, TN; 8West Coast Clinical Trials, LLC, Costa Mesa, CA; 9Orlando Clinical Research Center, Orlando, FL; 10Charles River Clinical Services Northwest, Inc., Tacoma, WA; 11Fundacion De Investigacion, San Juan

Background: GS-5816 is a second generation HCV NS5A inhibitor with picomolar antiviral activity against HCV genotypes 1-6, and with activity against signature NS5A resistance associated variants. Here we describe safety, pharmacokinetic (PK), and antiviral activity from a 3-day monotherapy study in patients with genotype 1, 2, 3, or 4 HCV infection. Methods: Eligible patients were randomized to receive placebo or GS-5816 once daily for 3 days at doses ranging from 5-150 mg. Safety was assessed by physical examination, ECG and laboratory tests during treatment and for 2 weeks post-treatment. GS-581 6 PK was performed by LC/MS/MS analysis of plasma after the first and third dose. Antiviral activity was evaluated by measuring HCV RNA using the Roche COBAS Taqman v2.0 HPS (LLOQ = 25IU/mL) in plasma. Results: Eighty seven (87) non-cirrhotic, treatment naïve patients with genotype 1 (63%), genotype 2 (12%), genotype 3 (23%) and genotype 4 (2%) HCV infection were enrolled in the study. The population was 87% male, with mean age 47 years (range 21-65) and BMI 28 kg/m2 (range 18-36). Median maximum reductions (log10 IU/mL) in HCV RNA are presented in the table below. Most adverse events (AEs) were mild or moderate in severity. The only AE occurring in ≥ 5% of patients was headache (7%). There were no serious AEs. One patient discontinued treatment after receiving one dose of GS-5816 150mg due to grade 1 nausea. There were no clinically significant lab abnormalities or changes in vital signs or ECGs. GS-5816 PK supported once daily dosing. Conclusions: At all doses tested, GS-5816 was well tolerated and demonstrated potent antiviral activity in treatment naïve patients with genotype 1,2 3, or 4 chronic HCV infection.

Table 2. Median (Q1, Q3) Maximum Reduction in Log10 HCV RNA
GS-5816 DoseGenotype laGenotype lbGenotype 2Genotype 3Genotype 4
5 mg3.85 (3.45, 3.92)
25 mg3.89 (3.84, 4.18)2.89 (2.82, 3.06)
50 mg4.17(2.94, 4.22)3.12(1.91, 3.27)
l00 mg3.67(3.18, 4.18)----
150 mg4.19(3.58, 4.52)4.29(4.18, 4.41)4.39(4.10, 4.75)3.14(2.90, 3.78)3.47 (3.05, 3.89)
Disclosures

Eric Lawitz - Advisory Committees or Review Panels: AbbVie, Achillion Pharmaceuticals, BioCryst, Biotica, Enanta, Idenix Pharmaceuticals, Janssen, Merck & Co, Novartis, Santaris Pharmaceuticals, Theravance, Vertex Pharmaceuticals; Grant/Research Support: AbbVie, Achillion Pharmaceuticals, Boehringer Ingel-heim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Merck & Co, Novartis, Presidio, Roche, Santaris Pharmaceuticals, Vertex Pharmaceuticals ; Speaking and Teaching: Gilead, Kadmon, Merck, Vertex

Bradley Freilich - Grant/Research Support: schering plough, vertex, roche, abbott, pharmaset, anadys, abbott, schering plough, vertex, roche, abbott, phar-maset, anadys, abbott, schering plough, vertex, roche, abbott, pharmaset, anadys, abbott, schering plough, vertex, roche, abbott, pharmaset, anadys, abbott; Speaking and Teaching: onyx, onyx, onyx, onyx

John O. Link - Employment: Gilead Sciences; Patent Held/Filed: Gilead Sciences; Stock Shareholder: Gilead Sciences, Pfizer

Polina German - Employment: GIlead Sciences, Inc; Stock Shareholder: GIlead Sciences, Inc

Christy Hebner- Employment: Gilead Sciences, Inc.

Diana M. Brainard - Employment: Gilead Sciences, Inc.

John McNally- Employment: Gilead Sciences, Inc

Thomas C. Marbury- Employment: Orlando Clinical Research Center

Maribel Rodriguez-Torres - Consulting: Hoffman La Roche, Abbott Labs, Phar-masset, Akros, Bristol-Myers Squibb, Merck, Vertex, Inhibitex, Genentech, Janssen R&D Ireland, Santaris; Grant/Research Support: Anadys, Novartis, Hoffman-LaRoche, Glaxo Smith Kline, Inhibitex, Bristol-Myers Squibb, Vertex, Idera, Phar-masset, Sanofi-Aventis, Merck, Abbott, Pfizer, Human Genome Sciences, Gilead, Johnson & Johnson, Zymogenetics, AKROS, Scynexis, Santaris, Boehringher, Idenix, Genentech, Beckman Coulter, Mochida Pharmaceutical

The following people have nothing to disclose: Steven J. Glass, Daniel Gruener, John M. Hill, Lingling Han, William B. Smith, Suzanne Kim, Jon Ruckle

1083

  1. Top of page

Pharmacokinetic interactions of faldaprevir and deleobuvir (BI 207127) and their individual and combined effect on selected cytochrome P450 (CYP) probe substrates in genotype 1 hepatitis C infected patients

Curtis Cooper1, Brian Conway2, Wayne Ghesquiere3, Richard Lalonde4, Alnoor Ramji5, Natasha Chandok6, Edward Tam7, Rucha S. Sane8, Naitee Ting8, Federico J. Mensa8, Mabrouk Elgadi9, John P. Sabo8; 1Division of Infectious Diseases, The Ottawa Hospital Research Institute, Ottawa, ON, Canada; 2Vancouver Infectious Diseases Centre, Vancouver, BC, Canada; 3Division of Infectious Diseases, University of British Columbia, Victoria, BC, Canada; 4McGill University Health Centre, Montreal, QC, Canada; 5Divi-sion of Gastroenterology, University Of British Columbia, Vancouver, BC, Canada; 6Division of Gastroenterology, University of Western Ontario, London, ON, Canada; 7LAIR Centre, Vancouver, BC, Canada; 8Boehringer Ingelheim Pharmaceuticals, Inc., Ridge-field, CT; 9Boehringer Ingelheim Canada Ltd./Ltée, Burlington, ON, Canada

Aim: Phase 2a study to evaluate the drug-drug interactions of a dual oral direct acting antiviral (DAA) regimen of faldaprevir (FDV; a HCV NS3/4A protease inhibitor) and deleobuvir (BI 207127, DLV; non-nucleoside NS5B inhibitor) and their individual and combined effect on CYP-mediated metabolism in patients with chronic genotype 1 HCV infection. Methods: Within an open-label, multi-center, parallel group study, treatment naïve or prior treatment relapse genotype 1 infected patients were randomized 1:1 to Group A (8-day lead-in with 120 mg qd FDV + pegylated interferon alpha-2a/ribavirin [PegIFN/RBV] followed by 24 weeks 120 mg qd FDV + 600 mg tid DLV + RBV) or Group B (8-day lead-in with 600 mg tid DLV + PegIFN/RBV followed by 24 weeks 600 mg tid DLV + 120 mg qd FDV + RBV). Caffeine, tolbutamide and midazolam given as single doses before and after the start of HCV treatment on Day 2 were used as CYP1A2, CYP2C9 and CYP3A4 probe substrates, respectively. Pharmacokinetic evaluations (FDV, DLV, metabolites and probe substrates) were performed on Days 1,9, 17, and 66 using validated assays. Results: Participants (15 male [57.7%]) were randomized to Group A (N = 12) and Group B (N = 14), no cirrhotic patients were included in the study. Preliminary bioanalytical results from an interim pharmacokinetic analysis indicated that addition of DLV (Group A) increased FDV plasma concentrations and addition of FDV (Group B) increased DLV plasma concentrations (Table 1). After 8 weeks of combined treatment, FDV concentrations approximated to those observed prior to DLV dosing, while DLV concentrations remained elevated, relative to pre-dual DAA exposure. Pharmacokinetic analysis of CYP probe data is limited to CYP2C9 and CYP3A4, and suggests weak induction of CYP2C9 (tolbutamide geometric mean ratio AUC0-24h Group A (N=7) and Group B (N=11) 0.85 and 0.65, respectively) and weak inhibition of CYP3A4 (midazolam geometric mean ratio AUC0 24h Group A (N=10) and Group B (N=14) 1.68 and 1.13, respectively) with this dual DAA regimen at Day 17. Conclusion: A 2-way drug interaction occurs when FDV is combined with DLV, increasing the exposure to both compounds, as well as weakly inducing CYP2C9 and weakly inhibiting CYP3A4. These data will help guide the use of concomitant mediations in HCV-infected patients receiving this dual DAA regimen.

Table 3. 
Geometric Mean ratioaEffect of DLV on FDVEffect of FDV on DLV
AUC0-24h,CmaxCminAUC0-6hCmaxCmin
  1. DLV=deleobuvir, FDV=faldaprevir

  2. aRatio of 1.00 indicates no change from baseline (Day 9)

Day 17 N=82.872.393.253.223.004.00
Day 66 N=41.071.090.882.992.763.45
Disclosures

Curtis Cooper - Advisory Committees or Review Panels: Vertex, MERCK, Roche; Grant/Research Support: MERCK, Roche; Speaking and Teaching: Roche, MERCK

Brian Conway - Advisory Committees or Review Panels: Vertex Pharmaceuticals, Merck, Boehringer Ingelheim, Jannsen Pharmaceuticals; Grant/Research Support: Vertex Pharmaceuticals, Merck, Boehringer Ingelheim, Jannsen Pharmaceuticals, AbbVie, Gilead Sciences, Gilead Sciences

Alnoor Ramji -Advisory Committees or Review Panels: Roche, Merck, Gilead, vertex, Janssen, Boehringer Ingelheim; Grant/Research Support: BMS, Roche, Merck, Gilead, Vertex, Novartis, Abbvie, Boehringer Ingelheim

Naitee Ting - Employment: Boehringer-Ingelheim Pharmaceuticals, Inc.; Stock Shareholder: Pfizer, Inc.

Federico J. Mensa - Employment: Boehringer Ingelheim Pharm. Inc

Mabrouk Elgadi - Employment: Boehringer Ingelheim

John P. Sabo - Employment: Boehringer Ingelheim Pharmaceuticals, Inc.

The following people have nothing to disclose: Wayne Ghesquiere, Richard Lalonde, Natasha Chandok, Edward Tam, Rucha S. Sane

1084

  1. Top of page

Initial Evaluation of the Sofosbuvir Compassionate Use Program for Patients with Severe Recurrent HCV Following Liver Transplantation

Xavier Forns1, Robert J. Fontana2, Dilip Moonka3, John G. McHutchison4, William T. Symonds4, Jill M. Denning4, Lindsay McNair4, Paul Chang4, Valerie A. Kivett4, Mitchell L. Shiffman5, Michael R. Charlton6; 1Liver Unit, Hospital Clinic, Barcelona, Spain; 2University of Michigan, Ann Arbor, MI; 3Henry Ford Health System, Detroit, MI; 4Gilead Sciences, Inc., Foster City, CA; 5Liver Institute of Virginia, Richmond, VA; 6Mayo Clinic, Rochester, MN

Background: Patients with severe, recurrent hepatitis C (HCV) after liver transplantation (LT), who have either failed to respond to or are unable to tolerate antiviral therapies, have no effective treatment options. The polymerase inhibitor sofosbuvir (SOF) has been shown to be effective in combination with ribavirin (RBV), with or without peginterferon (PEG), in patients with HCV infection of all genotypes (GT). Methods: SOF was provided in an IRB-approved compassionate use protocol (eIND or expanded access protocol) to treat patients with severe recurrent HCV infection following LT, including patients with fibrosing cholestatic hepatitis (FCH). The regimen included SOF 400 mg/day for up to 48 weeks, with appropriate doses of RBV and/or PEG at the physician's discretion. Treating physicians provide periodic updates of clinical status, lab tests, and serious adverse events (SAEs). Results: As of APR2013, 115 patients have been approved for compassionate use and 63 have started treatment. Of these, 45 have received >4 weeks of a SOF-containing regimen (36 SOF + RBV, 9 SOF+PEG/RBV). Baseline features of these 45 patients were: 33 GT1, 5 GT3, 7 other GTs; 29% female; mean age 55 years; mean baseline bilirubin 6.0 mg/dL (range 0.4-25.8) albumin 3.1 g/dL (2.0-4.8), INR 1.26 (0.96-2.07) and platelets 103 × 103/uL (27-316 × 103). Nineteen of the 45 (42%) had histologically-documented FCH. At week 4 of therapy, 28 of 36 patients (78%) who had reported HCV RNA levels were less than the limit of detection or quantification and 2 patients who received only 12 weeks of treatment have achieved SVR 12. The clinical condition of 32 of the 45 patients (71%) rapidly improved according to investigators' narratives (eg, normalization of ALT and/or bilirubin levels, resolution of ascites which had been refractory to diuretics or requiring paracentesis, resolution/improvement of encephalopathy, increased muscle mass) within 1-4 weeks after the start of treatment. Another six patients (13%) were reported to have stabilized from their prior decompensation. Seven patients (16%) died after initiating therapy, with all deaths attributed to progression of liver disease or associated complications. Forty-seven SAEs have been reported in 23 patients. None were attributed to study drug. Conclusions: In patients with severe post-LT HCV recurrence, a compassionate use regimen containing SOF and RBV (with or without PEG) has been well-tolerated and has demonstrated strong antiviral activity. The SOF-based regimen has resulted in notable clinical improvement and/or disease stabilization in many patients. Results will be updated at the time of presentation.

Disclosures

Xavier Forns - Consulting: Tibotec/Jansen, MSD, Boheringher Ingelheim; Grant/Research Support: Roche, MSD, Gilead

Robert J. Fontana - Consulting: GlaxoSmithKline, tibotec; Grant/Research Support: Gilead, vertex, Ocera

Dilip Moonka - Advisory Committees or Review Panels: Gilead; Grant/Research Support: Genentech; Speaking and Teaching: Merck, Genentech, Gilead, Novar-tis

John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead Sciences

William T. Symonds - Employment: Gilead

Jill M. Denning - Employment: Gilead Sciences, Inc.

Lindsay McNair - Independent Contractor: Gilead

Paul Chang - Employment: Gilead Sciences, Inc; Stock Shareholder: Gilead Sciences, Inc

Mitchell L. Shiffman - Advisory Committees or Review Panels: Merck, Gilead, Boehringer-Ingelheim, Bristol-Myers-Squibb, Abbott, Vertex, Janssen, Bayer, Gen-Probe, Novartis; Consulting: Roche/Genentech, GSK, Gen-Probe; Grant/Research Support: Merck, Gilead, Boehringer-Ingelheim, Bristol-Myers-Squibb, Abbott, Lumena, Intercept, Achillion, Beckman-Coulter, Novartis; Speaking and Teaching: Roche/Genentech, Merck, Gilead, GSK, Vertex, Janssen, Bayer

The following people have nothing to disclose: Valerie A. Kivett, Michael R. Charlton

1085

  1. Top of page

Sofosbuvir + Ribavirin for 12 or 24 Weeks for Patients with HCV Genotype 2 or 3: the VALENCE trial

Stefan Zeuzem1, Geoffrey M. Dusheiko2, Riina Salupere3, Alessan-dra Mangia4, Robert Flisiak5, Robert H. Hyland6, Ari Illeperuma6, Evguenia S. Svarovskaia6, Diana M. Brainard6, William T. Symonds6, John G. McHutchison6, Ola Weiland7, Hendrik W. Reesink8, Peter Ferenci9, Christophe Hezode10, Rafael Esteban11; 1Johann Wolfgang Goethe University, Frankfurt, Germany; 2Royal Free and University College School of Medicine, Royal Free Hospital, London, United Kingdom; 3Tartu University Hospital, Tartu, Estonia; 4“Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Italy; 5Medical University of Bialystok, Bialystok, Poland; 6Gilead Sciences, Inc., Foster City, CA; 7Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; 8Academic Medical Center, Amsterdam, Netherlands; 9Medical University of Vienna, Vienna, Austria; 10Hôpital Henri Mondor, Créteil, France; 11Hospital Universitario Val d'Hebron, Barcelona, Spain

Background and Aims: In phase 3 trials, 12 weeks of sofosbuvir (SOF) + ribavirin (RBV) has demonstrated high SVR rates in patients with genotype 2 and 3 HCV infection, with higher response rates in patients infected with genotype 2 than in those infected with genotype 3 HCV. VALENCE is a Phase 3 study conducted in Europe assessing the safety and efficacy of SOF+RBV administered for 12 or 24 weeks. Methods: Treatment-naïve or treatment-experienced patients infected with HCV genotype 2 or 3 were randomized 4:1 to receive SOF+RBV for 12 weeks or matching placebo. The study was subsequently amended to extend treatment duration to 24 weeks for patients with genotype 3 HCV irrespective of prior treatment history. The primary end point is SVR12. Results: 421 patients were randomized: 334 received SOF+RBV, 85 received placebo, and 2 did not initiate treatment. Of those randomized to receive SOF+RBV, 261 (78%) had HCV genotype 3, 195 (58%) were treatment-experienced, 70 (21%) were cirrhotic, and 114 (34%) had the IL28b CC genotype. All patients receiving SOF+RBV became and remained HCV RNA negative while on treatment; relapse has accounted for all virologic failures to date. Of the 73 genotype 2 patients, 68 (93%) achieved SVR4. The genotype 3 patients have not yet reached post-treatment Week 4. Final SVR 12 data for all patients will be presented. SOF+RBV for 12 or 24 weeks was generally well tolerated; 2 (<1%) patients have discontinued treatment early due to adverse events (malaise and headache in one patient, and suicide attempt in the other). Adverse events and laboratory abnormalities were generally consistent with the safety profile of RBV. The most frequent adverse events in patients who received SOF+RBV were: headache, 28%; fatigue, 27%; pruritus, 24%; asthenia, 22%; nausea, 17%; insomnia, 14%; dyspnoea, 11%; and dry skin, 11%. Conclusions: SOF+RBV was well tolerated in a predominantly treatment-experienced patient population treated for 12 (genotype 2) or 24 (genotype 3) weeks. Efficacy in genotype 2 patients is similar to that observed in recent Phase 3 studies. Data on the efficacy of SOF+RBV for 24 weeks in genotype 3 HCV-infected patients is critical to optimize the treatment duration for HCV genotype 3 infections and offer improved SVR rates.

Disclosures

Stefan Zeuzem - Consulting: Abbvie, Achillion Pharmaceuticals, Boehringer Ingelheim GmbH, Bristol-Myers Squibb Co., Gilead, Novartis Pharmaceuticals, Merck & Co., Idenix, Janssen, Roche Pharma AG, Vertex Pharmaceuticals, Presidio, Santaris, Inc

Geoffrey M. Dusheiko - Advisory Committees or Review Panels: Schering Plough, Vertex, Abbott, Boehringer Ingelheim, BMS, GSK, Pharmasett, Pfizer, Roche, Merck, Tibotec, Achillion, Schering Plough, Vertex, Abbott, Boehringer Ingelheim, BMS, GSK, Pharmasett, Pfizer, Roche, Merck, Tibotec, Achillion, Schering Plough, Vertex, Abbott, Boehringer Ingelheim, BMS, GSK, Pharmasett, Pfizer, Roche, Merck, Tibotec, Achillion, Schering Plough, Vertex, Abbott, Boehringer Ingelheim, BMS, GSK, Pharmasett, Pfizer, Roche, Merck, Tibotec, Achillion; Board Membership: Gilead Sciences, Gilead Sciences, Gilead Sciences, Gilead Sciences; Grant/Research Support: Gilead Sciences

Alessandra Mangia - Advisory Committees or Review Panels: ROCHE, Janssen, MSD, ROCHE, Janssen, MSD, Boheringer; Consulting: Gilead; Grant/Research Support: Shering-Plough, Shering-Plough

Robert Flisiak - Advisory Committees or Review Panels: Gilead, Merck, Roche, Bristol Myers Squibb, Janssen, Novartis, Achillion, Abbvie; Grant/Research Support: Roche, Bristol Myers Squibb, Janssen, Novartis, Gilead, Vertex, Merck; Speaking and Teaching: Janssen, Merck, Roche, Bristol Myers Squibb, Gilead

Robert H. Hyland - Employment: Gilead Sciences, Inc

Ari Illeperuma - Independent Contractor: Gilead Sciences, Inc.

Evguenia S. Svarovskaia - Employment: Gilead Sciences Inc.; Stock Shareholder: Gilead Sciences Inc.

Diana M. Brainard - Employment: Gilead Sciences, Inc. William T. Symonds - Employment: Gilead

John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead Sciences

Ola Weiland - Advisory Committees or Review Panels: MSD, BMS, Janssen, Gilead; Grant/Research Support, MSD, Roche, BMS; Speaking and Teaching: Novartis, Janssen, Abbott, Roche, Gilead

Hendrik W. Reesink - Consulting: Abbott, Gilead, Astex, Merck, Roche, Janssen-Cilag, GlaxoSmithKline, Tibotec/JJ, PRA-International; Grant/Research Support: Vertex, Boehringer Ingelheim, Anadys, Phenomix, Chugai, Japan Tobacco, Santaris, SGS, Idenix, BMS

Peter Ferenci - Advisory Committees or Review Panels: Roche, Idenix, Roche, MSD, Vertex, Salix, Madaus Rottapharm, Tibotec, B^dhringer Ingelheim, Achilleon, GSK; Grant/Research Support: MSD, Vertex, Madaus Rottapharm; Patent Held/Filed: Madaus Rottapharm; Speaking and Teaching: Roche, Gilead, Roche, Gilead, Salix

Christophe Hezode - Speaking and Teaching: Roche, BMS, MSD, Janssen, abbvie, Gilead Rafael Esteban - Speaking and Teaching: MSD, BMS, Novartis, Gilead, Glaxo, MSD, BMS, Novartis, Gilead, Glaxo, Janssen

The following people have nothing to disclose: Riina Salupere

1086

  1. Top of page

WITHDRAWN

  

1087

  1. Top of page

The Concordance between SVR4, SVR12, and SVR24 in Patients with Chronic HCV Infection who Received Treat-ment with Sofosbuvir in Phase 3 Clinical Trials

Eric M. Yoshida1, Mark S. Sulkowski2, Edward J. Gane3, Robert W. Herring4, Julie Ma5, John McNally5, Diana M. Brainard5, William T. Symonds5, John G. McHutchison5, Kimberly L. Beavers6, Ira M. Jacobson7, K. Rajender Reddy8, Eric Lawitz9; 1University of British Columbia, Vancouver, BC, Canada; 2Johns Hopkins Medical Center, Baltimore, MD; 3University of Auckland, Auckland City Hospital, Auckland, New Zealand; 4Nashville Gastrointestinal Specialists, Nashville, TN; 5Gilead Sciences, Inc., Foster City, CA; 6Asheville Gastroenterology Associates, PA, Asheville, NC; 7Weill Cornell Medical College, New York, NY; 8University of Pennsylvania, Philadelphia, PA; 9Texas Liver Institute, San Antonio, TX

Background and Aims: All virologic failures among treatment adherent patients in the Phase 3 clinical trials of sofosbuvir for hepatitis C were relapses after the end of treatment. The timing of relapse is important for validating the endpoint of SVR12 as a reliable assessment of HCV cure for IFN-free regimens. Methods: Sofosbuvir + ribavirin with or without peginterferon was administered to 982 patients in the registrational Phase 3 trials. HCV RNA concentrations were measured after the end of treatment to assess rates of SVR4, SVR12, and SVR24. We calculated the concordance between these assessments. Results: 964 patients had assessments available for post-treatment Weeks 4 and 1 2, 772 for post-treatment weeks 12 and 24. SVR24 data from the FUSION study are not yet available but will be incorporated into the final analysis. Most relapses occurred by post-treatment Week 4 (81%), and all but two patients who relapsed did so by post-treatment Week 12 (99%). In the peginterferon+ribavirin control arm of the FISSION study, 3 out of 159 patients achieving SVR12 subsequently relapsed (2%). Data for concordance between SVR12 and SVR24 are summarized in Table 1. Conclusion: For patients receiving sofosbuvir-based therapy, relapse after week 12 post-treatment is rare. Therefore, SVR12 is an appropriate time point for the reliable assessment of a durable treatment response to sofosbuvir-based therapy.

Table 4. Concordance of SVR12 and SVR24
 Overall tor SCF Regimens
 SVR24
  1. PPV = positive predictive value

  2. NPV = negative predictive value

 Yes (N=626)No(N=l46)
SVR12 Yes6252
SVRI2 No1144
Sensitivity>99%
Specificity99%
PPV>99%
NPV>99%
Disclosures

Eric M. Yoshida - Advisory Committees or Review Panels: Hoffman LaRoche, Gilead Sciences Inc, Vertex Inc; Grant/Research Support: Cangene Corporation, Hoffman LaRoche, Merck Inc/Schering Plough, Pfizer Inc, Norvartis Inc, Vertex Inc, Jannsen Inc, Gilead Sciences Inc, Boeringher Ingleheim Inc, Abbie (formerly Abbott Laboratories), Astellas; Speaking and Teaching: Gilead Sciences Inc, Cangene Corporation, Vertex Inc, Merck Inc

Mark S. Sulkowski - Advisory Committees or Review Panels: Pfizer; Consulting: Merck, AbbVie, BIPI, Vertex, Janssen, Gilead, BMS, BMS; Grant/Research Support: Merck, AbbVie, BIPI, Vertex, Janssen, Gilead

Edward J. Gane - Advisory Committees or Review Panels: Roche, AbbVie, Novar-tis, Tibotec, Gilead Sciences, Janssen Cilag, Vertex, Achillion; Speaking and Teaching: Novartis, Gilead Sciences, Roche

Julie Ma - Employment: Gilead Sciences

John McNally- Employment: Gilead Sciences

Diana M. Brainard - Employment: Gilead Sciences, Inc.

William T. Symonds - Employment: Gilead

John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead Sciences

Kimberly L. Beavers - Advisory Committees or Review Panels: Gilead, Janssen, Genentech; Grant/Research Support: Gilead, Pharmasset, Roche, Gilead, Pharmasset, Roche, BMS; Speaking and Teaching: Roche, Merck, Vertex, Roche, Merck, Vertex, Gilead

Ira M. Jacobson - Consulting: Vertex, Abbott, Achillion, Boehringer Ingelheim, Bristol Myers Squibb, Enanta, Gilead, Glaxo Smithkline, Idenix, Kadmon, Novartis, Presidio, Roche / Genentech, Merck, Janssen; Grant/Research Support: Abbott, Achillion, Vertex, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Novartis, Pfizer, Roche / Genentech, Schering / Merck, Tibotec / Janssen; Speaking and Teaching: Vertex, Bristol Myers Squibb, Gilead, Roche / Genentech, Schering / Merck

K. Rajender Reddy - Advisory Committees or Review Panels: Genentech-Roche, Merck, Janssen, Vertex, Gilead, BMS, Novartis, Idenix; Grant/Research Support: Genentech-Roche, Merck, BMS, Ikaria, Gilead, Hyperion, Janssen, AbbVie

Eric Lawitz - Advisory Committees or Review Panels: AbbVie, Achillion Pharmaceuticals, BioCryst, Biotica, Enanta, Idenix Pharmaceuticals, Janssen, Merck & Co, Novartis, Santaris Pharmaceuticals, Theravance, Vertex Pharmaceuticals; Grant/Research Support: AbbVie, Achillion Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Merck & Co, Novartis, Presidio, Roche, Santaris Pharmaceuticals, Vertex Pharmaceuticals ; Speaking and Teaching: Gilead, Kadmon, Merck, Vertex

The following people have nothing to disclose: Robert W. Herring

1088

  1. Top of page

A pooled analysis of two randomized, double-blind placebo-controlled Phase III trials (STARTVerso1&2) of faldaprevir plus pegylated interferon alfa-2a and rib-avirin in treatment-naïve patients with chronic hepatitis C genotype-1 infection

Donald M. Jensen1, Tarik Asselah2, Douglas T. Dieterich3, Graham R. Foster4, Mark S. Sulkowski5, Stefan Zeuzem6, Parvez S. Mantry7, Christophe Moreno8, Denis Ouzan9, Mark Wright10, Luis Morano11, Robert Buynak12, Marc Bourlière13, Tarek Hassanein14, Shuhei Nishiguchi15, Jia-Horng Kao16, Masao Omata17, Seung Woon Paik18, David K. Wong19, Edward Tam20, Kelly D. Kaita21, Victor S. Feinman22, Jerry O. Stern23, Miguel Garcia23, Anne-Marie Quinson23, Florian Voss24, John-Paul Gallivan24, Wulf O. Boecher24, Peter Ferenci25; 1University of Chicago Medicine, Chicago, IL; 2Hôpital Beaujon, APHP, University Paris-Diderot and INSERM CRB3, Clichy, France; 3Mount Sinai School of Medicine, New York, NY; 4Queen Mary, University of London, London, United Kingdom; 5Johns Hopkins University School of Medicine, Baltimore, MD; 6J.W.Goethe University Hospital, Frankfurt, Germany; 7The Liver Institute at Methodist Dallas Medical Center, Dallas, TX; 8Hôpital Universitaire Erasme, Université Libre de Bruxelles, Brussels, Belgium; 9Institut Arnault Tzanck, St Laurent du Var, France; 10Wellcome Trust Clinical Research Facility, Southampton, United Kingdom; 11Hospital Meixoeiro, Vigo, Spain; 12Northwest Indiana Center for Clinical Research, Valparaiso, IN; 13Hopital Saint Joseph, Marseille, France; 14Southern California Liver Centers, Coronado, CA; 15Hyogo College of Medicine, Hyogo, Japan; 16National Taiwan University Hospital, Taipei, Taiwan; 17Yamanishi Central and Kita Hospitals, Yamanishi, Japan; 18Samsung Medical Center, Sungkyunkwan University, Seoul, Republic of Korea; 19Toronto Western Hospital Liver Center, Toronto, ON, Canada; 20LAIR Centre, Vancouver, BC, Canada; 21HSC University of Manitoba, Winnipeg, MB, Canada; 22Hepatitis Centre, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada; 23Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT; 24Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany; 25Medical University of Vienna, Vienna, Austria

Background: Faldaprevir (FDV) is a potent HCV NS3/4A inhibitor. STARTVerso (SV) 1 (Europe and Japan) and SV2 (North America, South Korea, and Taiwan) assessed FDV plus pegylated interferon alfa-2a and ribavirin (PR) in treatment-naïve patients with chronic HCV genotype 1 (GT1) infection. Here we present results from a pooled analysis of SV1&2. Methods: Patients were randomized 1:2:2 to receive 48 weeks (W) of PR plus: placebo (Arm 1); FDV 120mg QD for 12W or 24W (Arm 2, response guided in SV1); or FDV 240mg QD for 12W (Arm 3). Patients in Arms 2 and 3 stopped all treatment at W24 after achieving early treatment success (ETS, HCV RNA <25IU/mL detected or undetected at W4 and undetected at W8). The primary endpoint in both studies was sustained virologic response at 12W after completion of treatment (SVR12). Results: 1309 (SV1, n=652; SV2, n=657) patients received treatment. Baseline characteristics for the pooled treatment groups (Arms 1/2/3) were (%): male 58/53/57; Caucasian 71/72/71; GT1a subtype 47/47/48; IL28B [rs12979860] CC 36/41/41; ≥F3 fibrosis 22/21/19. Compared with SV1, patients in SV2 were more likely to have HCV GT1a, higher BMI, psychiatric disorders, and more advanced fibrosis. SVR12 rates were 50% (Arm 1), 73% (Arm 2), and 72% (Arm 3). Results were similar between patients treated with FDV 120mg or 240mg in the whole population and across baseline subgroups (Table). For Arms 1, 2, and 3, discontinuation of all study medication due to AEs was reported in 4%, 5%, and 8% of patients, respectively. Serious AEs occurred in 6%, 7%, and 8% of patients. Severe rash was reported in 1 % of patients who received either FDV or placebo; no severe photosensitivity reactions were observed. Hemoglobin ≤8.5 g/dL occurred in 3%, 4%, and 3% of patients. Bilirubin >2.5 x the upper limit of normal occurred in 0.4%, 12%, and 46% of patients. Conclusions: FDV plus PR increased SVR12 rates in HCV GT1 patients compared with PR alone, and was well tolerated. FDV had similar efficacy at both the 120mg and 240mg doses. In patients treated with FDV, 84% were eligible to stop all treatment at W24, of whom 83% achieved SVR12.

Table 5. 
n(%)Placebo + PR (N=264)FDV 120mg + PR (N=521)FDV 240mg + PR(N=524)
SVR12131 (50)382(73)378 (72)
n/N (%) North America Europe Asia49/109 (45) 53/108 (49) 29/47 (62)135/215(63) 160/207 (77) 87/99 (88)129/216(60) 164/211 (78) 85/97 (88)
GTI subtype 1a l Ib53/125(42)77/138(56)158/247(64)222/272(82)164/253(65)213/270(79)
IL28B genotype l CC non-CC63/94(67)67/169(40)191/213(90)190/307(62)188/213(88)190/306(62)
Liver fibrosis Less than F3 / F3 or greater108/205(53)22/57(39)316/408(77)64/109(59)322/420(77)32/97(54)
ETS50(19)436(84)441 (84)
SVR12 in patients with ETS, n/N (%)41/50(82)362/436 (83)368/441 (83)
Disclosures

Donald M. Jensen - Advisory Committees or Review Panels: Abbvie, Boehringer, BMS, Genentech/Roche, Merck, Gilead, Janssen; Grant/Research Support: Abbvie, Boehringer, BMS, Genentech, Janssen, Gilead

Tarik Asselah - Consulting: BMS, Boehringer-Ingelheim, Roche, Merck-Schering Plough, Gilead, Janssen

Douglas T. Dieterich -Advisory Committees or Review Panels: Gilead, Genentech, Janssen, achillion, idenix, Merck, Tobira, Boehringer Ingelheim, TIbotec, Inhibitex, Roche, Vertex

Graham R. Foster - Advisory Committees or Review Panels: GlaxoSmithKline, Novartis, Boehringer Ingelheim, Tibotec, Chughai, Gilead, Janssen, Idenix, GlaxoSmithKline, Novartis, Roche, Tibotec, Chughai, Gilead, Merck, Janssen, Idenix, BMS; Board Membership: Boehringer Ingelheim; Grant/Research Support: Chughai, Roche, Chughai; Speaking and Teaching: Roche, Gilead, Tibotec, Merck, BMS, Boehringer Ingelheim, Gilead, Janssen

Mark S. Sulkowski - Advisory Committees or Review Panels: Pfizer; Consulting: Merck, AbbVie, BIPI, Vertex, Janssen, Gilead, BMS, BMS; Grant/Research Support: Merck, AbbVie, BIPI, Vertex, Janssen, Gilead

Stefan Zeuzem - Consulting: Abbvie, Achillion Pharmaceuticals, Boehringer Ingelheim GmbH, Bristol-Myers Squibb Co., Gilead, Novartis Pharmaceuticals, Merck & Co., Idenix, Janssen, Roche Pharma AG, Vertex Pharmaceuticals, Presidio, Santaris, Inc

Parvez S. Mantry - Grant/Research Support: Schering, Bayer, Hyperion, Boehringer -Ingelheim, Abbott; Speaking and Teaching: Onyx, Salix, Vertex, Genentech, Merck, Kadmon

Christophe Moreno - Board Membership: JANSSEN, Janssen Therapeutics; Consulting: Gilead, MSD; Grant/Research Support: ROCHE, Janssen, Novartis, Astellas, MSD; Speaking and Teaching: MSD, BMS, JANSSEN

Marc Bourlière - Advisory Committees or Review Panels: Schering-Plough, Bohringer inghelmein, Merck, Schering-Plough, Bohringer inghelmein, Merck ; Board Membership: Bristol-Myers Squibb, Gilead, Bristol-Myers Squibb, Gilead; Consulting: Roche, Novartis, Tibotec, Abott, glaxo smith kline, Roche, Novartis, Tibotec, Abott, glaxo smith kline

Tarek Hassanein - Grant/Research Support: Janssen R&D, Bristol-Myers Squibb, Salix Pharmaceuticals, Sundise Traditional Chinese Pharmaceuticals, Boehringer-Ingelheim, Vertex Pharmaceuticals, Ikaria Pharmaceuticals, Idenix Pharmaceuticals, Eiasi Pharmaceuticals, Gilead Sciences, Inc., AbbVie ; Speaking and Teaching: Bristol Myers Squibb, Gilead Sciences, Inc., Genentech, Salix

Masao Omata - Board Membership: Gilead sciece; Consulting: Bristol-Myers Squibb, Boehringer Ingelheim, Otsuka Pharmaceutical ; Speaking and Teaching: Bristol-Myers Squibb, Pfizer, Roche

David K. Wong - Grant/Research Support: Gilead, BMS, Vertex, BI

Kelly D. Kaita - Advisory Committees or Review Panels: Gilead, Merck, Roche, Janssen, Boehringer, BMS, GSK, Vertex; Grant/Research Support: Gilead, Merck, Roche

Jerry O. Stern - Employment: Boehringer Ingelheim

Miguel Garcia - Employment: Boehringer-Ingelheim

Anne-Marie Quinson - Employment: Boehringer Ingelheim

Florian Voss - Employment: Boehringer Ingelheim Pharma GmbH & Co. KG

John-Paul Gallivan - Employment: Boehringer-Ingelheim

Wulf O. Boecher - Employment: Boehringer Ingelheim GmbH

Peter Ferenci - Advisory Committees or Review Panels: Roche, Idenix, Roche, MSD, Vertex, Salix, Madaus Rottapharm, Tibotec, Bohringer Ingelheim, Achilleon, GSK; Grant/Research Support: MSD, Vertex, Madaus Rottapharm; Patent Held/Filed: Madaus Rottapharm; Speaking and Teaching: Roche, Gilead, Roche, Gilead, Salix

The following people have nothing to disclose: Denis Ouzan, Mark Wright, Luis Morano, Robert Buynak, Shuhei Nishiguchi, Jia-Horng Kao, Seung Woon Paik, Edward Tam, Victor S. Feinman

1089

  1. Top of page

Low Relapse Rate Leads to High Concordance of SVR4 and SVR12 with SVR24 After Treatment with ABT-450/r, ABT-267, ABT-333 + Ribavirin in Patients with Chronic HCV Genotype 1 Infection in the AVIATOR Study

Fred Poordad1, Kosh Agarwal2, Ziad Younes3, Daniel E. Cohen4, Wangang Xie4, Thomas Podsadecki4; 1The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX; 2Kings College Hospital, London, United Kingdom; 3Gastro One, Ger-mantown, TN; 4AbbVie, North Chicago, IL

Purpose: We previously reported SVR24 rates of 90-96% in patients with HCV genotype 1 (GT1) treated for 12 or 24 weeks with ABT-450/r (protease inhibitor dosed with ritonavir 1 00 mg, identified by AbbVie and Enanta) in combination with ABT-267 (NS5A inhibitor) and ABT-333 (non-nucleoside NS5B

inhibitor) + ribavirin (RBV) in the AVIATOR trial. We evaluated the concordance of SVR24 with rapid virologic response (RVR), SVR4 and SVR12 in these AVIATOR treatment groups. Methods: Non-cirrhotic, GT1 treatment-naïve patients and prior peginter-feron/RBV null responders received ABT-450/r (100/100-150/100mg QD), ABT-267 (25mg QD), ABT-333 (400mg BID), and RBV (weight-based 1000-1200 mg daily dose divided BID) for 1 2 or 24 weeks. For concordance analysis all outcomes were assessed in the ITT population (missing data=failure). Patients who had HCV RNA <LLOQ at 24 weeks post-treatment and at the earlier timepoint (week 4 of treatment, or 4 or 12 weeks post-treatment) were true positives; those who had quantifiable HCV RNA or missing data at 24 weeks post-treatment and at the earlier timepoint were true negatives. Positive and negative predictive values (PPV and NPV) of virologic response outcomes for SVR24 were calculated. Results: In the AVIATOR study, 247 patients were treated with ABT-450/r + ABT-267 + ABT-333 + RBV for 12 or 24 weeks. The table details concordance of virologic outcomes with SVR24. Conclusions: In AVIATOR, there was high concordance between SVR24 and the other virologic outcomes assessed among patients treated with 3DAA+RBV for 12 or 24 weeks. No virologic failures occurred after 4 weeks post-treatment; loss to follow-up accounted for all discordance between SVR rates. These results support the use of SVR12 as a primary efficacy endpoint for trials of this interferon-free regimen in patients with HCV GT1 infection.

Concordance with SVR24

Table 6. 
 ABT-4 50/r + ABT-267 + ABT-333 + RBV n=247
  1. RVR: Rapid virologic response, HCV RNA <LLOQ at week 4 of treatment

  2. LTFU: Lost to follow-up

 PPV (%)NPV (%)Reasons for discordance
RVR941004 breakthroughs; 2 relapses; 9 LTFU after week 4
SVR4971007 LTFU after SVR4
SVR12981005 LTFU after SVR 12
Disclosures

Fred Poordad - Advisory Committees or Review Panels: Abbott, Achillion, BMS, Inhibitex, Boeheringer Ingelheim, Pfizer, Genentech, Idenix, Gilead, Merck, Vertex, Salix, Janssen, Novartis; Grant/Research Support: Abbott, Anadys, Achillion, BMS, Boehringer Ingelheim, Genentech, Idenix, Gilead, Merck, Phar-massett, Vertex, Salix, Tibotec/Janssen, Novartis

Kosh Agarwal -Advisory Committees or Review Panels: Gilead, Novartis, Abbott; Grant/Research Support: Roche, MSD; Speaking and Teaching: BMS, Astellas, Janssen

Daniel E. Cohen - Employment: AbbVie; Stock Shareholder: AbbVie

Wangang Xie - Employment: AbbVie

The following people have nothing to disclose: Ziad Younes, Thomas Podsadecki

1090

  1. Top of page

Sofosbuvir plus Ribavirin in the Treatment of Chronic HCV Genotype 4 Infection in Patients of Egyptian Ancestry

Peter J. Ruane1, Dani Ain1, Joseph Riad1, Raymond G. Meshrekey1, Richard Stryker1, Peter R. Wolfe1, Lamese R. Basily-ous1, Deyuan Jiang2, Steven J. Knox2, Kathryn Kersey2, William T. Symonds2; 1Peter J Ruane, MD, Inc., Los Angeles, CA; 2Gilead Sciences, Inc., Foster City, CA

Background: The prevalence of hepatitis C is estimated to be approximately 10-15% of the Egyptian population, and over 90% of those infected have hepatitis C virus (HCV) genotype (GT) 4. The HCV-specific uridine nucleotide analog sofosbuvir

(SOF) administered with ribavirin (RBV) and peginterferon demonstrated an SVR12 rate of 96% in 28 treatment-naïve HCV GT4 patients in a phase 3 study in HCV GT1, 4, 5, and 6 patients (NEUTRINO; Lawitz et al. NEJM 2013;368:1878-87). We conducted a phase 2 study to evaluate the safety and efficacy of SOF+RBV (without interferon) in patients of Egyptian ancestry with chronic HCV GT4. Methods: We randomized treatment-naive and treatment-experienced patients with HCV GT4 infection 1:1 to receive either 12 or 24 weeks of SOF (400 mg daily) + RBV (1000-1200 mg daily). Patients were born in Egypt, with both maternal and paternal Egyptian ancestry documented. Randomization was stratified by prior treatment experience and by the presence or absence of cirrhosis. Results: 60 patients were enrolled (28 treatment-naive and 32 treatment-experienced). Patients were predominantly male (41/60); mean age of 54 years; mean BMI of 29.2 kg/m2; 23% had cirrhosis at baseline, 57% had baseline HCV RNA ≥6log10 IU/mL, and 83% were IL28B CTorTT. Among treatment-experienced patients, 62.5% were prior non-responders to therapy, 18.8% had experienced relapse or breakthrough on treatment, 12.5% were interferon-intolerant, and prior response was unknown for 6.2%. At the time of abstract submission, no virologic breakthrough had been observed. By Week 4, 98% of all patients had HCV RNA below the lower limit of quantification (LLOQ) of 25 IU/mL (rapid virologic response [RVR]). All patients who had completed treatment had HCV RNA <LLOQ at the end of treatment (end of treatment response [EOTR]). Of 18 patients who received 12 weeks of SOF+RBV and had reached the 4-week post-treatment visit, 15 had achieved SVR4 and 3 had relapsed (SVR4 rate of 83%). The most common adverse events (>30% of patients) were headache, insomnia, and fatigue. No AEs resulted in treatment discontinuation. The overall adverse event profile was consistent with that expected with a RBV-containing regimen. Complete SVR4 data will be presented. Conclusions: An oral regimen containing sofosbuvir plus ribavirin provided rapid and consistent antiviral suppression in treatment-naïve and -experienced patients with genotype 4 infection, with an initial encouraging high SVR rate.

Table 7. 
 SOF+RBV 12-weeks N=31SOF+RBV 24-weeks N=29
RVR30/31 (97%)29/29(100%)
EOTR24/24 (100%)8/8 (100%)
SVR415/18(83%)Pending
Disclosures

Peter J. Ruane - Advisory Committees or Review Panels: Gilead, Boehringer, Jannsen, Viiv, Abbott; Consulting: Gilead, Jannsen, Abbott, BMS; Grant/Research Support: Gilead, Boehringer, Jannsen, Idenix, Abbott, BMS; Speaking and Teaching: Gilead, Merck, Boehringer, Jannsen, VIIV, Abbott, BMS; Stock Shareholder: Gilead

Deyuan Jiang - Employment: Gilead Sciences Steven J. Knox - Employment: Gilead Sciences

Kathryn Kersey - Employment: Gilead Sciences, Inc; Stock Shareholder: Gilead Sciences, Inc

William T. Symonds - Employment: Gilead

The following people have nothing to disclose: Dani Ain, Joseph Riad, Raymond G. Meshrekey, Richard Stryker, Peter R. Wolfe, Lamese R. Basilyous

1091

  1. Top of page

Nucleotide Analog Levels in Liver Explants from HCV Infected Subjects Undergoing Liver Transplantation After up to 24 Weeks Sofosbuvir (GS-7977) with Ribavirin Treatment

Darius M. Babusis1, Michael P. Curry2, Jill M. Denning1, Yeojin Park1, Eisuke Murakami1, Nezam H. Afdhal2, William T. Symonds1, John G. McHutchison1, Adrian S. Ray1; 1Gilead Sciences, Inc., Foster City, CA; 2Beth Israel Deaconess Medical Center, Boston, MA

Purpose: Sofosbuvir is a uridine nucleotide analog prodrug that has demonstrated potent and selective antiviral activity against a broad range of HCV genotypes. However, little is known regarding intrahepatic concentrations of the pharmacologically active triphosphate metabolite achieved in humans following sofosbuvir administration. P7977-2025 (NCT01559844) is an ongoing open-label study exploring the clinical efficacy of sofosbuvir and RBV administered prior to liver transplantation to prevent HCV recurrence post-transplant and provided a unique opportunity to quantify nucleotide concentrations in human liver. Methods: As an exploratory analysis, nucleotide levels in liver tissue were quantified. At time of transplant, small sections of explanted liver were collected and flash frozen within 5 min. Following homogenization, nucleoside and nucleotide analog levels were determined using high performance liquid chro-matography coupled to tandem mass spectrometry. In addition, levels of endogenous adenosine nucleotides were determined to assess sample integrity. Untreated liver tissue was used to prepare calibration standards and quality control samples that were analyzed before and after each sample set to assure appropriate selectivity, accuracy and precision. Results: Liver samples from 25 subjects receiving between 3 and 24 wk of treatment with sofosbuvir 400 mg/day and RBV 1000-1200 mg/day before liver transplant were analyzed. High total concentrations (sum of nucleoside, mono-, di- and triphosphate) were observed in liver explants for sofosbuvir (mean ± SD, 71 ± 49 μM) and RBV (mean ± SD, 560 ± 500 μM). Total RBV concentrations were variable ranging from 82 to 1 800 μM. While analysis of adenosine nucleotides revealed that dephosphory-lation had taken place during sample collection, in vitro experiments with sofosbuvir found that the triphosphate metabolite accounts for > 80% of the total intracellular metabolites in primary human hepatocytes and illustrate that total concentrations detected in the explanted tissue can be equated to triphosphate. The three subjects with the lowest levels of sofosbuvir-related metabolites (≤ 1.2 μM) had completed therapy at least 3 wk prior to transplant. These subjects also had < 200 μM RBV-related metabolites. Conclusions: For the first time concentrations of nucleotide analogs in liver samples from subjects treated with sofosbuvir and RBV are reported. Estimated levels of the triphosphate of sofosbuvir in great excess of the inhibition constant measured in biochemical assays with the HCV NS5B polymerase (Ki = 0.42 μM) are consistent with the potent anti-HCV activity observed clinically.

Disclosures

Darius M. Babusis - Employment: Gilead Sciences, Inc.

Michael P. Curry - Grant/Research Support: Gilead Sciences, Mass Biologics, Merck, Ikaria; Stock Shareholder: Achilion, Idenix

Jill M. Denning - Employment: Gilead Sciences, Inc. Eisuke Murakami - Employment: Gilead Sciences

Nezam H. Afdhal - Consulting: Merck, Vertex, Idenix, GlaxoSmithKline, Spring-bank, Gilead, Pharmasett, Abbott; Grant/Research Support: Merck, Vertex, Idenix, GlaxoSmithKline, Springbank, Gilead, Pharmasett, Abbott

William T. Symonds - Employment: Gilead

John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead Sciences

Adrian S. Ray- Employment: Gilead Sciences, Inc.

The following people have nothing to disclose: Yeojin Park

1092

  1. Top of page

Simeprevir (TMC435) with peg-interferon α-2a/ribavirin for treatment of chronic HCV genotype 1 infection in patients who relapsed after previous interferon-based therapy: efficacy and safety in patient sub-populations in the PROMISE phase III trial

Xavier Forns1, Eric Lawitz2, Stefan Zeuzem3, Edward J. Gane4, Jean-Pierre Bronowicki5, Pietro Andreone6, Andrzej Horban7, Ashley S. Brown8, Monika Peeters9, Oliver Lenz9, Sivi Ouwerkerk-Mahadevan10, Jane A. Scott11, Ronald Kalmeijer12, Guy De La Rosa12, Rekha Sinha9, Maria Beumont-Mauviel9; 1Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red de Enfer-medades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain; 2Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX; 3J. W. Goethe University Hospital, Frankfurt, Germany; 4Auckland Hospital Clinical Studies Unit, Auckland, New Zealand; 5INSERM U954, université de Lorraine, Centre Hospital-ier Universitaire de Nancy, Vandoeuvre Les Nancy, France; 6Dipar-timento di Scienze Mediche e Chirurgiche, University of Bologna, Bologna, Italy; 7Medical University of Warsaw, Wolska, Warsaw, Poland; 8Imperial College Healthcare NHS Trust, London, United Kingdom; 9Janssen Infectious Diseases BVBA, Beerse, Belgium; 10Janssen Research & Development, Beerse, Belgium; 11Janssen Global Services LLC, High Wycombe, United Kingdom; 12Janssen Global Services, LLC, Titusville, NJ

Background The double-blind, multicenter, Phase III PROMISE study evaluated simeprevir (SMV), a once-daily (QD) investiga-tional HCV NS3/4A protease inhibitor, plus PegIFNα-2a/RBV (PR) in HCV genotype 1 patients with prior relapse. This analysis focuses on safety and efficacy of SMV/PR in difficult-to-cure patient sub-groups (IL28B TT, METAVIR F4, HCV genotype 1a with baseline Q80K). Methods Patients who had received IFN-based therapy for ≥24 wks and relapsed ≤1 yr thereafter were randomized 2:1 to SMV 150mg QD (12 wks) plus PR (response guided 24/48 wks) or to placebo (PBO, 12 wks) plus PR (48 wks). Primary efficacy end point was SVR12. Results The ITT population comprised 393 patients. SVR12 was significantly higher with SMV/PR vs PBO/PR overall (79.2% vs 36.8%; p<0.001). SVR12 was 88.7%, 85.9% and 82.0% in patients with IL28B CC genotype, HCV genotype 1b and METAVIR F0-F2, respectively, receiving SMV (all p<0.001 vs PBO). SVR12 was also statistically significantly higher with SMV/PR vs PBO/PR in difficult-to-cure IL28B TT genotype, METAVIR F4 and genotype 1a patients, and higher in genotype 1a patients with baseline Q80K (46.7% vs 27.8%, table). RVR rates were also higher with SMV/PR vs PBO/PR in patients with IL28B genotype TT (90.3% vs 0%), F4 (76.9% vs 0%) and genotype 1a with baseline Q80K (44.8% vs 5.9%). Of those patients who achieved RVR in the SMV/PR arm, 86.5% achieved SVR12. RVR was predictive of high SVR12 in the overall population as well as in difficult-to-cure subgroups. The incidence and profile of AEs was generally similar between the SMV and PBO treatment groups. Bilirubin increases with SMV/PR were mild, transient and without concomitant increases in ALT/AST and the incidence and severity (mostly low grade) of rash and anemia AEs were similar for SMV/PR and PBO/PR. Patient-reported fatigue and impairment in work and daily activities confirmed the safety and efficacy of simeprevir. Conclusions Simeprevir conferred clinical benefit and was well tolerated across different patient sub-populations with prior relapse on IFN, including patients with IL28B TT and

METAVIR score F4. SVR12 was higher in all subgroups treated with SMV/PR.

Table 8. 
 RVR,%(n/N)SVR12%(n/N)
 SMV/PR (N=260)PBO/PR(N=133)SMV/PR (N=260)PBO/PR(N=133)
  1. *p<0.001 vsPBO/PR

  2. pooled PBO 1a/other

All patients77.2 (200/259)*3.1 (4/129)79.2 (206/260)*36.8 (49/133)
METAVIR F476.9 (30/39)0.0 (0/19)74.4 (29/39)*26.3 (5/19)
IL28B TT90.3(28/31)0.0(0/15)64.5(20/31)*18.8(3/16)
HCV GT la68.2(75/110)3.9(2/51)70.3 (78/111 )*27.8(15/54)
With Q80K44.8 (13/29)5.9(1/17)46.7(14/30)27.8(l5/54)†
Disclosures

Xavier Forns - Consulting: Tibotec/Jansen, MSD, Boheringher Ingelheim; Grant/Research Support: Roche, MSD, Gilead

Eric Lawitz - Advisory Committees or Review Panels: AbbVie, Achillion Pharmaceuticals, BioCryst, Biotica, Enanta, Idenix Pharmaceuticals, Janssen, Merck & Co, Novartis, Santaris Pharmaceuticals, Theravance, Vertex Pharmaceuticals; Grant/Research Support: AbbVie, Achillion Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Merck & Co, Novartis, Presidio, Roche, Santaris Pharmaceuticals, Vertex Pharmaceuticals ; Speaking and Teaching: Gilead, Kadmon, Merck, Vertex

Stefan Zeuzem - Consulting: Abbvie, Achillion Pharmaceuticals, Boehringer Ingelheim GmbH, Bristol-Myers Squibb Co., Gilead, Novartis Pharmaceuticals, Merck & Co., Idenix, Janssen, Roche Pharma AG, Vertex Pharmaceuticals, Presidio, Santaris, Inc

Edward J. Gane-Advisory Committees or Review Panels: Roche, AbbVie, Novartis, Tibotec, Gilead Sciences, Janssen Cilag, Vertex, Achillion; Speaking and Teaching: Novartis, Gilead Sciences, Roche

Jean-Pierre Bronowicki - Consulting: Merck, Janssen, Boehringer Ingelheim, Gilead, BMS, Bayer, Novartis, GSK, Merck, Janssen, Boehringer Ingelheim, Gilead, BMS, Bayer, Novartis, GSK; Speaking and Teaching: Roche, Merck, Janssen, BMS, Bayer, Roche, Merck, Janssen, BMS, Bayer

Pietro Andreone - Advisory Committees or Review Panels: Roche, Janssen-Cilag, Gilead, MSD/Schering-Plough; Grant/Research Support: Roche, Gilead; Speaking and Teaching: Roche, MSD/Schering-Plough

Ashley S. Brown - Advisory Committees or Review Panels: MSD, Roche, Bristol-Myers-Squibb, Gilead, Novartis, Janssen, Abbvie, Achillion; Speaking and Teaching: MSD, Roche, Bristol-Myers Squibb, Gilead, Janssen, Abbvie

Monika Peeters - Employment: Janssen

Oliver Lenz - Employment: Janssen

Sivi Ouwerkerk-Mahadevan - Employment: Janssen

Jane A. Scott - Employment: Janssen; Stock Shareholder: J&J

Ronald Kalmeijer - Employment: Johnson and Johnson

Guy De La Rosa - Employment: Johnson & Johnson

Rekha Sinha - Employment: Janssen Pharmaceutica

Maria Beumont-Mauviel - Employment: Janssen

The following people have nothing to disclose: Andrzej Horban

1093

  1. Top of page

Efficacy and Safety of Sofosbuvir in Patients According to Fibrosis Stage: An Analysis of Phase 3 Data

Keyur Patel1, Stuart C. Gordon2, Aasim M. Sheikh3, Ziad Younes4, Julie Ma5, John McNally5, Diana M. Brainard5, William T. Symonds5, John G. McHutchison5, Ronald Nahass6, Eric M. Yoshida7, Hendrik W. Reesink8, David R. Nelson9; 1Duke University Medical Center, Durham, NC; 2Henry Ford Health System, Detroit, MI; 3GI Specialists of Georgia, Mariette, GA; 4Gastro One, Ger-mantown, TN; 5Gilead Sciences, Inc., Foster City, CA; 6ID Care, Inc., Hillsborough, NJ; 7University of British Columbia, Vancouver, BC, Canada; 8Academic Medical Center, Amsterdam, Netherlands; 9University of Florida, Gainesville, FL

Background and Aims: The degree of liver fibrosis can impact the safety and/or efficacy of HCV treatment. Enrollment of a high proportion of patients with advanced fibrosis in the sofos-

buvir (SOF) Phase 3 program allowed for analyses within these subgroups. Methods: SVR12 rates and safety data were retrospectively analyzed across four Phase 3 clinical trials (FISSION, POSITRON, FUSION, and NEUTRINO) by degree of liver fibrosis (F0-F4) and extent of thrombocytopenia. Results: Of 982 patients treated with a SOF-containing regimen, 857 (87%) had documentation of fibrosis stage by Fibrotest: 55% F0-F2, 1 7% F3, 28% F4. Thrombocytopenia (platelets <125/mm3) at baseline was present in 1 2% of patients, and 5% had platelets <100/mm3. SOF was well tolerated across all subgroups, including patients with cirrhosis and/or thrombocytopenia. The breakdown of SVR rates by study is provided in the table. The degree of fibrosis had little impact on efficacy in GT2 HCV-infected patients whereas rates of SVR12 in GT3 and GT1 patients with cirrhosis (19-61% and 80%, respectively) were generally lower than in patients without cirrhosis (37-71% and 92%, respectively). Detailed breakdown of SVR rates by genotype, prior treatment experience, SOF regimen, and fibrosis stage will be provided. SVR rates among patients with thrombocytopenia were similar to rates in cirrhotic patients across all HCV genotypes. Conclusions: In this large cohort of patients participating in SOF-containing Phase 3 studies, the safety profile of SOF did not differ by degree of hepatic fibrosis. Overall, SVR rates were lower in cirrhotics, although the impact of cirrhosis on efficacy was strongly influenced by genotype.

Table 9. SVR12 by SOF Regimen and Stage of Liver Disease
 SOF+RBV I2wksSOF+RBV 16 wksSOF+P/R12 wks
FISSIONPOSITRONFUSIONFUSIONNEUTRINO
GT2/3 TNGT2/3IFN incapableGT2/3 TEGT2/3 TEGT1/4/5/6TN
Overall67 (170/253)78(161/207)50 (50/100)73 (69/95)90 (295/327)
F0-F269 (62/90)81(107/132)70 (26/37)84 (36/43)97(173/179)
F355(12/22)76(19/25)40(10/25)50(8/16)86 (49/57)
F448(10/21)70 (35/50)37(14/38)71 (25/35)79 (69/87)
Platelets ≤12553(17/32)60(15/25)29 (7/24)73(11/15)82(14/17)
Platelets ≤10033(4/12)67(10/15)33 (4/12)63 (5/8)75 (3/4)
Disclosures

Keyur Patel - Consulting: Benitec, Santaris; Speaking and Teaching: Gilead Sciences, Vertex

Stuart C. Gordon - Advisory Committees or Review Panels: Tibotec; Consulting: Merck, CVS Caremark, Gilead Sciences, BMS; Grant/Research Support: Roche/Genentech, Merck, Vertex Pharmaceuticals, Gilead Sciences, BMS, Abbott, Intercept Pharmaceuticals, Exalenz Sciences, Inc.

Aasim M. Sheikh - Grant/Research Support: Genentech, Roche Pharmaceuticals, Vertex Pharmaceuticals, Pfizer, Idenix Pharmaceuticals, Gilead, Bristol Meyers Squibb, Tibotec, Cubist Pharmaceuticals; Speaking and Teaching: Genentech, Vertex Pharmaceuticals

Julie Ma - Employment: Gilead Sciences John McNally- Employment: Gilead Sciences Diana M. Brainard - Employment: Gilead Sciences, Inc. William T. Symonds - Employment: Gilead

John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead Sciences

Ronald Nahass - Advisory Committees or Review Panels: Gilead; Grant/Research Support: Gilead; Speaking and Teaching: Gilead

Eric M. Yoshida - Advisory Committees or Review Panels: Hoffman LaRoche, Gilead Sciences Inc, Vertex Inc; Grant/Research Support: Cangene Corporation, Hoffman LaRoche, Merck Inc/Schering Plough, Pfizer Inc, Norvartis Inc, Vertex Inc, Jannsen Inc, Gilead Sciences Inc, Boeringher Ingleheim Inc, Abbie (formerly Abbott Laboratories), Astellas; Speaking and Teaching: Gilead Sciences Inc, Cangene Corporation, Vertex Inc, Merck Inc

Hendrik W. Reesink - Consulting: Abbott, Gilead, Astex, Merck, Roche, Janssen-Cilag, GlaxoSmithKline, Tibotec/JJ, PRA-International; Grant/Research Support: Vertex, Boehringer Ingelheim, Anadys, Phenomix, Chugai, Japan Tobacco, Santaris, SGS, Idenix, BMS

David R. Nelson - Advisory Committees or Review Panels: Merck; Grant/Research Support: Abbot, BMS, Beohringer Ingelheim, Gilead, Genentech, Merck, Bayer, Idenix, Vertex, Jansen

The following people have nothing to disclose: Ziad Younes

1094

  1. Top of page

Sofosbuvir Selects the NS5B S282T Mutation In Vitro in Genotype 1 -6 Replicons and is not Cross-resistant to Resistance Associated Variants Selected by Other Classes of Antiviral Inhibitors

Sonal Rajyaguru, Simin Xu, Christy Hebner, Evguenia S. Svarovskaia, Viktoria Gontcharova, Brian Doehle, Michael D. Miller, Hongmei Mo; Clinical Virology, Gilead Sciences, Inc., Foster City, CA

Introduction: Sofosbuvir (SOF) is the prodrug of a uridine nucleotide analog inhibitor of the hepatitis C virus (HCV) NS5B polymerase with demonstrated broad-genotypic activity against HCV in vivo and in vitro. To determine the SOF resistance profile in genotypes (GTs) 1-6, in vitro resistance selection using stable replicon cells was performed. In addition, the activity of SOF against clinically relevant HCV resistance-associated variants (RAVs) was analyzed. Materials & Methods: HCV GT 1b, 2a, 3a, and 4a subgenomic replicons and NS5B chimeric GT 2b, 5a and 6a replicons were passaged in the presence of increasing concentrations of SOF. A luciferase assay was used to monitor changes in SOF susceptiblity. The emergence of NS5B variants during resistance selection was assessed by deep sequencing. Site-directed mutagenesis (SDM) was used to evaluate the contribution of observed NS5B variants to reductions in SOF susceptibility. Replicons encoding clinically relevant protease inhibitor (PI), NS5A inhibitor, non-nucleoside inhibitor (NNI) RAVs, the nucleoside inhibitor (NI) RAVs L159F and L320F, or the ribavirin (RBV)-associated variants T390I and F415Y were analyzed for cross resistance to SOF using transient replicon assay. Results: S282T was the primary NS5B mutation selected in all 7 genotypes examined with increased levels of S282T observed in conjunction with reduced susceptibility to SOF. SDM analysis of the S282T single mutant demonstrated a mild to modest reduction in SOF susceptibility (up to 18-fold) while remaining sensitive to the NS5A inhibitor ledi-pasvir. S282T mutants exhibited greatly reduced replication capacity compared to wild-type replicons. Additional variants were observed in selected replicon cell lines in conjunction with the S282T mutation, though by SDM analyses none of these variants conferred reduced susceptibility to SOF. SOF remained fully active against the NI RAVs L159F and L320F both individually and in combination. SOF also remained fully active against the RBV variants T390I and F415Yand against a panel of clinically relevant PI, NNI, and NS5A RAVs. Conclusions: The NS5B S282T mutation is the primary SOF resistance mutation selected in GT 1-6 in vitro. SDM analyses demonstrate that S282T mutants exhibit significantly reduced replication capacity as compared to wild-type replicons. SOF retains full activity against PI, NS5A and NNI RAVs as well as RBV-associated variants and the NI RAVs L159F and L320F.

Disclosures

Sonal Rajyaguru - Employment: Gilead Sciences

Simin Xu - Employment: Gilead Sciences

Christy Hebner - Employment: Gilead Sciences, Inc.

Evguenia S. Svarovskaia - Employment: Gilead Sciences Inc; Stock Shareholder: Gilead Sciences Inc

Brian Doehle - Employment: Gilead Sciences

Michael D. Miller- Employment: Gilead Sciences, Inc.; Stock Shareholder: Gilead Sciences, Inc.

Hongmei Mo - Employment: Gilead Science Inc

The following people have nothing to disclose: Viktoria Gontcharova

1095

  1. Top of page

Vaniprevir (MK-7009) Demonstrates Higher Exposures in Treatment-Experienced Genotype (GT) 1 Cirrhotic Than Non-cirrhotic HCV-Infected Patients

Wei Gao, Luzelena Caro, Melanie Anderson, Peggy Hwang, Amy Zhou, Jing Su, Niloufar Mobashery; Merck, Whitehouse Station, NJ

Background: Vaniprevir is a peptidic non-covalently binding inhibitor of the HCV NS4/4A protease which has demonstrated efficacy and safety when administered in combination with peg-interforeron alfa-2a (P) and ribavirin (R) in both treat-ment-naïve (TN) and treatment experienced (TE) patients. In this study, PK was assessed following BID administration of vaniprevir in combination with PR in TE non-cirrhotic and cirrhotic patients. Methods: GT1 TE non-cirrhotic (N=211) and compensated cirrhotic (N=74) patients were enrolled in a randomized, multicentered, partially double-blind, and placebo-controlled study with vaniprevir administered in combination with PR in 4 treatment regimens: 600mg BID with PR for 24 weeks, 600mg BID with PR for 24 weeks followed by PR for 24 weeks, 300mg BID with PR for 48 weeks, 600mg BID with PR for 48 weeks. Plasma samples for vaniprevir PK were collected until the end of treatment at select time points: Days 1, 3 and 7, Weeks 2, 4, 8, 12, 16, 20, 24 and 48 (where applicable). Results: Sustained viral response ranged from 67% to 84% vs 19% in PR control (P<0.001) and 53% to 77% vs 14% in PR control (P<0.001-0.012) in non-cirrhotic and cirrhotic patient cohorts, respectively. At both 300mg and 600mg BID dose levels, mean trough concentrations (Ctrough) of vaniprevir in cirrhotic and non-cirrhotic patients decreased from Day 3, with the steady-state achieved by approximately week 2. Geometric mean Ctrough at steady-state was ∼45% lower in non-cirrhotic compared to cirrhotic patients with GMRs (non-cirrhotic/cir-rhotic) [90% CI] of 0.53 (0.36, 0.78) and 0.57 (0.43, 0.76) at 300 mg BID and 600 mg BID, respectively. Conclusions: Vaniprevir exposure decreases in a time-dependent manner during the first 2 weeks of BID administration in both non-cirrhotic and cirrhotic patients and achieves steady-state at Week 2. The time-dependent PK may be attributed to overall improvement in liver function. Vaniprevir levels were increased in cirrhotic patients and may reflect impaired liver function, altered hepatic blood flow and/or reduced liver uptake compared with non-cirrhotic patients.

Disclosures

Wei Gao - Employment: Merck

Luzelena Caro - Employment: Merck & Co., Inc.

Melanie Anderson - Employment: Merck and Co., Inc.

Peggy Hwang - Employment: Merck, Merck

Amy Zhou - Employment: Merck Sharp & Dohme Corp.

Niloufar Mobashery- Employment: Merck; Stock Shareholder: Merck

The following people have nothing to disclose: Jing Su

1096

  1. Top of page

High Medication Adherence in HCV-Infected Patients taking a Triple-DAA Regimen for 12 Weeks

Marc Bourlière1, Fred Poordad2, Bernard Vrijens3, Daniel E. Cohen4, Wangang Xie4, Martin King4, Thomas Podsadecki4; 1Hôpital Saint Joseph, Marseille, France; 2The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX; 3MWV Healthcare, Richmond, VA; 4AbbVie Inc., North Chicago, IL

Purpose: AVIATOR, a phase 2b trial, evaluated various combinations of the direct acting antiviral agents (DAAs) ABT-450 (a protease inhibitor identified by AbbVie and Enanta, combined with ritonavir [r]), ABT-267 (NS5A inhibitor), and ABT-333 (non-nucleoside polymerase inhibitor) plus/minus ribavirin (RBV) in 571 treatment-naïve and experienced HCV-infected patients (pts). Sustained virologic response (SVR)-12 rates of 99% and 93% were achieved in treatment-naïve and treatment experienced pts, respectively, with 12 weeks (wks) of treatment. We present medication adherence data based on electronic compilation of drug dosing histories among 327 pts receiving 3 DAAs+RBV for 8, 12 or 24 wks. Methods: Study drug was dispensed in 5 separate bottles; MEMS® caps were used to automatically compile date and time of bottle openings/closing for 4 medications (3 DAAs and ritonavir). The dosing history data were used to derive the following adherence summary measures (from baseline to final dose), analyzed by treatment group: overall adherence based on percentage of prescribed doses taken (PDT); percentage of days with correct number of doses taken (PDC); and percentage of doses taken within prescribed dosing interval (PDI). Results: Mean overall adherence (PDT) for ABT-450 ranged from 100%-102% for the 12-wk arms, and from 94%-101% for the 24-wk arms. Mean adherence measures are tabulated by treatment groups for ABT-450 from baseline to final dose. Adherence was similar for all drugs and for the 8- and 12-wk duration arms. Mean proportion of ritonavir doses taken within 30 minutes of other DAAs was 95%. Although PDT declined during the second half of the 24-wk treatment arms, SVR12 rates were comparable in the 12-and 24-wk groups (97% [120/124] versus 94% [11 6/123]). Of 327 pts receiving 3 DAAs+RBV, 21 (6%) discontinued study drug prematurely, 6 due to adverse events. Conclusions: Study participants took 3 DAAs+RBV with excellent adherence, resulting in high SVR rates. Compared with 12 wks of treatment, 24 wks was associated with significantly lower mean adherence, but not with increased numbers of virologic failures, likely because of high adherence during the first 12 wks. We have previously shown that 24 wks of a multi-targeted regimen does not lead to an increased SVR rate compared with 12 wks. Phase 3 trials will include a co-formulated ABT-450/r/ABT-267 tablet to reduce pill burden.

Table 10. ABT-450 adherence from baseline to final dose
mean (SD)8-wk N=8012-wk N=12324-wk N=123
  1. * P<0.05 vs. 12-wk

PDT100.8(8.8)100.4(4.9)96.2 (13.3)*
PDC93.1 (10.1)93.8 (7.9)90.4(15.0)
PDI86.4(16.6)87.2(14.0)81.8(19.1)*
Disclosures

Marc Bourlière - Advisory Committees or Review Panels: Schering-Plough, Bohringer inghelmein, Merck, Schering-Plough, Bohringer inghelmein, Merck ; Board Membership: Bristol-Myers Squibb, Gilead, Bristol-Myers Squibb, Gilead; Consulting: Roche, Novartis, Tibotec, Abott, glaxo smith kline, Roche, Novartis, Tibotec, Abott, glaxo smith kline

Fred Poordad - Advisory Committees or Review Panels: Abbott, Achillion, BMS, Inhibitex, Boeheringer Ingelheim, Pfizer, Genentech, Idenix, Gilead, Merck, Vertex, Salix, Janssen, Novartis; Grant/Research Support: Abbott, Anadys, Achillion, BMS, Boehringer Ingelheim, Genentech, Idenix, Gilead, Merck, Pharmassett, Vertex, Salix, Tibotec/Janssen, Novartis

Bernard Vrijens - Employment: MWV Healthcare

Daniel E. Cohen - Employment: AbbVie; Stock Shareholder: AbbVie

Wangang Xie - Employment: AbbVie

Martin King - Employment: AbbVie

The following people have nothing to disclose: Thomas Podsadecki

1097

  1. Top of page

Minimum Production Costs of Direct Acting Antivirals, for Use in Large-Scale HCV Eradication Programmes in Developing Countries

Andrew M. Hill1, Saye H. Khoo1, Bryony Simmons2, Nathan Ford3; 1Pharmacology and Therapeutics, Liverpool University, Liverpool, United Kingdom; 2MetaVirology Ltd, London, United Kingdom; 3University of Cape Town, Cape Town, South Africa

Background: Eradication of HCV in developing countries will only be possible if treatment costs are very low. Combinations of ribavirin and Direct Acting Antivirals (DAAs) can cure HCV infection in the majority of Genotype 1 infected people. DAAs for HCV infection have similar mechanisms of action and chemical structures to antiretrovirals for HIV infection. Generic antiretrovirals are currently manufactured for treatment of over seven million people with HIV in developing countries. Methods: Four next generation HCV DAAs, currently in Phase 3 development (daclatasvir, sofosbuvir, simeprevir, faldaprevir) were classified by chemical structure, molecular weight, total daily dose, complexity of synthesis and patent expiry dates. The lowest manufacturing costs per gram of HIV antiretrovirals were calculated by treatment class, using Clinton Foundation / Medecins Sans Frontieres published prices for low income countries. The minimum cost of 12 weeks of treatment with each DAAwas then calculated, assuming a production cost per gram of HCV DAA between 1-10 times the equivalent HIV antiretroviral (to control for potential differences in complexity of chemical synthesis). Results: Minimum manufacturing costs of HIV antiretrovirals were $1.0-$2.1/g for protease inhibitors, $0.2-1.0/g for nucleoside analogues, $0.5/g for nucleotide analogues and $0.2/g for non-nucleosides. The complexity of chemical synthesis for HCV DAAs was ranked from lowest to highest: ribavirin, daclatasvir, sofosbuvir, faldaprevir and simeprevir. The predicted costs for a 12 week course of each DAA, assuming generic manufacture, are shown below: Conclusions: Within the next 15 years, large-scale manufacture of ribavirin plus two generic HCV DAAs is feasible, with target prices of $ 100-$200 per 12 week treatment course (for Genotype 1 HCV infection). Further progressive reductions in these costs may be possible through optimisation of chemical synthesis and cheaper sourcing of raw materials. These low prices could make widespread access to HCV treatment in low and middle income countries, and potentially even HCV eradication, a realistic goal.

Table 11. Minimum costs per person for 12 week treatment course
HCV DAAPatent expiryDaily doseTotal dosePredicted cost ($)
Ribaviringeneric1200mg84g$20-$63
Daclatasvir202760mg5g$10-S30
Sofosbuvir2029400mg34g$68-$136
Faldaprevir2029120mg10g$100-$200
Simeprevir2026150mg13g$130-270
Disclosures

Andrew M. Hill - Board Membership: Janssen

Saye H. Khoo - Grant/Research Support: Merck, Janssen, Gilead, ViiV

The following people have nothing to disclose: Bryony Simmons, Nathan Ford

1098

  1. Top of page

Interferon-free regimen containing setrobuvir (STV) in combination with ritonavir-boosted danoprevir (DNVr) and ribavirin (R) with or without mericitabine (MCB) in HCV genotype (G)1 treatment-naive patients: interim SVR4 results from the ANNAPURNA study

Donald M. Jensen1, Michael Brunda2, Rob Elston3, Edward J. Gane4, Jacob George5, Katerina Glavini3, Janet M. Hammond6, Isabel Najera2, Sharon Passe2, Anna Piekarska7, Ignacio Rodriguez2, Stefan Zeuzem8, Tom Chu2; 1University of Chicago Medicine, Chicago, IL; 2Hoffmann-La Roche Inc, Nutley, NJ; 3Roche Products Ltd, Welwyn, United Kingdom;4Auckland Clinical Studies, Grafton, New Zealand; 5Westmead Hospital and University of Sydney, Westmead, NSW, Australia; 6F. Hoffmann-La Roche Ltd, Basel, Switzerland; 7Department of Infectious Diseases and Hepatology, Medical University of Lodz, Lodz, Poland; 8Medi-zinische Klinik I, Johann-Wolfgang-Goethe University Hospital, Frankfurt, Germany

Background:STV is a direct-acting antiviral (DAA) non-nucleoside inhibitor of the HCV polymerase which is highly potent against G1 isolates. The ANNAPURNA study combined STV with the ritonavir-boosted HCV protease inhibitor DNV and R, with or without the nucleoside analog MCB. We present here the sustained virologic response rates (HCV RNA <25 IU/mL at 4wks post-treatment, SVR4) and safety of these treatment regimens in G1 HCV-infected treatment-naive patients. Methods:110 noncirrhotic patients were randomized to one of five treatment Arms: G1a patients receiving a 14-day MCB+R lead in followed by either 12 (Arm A) or 24 (Arm B) wks of STV+DNVr+R+MCB, or 24wks of STV+DNVr+R (Arm C); G1b patients receiving a 14-day MCB+R lead-in followed by 12wks of STV+DNVr+R+MCB (Arm D) or 12wks of STV+DNVr+R (Arm E). Dosages were: STV 800mg bid on Day 1 and 400mg bid thereafter, DNVr 100/100mg bid, MCB 1000mg bid and R 1000mg (<75kg) or 1200mg (≥75kg). Results:The majority of patients were Caucasian (90%) males (61%) with an average age of 48 yrs. Mean baseline HCV RNA was 6.44 log10 IU/mL. Approximately 25% were IL28B genotype CC. Two Arms were discontinued due to meeting predefined breakthrough (Arm C) or relapse (Arm A) futility rules. The remaining patients in Arm A were offered 12 additional wks of oral treatment. Rapid viral response (<25 IU/mL after 4wks of therapy, RVR) was 96% for G1a patients receiving 3 DAAs+R and 100% for G1 b patients. End of treatment (EOT) response was observed in all G1 b patients (45/45), and in most of the G1a patients (7/7 of those who received 14wks of therapy, and 42/47 of those who received 26wks of therapy). For G1a patients, the overall SVR4 rate was 74% for patients receiving 26wks of therapy compared with 43% for those receiving 14wks of therapy. For G1b patients, the SVR4 rate was 96% among patients receiving 3 DAAs+R versus 77% among those receiving 2 DAAs. Resistance to both DNV and STV, but not MCB, was observed in most patients experiencing treatment failure (viral breakthrough or relapse). Overall, these DAA combinations were well tolerated and most adverse events were mild to moderate. No major safety signals have been identified from laboratory monitoring. SVR12 data are pending. Conclusions:The ANNAPURNA study demonstrates a high virologic response in G1 HCV-infected, treatment-naive patients receiving three oral DAAs plus ribavirin. Hoffmann-La Roche Inc-funded

Table 12. 
%GlaGlb
Arm A 14 weeks (n=7)Arm A+B 26 weeks (n=47)Arm D 14 weeks (n=23)Arm E 12 weeks (n=22)
RVR96100100
EOT10089100100
SVR443749677
Disclosures

Donald M. Jensen - Advisory Committees or Review Panels: Abbvie, Boehringer, BMS, Genentech/Roche, Merck, Gilead, Janssen; Grant/Research Support: Abbvie, Boehringer, BMS, Genentech, Janssen, Gilead

Michael Brunda - Employment: Hoffmann La Roche

Rob Elston - Employment: Roche Pharmaceuticals; Stock Shareholder: Roche Pharmaceuticals

Edward J. Gane - Advisory Committees or Review Panels: Roche, AbbVie, Novar-tis, Tibotec, Gilead Sciences, Janssen Cilag, Vertex, Achillion; Speaking and Teaching: Novartis, Gilead Sciences, Roche

Jacob George - Advisory Committees or Review Panels: Roche, BMS, MSD, Gilead, Janssen

Katerina Glavini - Employment: Roche Products Ltd

Janet M. Hammond - Employment: Hoffmann-La Roche

Isabel Najera - Employment: Roche, Roche

Sharon Passe - Employment: Hoffmann-La Roche

Ignacio Rodriguez- Employment: Hoffmann - La Roche

Stefan Zeuzem - Consulting: Abbvie, Achillion Pharmaceuticals, Boehringer Ingel-heim GmbH, Bristol-Myers Squibb Co., Gilead, Novartis Pharmaceuticals, Merck & Co., Idenix, Janssen, Roche Pharma AG, Vertex Pharmaceuticals, Presidio, Santaris, Inc

Tom Chu - Employment: Roche

The following people have nothing to disclose: Anna Piekarska

1099

  1. Top of page

STARTVerso 4 Phase III trial of faldaprevir plus peg interferon alfa-2a and ribavirin (PR) in patients with HIV and HCV genotype 1 coinfection: end of treatment response

Jürgen K. Rockstroh1, Mark Nelson2, Vincent Soriano3, Keikawus Arastéh4, Jose Maria Guardiola5, Sanjay Bhagani6, Josep Mallo-las7, Christina Tural8, Massimo Puoti9, Patrick Ingiliz10, Manuel Battegay11, Mamta K. Jain12, Marina Nunez13, Kristen M. Marks14, Jens J. Kort15, Jerry O. Stern15, Richard Vinisko15, Montserrat Manero16, Douglas T. Dieterich17; 1University of Bonn, Bonn, Germany; 2Chelsea and Westminster Hospital, London, United Kingdom; 3Hospital Carlos III, Madrid, Spain; 4EPIMED, Vivantes Auguste-Viktoria Hospital, Berlin, Germany; 5Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 6Royal Free Hospital, London, United Kingdom; 7Hospital Clínic, Barcelona, Spain; 8Hospital Universitari Germans Trias i Pujol, Barcelona, Spain; 9AO Ospedale Niguarda Cà Granda, Milan, Italy; 10Medizinisches Infektiologiezentrum Berlin (MIB), Berlin, Germany; 11Division of Infectious Diseases and Hospital Epidemiology, Basel, Switzerland; 12UTSouthwestern Medical Center, Dallas, TX; 13Wake Forest University, Winston-Salem, NC; 14Weill Cornell Medical College, New York, NY; 15Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT; 16Boehringer Ingelheim España S.A., Barcelona, Spain; 17Mount Sinai School of Medicine, New York, NY

Background: Faldaprevir (FDV) is a potent, once-daily HCV NS3/4A protease inhibitor. The objective of the STARTVerso4 (SV4) study is to assess efficacy and safety of FDV plus PR, and evaluate a 24-week (W), shortened treatment duration in HIV patients coinfected with chronic HCV genotype (GT) 1. Methods: SV4 is an open-label, sponsor-blinded study in HCV/HIV coinfected patients who were HCV treatment-naïve (TN) or relapsed after previous HCV therapy. Arm A: patients received FDV 120 mg QD and PR for 24W; Arm B: patients received FDV 240 mg QD plus PR for 12W and were randomized at W12 to receive a further 12W FDV/PR or PR alone. At W24 all patients who achieved early treatment success (ETS, HCV RNA <25 IU/mL detected or undetected at W4 and undetected at W8) were re-randomized 1:1 to stop treatment at W24 or continue PR up to W48. Patients without ETS received PR through W48. Patients on HIV protease-based antiretroviral therapy (ART) or efavirenz were allocated to receive FDV 120 mg or 240 mg QD, respectively; those receiving other allowed ART (raltegravir or maraviroc) or no ART were randomized to either FDV dose. The primary endpoint was SVR12. Here we present interim data for patients who had reached the end of treatment (whether planned or not). Results: In total, 308 patients were treated (mean age 47 years, 81% male, 83% Caucasian, 14% Black/African American, 29% ≥F3 liver fibrosis, 79% GT1a, 66% IL28B non-CC rs12979860). ART was used by 96% of patients. At the time of abstract submission, 270 patients (88%) had reached end of treatment, of which 222 (82%) achieved end of treatment response (ETR, HCV RNA undetectable at end of all therapy; Table). ETR was achieved by 160/205 (78%) of TN patients and 62/65 (95%) of relapsers. Most common AEs were nausea (37%), fatigue (34%), and diarrhea (27%). Study medication was discontinued due to AEs in 7% of patients in Arm A and 8% in Arm B. Serious AEs occurred in 14% and 8% of patients, respectively. Hemoglobin ≤8.5 g/dL occurred in 6% of patients. Conclusions: In this interim analysis, 82% of patients coinfected with HIV and HCV GT1 achieved ETR. ETR rate was higher in relapsers than TN patients and similar for each FDV dose group. Based on high ETS rates 38.5% of patients were randomized to stop treatment at W24. FDV's safety profile was similar to that observed in HCV GT1 monoinfected patients.

Table 13. 
HCV RNA undetected n/N (%)Arm A: FDV 120 mgArm B: FDV 240 mgAll patients (N=270)
 24 weeks (N=106)12 weeks (N=73)24 weeks (N=77)Totala (N=164)
ETR84/106(79)64/73 (88)68/77 (88)138/164(84)222/270 (82)
ETS79/106 (75)60/73 (82)64/77 (83)130/164 (79)209/270 (77)
ETS and ETR b76/79 (96)59/60 (98)62/64 (97)127/130 (98)203/209 (97)
aIncludes patients who discontinued prior to Week 12 bDenominator = patients with ETS ETR, end of treatment response; ETS, early treatment success; FDV, faldaprevir
Disclosures

Jürgen K. Rockstroh - Advisory Committees or Review Panels: Abbvie, BI, BMS, Merck, Roche, Tibotec, Abbvie, Bionor, Tobira, ViiV, Gilead, Janssen; Consulting: Novartis; Grant/Research Support: Merck; Speaking and Teaching: Abbott, BI, BMS, Merck, Roche, Tibotec, Gilead, Janssen, ViiV

Mark Nelson - Advisory Committees or Review Panels: Boehringer Ingelheim, Janssen, MSD, BMS, Abbott, Viiv, Gilead; Consulting: Boehringer Ingelheim, Janssen, MSD, BMS, Abbott, Viiv, Gilead; Grant/Research Support: Boehringer Ingelheim, Janssen, MSD, BMS, Abbott, Viiv, Gilead, Roche; Speaking and Teaching: Boehringer Ingelheim, Janssen, MSD, BMS, Abbott, Viiv, Gilead

Vincent Soriano - Grant/Research Support: Boehringer, BMS, Merck, Jannsen, Gilead; Speaking and Teaching: BMS, Merck, Jannsen, Gilead, Boehringer

Keikawus Arastéh - Advisory Committees or Review Panels: MSD, Hexal, ViV, Gilead, BI

Sanjay Bhagani - Advisory Committees or Review Panels: BMS, MSD, Abbvie, Jannsen, Gilead Sciences; Grant/Research Support: Roche; Speaking and Teaching: BMS, Gilead Sciences, MSD, Roche, Jannsen, Abbvie

Josep Mallolas - Board Membership: Boehringer, Merck

Christina Tural - Advisory Committees or Review Panels: Janssen Pharmaceuticals, Inc

Mamta K. Jain - Advisory Committees or Review Panels: Merck, Vertex, Boehringer Ingelheim ; Grant/Research Support: Vertex, Bristol-Myers Squibb, Pfizer, Janssen, Gilead, Boehrnger Ingelheim , Viiv Healthcare, EMD Serono

Marina Nunez- Consulting: Gilead

Kristen M. Marks - Grant/Research Support: Vertex, BMS, Boerhinger-Ingelheim, Janssen, Gilead; Speaking and Teaching: BMS

Jens J. Kort - Employment: Boehringer Ingelheim

Jerry O. Stern - Employment: Boehringer Ingelheim

Richard Vinisko - Employment: Boehringer-Ingelheim

Montserrat Manero - Employment: Boehringer Ingelheim

Douglas T. Dieterich -Advisory Committees or Review Panels: Gilead, Genentech, Janssen, achillion, idenix, Merck, Tobira, Boehringer Ingelheim, TIbotec, Inhibitex, Roche, Vertex

The following people have nothing to disclose: Jose Maria Guardiola, Massimo Puoti, Patrick Ingiliz, Manuel Battegay

1100

  1. Top of page

STARTVerso3: A randomized, double-blind, placebo-controlled Phase III trial of faldaprevir in combination with pegylated interferon a lf a-2a and ribavirin in treatment-experienced patients with chronic hepatitis C genotype-1 infection

Ira M. Jacobson1, Tarik Asselah2, Peter Ferenci3, Graham R. Foster4, Donald M. Jensen5, Francesco Negro6, Parvez S. Mantry7, David Wright8, Xavier Forns9, Javier García-Samaniego10, Célia Oliveira11, Armando Carvalho12, Daniel M. Forton13, Kosh Agarwal14, Keikawus Arastéh15, Curtis Cooper16, Wayne Ghesquiere17, Jean-Francois Dufour18, Yoshiyuki Sakai19, Yasuhito Tanaka20, Jerry O. Stern21, Nanshi Sha21, Wulf O. Boecher22, Gerhard G. Steinmann22, Anne-Marie Quinson21; 1New York Presbyterian Weill Cornell Medical Center, New York, NY; 2Hôpital Beaujon, APHP, University Paris-Diderot and INSERM CRB3, Clichy, France; 3Medical University of Vienna, Vienna, Austria; 4Queen Mary, University of London, London, United Kingdom; 5University of Chicago Medicine, Chicago, IL; 6University Hospital, Geneva, Switzerland; 7The Liver Institute at Methodist Dallas Medical Center, Dallas, TX; 8Central Texas Clinical Research, Austin, TX; 9Hospital Clinic Liver Unit, Barcelona, Spain; 10Hospital Carlos III, CIBERehd, Unidad de Hepatología, Madrid, Spain; 11Hospital Infante D. Pedro, Aveiro, Portugal; 12Hospitais da Universidade de Coimbra, Coimbra, Portugal; 13St George's Hospital, London, United Kingdom; 14King's College Hospital, London, United Kingdom; 15EPIMED, Vivantes Auguste-Viktoria-Klinikum, Berlin, Germany; 16Ottawa Hospital Research Institute, Ottawa, ON, Canada; 17University of British Columbia, Victoria, BC, Canada; 18University Clinic for Visceral Surgery and Medicine, Bern, Switzerland; 19Hyogo College of Medicine Hospital, Hyogo, Japan; 20Nagoya City University Hospital, Aichi, Japan; 21Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT; 22Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany

Background STARTVerso3 is a Phase III trial that assessed the efficacy and safety of faldaprevir (FDV), a potent HCV NS3/4A inhibitor, plus pegylated interferon alfa-2a and ribavirin (PR) in patients with chronic HCV genotype-1 (GT1) infection who had virologic failure to prior PR treatment. Methods In this double blind, partially placebo-controlled trial, 3 cohorts were enrolled: cohort 1 (prior relapse), cohort 2 (prior partial response), and cohort 3 (prior null response). Cohorts 1&2 were each randomized 1:2:2 to receive 48 weeks (W) of PR plus: placebo, 12W FDV 240 mg QD (FDV12W) or 24W FDV 240 mg QD (FDV24W). In cohort 1, FDV-treated patients were eligible to stop all treatment at W24 on achievement of early treatment success (ETS: HCV RNA <25 IU/mL detected or undetected at W4, and undetected at W8). Cohort 3 was randomized 1:1 to receive FDV12W or FDV24W with PR for 48W. The primary endpoint was sustained virologic response 12W after planned completion of all treatment (SVR12). Futility rules stopped patients with <2log10 drop in HCV RNA at W4, rebound by W12, or breakthrough. Results 677 patients were treated; 60% male, 77% Caucasian, 1 8% Asian, 40% ≥F3 fibrosis, 53% GT1b, 16% IL28B (rs12979860) CC. Baseline characteristics varied between cohorts. Virologic responses are shown in the table. Discontinuation of all study medication due to AEs occurred in 5% (cohorts 1 &2 combined) and 6% (cohort 3) of patients treated with FDV (12W or 24W). Most AEs were mild, with nausea (53%), fatigue (34%), rash (31%), and anemia (22%) most commonly reported in the FDV arms. Of FDV-treated patients, 0.3% experienced severe rash and 9% had serious AEs, most commonly pyrexia, diarrhea, and anemia. No severe photosensitivity reactions were observed. Hemoglobin levels ≤8.5 g/dL occurred in 5% of FDV-treated patients. Total bilirubin >5 × the upper limit of normal, without ALT elevation, was reported in 1 1% of FDV-treated patients, and was mainly due to an increase in unconjugated bilirubin. Conclusions FDV 240 mg plus PR was effective and well tolerated in HCV GT1 treatment-experienced patients, with SVR12 rates of 70% in prior relapsers, up to 58% in prior partial responders, and 33% in prior null responders. Treatment with FDV 240 mg for 12W was as effective as for 24W.

Table 14. 
 Priorelapse (cchortl)Prior partial response (cohort 2)Prior null response (cohort 3)
n(%)Placebo (N=49)FDV12W (N=99)FDV24W (N=102)Placebo (N=29)FDV12W (N=57)FDV24W (N=55)FDV12W (N=145)FDV24W (N=14I)
SVR 127(14)69 (70)a71 (70)a1(3)33(58)a26 (47)a48(33)46 (33)
Virologic failure:
NullbyW4b16(33)1 (1)014 (48)1(2)04(3)5(4)
Breakthrough07(7)5(5)07(12)7(13)54 (37)50 (35)
Relapse11(22)13(13)17(17)8(28)9(16)11(20)19(13)20(14)
ap<0.0001 vs placebo (Cochran-Mantel-Haenszel test, adjusted for genotype). Of prior relapse patients, 87% achieved ETS, of whom 75% achieved SVR 12 b<21og IQ drop in HCV RNA at W4
Disclosures

Ira M. Jacobson - Consulting: Vertex, Abbott, Achillion, Boehringer Ingelheim, Bristol Myers Squibb, Enanta, Gilead, Glaxo Smithkline, Idenix, Kadmon, Novartis, Presidio, Roche / Genentech, Merck, Janssen; Grant/Research Support: Abbott, Achillion, Vertex, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Novartis, Pfizer, Roche / Genentech, Schering / Merck, Tibotec / Janssen; Speaking and Teaching: Vertex, Bristol Myers Squibb, Gilead, Roche / Genentech, Schering / Merck

Tarik Asselah - Consulting: BMS, Boehringer-Ingelheim, Roche, Merck-Schering Plough, Gilead, Janssen

Peter Ferenci - Advisory Committees or Review Panels: Roche, Idenix, Roche, MSD, Vertex, Salix, Madaus Rottapharm, Tibotec, B^dhringer Ingelheim, Achilleon, GSK; Grant/Research Support: MSD, Vertex, Madaus Rottapharm; Patent Held/Filed: Madaus Rottapharm; Speaking and Teaching: Roche, Gilead, Roche, Gilead, Salix

Graham R. Foster - Advisory Committees or Review Panels: GlaxoSmithKline, Novartis, Boehringer Ingelheim, Tibotec, Chughai, Gilead, Janssen, Idenix, GlaxoSmithKline, Novartis, Roche, Tibotec, Chughai, Gilead, Merck, Janssen, Idenix, BMS; Board Membership: Boehringer Ingelheim; Grant/Research Support: Chughai, Roche, Chughai; Speaking and Teaching: Roche, Gilead, Tibotec, Merck, BMS, Boehringer Ingelheim, Gilead, Janssen

Donald M. Jensen - Advisory Committees or Review Panels: Abbvie, Boehringer, BMS, Genentech/Roche, Merck, Gilead, Janssen; Grant/Research Support: Abbvie, Boehringer, BMS, Genentech, Janssen, Gilead

Francesco Negro - Advisory Committees or Review Panels: Roche, MSD, Gilead, Boehringer Ingelheim; Grant/Research Support: Roche, Gilead

Parvez S. Mantry - Grant/Research Support: Schering, Bayer, Hyperion, Boehringer -Ingelheim, Abbott; Speaking and Teaching: Onyx, Salix, Vertex, Genentech, Merck, Kadmon

Xavier Forns - Consulting: Tibotec/Jansen, MSD, Boheringher Ingelheim; Grant/Research Support: Roche, MSD, Gilead

Javier García-Samaniego - Consulting: Boehringer-Ingelheim

Armando Carvalho - Advisory Committees or Review Panels: Gilead Sciences, Bristol-Myers Squibb, Roche, Janssen, Bayer; Grant/Research Support: Boehringer-Ingelheim, AbbVie

Daniel M. Forton - Advisory Committees or Review Panels: Merck, Janssen, Abbvie; Grant/Research Support: Roche, Boehringer Infelheim, Gilead; Speaking and Teaching: BMS

Kosh Agarwal - Consulting: Boehringer-Ingelheim

Keikawus Arastéh - Advisory Committees or Review Panels: MSD, Hexal, ViV, Gilead, BI

Curtis Cooper - Advisory Committees or Review Panels: Vertex, MERCK, Roche; Grant/Research Support: MERCK, Roche; Speaking and Teaching: Roche, MERCK

Jean-Francois Dufour - Advisory Committees or Review Panels: Bayer, BMS, Gilead, Jansse, Novartis, Roche

Yasuhito Tanaka - Advisory Committees or Review Panels: Nippon Boehringer Ingelheim Co ., Ltd.; Grant/Research Support: Chugai Pharmaceutical CO., LTD., MSD, Mitsubishi Tanabe Pharma Corporation, Dainippon Sumitomo Pharma Co., Ltd., DAIICHI SANKYO COMPANY, LIMITED, Bristol-Myers Squibb

Jerry O. Stern - Employment: Boehringer Ingelheim

Nanshi Sha - Employment: Boehringer Ingelheim

Wulf O. Boecher - Employment: Boehringer Ingelheim GmbH

Gerhard G. Steinmann - Employment: Boehringer Ingelheim, Boehringer Ingelheim

Anne-Marie Quinson - Employment: Boehringer Ingelheim

The following people have nothing to disclose: David Wright, Célia Oliveira, Wayne Ghesquiere, Yoshiyuki Sakai

1101

  1. Top of page

Resistance analyses of HCV isolates from patients treated with simeprevir in phase 2b/3 studies

Oliver Lenz1, Bart Fevery1, Thierry Verbinnen1, Lotke Tambuyzer1, Leen Vijgen1, Monika Peeters1, Maria Beumont-Mauviel1, Gaston Picchio2, Sandra De Meyer1; 1Janssen Infectious Disease BVBA, Beerse, Belgium; 2Janssen Research & Development, LLC, Titusville, NJ

Background/aims Simeprevir (SMV, TMC435) is a potent, investigational, once-daily, single pill, oral HCV NS3/4A protease inhibitor. Here we describe NS3/4A baseline polymorphisms for all patients (pts), and emerging mutations in pts with chronic HCV genotype (gt) 1 who received 150 mg SMV combined with peginterferon/ribavirin (PR) in Phase 2b and 3 studies. Methods Baseline population sequencing data for NS3/4A were available for 2007 pts. Post-baseline data were available for 197 SMV-treated pts not achieving a sustained virologic response (SVR) for any reason. In vitro SMV susceptibility was assessed in a transient replicon assay as site-directed mutants, or in chimeric replicons with patient-derived NS3 protease sequences. Results Baseline NS3 polymorphisms at positions associated with reduced in vitro susceptibility to SMV activity (43, 80, 122, 155, 156, and/or 168; EC50 fold change ≥ 2) were generally uncommon (1.3%; 27/2007), with the exception of the low level resistance substitution Q80K, which was present in 13.7% of pts (274/2007): 29.5% (269/911) of pts with gt1a and 0.5% (5/1096) of pts with gt1b. In pooled, treatment naïve, Phase 3 studies (QUEST-1, QUEST-2) SVR12 rates in SMV-treated pts with gt1a and Q80K at baseline were lower (58.3%) than in those without Q80K (83.6%) but higher than in pts with gt1a who received PR alone (47.3%). Of the 1 97 SMV-treated pts without SVR who had sequence data, 1 80 (91.4%) had emerging mutations at NS3 positions 80, 122, 1 55 and/or 1 68. Mutations emerging at failure generally conferred high-level resistance (EC50 fold change >50) in a replicon assay. The majority of pts with gt1a (with and without baseline Q80K) had emerging R155K only. In pts without Q80K at baseline, emerging R1 55K was observed alone or in combination with mutations at NS3 positions 80, 122, and/or 1 68. In pts with gt1 b, emerging mutations at position 1 68 were observed most frequently. Emerging mutations detected at failure were no longer detectable at the last visit in 90/1 80 (50%) of pts (median follow up: 28 weeks). Median time to loss of emerging mutations was shorter in pts with D168V (mainly gt1 b, 1 7.4 weeks) and in gt1a pts with emerging R155K who had baseline Q80K (32.1 weeks), compared with gt1a pts who had emerging R155K without baseline Q80K (64.4 weeks). Conclusion In the SMV/PR Phase 2b and 3 studies, treatment failure was low and usually associated with emerging mutations that conferred high-level resistance to SMV. Emerging mutations were different in pts with gt1a and 1 b but consistent within each genotype. Resistant variants were no longer detectable during follow-up in half of all pts who previously failed.

Disclosures

Oliver Lenz - Employment: Janssen

Bart Fevery- Employment: Janssen Infectious Diseases BVBA

Thierry Verbinnen - Employment: Janssen Infectious Diseases bvba

Leen Vijgen - Employment: Janssen Infectious Diseases BVBA

Monika Peeters - Employment: Janssen

Maria Beumont-Mauviel - Employment: Janssen

Gaston Picchio - Employment: Janssen R&D; Stock Shareholder: J&J

Sandra De Meyer - Employment: Janssen Infectious Diseases bvba (J&J); Stock Shareholder: J&J

The following people have nothing to disclose: Lotke Tambuyzer

1102

  1. Top of page

Interferon-Free Treatment with Faldaprevir, Deleobuvir (BI 207127) and Ribavirin in SOUND-C3: 95% SVR12 in HCV-GT1b

Jean-Francois Dufour1, Maria Buti2, Vincent Soriano3, Robert Buy-nak4, Parvez S. Mantry5, Jawahar Taunk6, Jerry O. Stern7, Richard Vinisko7, John-Paul Gallivan8, Wulf O. Boecher8, Federico J. Mensa7, Stefan Zeuzem9; 1University Clinic for Visceral Surgery and Medicine, Bern, Switzerland; 2Hospital Vall d'Hebron, Barcelona, Spain; 3Hospital Carlos III, Madrid, Spain; 4Northwest Indiana Center for Clinical Research, Valparaiso, IN; 5The Liver Institute at Methodist Dallas Medical Center, Dallas, TX; 6Advance Gastroenterology Associates, LLC, Palm Harbor, FL; 7Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT; 8Boehringer Ingel-heim Pharma GmbH & Co KG, Ingelheim, Germany; 9J. W. Goethe University Hospital, Frankfurt, Germany

Background: In the SOUND-C2 study, SVR12 rates of 85% were reported for patients with HCV genotype (GT) 1b treated with faldaprevir, twice-daily deleobuvir (BI 207127) and ribavirin for 28 weeks. Lower SVR rates were reported for GT1a-infected patients overall, but patients with GT1a carrying the IL28B CC genotype (rs1 2979860, GT1a-CC), appeared to have similar SVR rates to GT1b patients. In SOUND-C2, an induction dose of deleobuvir was given on Day 1 leading to high plasma concentrations and increases in gastrointestinal adverse events (AEs). Here we investigated the same regimen, without an induction dose of deleobuvir, dosed for 1 6 weeks in GT1b or GT1a-CC patients. Methods: Patients infected with GT1 b (n=20) or GT1a-CC (n=12) received faldaprevir 120 mg once-daily, deleobuvir 600 mg twice-daily and weight-based ribavirin for 1 6 weeks. Patients with compensated cirrhosis were included in the study. The primary endpoint was SVR12 (undetectable HCV RNA 12 weeks after the end of treatment). Results: All 20 patients with GT1b and 8/12 of patients with GT1a-CC had undetectable HCV RNA at the end of treatment. SVR12 was achieved in 19/20 patients with GT1b. The only GT1b patient without SVR12 was a noncirrhotic patient who discontinued treatment at Week 8 with undetectable HCV RNA and relapsed 12 weeks later. In contrast, only 2/12 of patients with GT1a-CC achieved SVR12, with 6/8 patients with end-of-treatment response experiencing a relapse. Overall tolerability was good with 4/32 severe treatment-related AEs, 1 /32 serious AE (dehydration requiring hospitalization) and 3/32 early discontinuations due to an AE (dehydration, vomiting and pruritus). Conclusions: In SOUND-C3, optimizing treatment for GT1 b-infected patients improved efficacy compared with SOUND-C2: 95% of patients with GT1b (including patients with compensated cirrhosis) achieved SVR12 with 16 weeks treatment. The regimen is being studied in patients with GT1 b in Phase III studies for 1 6 and 24 weeks.

Disclosures

Jean-Francois Dufour - Advisory Committees or Review Panels: Bayer, BMS, Gilead, Jansse, Novartis, Roche

Maria Buti - Advisory Committees or Review Panels: Gilead, Janssen, Vertex; Grant/Research Support: Gilead, Janssen; Speaking and Teaching: Gilead, Janssen, Vertex, Novartis

Vincent Soriano - Grant/Research Support: Boehringer, BMS, Merck, Jannsen, Gilead; Speaking and Teaching: BMS, Merck, Jannsen, Gilead, Boehringer

Parvez S. Mantry-Consulting: Gilead, Janssen; Grant/Research Support: Vertex, Merck, Salix, Abbvie, Gilead, Boehringer-Ingelheim, Bristiol Myers Squibb, San-taris; Speaking and Teaching: Vertex, Merck, Sailx, Genentech, Bayer-Onyx, Kadmon

Jerry O. Stern - Employment: Boehringer Ingelheim Richard Vinisko - Employment: Boehringer-Ingelheim John-Paul Gallivan - Employment: Boehringer-Ingelheim Wulf O. Boecher - Employment: Boehringer Ingelheim GmbH Federico J. Mensa - Employment: Boehringer Ingelheim Pharm. Inc

Stefan Zeuzem - Consulting: Abbvie, Achillion Pharmaceuticals, Boehringer Ingelheim GmbH, Bristol-Myers Squibb Co., Gilead, Novartis Pharmaceuticals, Merck & Co., Idenix, Janssen, Roche Pharma AG, Vertex Pharmaceuticals, Presidio, Santaris, Inc

The following people have nothing to disclose: Robert Buynak, Jawahar Taunk

1103

  1. Top of page

Safety Profile of Peginterferon Lambda for Treatment of Chronic Hepatitis B (CHB) or Chronic Hepatitis C (CHC): Cross-Study Analysis of Patients Treated in Three Phase 2 Studies

Andrew J. Muir1, Claire Jurkowski2, Elizabeth L. Cooney2, Jan L. Hillson3, Max Lataillade2, Veronica Mas Casullo2, Todd Gray3, Dong Xu2, Logesvaran Yogendran2, Subasree Srinivasan2; 1Duke Clinical Research Institute, Duke University, Durham, NC; 2Research and Development, Bristol-Myers Squibb, Wallingford, CT; 3Bristol-Myers Squibb/ Zymogenetics, Seattle, WA

Background Peginterferon lambda-1a (Lambda) is a Type III interferon with limited extra-hepatic receptor distribution, which may result in fewer adverse events (AEs) than peginterferon alfa (Alfa). Lambda 180 μg weekly demonstrated more rapid early viral suppression than Alfa in patients with CHB and CHC. We present an integrated analysis of safety data for Lambda 180 μg weekly for 24-48 weeks in noncirrhotics from all 3 Lambda phase 2 studies. Methods Available on-treatment safety data from noncirrhotic patients who received Lambda monotherapy; Lambda plus ribavirin (RBV); or Lambda, RBV and a direct-acting antiviral (asunaprevir [ASV] or daclatasvir [DCV]) were grouped by regimen and compared with Alfa/RBV. Patients received Lambda monotherapy for CHB; all others were treated for CHC. Differences > 2-fold between groups are considered clinically significant. Results Analyses included 51 1 patients in 5 groups (table). Overall, 60% were male. Among CHB patients, mean age was 36 years, 89% were Asian, and mean baseline alanine aminotransferase (ALT) was 154 U/L. Among CHC patients, mean age across the 4 groups ranged from 46-48 years; 83% were white, 7% black/African American; and mean baseline ALT across the 4 groups ranged from 67-90 U/L. Fatigue was comparable across all groups (24%-46%); insomnia, asthenia, myalgia, arthralgia, rash, irritability, and decreased appetite were less frequent (<2-fold) with Lambda monotherapy (for CHB) compared to Lambda/RBV or Alfa/RBV (for CHC). Myalgia, arthralgia, chills, and pyrexia were less frequent with Lambda/RBV than with Alfa/RBV. Incidence of elevated ALT and elevated AST were more frequent with Lambda monother-apy and Lambda/RBV/ASV than with Alfa/RBV. Grade 3-4 laboratory abnormalities in hemoglobin, leukocytes, lymphocytes, platelets, and neutrophils were less frequent with Lambda-containing regimens than with Alfa/RBV. In Lambda-containing regimens, grade 3-4 ALT elevations were more frequent with CHB than CHC; grade 3-4 total bilirubin elevations were more frequent with CHC than CHB. Details of hepatic safety will be presented. Conclusions Lambda 1 80 μg once weekly/RBV for CHC is associated with significantly fewer hematologic abnormalities but higher rates of hepatic abnormalities than Alfa/RBV. Lambda monotherapy for CHB is associated with lower rates of systemic AEs than Lambda/RBV for CHC. Lambda is a better tolerated interferon than Alfa with a differentiated safety profile.

Table 15. 
 Lambda (CHB) (N=75)Lambda + RBV (CHC) (N=169)Lambda + RBV + DCV (CHC) (N=45)Lambda + RBV + ASV (CHC) (N=38)Alfa + RBV (CHC) (N=184)
Grade 3-4 laboratory abnormalities, emergent (%)     
Hemoglobin Ncutrophils+bands (absolute) Leukocytes Lymphocytes (absolute) Platelets ALT AST Bilirubin, total0 1.3 0 1.3 0 42.7 33.3 1.33.6 0.6 0.6 1.8 0 3.6 4.8 6.60 0 2.2 6.7 0 2.2 6.7 4.42.60000 15.8 26.3 10.523.0 20.8 7.1 14.2 1.6 4.9 5.5 3.3
Disclosures

Andrew J. Muir - Advisory Committees or Review Panels: Merck, Vertex, Gilead, BMS, Abbott, Achillion; Consulting: Profectus, GSK; Grant/Research Support: Merck, Vertex, Roche, BMS, Gilead, Achillion, Abbott, Pfizer, Salix, GSK

Claire Jurkowski - Employment: Bristol Myers Squibb

Elizabeth L. Cooney - Employment: Bristol-Myers Squibb Inc; Stock Shareholder: Bristol-Myers Squibb Inc

Jan L. Hillson - Employment: Bristol Meyers Squibb

Max Lataillade - Employment: Bristol-Myers Squibb

Veronica Mas Casullo - Employment: Bristol Myers Squibb

Dong Xu - Employment: Bristol-Myers Squibb

Subasree Srinivasan - Employment: Bristol Myers Squibb

The following people have nothing to disclose: Todd Gray, Logesvaran Yogendran

1104

  1. Top of page

VX-135, a once-daily nucleotide HCV polymerase inhibitor, was well tolerated and demonstrated potent antiviral activity when given with ribavirin in treatment-naïve patients with genotype 1 HCV

Serghei Popa1, Alina Berliba1, Nelea Ghicavii2, Alain A. Patat5, Robert S. Kauffman3, Julie Krop3, Varun Garg3, Myron Tong4, Sushmita M. Chanda6, Qingling Zhang6, Christopher Westland6, Matthew W. McClure6, Leo Beigelman6, Lawrence M. Blatt6, John Fry6; 1Republican Clinical Hospital, Chisinau, Moldova, Republic of; 2Arensia Exploratory Medicine, Chisinau, Moldova, Republic of; 3Vertex Pharmaceuticals Inc, Cambridge, MA; 4Liver Center, Huntington Medical Research Institutes, Passadena, CA; 5BioTrial, Rennes, France; 6Alios BioPharma Inc, South San Francisco, CA

Background: VX-135 is a uridine nucleotide analog currently in development for HCV. An ongoing Phase 2a randomized study is being conducted to assess the safety and antiviral activity of VX-135 in combination with ribavirin (RBV) for 12 weeks in treatment-naïve patients with genotype 1 (GT-1) chronic hepatitis C (CHC). Methods: Twenty patients were randomized in a 1:1 ratio to receive either 1 00 or 200 mg of VX-135 given in combination with weight-based RBV for 12 weeks. Patients were stratified by IL-28B genotype (CC vs non-CC). HCV RNA levels were measured at baseline and at multiple time points

during treatment and analyzed using the COBAS® TaqMan® HCV RNA Test (Version 2.0, Roche). Plasma samples were also obtained for viral RNA sequencing. This interim analysis was performed when the first 1 1 patients completed 1 0 weeks of treatment. Results: To date, 20 patients with GT1 CHC have been enrolled including 12 males and 8 females; all were GT-1 b; 5 patients had IL28B CC genotype and 15 had non-CC genotype. Baseline median HCV RNA levels were 6.65 and 6.43 log 10 IU/mL for the 100 and 200 mg groups, respectively. A summary of the antiviral activity over time is shown in Table 1. Initial safety data indicates that both doses of VX-135 were well tolerated. No SAEs were reported and no patients prematurely discontinued treatment. No clinically significant changes in vital signs, ECG readings or laboratory abnormalities, other than reductions in hemoglobin and sporadic, mild elevations in serum bilirubin (attributed to RBV), were observed. There was a rapid reduction in HCV RNA levels in both groups with the majority of patients having values below the level of quantification by week 2 (Table 1). Novirologic breakthrough occurred during the course of treatment. SVR12 data for all 20 patients will be presented. Conclusion: Preliminary data demonstrate that 1 0 weeks of treatment with VX-135 and RBV results in rapid viral suppression which is sustained throughout the course of treatment. The combination of VX-135 and RBV was well tolerated.

Table 1 HCV RNA Results

Table 16. 
 HCV RNAWeek 2Week 4Week 8Week 10
VX-135 100 mg + RBVLess than LLOQ, n/N8/109/105/55/5
Less than LOD, n/N1/107/105/54/5
VX-135 200 mg + RBVLess than LLOQ, n/N9/1010/106/66/6
Less than LOD, n/N1/108/106/66/6

LLOQ: lower limit of quantitation

LOD: Limit of detection, target not detected

Disclosures

Robert S. Kauffman - Employment: Vertex; Stock Shareholder: Vertex

Varun Garg - Employment: Vertex Pharmaceuticals, Incorporated; Stock Shareholder: Vertex Pharmaceuticals, Incorporated

Sushmita M. Chanda - Employment: Alios BioPharma

Qingling Zhang - Employment: Alios BioPharma

Christopher Westland - Employment: Alios Biopharma

Matthew W. McClure - Employment: Alios BioPharma

Lawrence M. Blatt - Management Position: Alios BioPharma

John Fry- Employment: Alios BioPharma

The following people have nothing to disclose: Serghei Popa, Alina Berliba, Nelea Ghicavii, Alain A. Patat, Julie Krop, Myron Tong, Leo Beigelman

1105

  1. Top of page

W48 Response Rate of Boceprevir-PegIFN-RBV in Treatment-Experienced HIV Coinfected Patients with HCV genotype 1: ANRS-HC27 BocepreVIH Study

Isabelle Poizot-Martin1, Eric Bellissant2, Lionel Piroth3, Alain Renault2, Marc Bourlière4, Philippe Halfon5, Caroline Solas6, Bruno Lacarelle6, Philippe Colson7, Rodolphe Garraffo8, Jean-Michel Molina9; 1Immuno-Hématological Clinical Unit, Aix Marseille University, APHM Sainte-Marguerite,Inserm U912 (SESSTIM), Marseille, France; 2Department of Clinical Pharmacology, Rennes 1 University, Rennes, France. Rennes University Hospital,INSERM 0203 CIC-P Clinical Investigation Centre, Rennes, France; 3Infectious Diseases Department, University Hospital, Dijon, France; 4Hepato-Gastro-Enterology unit, Hôpital Saint- Joseph, Marseille, France; 5Medical Clinical Unit, Hôpital Ambroise Paré, Marseille, France; 6Pharmacokinetic and toxicology unit, Aix Marseille Univ, APHM Timone, CRO2 INSERM U911, Marseille, France; 7Fédération de Microbiologie Hospitalière, Aix Marseille University, APHM Timone,URMITE UM 63 CNRS 7278 IRD 198 INSERM 1095, Marseille, France; 8Pharmacology Unit, Faculty of Medecine of Nice, Hôpital Pasteur,, Marseille, France; 9Infectious Diseases Unit, Paris VII - Denis Diderot University,Assistance Publique Hôpitaux de Paris (AP-HP) - Saint-Louis Hospital, Paris, France

Background: Boceprevir (BOC) added to pegylated-interferon (P) and ribavirin (R) increases sustained virological response rates in naive hepatitis C (HCV) genotype 1/HIV-co-infected patients. There is no data in HCV/HIV-co-infected patients who had previously failed treatment with PR. Methods: In this multienter single arm openlabel phase 2 trial, patients received a 4-week lead in of PR (peg-IFNα2b: 1.5 mg/kg/wk; weight based R 800 to 1400 mg/day), followed by PR+BOC (800 mg tid) for 44 weeks, with an additional 24 weeks of PR for patients with HCV RNA > 15 and ≤ 1000 IU/mL at W8. BOC was stopped if HCV RNA was > 1000 IU/mL at W8 or at W12. ART regimens had to include 2 NRTI (TDF or ABC + FTC or 3TC) with atazanavir/r (ATVr) or raltegravir (RAL). Cirrhotic previous null-responders were excluded. Results: 69 patients were enrolled, 64 started HCV therapy (31.3% prior relapsers, 7.8% with prior break through, 28.1% partial and 32.8% null responders). ART regimen was 2NRTI+ATVr in 50%, 2NRTI+RAL in 42.2% and others combinations in 7.8%. HCV genotype was 1a in 78% of cases. METAVIR fibrosis stage was F3 in 21.9% and F4 in 17.2%. Median CD4 cell count was 728/mm3 and HIV RNA was <50 cp/mL in 95.3%. Sixty-two patients started BOC after the lead-in phase. Four patients who reached W48 are still on the additional 24-week PR. The W48 virological response was achieved in 36/64 patients (56.3%) and varied according to ART regimen (ATVr 43.8%, RAL 70.4%, others 60%), previous response (relapse 90%, breakthrough 0%, partial response 61.1%, null response 33.3%), HCV subtype (1a 50%, 1b 78.6%) but not to fibrosis stage (F0-F2 59.0%, F3 50%, F4 54.5%). HCV treatment was discontinued in 29 (45.3%) patients due to virological non response in 9 (14%), HCV virological breakthrough in 4 (6.3%), patient's decision in 8 (12.5%) (7 before W16), infections in 3 (4.7%), general disorders in 3 (4.7%), acute pancreatitis in 1 and neutropenia in 1. Grade 4 adverse events occurred in 19 patients including leuconeutropenia (6.3%), infections (6.3%),ane-mia(3%) and general disorders (3%). Conclusions: Up to W48, response rate to BOC+PR in patients who failed previous treatment with PR is consistent with that observed in HCV monoinfected genotype 1 treatment experienced patients and with a low discontinuation rate related to toxicity.

Disclosures

Isabelle Poizot-Martin - Board Membership: Janssen, MSD, Bristol Myers Squibb, ABBOTT; Consulting: ViiV Healthcare

Marc Bourlière - Advisory Committees or Review Panels: Schering-Plough, Bohringer inghelmein, Merck, Schering-Plough, Bohringer inghelmein, Merck ; Board Membership: Bristol-Myers Squibb, Gilead, Bristol-Myers Squibb, Gilead; Consulting: Roche, Novartis, Tibotec, Abott, glaxo smith kline, Roche, Novartis, Tibotec, Abott, glaxo smith kline

Philippe Halfon -Consulting: roche; Management Position: genoscience; Speaking and Teaching: merck, janssen; Stock Shareholder: alphabio

Jean-Michel Molina - Board Membership: Gilead, BMS, Janssen, merck, Abbott, boehringer; Grant/Research Support: merck; Speaking and Teaching: merck, gilead, BMS

The following people have nothing to disclose: Eric Bellissant, Lionel Piroth, Alain Renault, Caroline Solas, Bruno Lacarelle, Philippe Colson, Rodolphe Garraffo

1106

  1. Top of page

Population Pharmacokinetics of Sofosbuvir and Its Major Metabolite (GS-331007) in Healthy and HCV infected Adult Subjects

Brian Kirby1, Toufigh Gordi2, William T. Symonds1, Brian P. Kearney1, Anita Mathias1; 1Gilead Sciences, Foster City, CA; 2ROSA& Co, San Carlos, CA

Background: Sofosbuvir (SOF, formerly GS-7977), is an orally administered, once-daily, potent and specific uridine nucleotide analog hepatitis C virus (HCV) polymerase inhibitor prodrug that rapidly and durably suppresses HCV RNA. Population based pharmacokinetic (POPPK) models were developed to understand the clinical covariates of the PK of SOF and GS-331 007 (the renally eliminated inactive metabolite of SOF, representing >90% of systemic drug exposure, and the primary PK analyte of interest), in patients with chronic hepatitis C. Materials and Methods: GS-331007 and SOF POPPK models were developed from 18 (N=2089 subjects) and 14 (N = 1374 subjects) studies respectively, using pooled intensive and sparse samples from healthy and HCV infected subjects. Mixed effects modeling using NONMEM version 7.2 was applied. Covariates of age, gender, body mass index (BMI), race, HCV infection status, creatinine clearance (CLcr), concomitant medications and cirrhosis were evaluated for their effect on GS-331007 and SOF PK. Results: GS-331007 PK was best described by a 2-compartment model with zero and first order absorption (KA), and absorption lag time (Tlag). Typical values of oral clearance (CL/F), apparent central distribution volume (Vc/F), and KA were 39.5L/h, 21 8L, and 0.046h-1 respectively with interindividual variability (IIV) of 4.7, 12.4, and 5.6% respectively. HCV infection status was a significant, negatively correlated covariate of GS-331007 PK; mean GS-331007 systemic exposure (AUC) was 39% lower in HCV infected vs. healthy subjects. In addition, CLcr was a small but significant covariate (over the evaluated range of CLcr: >50 mL/min based on Phase 3 IE criteria) of GS-331 007 PK. These results are consistent with those of a renal impairment PK study that identified need for SOF dose adjustment only when CLcr < 30 mL/min. SOF PK was best described by a 1-compartment model with KA and Tlag. Typical values of CL/F, apparent distribution volume (V/F), and KA were 652L/h, 127L, and 0.96h-1 respectively with IIV of 10.9, 43.8, and 16.1% respectively. Consistent with its effect on GS-331007, HCV infection status was a significant, but positively correlated covariate of SOF PK; mean SOF AUC was 36% higher in HCV infected vs. healthy subjects. Age, gender, BMI, race, concomitant medications and cirrhosis were not significant predictors of GS-331 007 or SOF PK. Conclusions: Demographic variables such as age, gender, BMI, race, common concomitant medications, and cirrhosis do not influence GS-331 007 or SOF exposure in HCV infected subjects. No SOF dose modification is required in HCV infected subjects with CLcr ≥ 30mL/min.

Disclosures

Brian Kirby- Employment: Gilead Sciences

Toufigh Gordi - Consulting: Gilead Sciences

William T. Symonds - Employment: Gilead

Brian P. Kearney- Employment: Gilead Sciences Anita Mathias - Employment: Gilead Sciences Inc.,

1107

  1. Top of page

Long-term outcomes of sofosbuvir (SOF) for the treatment of chronic hepatitis C infected (CHC) patients

Sandrine Cure1, Ines Guerra1, Henrike Granzow1, Geoffrey M. Dusheiko2; 1HEOR, OptumInsight, Uxbridge, United Kingdom; 2UCL Institute for Liver and Digestive health, Royal free hospital, London, United Kingdom

Objectives: Sofosbuvir (SOF) is a uridine analogue polymerase inhibitor. Pan-genotypic efficacy and safety have been demonstrated in four phase III clinical trials of SOF administered with ribavirin (RBV) or with a combination of pegylated interferon alfa and RBV (PR). This analysis evaluated the long-term outcomes of SOF/RBV in treatment-naïve (TN) genotype (GT) 1 /4/5/6 and TN, treatment-experienced (TE), interferon ineligible (TNI) GT 2 and 3 HCV patients. Outcomes included cirrhosis, hepatocellular carcinoma (HCC) cases and liver transplants (LT) avoided, as well as life years (LY) and quality- adjusted life years (QALYs) gained. Methods: A Markov-model was developed to evaluate SOF-based regimens. Results are based on cohorts of 10,000 patients, with 50% initiating treatment at the compensated cirrhotic stage, followed up for a life time (100 years of age). In GT 1, 4/5/6 TN patients, SOF/PR for 12 weeks was compared to, telaprevir (TVR) or PR respectively. SOF/RBV for 12 or 16 weeks for GT 2 and 3 respectively, was compared to no treatment for TNI and TE, and PR for 24 or 48 weeks (PR24/PR48) for TN and TE respectively. SVR 12 weeks have been reported as 89% for TN GT 1 and 97% for GT 4/5/6 patients; 78% for patients with no treatmentoption (TNI and TE); 97% and 56% for GT 2 and 3 TN; for GT 2 and 3 TE, 86% and 30% with 12-week and, 94% and 62% with 1 6-week regimens respectively. Results: SOF was shown to be highly effective in preventing advanced liver disease (ALD) across all genotypes, most particularly for patients with no current treatment option (TNI and TE). The model also demonstrated that in GT 1 and 4/5/6 TN patients, SOF/PR prevented more ALD cases than in the PR and TVR treatment arms. Conclusions: SOF, including within interferon-free regimens were shown to be highly effective in preventing progression to ALD even in patients with no current treatment option. This treatment can change the way patients are currently managed with the potential to significantly reduce HCV-related mortality and long-term cost associated with disease management.

Table 17. 
IndicationSOF vs.Cirrhosis avoidedHCC avoidedLT avoidedDeaths avoidedLY gainedQALY gained
GT 1 TNTVR PR48-557 -2,664-212 -1,068-74 -363-37-1820.49 2.410.48 2.12
GT 4/5/6 TNPR48-813-241-69-390.320.65
GT 2 TNINo treatment-4,450-1,441-505-2633.363.03
GT2TNPR24-1,284-456-163-781.171.02
GT 2 TENo treatment PR48-3,487 -950-1,003 -255-350 -74-188-432.23 0.352.24 0.62
GT 3 TNINo treatment-3,689-1,183-415-2172.742.50
GT3TNPR24-2,452-776-276-1371.931.77
GT3TENo treatment PR48-2,926 -389-940-193-330 -54-173-272.17 0.281.98 0.36
Disclosures

Sandrine Cure - Consulting: Gilead Sciences

Ines Guerra - Consulting: Gilead Sciences

Henrike Granzow - Consulting: Gilead Sciences

Geoffrey M. Dusheiko - Advisory Committees or Review Panels: Schering Plough, Vertex, Abbott, Boehringer Ingelheim, BMS, GSK, Pharmasett, Pfizer, Roche, Merck, Tibotec, Achillion, Schering Plough, Vertex, Abbott, Boehringer Ingelheim, BMS, GSK, Pharmasett, Pfizer, Roche, Merck, Tibotec, Achillion, Schering Plough, Vertex, Abbott, Boehringer Ingelheim, BMS, GSK, Pharmasett, Pfizer, Roche, Merck, Tibotec, Achillion, Schering Plough, Vertex, Abbott, Boehringer Ingelheim, BMS, GSK, Pharmasett, Pfizer, Roche, Merck, Tibotec, Achillion; Board Membership: Gilead Sciences, Gilead Sciences, Gilead Sciences, Gilead Sciences; Grant/Research Support: Gilead Sciences

1108

  1. Top of page

High End-Of-Treatment (EOT) Response Rate with Telaprevir-PegIFN-RBV in Treatment-Experienced HIV Coinfected Patients with HCV genotype 1: ANRS HC26 TelapreVIH Study

Laurent Cotte1,2, Joséphine Braun3, Philippe Sogni4,5, Corine Vincent3, Marc-Antoine Valantin6,7, Daniel Vittecoq8,9, Christian Michelet10,11, Dominique Batisse12, Philippe Morlat13,14, Anne Gervais15, Jean-Michel Pawlotsky16,17, Jean-Pierre Aboulker3, Jean-Michel Molina18,19; 1Infectious Diseases Unit, Hospices Civils de Lyon - Croix-Rousse Hospital, Lyon, France; 2U1052, INSERM, Lyon, France; 3SC10-US019, INSERM, Villejuif, France; 4Hepatology Unit, Assistance Publique - Hôpitaux de Paris (AP-HP) - Cochin Hospital, Paris, France; 5Paris Descartes University, Paris, France; 6Infectious Diseases Unit, Assistance Publique - Hôpitaux de Paris (AP-HP) - Pitié-Salpêtrière Hospital, Paris, France; 7Paris VI University, Paris, France; 8Infectious Diseases Unit, Assistance Publique -Hôpitaux de Paris (AP-HP) - Kremlin-Bicêtre Hospital, Paris, France; 9Paris Sud - Bicêtre University, Paris, France; 10Infectious Diseases Unit, Pontchaillou University Hospital, Rennes, France; 11Rennes 1 University, Rennes, France; 12Clinical Immunology Unit, Assistance Publique - Hôpitaux de Paris (AP-HP) - Georges Pompidou European Hospital, Paris, France; 13Internal Medicine Unit, Saint André Hospital, Bordeaux, France; 14Bordeaux Segalen University, Bordeaux, France; 15Infectious Diseases Unit, Assistance Publique -Hôpitaux de Paris (AP-HP) - Bichat-Claude Bernard Hospital, Paris, France; 16Department of Virology, Assistance Publique - Hôpitaux de Paris (AP-HP) - Henri Mondor Hospital, Paris, France; 17Paris Est University, Paris, France; 18Infectious Diseases Unit, Assistance Publique Hôpitaux de Paris (AP-HP) - Saint-Louis Hospital, Paris, France; 19Paris VII - Denis Diderot University, Paris, France

Background Retreatment with PegInterferon (PegIFN) + Ribavirin (RBV) results in poor SVR rates in HIV-HCV coinfected patients. There is no data regarding the use of Telaprevir (TVR) + PegIFN-RBV in these patients. Methods HIV-1 infected patients who had previously failed ≥12 weeks PegIFN-RBV for HCV genotype 1 coinfection were enrolled in a single-arm, phase 2 trial. Authorized ARTs were Tenofovir (TDF), Emtricitabine (FTC), Efavirenz (EFV), boosted Atazanavir (ATVr) and Raltegravir (RAL). Null-responders with cirrhosis were excluded. All patients received PegIFN α2a 1 80μg/week + RBV 1000-1200mg/day for 4 weeks (lead-in phase), followed by TVR 750mg tid (1125mg tid if EFV-based ART) + PegIFN-RBV for 12 weeks and finally PegIFN-RBV for 32 to 56 weeks, based upon Rapid Virologic Response at W8. Results 70 patients were enrolled, 69 started treatment (39% prior relapsers, 9% with prior breakthrough, 22% partial and 30% null responders). Median [IQR] CD4 cell count was 630 cells/mm3 [459-736]. ART regimen was TDF-FTC-ATVr in 49%, TDF-FTC-EFV in 19%, TDF-FTC-RAL in 1 7% and other combinations in 14%. HCV genotype was 1a in 68% of cases, METAVIR fibrosis stage was F3 in 16% and F4 in 23%. The EOT response was achieved in 57/69 patients (82.6%) and was not influenced by the fibrosis stage (F1-2 83%, F3-4 81%), the ART regimen (ATVr 84%, EFV 88%, RAL 71%), the HCV subtype (1a 81%, 1 b 90%) or the type of previous response (relapse 78%, breakthrough 83%, partial response 100%, null response 76%). 26% of the patients discontinued HCV treatment for non-response (1.5%), breakthrough (4%), cutaneous (4%), psychiatric (4%), hematological (6%) or other (6%) adverse events (AEs). Grade 4 AEs occurred in 20% of cases, including anemia (10%), leuconeutropenia (6%), thrombocytopenia (1.5%) and infections (3%). 9% of the patients were hospitalized for bacterial infections. PegIFN or RBV dose reduction was required in 22% and 42 % respectively. 65% of the patients required EPO, 22% blood transfusions, 6% G-CSF and 1.5% platelet transfusions and TPO-R agonist. No decompensation of cirrhosis was observed but one patient died at W40 from an intracerebral hemorrhage associated with autoimmune thrombocytopenia. Conclusion Despite a high discontinuation rate related to toxicity, a high EOT virological response rate was achieved with TVR-PegIFN-RBV in PegIFN-RBV-experienced HIV-HCV coinfected patients.

Disclosures

Laurent Cotte - Grant/Research Support: MSD, ViiV, Janssen, Gilead, Boehringer, BMS, Oncolys

Philippe Sogni - Independent Contractor: Gilead, Roche, MSD, BMS, Janssen, Mayoli-Spindler

Marc-Antoine Valantin - Board Membership: Gilead, Bristol-Myers; Speaking and Teaching: Janssen-cilag

Christian Michelet - Board Membership: BMS; Speaking and Teaching: GILEAD, JANSSEN

Jean-Michel Pawlotsky-Consulting: Abbott, Achillion, Boehringer-Ingelheim, Bristol-Myers Squibb, Idenix, Gilead, Janssen, Madaus-Rottapharm, Merck, Novartis, Roche; Grant/Research Support: Gilead; Speaking and Teaching: Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead, Madaus-Rottapharm, Merck, Janssen-Cilag, Novartis, Abbott

Jean-Michel Molina - Board Membership: Gilead, BMS, Janssen, merck, Abbott, boehringer; Grant/Research Support: merck; Speaking and Teaching: merck, gilead, BMS

The following people have nothing to disclose: Joséphine Braun, Corine Vincent, Daniel Vittecoq, Dominique Batisse, Philippe Morlat, Anne Gervais, Jean-Pierre Aboulker

1109

  1. Top of page

Modeling the epidemiological impact of upcoming direct antiviral agents in hepatitis C treatment

Henri Leleu1, Homie Razavi2, Chris Estes2, Christophe Hezode3, Martin Blachier1, Francoise Roudot-Thoraval4; 1Public health expertise, Loos, France; 2Center for Disease Analysis, Louisville, CO; 3Service d'Hépato-Gastroentérologie, Hopital Henri Mondor, Créteil, France; 4Département Santé Publique, Hopital Henri Mondor, Créteil, France

Background: Several direct antiviral agents (DAA) for viral hepatitis C (VHC) are currently undergoing clinical trials that are showing very promising sustained virologic response rates (SVR). These therapies have the potential to dramatically change the epidemiological profile of VHC in the upcoming year, if they are widely made available to patients. Methods: We used a system dynamic model to estimate the impact of making available the upcoming DAA on the epidemiological burden of hepatitis C in France. The model is based on prevalence, incidence, screening rates, genotype distribution in France as well as the results of the ongoing DAA clinical trials. The model can be used to simulate the epidemiological impact of treatment scenarios based on drugs availability, eligibility and effectiveness. We choose to compare the current strategy to the following scenario. HCV screening rate remains unchanged. Starting in 2014, new interferon-free therapies increased SVR to 90% for genotype 2 (G2) and to 60% for G3; rate of eligible patients increased from 60% to 100%; F1-F4 patients are treated. For G1 /4, new therapies increased SVR to 80% for G1 and to 90% for G4; rate of eligible patients unchanged at 60%; F2-F4 patients are treated. Starting in

2016, oral interferon-free for G1/4 increased SVR to 90% for G1 and 1 00% for G4; rate of eligible patients increased from 60% to 1 00%; F1 patients are also treated. Treatment for G2/3 remains unchanged. Starting in 2018, all treatments are extended to F0 patients. We did sensitivity analysis based on hypothetical for real-life effectiveness of DAA (up to 20% lower than in clinical trials). Results: Compared to the current strategies, in our scenario, by 2030, HCV-related mortality would be 44% lower in France, with, overall, 1,181 deaths averted; HCV related cancer would be 52% lower with, overall, 153 cases averted. Total prevalence of HCV infected patients would be 40,727 cases lower at 10,705, with overall 2,985 cases of cirrhosis averted. Due to decreased transmission between intravenous drug users, 2,053 new infections in total would be also averted. Conclusion: Based on available clinical trials results, and our hypothesis, the introduction of new DAA-based therapies, in particular interferon-free strategies, may result in a twofold decreased in HVC related death and complications and in a fivefold decreased in prevalence by 2030 in France compared to the currently available strategies, substantially reducing the burden of VHC.

Disclosures

Henri Leleu - Consulting: Gilead

Homie Razavi - Consulting: Gilead, Abbott, Boehringer Ingelheim

Chris Estes - Consulting: Abbott, Gilead

Christophe Hezode - Speaking and Teaching: Roche, BMS, MSD, Janssen, abb-vie, Gilead

Martin Blachier - Consulting: GILEAD Sciences

Francoise Roudot-Thoraval - Advisory Committees or Review Panels: Roche, Roche; Consulting: LFB; Speaking and Teaching: Gilead, Gilead, Roche

1110

  1. Top of page

Efficacy and Safety of an Interferon-Free Regimen of MK-5172 + Ribavirin for 12 Weeks or 24 Weeks in Treatment Naive, Noncirrhotic Subjects With HCV GT1 Infection: The C-SPIRIT Study

Edward J. Gane1, Ziv Ben Ari2, Lindsay Mollison3, Eli. Zucker-man4, Rafael Bruck5, Yaacov Baruch6, Janice Wahl7, Sanhita Bhanja8, Peggy Hwang8, Yue Zhao8, Michael Robertson8; 1New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand; 2Liver Disease Center, Sheba Medical Center, Ramat Gan, Israel; 3Fremantle Hepatitis Services, Fremantle Hospital, Fremantle, WA, Australia; 4Liver Unit, Carmel Medical Center, Haifa, Israel; 5Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; 6Liver Unit, Rambam Healthcare Campus, Haifa, Israel; 7Merck Research Laboratories, Kenilworth, NJ; 8Merck Research Laboratories, Upper Gwynedd, PA

Purpose: MK-5172 is a potent, pan-genotypic, second generation hepatitis C virus (HCV) NS3/4A protease inhibitor with a high genetic barrier to resistance. Several interferon-free regimens of direct-acting antiviral agents (DAAs) have been reported to achieve high rates of SVR. Efficacy appears to depend on potency, viral genotype (GT), and patient characteristics. This study evaluates the interferon-free, single DAA regimen of MK-5172 + ribavirin (RBV) in patients with HCV GT 1 infection who express the IL28B CC genotype. Methods: Treatment-naive, non-cirrhotic, IL28B CC genotype patients with HCV GT1 infection were randomized to receive 12 or 24 weeks of MK-5172 100 mg QD + weight-based RBV BID. Patients in the 12-week arm with detectable HCV RNA at treatment week (TW) 4 had their treatment duration extended to 24 weeks. Weekly assessments were performed during treatment. Follow-up visits occurred 4, 12, and 24 weeks after end of treatment. HCV-RNA samples were assessed using COBAS Taq-Man v2.0. Futility was defined as HCV-RNA ≥25 IU/mL at TW4. Results: 26 patients (17 male / 9 female) were enrolled. One patient discontinued on day 1 because his wife was pregnant. Of the remaining patients, 12 had HCV GT1a infection and 13 had GT1 b. Mean baseline HCV-RNA was approximately 9.0 × 106 IU/mL. All but two patients had achieved HCV-RNA of TND by TW6. As of May 28, 2013, 15 subjects had completed TW12. One patient had confirmed viral breakthrough at TW6 and stopped treatment. All remaining patients maintained viral suppression during treatment. The most frequently reported adverse events (>10%) were headache (6, 23%), asthenia (6, 23%), anemia (3, 12%), dyspepsia (3, 12%), nausea (3, 12%), and insomnia (3, 12%). There were no SAEs or treatment discontinuations. ALT was elevated at baseline in 16 patients (range, 34-252), but normalized on treatment in all patients. Nine patients had transient, mild (grade 1-2) elevations in total bilirubin on treatment (range, 1.12-2.45). Conclusion: Patients with HCV GT1a or GT1 b infection receiving MK-51 72 + RBV achieved rapid and sustained HCV-RNA suppression. One patient had viral breakthrough at TW6. SVR12 and resistance data will be presented. These results support further evaluation of IFN-free regimens with MK-51 72.

Table 18. 
 GT1aGl1b
 n*TD(q)TD(u)TNDn*TD(q)TD(u)TND
TW2<br>TW4<br>TW8<br>TW1212<br>12<br>10<br>61<br>0<br>1†<br>1†9<br>5<br>0<br>02<br>7<br>9<br>513<br>13<br>13<br>90<br>0<br>0<br>06<br>3<br>0<br>07<br>10<br>13<br>9

*Number of subjects with data available.‡One subject had confirmed virological breakthrough atTW6.TD(q), HCV-RNA target detected quantifiable; TD(u), HCV-RNA target detected unquantifi-able; TND, HCV-RNA target non-detectable.

Disclosures

Edward J. Gane-Advisory Committees or Review Panels: Roche, AbbVie, Novartis, Tibotec, Gilead Sciences, Janssen Cilag, Vertex, Achillion; Speaking and Teaching: Novartis, Gilead Sciences, Roche

Ziv Ben Ari - Advisory Committees or Review Panels: MSD, Jenssen, Boehringer Ingelheim, BMS

Yaacov Baruch - Consulting: Coeruleus Ltd, MSD

Janice Wahl - Employment: Merck & Co,

Sanhita Bhanja - Employment: Merck

Peggy Hwang - Employment: Merck, Merck

Yue Zhao - Employment: Merck & Co., Inc

Michael Robertson - Employment: Merck; Stock Shareholder: Merck

The following people have nothing to disclose: Lindsay Mollison, Eli. Zuckerman, Rafael Bruck

1111

  1. Top of page

Analysis of HCV Resistance Variants in a Phase 3 Trial of Daclatasvir Combined With Asunaprevir for Japanese Patients with Genotype 1 b Infection

Fiona McPhee1, Joji Toyota2, Kazuaki Chayama3, Hidetaka Miyagoshi4, Etsuko Tamura4, Hiroki Ishikawa4, Eric A. Hughes5, Dennis Hernandez1, Hiromitsu Kumada6; 1Research & Development, Bristol-Myers Squibb, Wallingford, CT; 2Sapporo Kosei General Hospital, Sapporo, Japan; 3Hiroshima University, Hiroshima, Japan; 4Bristol-Myers KK, Tokyo, Japan; 5Research & Development, Bristol-Myers Squibb, Lawrenceville, NJ; 6Toranomon Hospital, Tokyo, Japan

Background The all-oral combination of daclatasvir 60mg QD, a first-in-class HCV NS5A inhibitor with pan-genotypic activity in vitro, and asunaprevir 1 00mg BID, a selective NS3 protease inhibitor, was evaluated in a phase 3, open-label study in 222 Japanese patients with HCV genotype 1b infection. Patients had prior nonresponse or intolerance to peginterferon/ribavirin (alfa/RBV) or were medically ineligible for alfa/RBV. Here we examine baseline NS3 and NS5A sequences and the emer-

gence and persistence of resistance-associated variants (RAV) from this study. Methods The frequency of RAV at baseline was determined using in-house sequence alignment software. HCV NS5A and NS3/4A regions were PCR-amplified and sequenced from patients with treatment failure when HCV RNA was >1000 IU/mL. Results Baseline variants: Among 214 patient samples analyzed for NS5A RAV at baseline, 22/38 (58%) patients with RAV subsequently failed therapy, including 5/8 with NS5A-L31M/F, 16/29 with NS5A-Y93H, and 1/1 with NS5A-L31V-Y93H. Among 221 patient samples analyzed for NS3 RAV at baseline, 15/82 (1 8%) patients with RAV subsequently failed therapy, including 1/2 with NS3-T54S, 0/3 with NS3-T54S-Q80L, 4/19 with Q80L, 1/4 with NS3-Q80L-S122G, 8/52 with S122G, and 1/2 with D168E. Among 34 patients who failed therapy, 11 (32%) or 19 (56%) patients had no baseline NS5A (L31 and/or Y93) or NS3 RAV, respectively. Failure-associated variants: NS5A RAV were detected in 33 patients at or close to the time of virologic failure, but not in 1 patient who discontinued after 4 weeks. NS5A-L31 M/V/I-Y93H/N was detected in 28 failures; L31 M/V was detected in 1 failure after 2 weeks of treatment with no emergent NS3 RAVs, and NS5A-Y93H emerged in 1 patient with baseline RAV L28M-R30Q. NS5A-R30H/Q-Y93H emerged in 2 patients, and delP32 in 1 patient. NS3 RAV at D168 (D168A/E/N/T/V/Y) were detected in 28 patients with virologic failure, but not in 2 patients who discontinued after <5 weeks of treatment or in 4 patients tested at follow-up week 24. Among patients with available data at follow-up Week 24, 1/29 had no detectable NS5A RAV at L31 and/or Y93 or P32 compared with 12/29 patients with no detectable NS3-D168 RAV. Conclusions Among Japanese GT1 b patients treated with daclatasvir + asunaprevir, presence of the minor baseline NS5A polymorphisms L31 and Y93H indicated an association with virologic outcome. A similar association with baseline NS3 RAV was not apparent; patients with these variants achieved SVR at a higher rate than results reported for alfa/RBV combined with an approved protease inhibitor. Both NS3 and NS5A RAV emerged in most patients with virologic failure.

Disclosures

Fiona McPhee - Employment: Bristol-Myers Squibb

Joji Toyota - Speaking and Teaching: MSD

Kazuaki Chayama - Consulting: Abbvie; Grant/Research Support: Dainippon Sumitomo, Chugai, Mitsubishi Tanabe, DAIICHI SANKYO, Toray, BMS, MSD; Speaking and Teaching: Chugai, Mitsubishi Tanabe, DAIICHI SANKYO, KYORIN, Nihon Medi-Physics, BMS, Dainippon Sumitomo, MSD, ASKA, Astellas, AstraZeneca, Eisai, Olympus, GlaxoSmithKline, ZERIA, Bayer, Minophagen, JANSSEN, JIMRO, TSUMURA, Otsuka, Taiho, Nippon Kayaku, Nippon Shinyaku, Takeda, AJINOMOTO, Meiji Seika, Toray

Hidetaka Miyagoshi - Employment: Bristol-Myers KK

Hiroki Ishikawa - Employment: Bristol-Myers Squibb, Bristol-Myers Squibb

Eric A. Hughes - Employment: Bristol-Myers Squibb

Dennis Hernandez- Employment: Bristol-Myers Squibb

Hiromitsu Kumada - Speaking and Teaching: Bristol-Myers Squibb,Pharma International

The following people have nothing to disclose: Etsuko Tamura

1112

On Treatment HCV RNA as a Predictor of Virologic Response in Sofosbuvir-Containing Regimens for Genotype 2/3 HCV Infection: Analysis of the FISSION, POSITRON, and FUSION Studies

David L. Wyles1, David R. Nelson2, Mark G. Swain3, Robert G. Gish1, Julie Ma4, John McNally4, Diana M. Brainard4, William T. Symonds4, John G. McHutchison4, David E. Bernstein5, Alexander J. Thompson6, Alessandra Mangia7, Ira M. Jacobson8; 1University of California, San Diego, San Diego, CA; 2University of Florida, Gainesville, FL; 3University of Calgary, Gainesville, AB, Canada; 4Gilead Sciences, Inc., Foster City, CA; 5Hofstra North Shore LIJ School of Medicine, Manhasset, NY; 6St Vincent's Hospital, Melbourne, VIC, Australia; 7IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Italy; 8Weill Cornell Medical College, New York, NY

Background: Response guided therapy utilizing HCV RNA quantification at early timepoints during treatment is used to guide duration and assess futility of treatment with pegylated interferon based regimens. A retrospective analysis of on-treat-ment HCV RNA levels in genotype 2/3 HCV infected patients treated in the Phase 3 sofosbuvir (SOF) program was performed to determine if there was similar utility of HCV RNA quantification at early timepoints during treatment in predicting response to SOF-based regimens. Methods: Patients with genotype 2 and 3 HCV infection were treated with SOF 400 mg + RBV 1000-1200mg for 12 weeks in the FISSION and POSITRON studies and for 12 or 16 weeks in the FUSION study. Serum samples were collected for HCV RNA quantification using the COBAS Taqman v2.0 HPS with LLOQ= 25 IU/mL. The positive predictive value (PPV) and negative predictive value (NPV) of HCV RNA ≥ LLOQ for SVR12 were calculated. PPV was defined as the proportion of patients achieving SVR12 in patients who achieved HCV RNA < LLOQ at the specified timepoint. NPV was defined as the proportion of patients who did not achieve SVR12 who had HCV RNA > LLOQ at the specified timepoint. Analyses of PPV and NPV of HCV RNA < LLOQ in patient subgroups (genotype, stage of fibrosis) and PPV and NPV for SVR12 of HCV RNA < LLOQ target not detected were also performed. Results: In all 3 studies there were rapid and sustained declines in HCV RNA during treatment with HCV RNA < LLOQ at week 4 in > 99% of patients. Table 1 presents the overall SVR12 rates, and PPV and NPV of HCV RNA < LLOQ at weeks 1, 2, and 4 for the FISSION, POSITRON, and FUSION studies. The PPV in each study was relatively unchanged at week 1, 2 and 4. The NPV was 1 00% at week 4 in several studies; however the interpretation of this result is limited by the small number of patients with HCV RNA > LLOQ at this timepoint (<1% across all studies). Conclusion: Assessment of HCV RNA at early timepoints during treatment with SOF + RBV for genotype 2/3 HCV infection has limited clinical utility for determining treatment futility.

Table 19. Positive Predictive Value and Negative Predictive Value of HCV RNA < LLOQ
 FISSION N= 253POSITRON N= 207FUSION 12 Week N=100FUSION 16 Week N= 95
SVR1267%78%50%73%
Week 1 PPV76% (84/110)84% (66/79)58% (15/26)75% (18/24)
Week 1 NPV39% (56/142)26% (33/128)53% (39/74)28% (20/71)
Week 2 PPV70% (161/231)81% (150/186)54% (44/81)73% (61/83)
Week 2 NPV55* (11/20)42% (8/19)68% (13/19)33% (4/12)
Week 4 PPV68% (170/249)79% (160/202)52% (50/97)74% (69/93)
Week 4 NPV100% (1/1)50% (1/2)100% (3/3)100% (2/2)
Disclosures

David L. Wyles - Advisory Committees or Review Panels: Bristol Myers Squibb, Merck, AbbVie, Janssen; Grant/Research Support: Gilead, Merck, Vertex, Pharmassett, AbbVie

David R. Nelson -Advisory Committees or Review Panels: Merck; Grant/Research Support: Abbot, BMS, Beohringer Ingelheim, Gilead, Genentech, Merck, Bayer, Idenix, Vertex, Jansen

Mark G. Swain - Advisory Committees or Review Panels: Roche, Gilead, Idenix, Boehringer-Ingelheim, Janssen; Grant/Research Support: Roche, Gilead, Bristol Myers-Squibb, Boehringer-Ingelheim, Janssen

Robert G. Gish - Advisory Committees or Review Panels: Merck, Genentech, Roche, BMS, Gilead, Arrowhead; Stock Shareholder: Hepahope, Kinex, Arrowhead

Julie Ma - Employment: Gilead Sciences

John McNally - Employment: Gilead Sciences, Inc

Diana M. Brainard - Employment: Gilead Sciences, Inc.

William T. Symonds - Employment: Gilead

John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead Sciences

David E. Bernstein - Advisory Committees or Review Panels: Merck, BMS, Vertex, Abbvie, Janssen, Boehringer Ingelheim, GIlead; Grant/Research Support: Merck, BMS, Vertex, ABBVIE, Janssen, Boehringer Ingelheim, Genentech, Gilead; Speaking and Teaching: Gilead

Alexander J. Thompson - Advisory Committees or Review Panels: Merck, Inc, Roche, Janssen (Johnson & Johnson), BMS, GSK Australia, Novartis, GILEAD Sciences, Inc; Consulting: GILEAD Sciences, Inc; Grant/Research Support: Merck, Inc, Roche, GILEAD Sciences, Inc; Speaking and Teaching: Merck, Inc, Roche, BMS

Alessandra Mangia - Advisory Committees or Review Panels: ROCHE, Janssen, MSD, ROCHE, Janssen, MSD, Boheringer; Consulting: Gilead; Grant/Research Support: Shering-Plough, Shering-Plough

Ira M. Jacobson - Consulting: Vertex, Abbott, Achillion, Boehringer Ingelheim, Bristol Myers Squibb, Enanta, Gilead, Glaxo Smithkline, Idenix, Kadmon, Novartis, Presidio, Roche / Genentech, Merck, Janssen; Grant/Research Support: Abbott, Achillion, Vertex, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Novartis, Pfizer, Roche / Genentech, Schering / Merck, Tibotec / Janssen; Speaking and Teaching: Vertex, Bristol Myers Squibb, Gilead, Roche / Genentech, Schering / Merck

1113

  1. Top of page

Health-Related Quality of Life (HRQoL), Health State, Function and Wellbeing of Chronic HCV Patients Treated with Interferon-Free, Oral DAA Regimens: Patient Reported Outcome (PRO) Results from the AVIATOR Study

Robert W. Baran1, Wangang Xie2, Yan Liu1, Daniel E. Cohen3, Katherine L. Gooch1; 1Global HEOR, AbbVie, North Chicago, IL; 2Statistics, AbbVie, North Chicago, IL; 3Global Pharmaceutical R & D, AbbVie, North Chicago, IL

Background AVIATOR is a phase 2b trial of multiple interferon-free regimens using 3 DAAs ± ribavirin (RBV): ABT-450/r (riton-avir-enhanced protease inhibitor), ABT-267 (NS5A inhibitor), and ABT-333 (non-nucleoside polymerase inhibitor). Overall ITT SVR12 rates after 12-week treatment with 3 DAAs+RBV were 99% in GT1 treatment-naïve patients and 93% in prior null responders. PRO results have not previously been reported for oral interferon-free treatment of chronic HCV. Peginterferon plus approved protease inhibitor regimens may impair health state by 15% during treatment [Younossi ZM. DDW 2012]. We report PRO responses in patients receiving 12-week oral DAA treatment regimens in AVIATOR. Methods Three PRO instruments were self-administered at baseline, weeks 4, 8, 12, and post treatment week 24 (PTW24) in AVIATOR: SF-36v.2 HRQoL survey (score 0-1 00); EQ-5D 5L health state instrument (score 0-1); and the disease specific HCV-PRO [Baran RW. ILC 2012] function and wellbeing survey (score 0-1 00). SF-36v.2 Physical Component Score (PCS) and Mental Component Score (MCS) were calculated. Minimum Important Difference (MID) for SF-36 PCS/MCS was defined as 3 points. ITT mean change from baseline is descriptively presented. All patients received 12-week regimens of 3 DAAs+RBV. Results Among 79 treatment-naïve patients/45 null responders, 56%/62% were male, 16%/13% were black, 72%/96% had IL28B non-CC genotype, and mean age was 50.2/49.8 years. PRO completion was ≥ 89% at all assessments. PRO results are summarized in Table 1. Baseline SF-36 PCS/MCS and EQ-5D scores approximated normal population means. Mean PRO scores changed minimally during treatment and no decline in mean SF-36 score reached MID threshold. At PTW 24, all mean scores were improved over baseline. Conclusions Interferon-free DAA regimens in AVIATOR were observed to have minimal impact on PRO response during treatment, suggesting that patient HRQoL, health state, function and wellbeing are preserved. PRO scores at PTW24 were observed to improve compared to baseline.

Table 20. Mean Baseline (SD) and Change from Baseline (SD) in PRO Response
NaiveBaselineWk4Wk8Wkl2PTW24
SF-36 PCS, n=7849.5 (9.3)-0.1 (5.4)-1.0(8.1)-0.3 (8.7)1.8 ((6.2)
SF-36 MCS, n=7848.4(11.5)0.2 (8.8)-1.0(9.3)-0.1 (10.3)2.7 (9.5)
EQ-5D Index, n=770.85(0.1)-0.01 (0.1)-0.01 (0.1)-0.01 (0.1)0.03(0.1)
HCV-PRO, n=7876.1 (20.4)2.0(14.6)0.7 (16.5)1.3(15.5)6.5 (14.9)
Null responders     
SF-36 PCS, n=4550.7 (9.7)-2.0 (7.6)-1.3(7.4)-0.8 (7.4)2.9(8.1)
SF-36 MCS, 0-4549.2(12.2)1.1 (6.6)-0.3 (8.0)0.7 (9.5)4.2 (9.4)
EQ-5D Index, n=450.88(0.1)-0.02(0.1)-0.01 (0.1)-0.01 (0.1)0.02(0.1)
HCV-PRO, n=4577.5(23.1)-0.4(12.1)2.1 (13.3)0.1 (16.5)10.3 (16.2)
Disclosures

Robert W. Baran - Employment: Abbvie

Wangang Xie - Employment: AbbVie

Yan Liu - Employment: Abbvie Inc; Stock Shareholder: Abbvie Inc

Daniel E. Cohen - Employment: AbbVie; Stock Shareholder: AbbVie

Katherine L. Gooch - Employment: Abbvie

1114

  1. Top of page

Subgroup analyses and baseline predictors of response with faldaprevir plus pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic hepatitis C genotype-1 infection: A pooled analysis of STARTVerso1 and 2

Eric M. Yoshida1, Tarik Asselah2, Christophe Moreno3, Marina V. Maevskaya4, Jia-Horng Kao5, Javier Crespo6, Jean-Francois Dufour7, David K. Wong8, Edward Tam9, Victor S. Feinman10, Marcus Schuchmann11, Masao Omata12, Peter Ferenci13, Kris V. Kowd-ley14, Youn-Jae Lee15, Eiichi Tomita16, Seung Woon Paik17, Hiroshi Yatsuhashi18, Jerry O. Stern19, Anne-Marie Quinson19, Florian Voss20, Joe Scherer19, Yakov Datsenko20, Donald M. Jensen21; 1University of British Columbia, Vancouver, BC, Canada; 2Hôpital Beaujon, APHP, University Paris-Diderot and INSERM CRB3, Clichy, France; 3Hôpital Universitaire Erasme, Université Libre de Brux-elles, Brussels, Belgium; 4First Moscow State Medical University, Moscow, Russian Federation; 5National Taiwan University Hospital, Taipei, Taiwan; 6Hospital Univ. de Valdecilla, Santander, Spain; 7University Clinic for Visceral Surgery and Medicine, Bern, Switzerland; 8Toronto Western Hospital Liver Center, Toronto, ON, Canada; 9LAIR Centre, Vancouver, BC, Canada; 10Hepatitis Centre, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada; 11University Hospital Mainz, Mainz, Germany; 12Yaman-ishi Central and Kita Hospitals, Yamanishi, Japan; 13Medical University of Vienna, Vienna, Austria; 14Virginia Mason Medical Center, Seattle, WA; 15Inje University Busan Paik Hospital, Busan, Republic of Korea; 16Gifu Municipal Hospital, Gifu, Japan; 17Samsung Medical Center, Sungkyunkwan University, Seoul, Republic of Korea; 18Nagasaki Medical Centre, Nagasaki, Japan; 19Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT; 20Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany; 21University of Chicago Medicine, Chicago, IL

Background: STARTVerso (SV) 1 &2 Phase III studies evaluated faldaprevir (FDV) plus pegylated interferon alfa-2a and ribavirin (PR) in treatment-naïve patients with chronic HCV genotype (GT) 1 infection. Here we present an analysis of baseline variables predictive of virologic response in SV1&2. Methods: Patients received 48 weeks (W) of PR plus: placebo (Arm 1); FDV 120 mg QD for 12W or 24W (Arm 2); or FDV 240 mg QD for 12W (Arm 3). Patients in Arms 2 and 3 stopped all treatment at W24 on achievement of early treatment success (ETS, HCV RNA <25 IU/mL detected or undetected at W4 and undetected at W8). Rates of sustained virologic response 12W after completion of all treatment (SVR12) were assessed based on age, race, gamma-glutamyl transferase (GGT), IL28B genotype (rs12979860), HCV GT1 subtype, baseline viral load (VL), and cirrhosis. These parameters were identified by step wise logistic regressions to be baseline variables associated with SVR12 or ETS for FDV-based treatment. Results: 1309 patients (Arm 1 =264; Arm 2=521; Arm 3=524) received treatment: 19% <40 years, 71 % Caucasian, 43% GGT >ULN, 40% IL28B CC, 48% GT1a, 78% VL ≥800,000 IU/mL, 9% cirrhosis. SVR12 rates were 50%, 73%, and 72% for Arms 1, 2, and 3, respectively. SVR12 rates (%) by subgroup in arms 1/2/3 were 45/70/69 vs 71/88/86 (age ≥40 vs <40); 49/72/71 vs 58/88/87 vs 32/44/44 (Caucasian vs Asian vs Black); 36/57/58 vs 61/85/82 (GGT >ULN vs normal); 67/90/88 vs 40/62/62 (IL28B CC vs nonCC); 42/64/65 vs 56/82/79 (GT1a vs 1b); 71/91/87 vs 44/69/68 (VL <800,000 vs >800,000 IU/mL); 40/47/48 vs 51/76/75 (cirrhosis yes vs no). Baseline variables and their association with SVR12 and ETS are shown (Table). There were no significant differences in SVR12 or ETS between FDV dose groups. Conclusions: In a multivariate analysis of SV1 &2, normal baseline GGT, IL28B CC, GT1b, and VL <800,000 IU/mL were associated with higher SVR12 and ETS rates. FDV dose did not have a significant effect on SVR12 rate, which was higher than placebo for all subgroups.

Table 21. 
 SVR 12ETS
FactorOR (95% Cl)p-valueOR (95% CI)p-value
Treatment (120 mg vs 240 mg)1.057(0.772; 1.449)0.72810.962 (0.675, 1.370)0.8279
Age, years (≥40 vs <40)0.48 (0.30:0.78)0.0027****
Race 0.0123****
Asian vs other1.05 (0.60; 1.82)   
Black vs other0.44 (0.26;0.76)   
GGT (>ULN vs normal)0.50 (0.36;0.69)<0.000l0.49(0.34;0.71)0.0002
IL28B (CC vs CT/TT)*4.35 (2.94;6.44)<0.00012.67(1.75:4.07)<0.000l
HCVGT(lavslb)*0.58(0.41:0.82)0.00230.38(0.26:0.55)<0.0001
Baseline viral load (<800,000 vs >800,000 IU/mL)3.34 (2.06:5.42)<0.000l2.16(1.26:3.71)0.0050
Cirrhosis (yes vs no)0.37 (0.22;0.63)0.0002****

*Treatment, GTI subtype, and IL28B were fixed to slay in the model. Other variables included for

selection were: race (Black, Asian, Other), cirrhosis (yes, no), baseline VL (<800,000, >800,000

IU/mL), baseline GGT (normal, elevated), baseline ALT (normal, elevated), gender (male, female),

age (<40, ≥40 years), BMI (<25, ≥25 kg/m2). **Nol retained in the model after stepwise selection

(p<0.05). CI, confidence interval; OR, odds ratio; ULN, upper limit of normal

Disclosures

Eric M. Yoshida - Advisory Committees or Review Panels: Hoffman LaRoche, Gilead Sciences Inc, Vertex Inc; Grant/Research Support: Cangene Corporation, Hoffman LaRoche, Merck Inc/Schering Plough, Pfizer Inc, Norvartis Inc, Vertex Inc, Jannsen Inc, Gilead Sciences Inc, Boeringher Ingleheim Inc, Abbie (formerly Abbott Laboratories), Astellas; Speaking and Teaching: Gilead Sciences Inc, Cangene Corporation, Vertex Inc, Merck Inc

Tarik Asselah - Consulting: BMS, Boehringer-Ingelheim, Roche, Merck-Schering Plough, Gilead, Janssen

Christophe Moreno - Board Membership: JANSSEN, Janssen Therapeutics; Consulting: Gilead, MSD; Grant/Research Support: ROCHE, Janssen, Novartis, Astellas, MSD; Speaking and Teaching: MSD, BMS, JANSSEN

Javier Crespo - Board Membership: MSD, Roche, Janssen, Gilead

Jean-Francois Dufour - Advisory Committees or Review Panels: Bayer, BMS, Gilead, Jansse, Novartis, Roche

David K. Wong - Grant/Research Support: Gilead, BMS, Vertex, BI

Marcus Schuchmann - Advisory Committees or Review Panels: Roche, BMS, Norgine, Boehringer; Speaking and Teaching: Gilead, Merck, Falk

Masao Omata - Consulting: Bristol-Myers Squibb, Boehringer Ingelheim, Otsuka Pharmaceutical, Bristol-Myers Squibb, Boehringer Ingelheim, Otsuka Pharmaceutical; Speaking and Teaching: Bristol-Myers Squibb, Pfizer, Roche, Bristol-Myers Squibb, Pfizer, Roche

Peter Ferenci - Advisory Committees or Review Panels: Roche, Idenix, Roche, MSD, Vertex, Salix, Madaus Rottapharm, Tibotec, BVdhringer Ingelheim, Achilleon, GSK; Grant/Research Support: MSD, Vertex, Madaus Rottapharm; Patent Held/Filed: Madaus Rottapharm; Speaking and Teaching: Roche, Gilead, Roche, Gilead, Salix

Kris V. Kowdley-Advisory Committees or Review Panels: Abbott, Gilead, Merck, Novartis, Vertex; Grant/Research Support: Abbott, Beckman, Boeringer Ingelheim, BMS, Gilead Sciences, Ikaria, Janssen, Merck, Mochida, Vertex

Jerry O. Stern - Employment: Boehringer Ingelheim

Anne-Marie Quinson - Employment: Boehringer Ingelheim

Florian Voss - Employment: Boehringer Ingelheim Pharma GmbH & Co. KG

Joe Scherer - Employment: Boehringer-Ingelheim

Yakov Datsenko - Employment: Boehringer Ingelheim Pharma GmbH & Co. KG

Donald M. Jensen - Advisory Committees or Review Panels: Abbvie, Boehringer, BMS, Genentech/Roche, Merck, Gilead, Janssen; Grant/Research Support: Abbvie, Boehringer, BMS, Genentech, Janssen, Gilead

The following people have nothing to disclose: Marina V. Maevskaya, Jia-Horng Kao, Edward Tam, Victor S. Feinman, Youn-Jae Lee, Eiichi Tomita, Seung Woon Paik, Hiroshi Yatsuhashi

1115

  1. Top of page

Virologic Response Rates to Sofosbuvir-Containing Regimens Are Similar in Patients With and Without Traditional Negative Predictive Factors: A Retrospective Analysis of Phase 3 Data

Alessandra Mangia1, Marcelo Kugelmas2, Gregory T. Everson3, Federico Hinestrosa4, Julie Ma5, John McNally5, Diana M. Brainard5, William T. Symonds5, John G. McHutchison5, Edward J. Gane6, Stephen D. Shafran7, Raymond T. Chung8, Eric Lawitz9; 1IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy; 2South Denver Gastroenterology, Englewood, CA; 3University of Colorado, Aurora, CO; 4Orlando Immunology Center, Orlando, FL; 5Gilead Sciences, Foster City, CA; 6Auckland City Hospital, Aukland, New Zealand; 7University of Alberta Hospital, Edmonton, AB, Canada; 8Massachusetts General Hospital, Boston, MA; 9Texas Liver Institute, San Antonio, TX

Background and Aims: The entry criteria of the Phase 3 studies of sofosbuvir (SOF) + ribavirin (RBV) with or without peginterferon were designed with minimal exclusions to safely enroll patients representative of the real-world HCV population. Many of these patients, therefore, had baseline characteristics associated with a poor response to interferon-based therapy. We compared SVR rates in Phase 3 trials among patients with and without these negative predictive factors. Methods: This was a retrospective analysis of data from 982 patients with HCV genotypes 1-6 treated with SOF combination therapy in 4 Phase 3 clinical trials (FISSION, POSITRON, FUSION, and NEUTRINO). Results: Overall, 21% of the patients had cirrhosis, 5% were ≥65 years, 33% obese (BMI ≥30), 14% had IL28B TT genotype, 8% had diabetes (HbA1c ≥6.5), 7% were black (with the highest percentage (17%) in the NEUTRINO study in genotype 1 patients), 16% had very high viral load at baseline (≥107 IU/mL), and 6% were on opiate replacement therapy. Table 1 provides SVR1 2 rates for these groups as compared to patients without these characteristics. Outcomes in patients with multiple negative predictive factors (e.g., blacks with advanced fibrosis) will be presented. Conclusion: In this large cohort of patients participating in SOF-containing Phase 3 studies with or without peginterferon and across genotypes 1-6, traditional negative predictive factors did not have a consistent influence on response rates with the exception of cirrhosis and sex. Inclusion of patients typically excluded from clinical trials provides important “real world” data for physicians and patients.

Table 22. SVR According to Baseline Factors
 FUSSIONPOSITRONFUSONNEUTRINO
 SOF+RBV × 12 wksSOF+RBV × 12 wksSOF+RBV × 12 wksSOF+RBV × 16 wksSOF+PEG+RBV × 12 wks
Cirrhosis47 (23/49)61 (19/31)31 (11/36)66(21/32)80 (43/54)
No cirrhosis72 (147/204)81 (142/176)61 (39/64)76 (48/63)92 (252/273)
Male61 (103/168)73(85/117)42(30/71)66 (42/64)88(184/209)
Female79 (67/85)84 (76/90)69 (20/29)87 (27/31)94(111/118)
Age ≥65100(7/7)73(11/15)50 (2/4)100(5/5)75(15/20)
Age <6566(163/246)78 (150/192)55(39/71)71 (64/90)91 (280/307)
IL28B TT56(14/25)65(17/26)79(15/19)58(7/12)86(44/51)
IL28B non-TT69(156/226)80(144/181)43(35/81)75 (62/83)91 (251/276)
BMI ≥3065 (50/77)82(58/71)38(11/29)77 (26/34)86(111/129)
BMI <3068(120/176)76(103/136)52 (46/88)71 (43/61)93(184/198)
HbAlc≥6.542(5/12)92(11/12)46(5/11)87(13/15)94 (32/34)
HbAIc<6.569(165/240)77 (150/195)51 (45/89)70 (56/80)90 (262/292)
Black75(9/12)89 (8/9)100(5/5)100(1/1)87 (47/54)
Non-black67(161/241)77(153/198)47 (45/95)72 (68/94)91 (248/273)
HCV UNA ≥10761 (11/18)93 (26/28)56(15/27)76 (22/29)90 (62/69)

HCV

RNA<107
68 (159/235)75(135/179)48 (35/73)71 (47/66)90 (233/258)
Opiate replacement50(12/24)88(15/17)0 (0/3)50(1/2)92(11/12)
No opiate replacement69(158/229)77(146/190)52 (50/97)73 (68/93)90(284/315)
Disclosures

Alessandra Mangia - Advisory Committees or Review Panels: ROCHE, Janssen, MSD, ROCHE, Janssen, MSD, Boheringer ; Consulting: Gilead; Grant/Research Support: Shering-Plough, Shering-Plough

Marcelo Kugelmas - Advisory Committees or Review Panels: Merck, Vertex, Genentech; Consulting: Vertex, Merck, Gilead; Grant/Research Support: Vertex, Bristol Myers Squibb, Boehringer-Ingelheim, Gilead, Janssen, Roche, Anadys, Merck; Speaking and Teaching: Vertex, Gilead, Merck, Genentech

Gregory T. Everson - Advisory Committees or Review Panels: Roche/Genentech, Merck, HepC Connection, Roche/Genentech, Merck, HepC Connection; Board Membership: HepQuant LLC, PSC Partners, HepQuant LLC, PSC Partners; Consulting: Roche/Genentech, BMS, Gilead, Roche/Genentech, Bristol-Myers Squibb, Abbott; Grant/Research Support: Roche/Genentech, Pharmassett, Vertex, GSK, Schering-Plough, Bristol-Myers Squibb, Tibotec, GlobeImmune, Pfizer, Abbott, Conatus, Zymogenetics, PSC Partners, Roche/Genentech, Pharmassett, Vertex, GSK, Schering-Plough, Tibotec, GlobeImmune, Pfizer, Gilead, Conatus, Zymogenetics, PSC Partners, Abbott; Management Position: HepQuant LLC, HepQuant LLC; Patent Held/Filed: Univ of Colorado, Univ of Colorado

Federico Hinestrosa - Advisory Committees or Review Panels: Gilead, Vertex; Grant/Research Support: Gilead, Vertex, BMS, BI, Achillion, Janssen, Idenix; Speaking and Teaching: Gilead, Vertex

Julie Ma - Employment: Gilead Sciences

John McNally- Employment: Gilead Sciences

Diana M. Brainard - Employment: Gilead Sciences, Inc.

William T. Symonds - Employment: Gilead

John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead Sciences

Edward J. Gane -Advisory Committees or Review Panels: Roche, AbbVie, Novartis, Tibotec, Gilead Sciences, Janssen Cilag, Vertex, Achillion; Speaking and Teaching: Novartis, Gilead Sciences, Roche

Stephen D. Shafran - Advisory Committees or Review Panels: Merck, Roche, Bristol Myers Squibb, Vertex, Pfizer, Gilead, Boehringer Ingelheim, Janssen; Consulting: AbbVie; Grant/Research Support: Merck, Roche, Bristol Myers Squibb, Boehringer Ingelheim, Pfizer, Vertex, Gilead, AbbVie

Raymond T. Chung - Advisory Committees or Review Panels: Idenix; Consulting: Enanta; Grant/Research Support: Gilead, Merck, Mass Biologic, Gilead

Eric Lawitz - Advisory Committees or Review Panels: AbbVie, Achillion Pharmaceuticals, BioCryst, Biotica, Enanta, Idenix Pharmaceuticals, Janssen, Merck & Co, Novartis, Santaris Pharmaceuticals, Theravance, Vertex Pharmaceuticals; Grant/Research Support: AbbVie, Achillion Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Merck & Co, Novartis, Presidio, Roche, Santaris Pharmaceuticals, Vertex Pharmaceuticals ; Speaking and Teaching: Gilead, Kadmon, Merck, Vertex

1116

  1. Top of page

Adding simeprevir to peginterferon/ribavirin for HCV shortens time with patient-reported symptoms and impairment in quality of life: Results from the simeprevir Phase III QUEST 1, QUEST 2 and PROMISE studies

Jane A. Scott1, Leen Gilles2, Min Fu3, Monika Peeters2, Elaine Brohan4, Ramesh Amatya4, Wolfgang Jessner2, Maria Beumont-Mau-viel2; 1Janssen Global Services LLC, High Wycombe, United Kingdom; 2Janssen Research and Development, Beerse, Belgium; 3Janssen Research and Development, Titusville, NJ; 4Adelphi Values Ltd, Manchester, United Kingdom

Background: Patients with HCV infection often experience fatigue and depressive symptoms that can worsen during treatment and impair functioning and quality of life (QOL). Three double-blind, placebo-controlled, Phase III studies (QUEST-1, QUEST-2, and PROMISE) evaluated simeprevir (SMV) 150 mg, a once-daily investigational NS3/4A protease inhibitor, plus peginterferon/ribavirin (PR) in HCV genotype 1 patients. Data from the 60-wk primary analysis of these studies were pooled to examine the impact of adding SMV to PR on symptoms, functioning, and QOL from the patient's perspective. Methods: Treatment-naïve (QUEST-1, n=394; QUEST-2, n=391) and prior relapser (PROMISE, n=393) patients received either SMV for 12 wks plus PR for 24 or 48 wks (response-guided therapy, RGT), or placebo (PBO) for 12 wks plus PR for 48 wks. Patient-reported outcomes (PRO) for fatigue (Fatigue Severity Scale total scores, FSS), depressive symptoms (Center for Epidemiologic Studies Depression total score, CES-D), work productivity and daily activity impairment (hepatitis C-specific version of Work Productivity and Activity Impairment score, WPAI) and QOL (EuroQoL 5 Dimension Valuation Index, EQ-5D) were completed by patients in their native language at baseline and throughout the studies. Results: Of 1178 patients, 1161 (SMV/PR, n=768; PBO/PR, n=393) were included in this analysis. Mean scores for all PROs worsened by comparable amounts in both treatment groups from baseline to Wks 4 through 24. Mean scores returned to levels at, or improved beyond, baseline on or after Wk 24 in SMV/PR patients but not until after Wk 48 in PBO/PR patients resulting in an area under the curve from baseline to Wk 60 that significantly favored SMV/PR vs PBO/PR (p≤0.001; for all PROs except WPAI absenteeism); this was reflected in a similar incidence of fatigue adverse events (AEs) between groups. Mean FSS (p≤0.001) and Productivity Impairment (p<0.007) scores were significantly improved compared to baseline at Wk 60 in the SMV/PR group but not in the PBO/PR group. Compared to PBO/PR, the SMV/PR group had significantly shorter duration of worsened FSS (6.9 wks less), CES-D (6.8 wks less), WPAI Productivity (7.4 wks less) and WPAI Daily Activities scores (6.1 wks less; all p<0.001). In both groups, anemia AEs were closely related to FSS scores. Conclusions: Adding SMV to PR results in significantly less time with fatigue and depressive symptoms, and with impairment in daily activities, work productivity, and QOL. PRO symptom scores confirm equivalent severity but reduced time with AEs for SMV/PR vs PBO/PR.

Disclosures

Jane A. Scott - Employment: Janssen; Stock Shareholder: J&J

Leen Gilles - Employment: Johnson&Johnson; Stock Shareholder: johnson&John-son

Min Fu - Employment: Jassen R&D US; Stock Shareholder: Jassen R&D US

Monika Peeters - Employment: Janssen

Elaine Brohan - Employment: Adelphi Values Ltd

Wolfgang Jessner - Employment: Janssen Infectious Diseases Diagnostics

Maria Beumont-Mauviel - Employment: Janssen

The following people have nothing to disclose: Ramesh Amatya

1117

  1. Top of page

A Bayesian Bridging Model Using Phase 3 Data in Treatment-Experienced HCV Genotype 3 Patients Demonstrates Extending Sofosbuvir+Ribavirin Treatment from 12 to 16 Weeks in Treatment-Naïve Genotype 3 Patients May Significantly Increase SVR Rates

B. Nebiyou Bekele1, David R. Nelson2, Stuart C. Gordon3, Jordan J. Feld4, Keyur Patel5, Eric Lawitz6, Aasim M. Sheikh7, Diana M. Brainard1, William T. Symonds1, John G. McHutchison1, Alessandra Mangia8, Edward J. Gane9; 1Gilead Sciences, Inc., Foster City, CA; 2University of Florida, Gainesville, FL; 3Henry Ford Health Systems, Detroit, MI; 4University of Toronto, Toronto, ON, Canada; 5Duke University, Durham, NC; 6Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX; 7GI Specialists of GA, Marietta, GA; 8“Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Italy; 9Aukland City Hospital, Aukland, New Zealand

Background and Aims: Sofosbuvir (SOF) + ribavirin (RBV) is the first all-oral regimen for patients with HCV genotype (GT) 2 or 3. In phase 3 trials of SOF+RBV, SVR 12 rates were higher in patients with HCV GT 2 than HCV GT 3. In the FUSION trial, in which previously treated patients received 12 or 1 6 weeks of SOF+RBV, 62% of patients with GT 3 HCV receiving 16 weeks of treatment achieved SVR12, as compared with 30% of those receiving 12 weeks of treatment. In the FISSION trial, in which treatment-naïve patients received 12 weeks of SOF+RBV, 56% of GT 3 patients achieved SVR 12 (34% with cirrhosis and 61% without cirrhosis). FISSION did not include a 16-week arm. Using a Bayesian bridging analysis, we attempted to determine if treatment-naïve subjects with GT 3 HCV might benefit from extending treatment duration to 16 weeks. Methods: We used a Bayesian logistic regression model to bridge knowledge between the FISSION and FUSION trials. The key assumption in this analysis is that the observed benefit of 16 weeks of SOF+RBV over 12 weeks of SOF+RBV in treatment-experienced patients would be similar in treatment-naïve patients. We also performed a sensitivity analysis to explore how much of the treatment duration response must be retained and still result in better and/or comparable response to PEG+RBV in patients with GT 3 HCV. Results: Our analysis predicts that treatment-naïve GT 3 patients receiving 16 weeks of SOF+RBV would achieve an SVR12 rate of 78.2% (95% credible set: 62.5%, 89.6%), which is 22.5 percentage points higher than the rate observed with 12 weeks of treatment. Our analysis also predicted that cirrhotic and non-cirrhotic GT 3 patients receiving 16 weeks of SOF+RBV would have SVR rates of 76.3% (95% credible set: 55.1%, 91.0%) and 78.7% (95% credible set: 61.9%, 90.6%), respectively. These rates are 42.1 and 17.3 percentage points higher, respectively, than rates for cirrhotic and non-cirrhotic patients receiving 12 weeks of treatment. Results of the sensitivity analysis are given in the table. Conclusions: This bridging analysis suggests that extending treatment duration to 16 weeks in treatment-naïve patients with GT 3 HCV may increase the SVR rate. The results of this modeling analysis are being tested in a randomized clinical trial.

Table 23. Sensitivity analysis GT 3 patients, including patients with and without cirrhosis
% Retained BenefitPredicted SVR12 Rate
0% retained55.7%
25% retained61.9%
50% retained68.0%
75% retained73.5%
100% retained78.2%
Disclosures

B. Nebiyou Bekele - Employment: Gilead Sciences

David R. Nelson -Advisory Committees or Review Panels: Merck; Grant/Research Support: Abbot, BMS, Beohringer Ingelheim, Gilead, Genentech, Merck, Bayer, Idenix, Vertex, Jansen

Stuart C. Gordon - Advisory Committees or Review Panels: Tibotec; Consulting: Merck, CVS Caremark, Gilead Sciences, BMS; Grant/Research Support: Roche/Genentech, Merck, Vertex Pharmaceuticals, Gilead Sciences, BMS, Abbott, Intercept Pharmaceuticals, Exalenz Sciences, Inc.

Jordan J. Feld - Advisory Committees or Review Panels: Roche, Merck, Vertex, Gilead, Abbott, Tibotec, Theravance, Achillion; Speaking and Teaching: Merck, Roche, Abbott

Keyur Patel - Consulting: Benitec, Santaris; Speaking and Teaching: Gilead Sciences, Vertex

Eric Lawitz - Advisory Committees or Review Panels: AbbVie, Achillion Pharmaceuticals, BioCryst, Biotica, Enanta, Idenix Pharmaceuticals, Janssen, Merck & Co, Novartis, Santaris Pharmaceuticals, Theravance, Vertex Pharmaceuticals; Grant/Research Support: AbbVie, Achillion Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Merck & Co, Novartis, Presidio, Roche, Santaris Pharmaceuticals, Vertex Pharmaceuticals ; Speaking and Teaching: Gilead, Kadmon, Merck, Vertex

Aasim M. Sheikh - Grant/Research Support: Genentech, Roche Pharmaceuticals, Vertex Pharmaceuticals, Pfizer, Idenix Pharmaceuticals, Gilead, Bristol Meyers Squibb, Tibotec, Cubist Pharmaceuticals; Speaking and Teaching: Genentech, Vertex Pharmaceuticals

Diana M. Brainard - Employment: Gilead Sciences, Inc. William T. Symonds - Employment: Gilead

John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead Sciences

Alessandra Mangia - Advisory Committees or Review Panels: ROCHE, Janssen, MSD, ROCHE, Janssen, MSD, Boheringer; Consulting: Gilead; Grant/Research Support: Shering-Plough, Shering-Plough

Edward J. Gane - Advisory Committees or Review Panels: Roche, AbbVie, Novartis, Tibotec, Gilead Sciences, Janssen Cilag, Vertex, Achillion; Speaking and Teaching: Novartis, Gilead Sciences, Roche

1118

  1. Top of page

Safety of Ribavirin-containing Regimens of ABT-450/r, ABT-333, and ABT-267 for the Treatment of HCV Genotype 1 Infection and Efficacy in Subjects with Ribavirin Dose Reductions

Daniel E. Cohen, Wangang Xie, Lois Larsen, Christal Marincic, Mary Knauss-Townsend, Amit Khatri, Thomas Podsadecki, Barry Bernstein; AbbVie Inc., North Chicago, IL

Background: Sustained virologic response (SVR12) rates of 93-99% have been reported for HCV genotype 1 (GT1 )-infected subjects treated with a peginterferon (pegIFN)-free, 3 direct-acting antiviral (DAA) regimen of ABT-450/r (HCV protease inhibitor dosed with ritonavir 1 00 mg, identified as a lead compound by AbbVie and Enanta), ABT-267 (NS5A inhibitor), and ABT-333 (non-nucleoside NS5B inhibitor) plus ribavirin (RBV). When used with pegIFN, RBV has been associated with adverse events (AEs) including anemia, necessitating frequent RBV dose reductions. Rate of RBV dose reduction was approximately 30% in HCV GT1-infected subjects treated with pegIFN/RBV in the IDEAL study. We examined the safety of a RBV-containing, 3-DAA, pegIFN-free regimen and the impact of RBV dose reduction on treatment response. Methods: 571 non cirrhotic treatment-naïve and previous pegIFN/RBV null responding patients with chronic HCV GT1 infection were enrolled in Study M1 1-652. We analyzed the subset receiving ABT-450/r (100/100-150/100 mg QD), ABT-267 (25 mg QD), and ABT-333 (400 mg BID) plus weight-based RBV for 12 or 24 weeks. SVR 12 rates (percent of patients with HCV RNA <25 IU/mL at post-treatment week 12) were analyzed (ITT). Results: 247 patients (159 treatment-naïve and 88 previous null responders) received a 12- or 24-week regimen of 3 DAAs + RBV. Four patients (1.6%) discontinued due to study drug-related AEs, and 1 patient (0.4%) had a serious AE (arthralgia) considered possibly related to study drug. Hemoglobin values <10 g/dL and <8.5 g/dL occurred in 1 6 (6.5%) and 1 (0.4%) subjects during treatment, respectively. RBV dose was reduced in 27 subjects (1 0.9%) due to toxicity. Sixteen of the 27 reductions were due to anemia AEs. Other AEs, including diarrhea, fatigue, increased blood creatinine, and dizziness, led to RBV dose reductions less frequently. The table shows SVR12 rates. Conclusions: RBV dose reductions were required less frequently with this pegIFN-free regimen than in previously reported studies of subjects receiving pegIFN-containing regimens. High SVR12 rates (100%) were achieved among subjects requiring RBV dose reduction.

ITT SVR12 Rates by RBV Dose Reduction Status

Table 24. 
 Treatment-naive SubjectsPrevious Null Responders
RBV dose reduced21/21 (100)6/6(100)
RBV dose nol reduced129/138(93.5)76/82 (92.7)
Disclosures

Daniel E. Cohen - Employment: AbbVie; Stock Shareholder: AbbVie

Wangang Xie - Employment: AbbVie

Lois Larsen - Employment: AbbVie; Stock Shareholder: Abbott

Christal Marincic - Employment: AbbVie

Mary Knauss-Townsend - Employment: Abbvie

Amit Khatri - Employment: AbbVie, Inc; Stock Shareholder: AbbVie, Inc

Barry Bernstein - Employment: AbbVie; Stock Shareholder: AbbVie

The following people have nothing to disclose: Thomas Podsadecki

1119

  1. Top of page

Inosine triphosphatase deficiency does not predict anemia severity nor anemia management in patients with advanced fibrosis receiving Telaprevir

Alessio Aghemo1, Eleonora Grassi1, Mariagrazia Rumi2, Roberta D'Ambrosio1, Riccardo Perbellini1, Elisabetta Degasperi2, Roberta Soffredini1, Massimo Colombo1; 1A.M. and A. Migliavacca Center for Liver Disease, First Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy; 2Hepatology Unit, Ospedale San Giuseppe, IRCCS Multimedica, Università degli Studi di Milano, Milan, Italy

Background: Anemia during the first 12 week of therapy is the most common side effect of Pegylated Interferon (PegIFN)/ Ribavirin (RBV) and Telaprevir (TVR) in HCV genotype 1 patients with advanced fibrosis or cirrhosis (F3-F4). Inosine triphosphatase (ITPA) genetic variants are associated with RBV-induced anemia and dose reduction but their role as predictors of anemia in TVR based therapies is unknown. Aim: To test the association of ITPA polymorphisms rs1 127354 and rs7270101 with hemoglobin (Hb) decline, need for RBV dose reduction (RBV DR), erythropoietin (EPO) support and blood transfusions during the first 12 weeks of triple therapy. Materials and Methods: 62 consecutive HCV-1 patients with F3-F4 who were treated with standard regimens of PegIFNalfa/RBV and TVR 750mg/Q8h were genotyped for ITPA polymorphisms rs1 127354 and rs7270101 using TaqMan probes. Estimated ITPA deficiency was graded on severity (0-3, no deficiency/mild/moderate/severe) Results: Patients mean age was 57 years, 51 (82%) had HCV-1 b, 5 (8%) were treatment naive and 47 (65%) had cirrhosis. No ITPA deficiency was found in 42 patients (68%), mild deficiency was found in 12 (19%) and moderate in 8 patients (13%). Mean week 4 Hb decline was more pronounced in non ITPA deficient patients (3.99 g/dL) than in mild ITPA deficient patients (3.08 g/dL) and moderate ITPA deficient patients (1.73 g/dL) (p=0.01 and p<0.001, respectively). Hb decline at week 8 and 12 was similar between ITPA deficient groups. Grade of ITPA deficiency was not associated with RBV DR (no deficiency: 62%, mild deficiency: 58%, moderate deficiency: 62%; p=ns), EPO use (no deficiency: 57%, mild deficiency: 58%, moderate deficiency: 62%; p=ns) or need for blood transfusion (no deficiency: 21%, mild deficiency: 16%, moderate deficiency: 37%; p=ns). Grade 3-4 anemia developed in 69% of non ITPA deficient patients versus 42% of mild deficient patients and 50% of moderate deficient patients (p=ns). Conclusions. In patients with F3-F4 chronic hepatitis C receiving TVR based therapy, ITPA genotype does not impact on the management of early anemia

Disclosures

Alessio Aghemo - Board Membership: Janssen; Grant/Research Support: Gilead, Roche; Speaking and Teaching: Merck, Janssen, Roche

Mariagrazia Rumi - Speaking and Teaching: Roche, Roche, Roche, Roche

Massimo Colombo - Advisory Committees or Review Panels: BRISTOL-MEYERSSQUIBB, SCHERING-PLOUGH, ROCHE, GILEAD, BRISTOL-MEYERS-SQUIBB, SCHERING-PLOUGH, ROCHE, GILEAD, Janssen Cilag, Achillion; Grant/Research Support: BRISTOL-MEYERS-SQUIBB, ROCHE, GILEAD, BRISTOL-MEYERS-SQUIBB, ROCHE, GILEAD; Speaking and Teaching: Glaxo Smith-Kline, BRISTOL-MEYERS-SQUIBB, SCHERING-PLOUGH, ROCHE, NOVARTIS, GILEAD, VERTEX, Glaxo Smith-Kline, BRISTOL-MEYERS-SQUIBB, SCHERING-PLOUGH, ROCHE, NOVARTIS, GILEAD, VERTEX

The following people have nothing to disclose: Eleonora Grassi, Roberta D'Ambrosio, Riccardo Perbellini, Elisabetta Degasperi, Roberta Soffredini

1120

  1. Top of page

Alisporivir (ALV) plus peginterferon/ribavirin (P/R) achieves high response rates in patients with negative prognostic factors

Louis H. Griffel1, Clifford Brass1, Min Wu1, Qingyan Bo3, Roberto Orsenigo2, Nikolai V. Naoumov2; 1IHC, Novartis Pharmaceuticals Corporation, East Hanover, NJ; 2IHC, Novartis Pharma AG, Basel, Switzerland; 3Shanghai Novartis Trading Ltd., Shanghai, China

Background: ALV inhibits cyclophilin A, an essential host protein for HCV replication. We investigated the efficacy of ALV+P/R vs ALV placebo+P/R in two ongoing studies in HCV G1 previous P/R failure (Study 2210; all patients have reached SVR12) and treatment naïve cirrhotic (Study 2301; 35% have reached SVR12) patients. Methods: 461 previous P/R failure subjects and 214 cirrhotic treatment naïve subjects were randomized, with 347 and 158 respectively assigned to ALV treatment. Due to a partial clinical hold ALV was limited to at least 3 1 weeks of treatment in Study 221 0 whereas the majority in Study 2301 received > 12 weeks of ALV/P/R treatment, completing 24 or 48 weeks with P/R alone. Results: No cirrhotic patients achieved SVR12 with P/R re-treatment in the control arm, while up to 44% achieved SVR12 with ALV based therapy. In prior treatment failures, all groups responded well to ALV based therapy with best results with the 400 mg BID group. At this dose, IL-28 CT/TT and prior null-responders responded well with ALV therapy compared to control, with SVR12 comparable to IL28CC and prior partial non-responders. In treatment naïve subjects, high rates of RVR (up to 62% compared with 1 8% for control) and cEVR (up to 89% compared to 54% for control) were achieved in cirrhotic patients. SVR4 for these patients will be available at time of presentation. Conclusion: In patients with the historically worst prognostic factors (cirrhosis, IL28 CT/TT, prior null-response), all ALV doses (+P/R) achieved high rates of SVR12 compared to P/R retreatment alone. High rates of on-treatment response are seen in treatment naïve cirrhotic patients as well. Although the ALV regimens included P/R, the poor response in the P/R control infers potency of ALV in these difficult to treat patients. Moving forward ALV will be developed in combination with DAAs for G1 patients as an IFN free treatment.

Study 2210 Sustained Virologic Response 12

Table 25. 
 CirrhoticsNon-CirrhoticsIL28 CT/TTIL28 CCNull-respondersPartial Non-Responders
ALV 600QD/P/R8/26 (31%)36/80 (45%)31/88 (35%)13/21 (62%)11/48(23%)6/14(43%)
ALV 800QD/P/R13/34 (38%)40/70 (57%)35/87 (40%)18/21 (86%)14/36(39%)10/22(46%)
ALV400BID/P/R

10/23

(44%)
54/82 (66%)54/89 (61%)11/20 (55%)22/34 (65%)17/27(63%)
P/R Control0/29 (0%)16/79 (20%)10/87 (12%)6/23 (26%)1/36(3%)1/20(5%)
Disclosures

Louis H. Griffel - Employment: Novartis; Stock Shareholder: Novartis

Clifford Brass - Employment: Merck, Novartis; Patent Held/Filed: Merck, Novartis; Stock Shareholder: Merck, Novartis

Qingyan Bo - Employment: Novartis

Roberto Orsenigo - Employment: Novartis Pharma AG

Nikolai V. Naoumov- Employment: Novartis Pharma AG, Novartis Pharma AG

The following people have nothing to disclose: Min Wu

1121

  1. Top of page

The relative efficacy and safety of simeprevir-based triple therapy compared to boceprevir and telaprevir in treatment naïve patients chronically infected with genotype-1 hepatitis C virus: Bayesian network meta-analy-ses

Peter A. Bryden1, Joan M. Quigley1, Amie Padhiar1, Karin Cerri2, David A. Scott1; 1Oxford Outcomes, Oxford, United Kingdom; 2Janssen Pharmaceutica NV, Beerse, Belgium

Objective: In randomized controlled trials (RCTs), simeprevir (SMV), boceprevir (BOC) and telaprevir (TVR) based triple therapies have shown significant efficacy improvements in treatment-naive chronic hepatitis C (CHC) genotype-1 infected patients, compared to peginterferon alpha 2a/b and ribavirin (pegIFN/RBV) therapy alone. In the absence of head-to-head studies comparing SMV to BOC or TVR, the relative efficacy and safety of these regimens was indirectly compared. Methods: A systematic review was conducted to identify Phase II/III RCTs of SMV, BOC and TVR in a treatment naïve population with genotype-1 CHC. Additionally, results from unpublished SMV studies meeting the inclusion criteria were obtained. PegIFN 2a/RBV and pegIFN 2b/RBV were considered comparable and pooled. A series of Bayesian network meta-analyses assuming fixed study effects were used to compare treatments in terms of sustained viral response (SVR), discontinuation of all medications due to adverse events (AEs), and incidence of anaemia and rash (all grades). Results: 9 studies were compared. Results are presented for SMV 150mg administered for 12 weeks in combination with pegIFN/RBV response guided therapy (RGT) (24 or 48 weeks) (SMV12PR24/48) versus pegIFN/RBV administered for 48 weeks, TVR administered for 12 weeks in combination with pegIFN/RBV RGT (24 or 48 weeks) (TVR12PR24/48) and BOC administered for 24 weeks in combination with pegIFN/RBV RGT (28 or 48 weeks) (BOC24PR28/48). SMV12PR24/48 showed similar SVR results to BOC and TVR regimens, and statistically significantly lower incidence of anaemia (all grades) compared to both TVR and BOC regimens and for discontinuation due to AEs compared to TVR. Conclusions: Simeprevir, in combination with pegIFN/RBV, when compared to boceprevir and telaprevir triple based therapy, showed a similar chance of achieving an SVR with a lower probability of both the incidence of CHC-relevant AEs, and discontinuation due to AEs.

Network Meta-analysis Results (odds ratios (ORs) with 95% credible intervals)

Table 26. 
ComparisonSVRDiscontinuation due to AEsAnaemiaRash
SMV12PR24/48vsPR483.76 (2.80 to 5.09)0.38 (0.20 to 0.71)0.79 (0.57 to 1.11)1.15 (0.82 to 1.62)
TVR12PR24/48 vs PR483.80 (2.79 to 5.23)1.43 (0.84 to 2.45)2.47 (1.76 to 3.46)1.80 (1.30 to 2.49)
BOC24PR28/48 vs PR482.98 (2.23 to 4.01)0.75 (0.49 to 1.13)2.38(1.77 to 3.20)1.14(0.81 to 1.61)
SMV12PR24/48vs TVR12PR24/480.99 (0.64 to 1.52)0.27 (0.12 to 0.60)0.32 (0.20 to 0.52)0.64 (0.40 to 1.02)
SMV12PR24/48 vs BOC24PR28/481.26 (0.83 to 1.92)0.51 (0.24 to 1.07)0.33 (0.21 to 0.52)1.01 (0.62 to 1.65)
Disclosures

Karin Cerri - Employment: Janssen Pharmaceutica, NV

David A. Scott - Consulting: Johnson & Johnson

The following people have nothing to disclose: Peter A. Bryden, Joan M. Quigley, Amie Padhiar

1122

  1. Top of page

Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in treatment-naïve patients: efficacy in difficult-to-treat patient sub-populations in the QUEST 1 and 2 phase III trials

Ira M. Jacobson1, Gregory J. Dore2, Graham R. Foster3, Michael W. Fried4, Michael P. Manns5, Patrick Marcellin6, Fred Poordad7, Evaldo S. Araujo8, Monika Peeters9, Oliver Lenz9, Sivi Ouwerkerk-Mahadevan10, Guy De La Rosa11, Ronald Kalmeijer11, Rekha Sinha9, Maria Beumont-Mauviel9; 1Weill Cornell Medical College, New York, NY; 2The Kirby Institute, University Of New South Wales, Darlinghurst, NSW, Australia; 3Queen Mary's, University of London, London, United Kingdom; 4University of North Carolina at Chapel Hill, Chapel Hill, NC; 5Medizinische Hochschule Hannover, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany; 6Hôpital Beaujon, Service d'Hépatologie, Clichy, France; 7Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX; 8Hospital das Clin-icas of the University of São Paulo School of Medicine, Faculty of Medicine, University of São Paulo, Avenida Dr. Eneas de Carvalho Aguiar, Cerqueira Cesar, Sao Paulo, Brazil; 9Janssen Infectious Diseases BVBA, Beerse, Belgium; 10Jansssen Research & Development, Beerse, Belgium; 11Janssen Global Services, LLC, Titusville, NJ

Background: QUEST-1 and QUEST-2 were Phase III, randomized, double-blind studies evaluating simeprevir (SMV), an investigational, once-daily (QD), oral HCV NS3/4 protease inhibitor, with PegIFN α-2a (QUEST-1) or PegIFN α-2a/2b (QUEST-2) plus RBV (PR) in treatment-naïve HCV genotype-1 (GT 1) adult patients. This pooled analysis focuses on the comparison of the efficacy of SMV/PR versus PR in patient subgroups (IL28B genotype, METAVIR score, HCV GT subtype, and baseline HCV non-structural protein 3 [NS3] Q80K polymorphism). Methods: Patients (QUEST-1, n=394; QUEST-2, n=391) were randomized 2:1 to SMV 150mg QD (12 wks) plus PR (24/48 wks) or to placebo (PBO, 12 wks) plus PR (48 wks). The primary efficacy endpoint was SVR12. Results: The pooled analysis included 785 patients: IL28B TT, 14.6%; METAVIR F4, 1 0.4%; GT 1a, 48.4%; Q80K+, 16.8% (all but 2 patients with Q80K had GT 1a). Overall, SVR 12 rate was significantly superior with SMV/PR versus PBO/PR (80.4% vs 50.0%; p<0.001). Among patients who achieved rapid virologic response (RVR; defined as HCV RNA < 25 IU/mL undetectable at Week 4) in the SMV/PR arm (77.5% overall), 89.6% went on to achieve SVR12. SVR12 rates of 94.7%, 92.3%, 85.4% and 83.9% were achieved in patients receiving SMV/PR who had CC IL28B genotype, baseline HCV RNA ≤ 800,000 IU/ml, GT 1 b and METAVIR F0-F2, respectively. SVR12 rates were also significantly higher in the SMV/PR vs PBO/PR arm for each of the difficult-to-treat subgroups analysed, including patients with cirrhosis (F4) (table). As in the overall population, high RVR rates were observed in patients with TT, F4 and Q80K (68.8, 66.7 and 63.1%, respectively), with high SVR rates among them (77.4, 75.0 and 79.2%, respectively; table). Conclusions: Simeprevir conferred clinical benefit across all patient sub-populations, including not only those with positive predictors of response (IL28B CC, METAVIR F0-F2, GT 1b and GT 1a/Q80K-), but also patients with unfavourable baseline characteristics, such as IL28B TT, METAVIR F4 and GT 1a/Q80K+. Week 4 HCV RNA determination allows identification of those patients who are most likely to benefit from SMV therapy.

Table 27. 
 SVR 12, n/N (%)RVR, n/N (%)SVR 12, n/N (%) in those who achieved RVR
 SMV/PRPBO/PRSMV/PRSMV/PR
All patients419/521 (80.4)132/264 (50.0)404/521 (77.5)362/404 (89.6)
META VIR F429/48 (60.4)*11/32(34.4)32/48 (66.7)24/32 (75.0)
IL28B TT47/77(61.0)*8/38(21.1)53/77 (68.8)41/53(77.4)

HCV GT la

overall
191/254 (75.2)*

62/131

(47.3)
184/254 (72.4)160/184(87.0)
With Q80K49/84 (58.3)*62/131 (47.3)†53/84(63.1)42/53 (79.2)

*p<0.05 for all comparisons SMV vs PBO; †Pooled placebo, includes all GT 1a patients

Disclosures

Ira M. Jacobson - Grant/Research Support: Schering/Merck, Tibotec, Roche/Genentech, Pharmasset, Anadys, Boehringer Ingelheim, Novartis, Gilead, Vertex, GlobeImmune, Human Genome Sciences, Bristol Myers Squibb, Pfizer, Zymogenetics, Abbott, Sanofi-Aventis

Gregory J. Dore - Board Membership: Bristol-Myers Squibb, Roche, Gilead, Merck, Janssen, Abbvie; Grant/Research Support: Janssen, Bristol-Myers Squibb, Vertex, Roche, Gilead, Merck, Abbvie; Speaking and Teaching: Roche, Merck, Janssen

Graham R. Foster - Advisory Committees or Review Panels: GlaxoSmithKline, Novartis, Boehringer Ingelheim, Tibotec, Chughai, Gilead, Janssen, Idenix, GlaxoSmithKline, Novartis, Roche, Tibotec, Chughai, Gilead, Merck, Janssen, Idenix, BMS; Board Membership: Boehringer Ingelheim; Grant/Research Support: Chughai, Roche, Chughai; Speaking and Teaching: Roche, Gilead, Tibotec, Merck, BMS, Boehringer Ingelheim, Gilead, Janssen

Michael W. Fried - Consulting: Genentech, Merck, Abbvie, Vertex, Janssen, Bristol Myers Squibb, Gilead; Grant/Research Support: Genentech, Merck, AbbVie, Vertex, Janssen, Bristol Myers Squibb, Gilead; Patent Held/Filed: HCCPlex

Michael P. Manns - Consulting: Roche, BMS, Gilead, Boehringer Ingelheim, Novartis, Idenix, Achillion, GSK, Merck/MSD, Janssen, Medgenics; Grant/Research Support: Merck/MSD, Roche, Gilead, Novartis, Boehringer Ingelheim, BMS; Speaking and Teaching: Merck/MSD, Roche, BMS, Gilead, Janssen, GSK, Novartis

Patrick Marcellin - Consulting: Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec, MSD, Boehringer, Pfizer, Abbott, Alios BioPharma; Grant/Research Support: Roche, Gilead, BMS, Novartis, Janssen-Tibotec, MSD, Alios BioPharma; Speaking and Teaching: Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec, MSD, Abbott

Fred Poordad - Advisory Committees or Review Panels: Abbott, Achillion, BMS, Inhibitex, Boeheringer Ingelheim, Pfizer, Genentech, Idenix, Gilead, Merck, Vertex, Salix, Janssen, Novartis; Grant/Research Support: Abbott, Anadys, Achillion, BMS, Boehringer Ingelheim, Genentech, Idenix, Gilead, Merck, Phar-massett, Vertex, Salix, Tibotec/Janssen, Novartis

Monika Peeters - Employment: Janssen

Oliver Lenz - Employment: Janssen

Sivi Ouwerkerk-Mahadevan - Employment: Janssen

Guy De La Rosa - Employment: Johnson & Johnson

Ronald Kalmeijer - Employment: Johnson and Johnson

Rekha Sinha - Employment: Janssen Pharmaceutica

Maria Beumont-Mauviel - Employment: Janssen

The following people have nothing to disclose: Evaldo S. Araujo

1123

  1. Top of page

High Efficacy at Lower Doses of MK-5172 25 mg and 50 mg Daily for 12 Weeks in HCV Genotype (G) 1 Treatment-Naive Non-cirrhotic Patients

John M. Vierling1, Martin Lagging2, Ashley S. Brown3, Ola Weiland4, Parvez S. Mantry5, Alnoor Ramji6, Frank Weilert7, Isaias N. Gendrano8, Christopher L. Gilbert9, Boan Zhang10, Peggy Hwang9, Janice Wahl9, Michael Robertson9, Niloufar Mobashery9; 1Baylor College of Medicine, Houston, TX; 2Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden; 3Liver & Antiviral Unit, Imperial College Healthcare, London, United Kingdom; 4Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; 5The Liver Institute at Methodist Dallas Medical Center, Dallas, TX; 6Division of Gastroenterology, University of British Columbia, Vancouver, BC, Canada; 7Waikato District Health Board, Hamilton, New Zealand; 8Merck and Company, Whitehouse Station, NJ; 9Merck Research Laboratories, Upper Gwynedd, PA; 10Merck Research Laboratories, Kenilworth, NJ

Background: MK-51 72 is a potent HCV NS3/4A protease inhibitor with a high barrier to resistance. In a phase 2 study (Protocol 003), administration of MK-5172 100-800 mg QD with peginterferon alfa-2b and ribavirin (PR) resulted in SVR24 or HCV RNA target not detected (TND) at last visit in 92% to 99% of non-cirrhotic G1-infected patients. The present study evaluates a lower dose range of MK-5172 + PR. Methods: Treatment-naive HCV G1-infected patients were randomized to receive MK-5172 25-, 50-, or 1 00-mg + PR for 12 weeks. Futility was defined as confirmed HCV RNA ≥25 IU/mL at treatment week (TW) 4; patients had their PR treatment extended by 12 weeks if they were not TND at TW4. HCV RNA was measured by Roche Cobas TaqMan v2.0. Results: Of 87 enrolled patients: 80% were G1a, 80% were IL28B non-CC, and 1 8% were African American. Decline in HCV RNA was comparable for all doses (Figure). Among patients who have reached TW4, 72 of 73 (99%) were TND or <25 IU/mL, and will receive 12 weeks of therapy. Among patients who have reached TW8, 33 of 36 patients (92%) were TND. No patient has experienced virologic failure. Myositis with transaminase levels >3x ULN, total bilirubin >2x ULN, and CPK of 1032 U/L after 7 days of dosing occurred in 1 patient on the 1 00-mg dose. Values normalized off therapy. No other patient has had clinically significant transaminase elevations. Rates of adverse events and laboratory abnormalities were comparable across the 3 doses. On-treatment response, SVR4, and SVR12 will be presented. Conclusions: MK-51 72 is a highly potent agent as indicated by comparable efficacy of 12-week regimens of MK-51 72 25-1 00 mg + PR. All 3 doses of MK-51 72 were well tolerated.

Thumbnail image of
Disclosures

John M. Vierling - Advisory Committees or Review Panels: National Institutes of Health, US Food and Drug Administration CDER, Centers for Disease Control and Prevention, Abbott, Bristol-Myers Squibb, Excalenz, Gilead, Globeimmune, HepQuant, Idenix, Immuron, Janssen, Novartis, Roche, Salix, Schering (now Merck), Sundise, Vertex, HepaLife Technologies, Herbal ife, Ocera, SciGen; Grant/Research Support: Abbott, Bristol-Myers Squibb, Conatus, Excalenz, Gen-fit, Gilead, Globeimmune, Hyperion, Idenix-Novartis, Ikaria, Intercept, Merck, Mochida, Novartis, Ocera, Pfizer, Pharmasset, Roche

Martin Lagging - Advisory Committees or Review Panels: Roche, MSD, Janssen, Gilead, Medivir; Speaking and Teaching: Roche, MSD, Janssen, Abbott, Gilead

Ashley S. Brown - Advisory Committees or Review Panels: MSD, Roche, Bristol-Myers-Squibb, Gilead, Novartis, Janssen, Abbvie, Achillion; Speaking and Teaching: MSD, Roche, Bristol-Myers Squibb, Gilead, Janssen, Abbvie

Ola Weiland - Advisory Committees or Review Panels: MSD, BMS, Janssen, Gilead; Grant/Research Support, MSD, Roche, BMS; Speaking and Teaching: Novartis, Janssen, Abbott, Roche, Gilead

Parvez S. Mantry- Consulting: Gilead, Janssen; Grant/Research Support: Vertex, Merck, Salix, Abbvie, Gilead, Boehringer-Ingelheim, Bristiol Myers Squibb, Santaris; Speaking and Teaching: Vertex, Merck, Sailx, Genentech, Bayer-Onyx, Kadmon

Alnoor Ramji - Advisory Committees or Review Panels: Roche, Merck, Gilead, vertex, Janssen, Boehringer Ingelheim; Grant/Research Support: BMS, Roche, Merck, Gilead, Vertex, Novartis, Abbvie, Boehringer Ingelheim

Isaias N. Gendrano - Employment: Merck Sharp & Dohme Corp; Stock Shareholder: Merck Sharp & Dohme Corp

Christopher L. Gilbert - Employment: Merck & Co., Inc.; Stock Shareholder: Merck & Co., Inc.

Peggy Hwang - Employment: Merck, Merck

Janice Wahl - Employment: Merck & Co,

Michael Robertson - Employment: Merck; Stock Shareholder: Merck

Niloufar Mobashery - Employment: Merck; Stock Shareholder: Merck

The following people have nothing to disclose: Frank Weilert, Boan Zhang

1124

  1. Top of page

Hepatitis C virus kinetic comparison between non-cirrhotic patients and patients awaiting liver transplantation treated with intravenous silibinin monotherapy

Laetitia Canini1, Swati DebRoy2,3, Zoe Mariño4, Gonzalo Crespo4, Miquel Navasa4, Massimo D'Amato5, Scott Cotler2, Xavier Forns4, Alan S. Perelson1, Harel Dahari1,2; 1Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM; 2Department of Medicine, Loyola University Medical Center, Maywood, IL; 3Department of Mathematics and Statistics, University of Missouri, Kansa CityMaywood, MO; 4Liver Unit, CIBERehd, IDIBAPS, Barcelona, Spain; 5Rottapharm, Monza, Italy

Background&Aims: HCV kinetic data are limited in patients awaiting liver transplantation (LT) due to the toxicity of current antiviral therapy in patients with advanced liver disease and/or hepatocellular carcinoma. Here we estimate viral kinetic parameters and treatment effectiveness, using a mathematical model, in non-cirrhotic patients and patients awaiting LT treated with daily intravenous silibinin (SIL) monotherapy for 7 days. Method: We fit kinetic data from two published studies where 20mg/kg/d of SIL was administered intravenously in 8 genotype 1 cirrhotic patients awaiting LT (Child A with hepatocellular carcinoma (n=2); decompensated Child C (n=6)) [J Hepatol.2013,58(3):415-20] and in 17 non-cirrhotic patients (n = 15 genotype 1 and n=2 genotype 4) [J Hepa-tol.2012,56(5): 1019-24] to a standard biphasic model, using a population approach. Parameters were estimated by likelihood maximization using the SAEM algorithm. We found that using a varying effectiveness (VE) model of SIL provided a better fit (Akaike Information Criteria, AIC=116.98) than the constant-effectiveness model (AIC = 132.49). Therefore the VE model, that implies a gradual increase in SIL effectiveness, was used for the comparison. Results: The initial viral load, V0, was significantly lower (P<0.0001) in patients awaiting LT (V0=5.18 ± 2.59 Log10 IU/mL) than in the non-cirrhotic group (V0=6.48 ± 2.14 Log10 IU/mL). SIL effectiveness reached its maximal value (εmax) within 2 days with the same rate of change of effectiveness (k=2.32±0.21 d-1) in both groups. However, SIL effectiveness was lower (p=0.05) in patients awaiting LT (εmax =0.61±0.08) compared to the non-cirrhotic group (εmax =0.79±0.05). No evidence of a difference in infected cell death/loss rate (δ=0.62±0.05 d-1) was found between the two groups. Discussion: The significant lower viral load in patients awaiting LT compared to non-cirrhotic patients is in agreement with larger cohorts (J Hepatol 2005,42 (4) :491-8). Modeling results suggest that SIL effectiveness reaches its maximum effectiveness after the administration of the 2nd dose (ie., day 2 after treatment initiation). The antiviral effectiveness (first phase decline) with 20mg/kg/d of SIL was significantly lower in patients awaiting LT than in non-cirrhotic patients, while the second phase viral decline was similar between groups. These findings suggest that newer DAA with limited toxicity should be able to achieve sustained virological response, SVR, in patients awaiting liver transplantation, provided sufficient duration of therapy is ensured.

Disclosures

Massimo D'Amato - Employment: Rottapharm

Scott Cotler - Speaking and Teaching: Genentech, Vertex, Brystal Myers, Gilead

Xavier Forns - Consulting: Tibotec/Jansen, MSD, Boheringher Ingelheim; Grant/Research Support: Roche, MSD, Gilead

Alan S. Perelson - Consulting: Achillion Pharmaceuticals, Merck, Roche, Santaris Pharma, Gilead; Grant/Research Support: Roche, Novartis; Stock Shareholder: Pfizer, Merck, Glaxo

Harel Dahari - Consulting: Roche TCRC, Inc

The following people have nothing to disclose: Laetitia Canini, Swati DebRoy, Zoe Mariño, Gonzalo Crespo, Miquel Navasa

1125

  1. Top of page

HCV RNA “Target Detected” after “Target Not Detected” During IFN-Free Treatment: Time to Worry or Not?

Martin King, Wangang Xie, Daniel E. Cohen, Thomas Podsadecki; AbbVie, Inc., North Chicago, IL

Background. HCV RNA results that are below the limit of quantitation may be classified as “target detected” or “target not detected” (Lontok, et al., CID 2013). An HCV RNA result of “target detected” that occurs after 1 or more results of “target not detected” can be distressing to both patients and health care providers, by raising the possibility of impending virologic failure. We assessed the frequency of such occurrences and the likelihood of subsequent virologic failure in subjects treated with an IFN-free DAA combination regimen associated with SVR rates > 90% in both treatment-naïve subjects and null responders in the AVIATOR study (M1 1-652). Methods. Treatmentnaïve and prior null responder subjects randomized to a regimen of ABT-450/r + ABT-267 + ABT-333 + ribavirin for 12 or 24 weeks in study M1 1-652 were included in the analysis. TDAN (Target Detected After Not detected) was defined as an HCV RNA value that was unquantifiable (with HCV RNA detected) after at least one HCV RNA value with HCV RNA not detected. Based on the Roche COBAS TaqMan RT-PCR v2.0 assay used for this study, a TDAN corresponds to a result of “<25 IU/mL HCV RNA Detected” after any number of consecutive results of “HCV RNA Not Detected.” The frequency of TDANs was summarized, as was the incidence of virologic breakthrough or relapse following a TDAN. Results. N=247 subjects were randomized to 12 or 24 weeks of ABT-450/r + ABT-267 + ABT-333 + RBV and were included in the analysis. TDANs occurred in 30/247 subjects (12%), including 4 of the previously reported 7 virologic failures in these treatment groups and 26 subjects who did not have subsequent virologic failure. Thus, in most cases TDANs did not lead to virologic failure, as 26/30 subjects with TDANs (87%) achieved SVR12. Most TDANs occurred early; 18/20 with TDANs during the first 4 weeks did not have subsequent virologic failure. Two subjects had TDANs in the post-treatment period; both subjects achieved SVR12. Conclusions. TDANs occurred in 12% of subjects receiving ABT-450/r + ABT-267 + ABT-333 + RBV for 12 or 24 weeks. TDANs generally occurred early, in the first 4 weeks of treatment, and most subjects with TDANs did not experience virologic failure. Of 2 subjects with TDANs in the post-treatment period, neither experienced virologic relapse. These results suggest that TDANs occurring with this regimen are usually artifacts of assay variability. These findings may be different for regimens with different potency.

Disclosures

Martin King - Employment: AbbVie, Inc.

Wangang Xie - Employment: AbbVie

Daniel E. Cohen - Employment: AbbVie; Stock Shareholder: AbbVie

The following people have nothing to disclose: Thomas Podsadecki

1126

  1. Top of page

Safety and Efficacy of BMS-791325, a Non-Nucleoside NS5B Polymerase Inhibitor, Combined with Peginter-feron Alfa-2a and Ribavirin in Treatment-Naive Patients Infected with Hepatitis C Virus Genotype 1

Harvey A. Tatum1, Paul J. Thuluvath2, Eric Lawitz3, Claudia Mar-torell4, Stanley M. Cohen5, Vinod K. Rustgi6, Natarajan Ravendhran7, Reem H. Ghalib8, John Hanson9, Joann Zamparo10, JingZhao11, Michelle Treitel12, Eric A. Hughes12; 1Options Health Research, Tulsa, OK; 2Mercy Medical Center, Baltimore, MD; 3The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX; 4The Research Institute, Springfield, MA; 5University Hospital/Case Western Medical Center, Cleveland, OH; 6Metro-politan Research, Arlington, VA; 7Digestive Disease Associates, Baltimore, MD; 8Texas Clinical Research Institute, Arlington, TX; 9Charlotte Gastroenterology and Hepatology, Charlotte, NC; 10Bristol-Myers Squibb, Wallingford, CT; 11Bristol-Myers Squibb, Hopewell, NJ; 12Bristol-Myers Squibb, Princeton, NJ

Background and Aims: BMS-791325 is a potent, selective, non-nucleoside NS5B polymerase inhibitor with antiviral activity against genotypes (GT) 1, 3, 4, 5, and 6 in vitro. Interim on-treatment Week 12 results demonstrated that combination of BMS-791325 with peginterferon alfa-2a and ribavirin (alfa/RBV) provided greater early suppression of HCV RNA than alfa/RBV alone in HCV GT 1-infected patients. Here, we report the final data on safety through on-treatment Week 48 and efficacy to post-treatment Week 24 (SVR24). Methods: This double-blind, phase 2a study randomized 39 treatment-naive, non-cirrhotic, HCV GT1-infected patients to receive BMS-791 325 75 or 150 mg, or placebo (PBO) BID (1:1:1) in combination with alfa/RBV for 48 weeks and followed patients for 24 to 48 weeks post-treatment. Results: Baseline characteristics were similar between groups except 85% patients in the 150 mg group were IL28B non-CC compared to 54% and 77% in 75 mg and PBO, respectively. In this primarily GT 1a (80%) population, higher virologic responses were observed with BMS-791325 75 mg group than 150 mg or PBO (Table). No patients who received 75 mg experienced viral breakthrough (VBT) or relapse; 3 patients (150 mg) experienced VBT and 3 patients (PBO) experienced relapse. No deaths occurred. Two patients (1 each in 75 mg and PBO) experienced serious adverse events while on-treatment (1-75 mg patient had constipation and neutropenia and 1-PBO patient had serotonin syndrome). Six patients (1-75 mg, 2-150 mg, and 3-PBO) discontinued due to adverse events (AEs). The most common AEs were fatigue, headache and nausea which are consistent with alfa/RBV treatment. On-treatment grade 3/4 laboratory results of interest were: 1 elevated aspartate aminotransferase (75 mg), 2 bilirubin increases (both PBO), and 1 hemoglobin decrease (PBO). Conclusions: Higher virologic responses occurred with the addition of BMS-791325 75 mg BID to alfa/RBV. AEs were similar with and without BMS-791325 and typical of alfa/RBV treatment. These data support further study of BMS-791325 75 mg BID with other antiviral agents.

Table 28. 
Modified intent-to-treat analysis, HCV RNA < l0 IU/mL, n/N (%)peginterferon alfa-2a and ribavirin +
BMS-791325 75 mg BIDBMS-791325 150 mgBIDPlacebo
  1. aOne patient missing value; bRelapse: undetectable HCV RNA at EOT and confirmed HCV RNA in any follow-up visit. If discontinued while suppressed before post-treatment Week 24, patients were excluded from numerator.

End of treatment (EOT)12/13(92)9/13(69)11/13(85)
SVR129/13(69)6/13(46)5/13(38
SVR 249/13(69)5/13(38)a5/13(38)
Viral breakthrough0/13(0)3/13(23)0/13(0)
Relapseb0/12(0)0/9(0)3/11(27)

Disclosures

Paul J. Thuluvath -Advisory Committees or Review Panels: Bayer, Gilead, Vertex; Grant/Research Support: Gilead, Abbott, BMS, Boehringer, Salix; Speaking and Teaching: Bayer/Onyx, Vertex, Gilead

Eric Lawitz - Advisory Committees or Review Panels: AbbVie, Achillion Pharmaceuticals, BioCryst, Biotica, Enanta, Idenix Pharmaceuticals, Janssen, Merck & Co, Novartis, Santaris Pharmaceuticals, Theravance, Vertex Pharmaceuticals; Grant/Research Support: AbbVie, Achillion Pharmaceuticals, Boehringer Ingel-heim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Merck & Co, Novartis, Presidio, Roche, Santaris Pharmaceuticals, Vertex Pharmaceuticals ; Speaking and Teaching: Gilead, Kadmon, Merck, Vertex

Claudia Martorell - Grant/Research Support: Gilead, BMS, BI, Abbie; Speaking and Teaching: BMS, Vertex, Merck

Stanley M. Cohen - Advisory Committees or Review Panels: Gilead, BMS; Speaking and Teaching: Gilead, BMS, Vertex, Genentech

Vinod K. Rustgi - Grant/Research Support: gilead, bristol myers squibb, abbott, achillion; Speaking and Teaching: merck, genentech, vertex

Natarajan Ravendhran - Grant/Research Support: BMS, GILEAD, merck

Reem H. Ghalib - Grant/Research Support: Bristol Myers Squibb Pharmaceuticals, Vertex Pharmaceuticals, Merck, Genentech, Zymogenetics, Pharmasset, Anadys, Duke Clinical Research Institute, Achillion, Boehringer Ingelheim, Gilead Pharmaceuticals, Virochem Pharmaceuticals, Abbott, Medtronic Inc, Novartitis, Roche, Schering Plough, tibotec, Inhibitex; Speaking and Teaching: Merck, Genentech, Vertex Pharmaceuticals

John Hanson - Speaking and Teaching: Janssen, Abbvie, Prometheus

Jing Zhao - Employment: Bristol-Myers Squibb

Michelle Treitel - Employment: Merck, BMS

Eric A. Hughes - Employment: Bristol-Myers Squibb

The following people have nothing to disclose: Harvey A. Tatum, Joann Zamparo