W. Jessner

Efficacy and safety of simeprevir with PegIFN/ribavirin in naïve or experienced patients infected with chronic HCV genotype 4.

BACKGROUND & AIMSnSimeprevir (SMV) is a once-daily (QD), oral hepatitis C virus (HCV) NS3/4A protease inhibitor approved for treatment of genotype (GT) 1 and GT4 infection. This Phase III, open-label, single-arm study (RESTORE; NCT01567735) evaluated efficacy/safety of SMV with peginterferon-α-2a/ribavirin (PR) in patients with chronic HCV GT4 infection.nnnMETHODSn107 patients were included. Treatment-naïve (n=35) and prior relapse patients (n=22) received SMV 150mg QD+PR (12 weeks), followed by PR alone (12 or 36 weeks, response-guided [HCV RNA <25IU/ml detectable/undetectable at week 4 and <25IU/ml undetectable at week 12]). Prior non-responders (partial, n=10; null, n=40) received SMV/PR (12 weeks), followed by PR for 36 weeks. The primary endpoint was sustained virologic response 12 weeks after end of treatment (SVR12).nnnRESULTSnMedian age: 49.0years; 28.0% Black/African; 7.5% IL28B CC; 28.8% METAVIR F4. Overall, 65.4% (70/107) of patients achieved SVR12 (82.9% [29/35] treatment-naïve; 86.4% [19/22] prior relapsers; 60.0% [6/10] prior partial responders; 40.0% [16/40] prior null responders). In treatment-naïve and prior relapser patients fulfilling response-guided criteria for 24 weeks of treatment (88.6% [31/35] and 90.9% [20/22]), SVR12 rates were high: 93.5% [29/31] and 95.0% [19/20], respectively. Overall on-treatment failure and relapse rates were 23.4% (25/107) and 14.6% (12/82), respectively. Adverse events (AEs) were mainly grade 1/2; serious AEs were infrequent (4.7%) and considered unrelated to SMV.nnnCONCLUSIONSnEfficacy and safety of SMV 150mg QD for 12 weeks with PR in treatment-naïve or -experienced patients with chronic HCV GT4 infection were in line with previous reports for HCV GT1 infection.

Simeprevir (TMC435) With Pegylated Interferon/Ribavirin in Patients Coinfected With HCV Genotype 1 and HIV-1: A Phase 3 Study

BACKGROUNDnSimeprevir is an oral, once-daily, hepatitis C virus (HCV) NS3/4A protease inhibitor for the treatment of chronic HCV genotype 1 infection. Human immunodeficiency virus (HIV) coinfection accelerates progression of liver disease. This uncontrolled, open-label trial explored the safety and efficacy of simeprevir in patients with HCV genotype 1/HIV type 1 (HIV-1) coinfection.nnnMETHODSnPatients received simeprevir (150 mg once daily) with pegylated interferon alfa-2a/ribavirin (peg-IFN/RBV) for 12 weeks. Noncirrhotic HCV treatment-naive patients and prior relapsers received response-guided therapy (RGT) with peg-IFN/RBV for 24 or 48 weeks. Prior null responders, prior partial responders, and patients with cirrhosis received peg-IFN/RBV for 48 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12).nnnRESULTSnOne hundred and six patients (93 on antiretroviral therapy) were enrolled and treated. SVR12 rates were 79.2% in HCV treatment-naive patients, 57.1% in prior null responders, 86.7% in prior relapsers, and 70.0% in prior partial responders. Fifty-four of 61 eligible patients (88.5%) met RGT criteria for 24 weeks of peg-IFN/RBV, of whom 87.0% (47/54) achieved SVR12. SVR12 rates were 80.0% (36/45) and 63.6% (14/22) for patients with METAVIR scores of F0-F2 and F3-F4, respectively. Common adverse event (AE) rates were consistent with peg-IFN/RBV therapy (fatigue, headache, nausea, neutropenia). Most AEs were grade 1/2; serious AEs occurred in 5.7% of patients, none of which were fatal.nnnCONCLUSIONSnSimeprevir was generally well tolerated with safety similar to that observed in HCV-monoinfected patients and high SVR12 rates in HCV treatment-naive patients, prior relapsers, prior partial responders, and prior null responders with HIV-1 coinfection.nnnCLINICAL TRIALS REGISTRATIONnNCT01479868.

Simeprevir versus telaprevir with peginterferon and ribavirin in previous null or partial responders with chronic hepatitis C virus genotype 1 infection (ATTAIN): a randomised, double-blind, non-inferiority phase 3 trial

BACKGROUNDnWe did a phase 3 study in previous non-responders with chronic hepatitis C virus (HCV) genotype 1 infection and compensated liver disease that related to the standard of care for these patients at the time this study was initiated. We investigated whether simeprevir is non-inferior in terms of efficacy to telaprevir, each in combination with peginterferon alfa-2a and ribavirin.nnnMETHODSnWe did this randomised, double-blind, phase 3 trial at 169 investigational sites in 24 countries. We enrolled adults (≥18 years) with chronic HCV genotype 1 infection, compensated liver disease, and plasma HCV RNA higher than 10u2008000 IU/mL who were null or partial responders during at least one previous course of peginterferon alfa-2a and ribavirin treatment. We randomly assigned (1:1) patients (stratified by HCV genotype 1 subtype [1a plus other/1b] and previous treatment response [partial or null]) to receive simeprevir (150 mg once a day) plus telaprevir placebo (three times a day 7-9 h apart) or telaprevir (750 mg three times a day) plus simeprevir placebo (once a day) in combination with peginterferon alfa-2a and ribavirin for 12 weeks followed by 36 weeks of peginterferon alfa-2a and ribavirin alone. The primary efficacy endpoint was sustained virological response 12 weeks after end of treatment (SVR12) in the intention-to-treat and the per-protocol population. We compared groups with the Cochran-Mantel-Haenszel test. We established a non-inferiority margin of 12%. Adverse events were reported descriptively. This trial is registered with ClinicalTrials.gov, number NCT01485991.nnnFINDINGSnPatient screening began on Jan 19, 2012, and the last visit was on April 7, 2014. We included 763 patients (472 previous null responders [62%]). Simeprevir and peginterferon alfa-2a and ribavirin was non-inferior to telaprevir and peginterferon alfa-2a and ribavirin for SVR12 (54% [203/379] vs 55% [210/384]; difference -1·1%, 95% CI -7·8 to 5·5; p=0·0007). SVR12 was achieved in 70% (101/145) versus 68% (100/146) of previous partial responders and 44% (102/234) versus 46% (110/238) of previous null responders with simeprevir and peginterferon alfa-2a and ribavirin and telaprevir and peginterferon alfa-2a and ribavirin treatment, respectively. We recorded differences between treatment groups in simeprevir or telaprevir-related adverse events (69% [261/379] in the simeprevir group vs 86% [330/384] in the telaprevir group), serious adverse events (2% [8/379] vs 9% [33/384]), and adverse events leading to simeprevir or telaprevir discontinuation (2% [7/379] vs 8% [32/384]).nnnINTERPRETATIONnSimeprevir once a day with peginterferon alfa-2a and ribavirin was well tolerated in HCV genotype 1-infected previous non-responders and was non-inferior to telaprevir, thus providing an alternative treatment in areas of the world where all-oral HCV regimens are not available or accessible.nnnFUNDINGnJanssen.

P1319 ONCE-DAILY SIMEPREVIR (TMC435) WITH PEGINTERFERON/RIBAVIRIN IN TREATMENT-NAIVE OR TREATMENT-EXPERIENCED CHRONIC HCV GENOTYPE 4-INFECTED PATIENTS: FINAL RESULTS OF A PHASE III TRIAL

P1319 ONCE-DAILY SIMEPREVIR (TMC435) WITH PEGINTERFERON/ RIBAVIRIN IN TREATMENT-NAIVE OR TREATMENT-EXPERIENCED CHRONIC HCV GENOTYPE 4-INFECTED PATIENTS: FINAL RESULTS OF A PHASE III TRIAL C. Moreno, C. Hezode, P. Marcellin, S. Bourgeois, S. Francque, D. Samuel, F. Zoulim, J.-D. Grange, O. Lenz, S. OuwerkerkMahadevan, M. Peeters, M. Beumont-Mauviel, W. Jessner. ULB Hôpital Erasme, Brussels, Belgium; Hôpital Henri Mondor, Créteil, Hôpital Beaujon, Clichy, France; ZNA Campus Stuivenberg, UZ Antwerpen, Antwerp, Belgium; Hôpital Paul-Brousse, Villejuif, Hôpital de la Croix Rousse, Lyon, Hôpital Tenon, Paris, France; Janssen Infectious Diseases BVBA, Janssen Research & Development, Beerse, Belgium E-mail: christophe.moreno@erasme.ulb.ac.be

Simeprevir with peginterferon/ribavirin for treatment of chronic hepatitis C virus genotype 1 infection: Pooled safety analysis from Phase IIb and III studies

This pooled analysis of five Phase IIb and III studies evaluated the safety and tolerability of simeprevir, a once daily, oral hepatitis C virus (HCV) NS3/4A protease inhibitor. Data were summarised for patients who received simeprevir 150 mg once daily (n = 924) or placebo (n = 540) plus pegylated interferon‐α/ribavirin for 12 weeks. During the first 12 weeks of treatment, few patients discontinued simeprevir or placebo due to adverse events (AEs) (both 2.2%). Pruritus (23.8% vs 17.4%), rash (any; 22.9% vs 16.7%) and photosensitivity (3.2% vs 0.6%) [Correction added on 16 January 2015, after first online publication: In the above sentence, the values in ‘Photosensitivity’ were previously incorrect and have now been changed to 3.2% vs 0.6%.] were more prevalent in the simeprevir vs the placebo groups. Most AEs were grade 1/2 (72.4% for simeprevir vs 71.3% for placebo). All grade 3/4 AEs occurred in <5.0% of patients, except neutropenia (9.8% vs 7.6%). Overall incidence of neutropenia was similar (17.3% vs 15.7%). Incidence of anaemia was 13.2% for simeprevir vs 10.9% for placebo, and incidence of increased bilirubin was 8.4% vs 2.8%. Bilirubin increases were mild‐to‐moderate and transient without concurrent transaminase increases or association with hepatic injury. Safety and tolerability did not vary with METAVIR score, although increased bilirubin and anaemia were more frequent in simeprevir‐treated patients with METAVIR F4 (increased bilirubin, 13.0% vs 3.3%; anaemia, 19.0% vs 14.8%). Serious AEs were infrequent (2.1% for simeprevir vs 3.0% for placebo). No deaths were reported during the first 12 weeks of treatment. Patient‐reported fatigue and other outcomes were comparable for both groups, but were of shorter duration for simeprevir due to the use of response‐guided therapy. Simeprevir is well tolerated in HCV genotype 1‐infected patients.

Simeprevir added to peginterferon and ribavirin lessens time with fatigue, depressive symptoms and functional limitations in patients with chronic hepatitis C compared with peginterferon and ribavirin: results from 1161 patients in the QUEST‐1, QUEST‐2 and PROMISE studies

The value of adding simeprevir (SMV) vs placebo (PBO) to peginterferon and ribavirin (PR) for treatment of chronic hepatitis C virus infection was examined using patient‐reported outcomes (PROs); further, concordance of PROs with virology endpoints and adverse events (AEs) was explored. Patients (n = 768 SMV/PR, n = 393 PBO/PR) rated fatigue (FSS), depressive symptoms (CES‐D) and functional impairment (WPAI: Hepatitis C Productivity, Daily Activity and Absenteeism) at baseline and throughout treatment in three randomised, double‐blind trials comparing the addition of SMV or PBO during initial 12 weeks of PR. PR was administered for 48 weeks (PBO group) and 24/48 weeks (SMV group) using a response‐guided therapy (RGT) approach. Mean PRO scores (except Absenteeism) worsened from baseline to Week 4 to the same extent in both groups but reverted after Week 24 for SMV/PR and only after Week 48 for PBO/PR. Accordingly, there was a significantly lower area under the curve (baseline–Week 60, AUC60) and fewer weeks with clinically important worsening of scores in the SMV/PR group at any time point. Incidences of patients with fatigue and anaemia AEs were similar in both groups, but FSS scores showed that clinically important increases in fatigue lasted a mean of 6.9 weeks longer with PBO/PR (P < 0.001). PRO score subgroup analysis indicated better outcomes for patients who met the criteria for RGT or achieved sustained virological response 12 weeks post‐treatment (SVR12); differences in mean PRO scores associated with fibrosis level were only observed with PBO/PR. Greater efficacy of SMV/PR enabled reduced treatment duration and reduced time with PR‐related AEs without adding to AE severity.

Efficacy, safety, and pharmacokinetics of simeprevir, daclatasvir, and ribavirin in patients with recurrent hepatitis C virus genotype 1b infection after orthotopic liver transplantation: The Phase II SATURN study

Recurrent hepatitis C virus (HCV) infection following liver transplantation is associated with accelerated progression to graft failure and reduced patient survival.

A 3-year follow-up study after treatment with simeprevir in combination with pegylated interferon-α and ribavirin for chronic hepatitis C virus infection

BackgroundSimeprevir is approved with pegylated interferon and ribavirin (PR) for chronic hepatitis C virus (HCV) genotype (GT) 1 and GT4 infection in the USA and the European Union.MethodsThis 3-year follow-up study assessed the durability of sustained virologic response (SVR) (undetectable HCV RNA 12 or 24xa0weeks after treatment end), and evaluated the persistence of treatment-emergent NS3/4A protease inhibitor resistance in patients not achieving SVR following treatment with simeprevir plus PR in the parent study. The maintenance of SVR after the last post-therapy follow-up visit of the parent study (LPVPS) was assessed using HCV RNA measurements. The persistence of treatment-emergent NS3 amino acid substitutions in patients with no SVR at LPVPS was assessed using population sequencing. No study medications were administered.ResultsOverall, 249 patients were enrolled (200 with SVR at LPVPS; 49 with no SVR at LPVPS); 40 patients discontinued prematurely (18 with SVR; 22 with no SVR). All 200 enrolled patients who achieved SVR in the parent study maintained SVR until the last available visit in this study (median follow-up time: 35.8xa0months). The treatment-emergent NS3 amino acid substitutions detected at time of failure in the parent study in 43/49 enrolled patients were no longer detected in 37/43 (86.0%) at the end of this study (median follow-up time: 179.9xa0weeks [41.3xa0months]).ConclusionThis 3-year follow-up study provides evidence for the long-term durability of SVR (100%) after successful treatment with simeprevir plus PR. Treatment-emergent NS3 amino acid substitutions became undetectable in the majority of patients.Trial registrationNCT01349465; ClinicalTrials.gov.

Virology analyses of HCV genotype 4 isolates from patients treated with simeprevir and peginterferon/ribavirin in the Phase III RESTORE study

Simeprevir is a hepatitis C virus NS3/4A protease inhibitor. Hepatitis C virus baseline NS3/4A polymorphisms and emerging mutations were characterized in treatment‐naїve and treatment‐experienced genotype 4‐infected patients treated with simeprevir+peginterferon/ribavirin in the RESTORE study. Population sequencing of the NS3/4A region was performed and in vitro simeprevir activity against site‐directed mutants or chimeric replicons with patient‐derived NS3 protease sequences was assessed in a transient replicon assay. Simeprevir remained active against most (83/91 [91%]) baseline isolates tested in the chimeric replicon assay. Eight baseline isolates reduced simeprevir activity; these carried I132L or D168E substitutions reducing simeprevir median activity by 4.6‐ and 39‐fold, respectively. Six of these eight isolates were from patients achieving sustained virologic response. Baseline NS3 Q80K polymorphism was not observed in the genotype 4‐infected patients. Of the 107 simeprevir‐treated patients, 37 did not achieve sustained virologic response for any reason. Of the 32 patients who failed treatment and had sequencing information, 28 (88%) had emerging mutations at NS3 positions 80, 122, 155, 156 and/or 168 at time of failure, similar to those in genotype 1. Emerging mutations were mainly D168V and D168E alone or combined with mutations at position 80. In general, isolates obtained at time of failure displayed high‐level in vitro resistance to simeprevir (fold change ≥50) in a chimeric replicon assay with a median simeprevir fold change value of 440, consistent with observed mutations. In conclusion, emerging mutations in genotype 4 patients failing simeprevir+peginterferon/ribavirin treatment were similar to those in genotype 1 and conferred high‐level resistance to simeprevir.

Clinical impact of pharmacokinetic interactions between the HCV protease inhibitor simeprevir and frequently used concomitant medications

Aims Direct‐acting antiviral agents (DAAs) for the treatment of hepatitis C (HCV) can be associated with drug–drug interactions (DDIs) with concomitant medications. The practical clinical implications of such DDIs are poorly understood. We assessed the clinical impact of possible pharmacokinetic (PK) interactions between simeprevir and frequently prescribed concomitant medications. Methods This post hoc analysis pooled data from nine studies which evaluated simeprevir (SMV)‐based interferon‐free HCV treatment. Three classes of frequently used concomitant medications of interest (CMOIs) were analysed [antihypertensive drugs (AHDs), anxiolytic drugs (AXDs) and lipid‐lowering drugs (LLDs)] and categorized as amber or green according to their DDI potential with SMV (green: no DDIs; amber: potential/known PK interactions). Concomitant medications not recommended to be coadministered with SMV were not included. The composite primary endpoint was defined as the frequency of either discontinuation, interruption or dose modification of the CMOI during 12 weeks of SMV treatment. Results Few patients met the composite endpoint in the various subgroups. Patients on amber CMOIs tended to experience CMOI modification more often (13.4–19.4%) than those on green CMOIs (3.1–10.8%). There was no difference in the frequency of adverse events between patients taking green and those taking amber CMOIs. Conclusions In this large pooled analysis, coadministration of the evaluated commonly prescribed medications with known or potential PK interactions with SMV was manageable and resulted in few adjustments of concomitant medications. Our method could serve as a blueprint for the evaluation of the impact of DDIs.