Simeprevir With Peginterferon and Ribavirin Leads to High Rates of SVR in Patients With HCV Genotype 1 Who Relapsed After Previous Therapy: A Phase 3 Trial

All studies published in Gastroenterology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.

Gastroenterology 2014;-:1–11

60 61 62 63 64 65 66 67 68 1 2 3 4 5 Q35 Xavier Forns, Eric Lawitz, Stefan Zeuzem, Ed Gane, Jean Pierre Bronowicki, 69 70 Pietro Andreone,6 Andrzej Horban,7 Ashley Brown,8 Monika Peeters,9 Oliver Lenz,9 10 11 12 12 71 Sivi Ouwerkerk–Mahadevan, Jane Scott, Guy De La Rosa, Ronald Kalmeijer, 72 9 9 Rekha Sinha, and Maria Beumont–Mauviel 73 74 1 Liver Unit, Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer and Centro de Investigación Biomédica en 75 2 Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; Texas Liver Institute, University of Texas Health Science 3 4 76 Center, San Antonio, Texas; J.W. Goethe University Hospital, Frankfurt, Germany; Auckland Hospital Clinical Studies Unit, 5 77 Auckland, New Zealand; INSERM U954, Université de Lorraine, Centre Hospitalier Universitaire de Nancy, Vandoeuvre Les 78 Nancy, France; 6Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum, University of Bologna, Bologna, Italy; 7 Medical University of Warsaw, Wolska, Warsaw, Poland; 8Imperial College Healthcare NHS Trust, London, United Kingdom; 79 Q1 9Janssen Infectious Diseases BVBA, Beerse, Belgium; 10Janssen Research and Development, Beerse, Belgium; 11Janssen 80 Q2 Global Services, LLC, High Wycombe, United Kingdom; 12Janssen Global Services, LLC, Titusville, New Jersey 81 82 BACKGROUND & AIMS: Simeprevir is an oral, once-daily in- with 350,000 people dying annually of HCV-related condi83 1 hibitor of hepatitis c virus (HCV) protease NS3/4A. We inves- tions. Historically, the standard of care for chronic HCV 84 tigated the safety and efficacy of simeprevir with peg-interferon infection was peginterferon (PegIFN)a and ribavirin 85 a-2a and ribavirin (PR) in a randomized, double-blind, placebo- (RBV).2–4 However, 50%–60% of HCV genotype 1–infected 86 controlled, phase 3 trial of patients with HCV genotype 1 patients do not achieve sustained virologic response (SVR) 87 infection who relapsed after previous interferon-based therapy. with PegIFNa/RBV,5,6 and up to 32% of responders relapse 88 METHODS: Patients were assigned randomly (2:1) to groups after cessation of therapy.7 Re-treatment of relapsed pa89 given simeprevir (150 mg, once daily) and PR (n ¼ 260) or tients with PegIFNa/RBV has SVR rates of approximately 90 placebo and PR (n ¼ 133) for 12 weeks. Patients then were 20%–50%.8–10 91 given PR alone for 12 or 36 weeks (simeprevir group, based on The direct-acting antiviral agents (DAAs), boceprevir and 92 response-guided therapy criteria) or 36 weeks (placebo group). telaprevir, can improve SVR rates when dosed with 93 RESULTS: Simeprevir and PR was significantly superior to placebo PegIFNa/RBV,11–14 with the potential for a shorter treat94 and PR; rates of sustained virologic response 12 weeks after planned ment duration in some patients.11,13,15 The telaprevir me95 end of treatment (SVR12) were 79.2% vs 36.1%, respectively (43.8% Q12 96 difference; 95% confidence interval, 34.6–53.0; P < .001). Among dian inhibitory concentration values in a genotype 1b HCV patients given simeprevir, 92.7% met the response-guided therapy replicon and in genotype 1a HCV-infected human fetal he97 16 criteria and were eligible to complete PR at week 24; of these, 83.0% patocytes were 354 nmol/L and 280 nmol/L, respectively, 98 achieved SVR12. HCV RNA was undetectable at week 4 in 77.2% of whereas the boceprevir median effective concentration 99 patients given simeprevir and 3.1% given placebo. On-treatment (EC50) in a genotype 1b HCV replicon was approximately 100 failure and relapse rates were lower among patients given sime- 200 nmol/L, with an approximately 2-fold lower value in a 101 17 previr and PR than those given placebo and PR (3.1% vs 27.1%, and genotype 1a HCV replicon. Data concerning the efficacy of 102 18.5% vs 48.4%, respectively). Patients given simeprevir did not response-guided treatment (RGT) with telaprevir in patients 103 have adverse events beyond those that occurred in patients given PR who have relapsed after prior IFN-based therapy are lack104 alone. Most adverse events were grades 1/2; the prevalence of ane- ing. Boceprevir must be administered as 4 pills, 3 times 105 mia and rash was similar in both groups. Patients in both groups daily, whereas telaprevir must be administered 2 or 3 times 106 reported similar severity of fatigue and functional impairments 107 during the study, but duration was reduced among patients given 108 simeprevir. CONCLUSIONS: In a phase 3 trial of patients who had Abbreviations used in this paper: AE, adverse event; CI, confidence 109 relapsed after interferon-based therapy, the addition of simeprevir interval; DAA, direct-acting antiviral agent; EC50, median effective 110 to PR was generally well tolerated, with an SVR12 rate of 79.2%. concentration; EOT, end of treatment; FDA, Food and Drug Administration; 111 HCV, hepatitis C virus; IQR, interquartile range; METAVIR, Most patients (92.7%) receiving simeprevir were able to shorten ___________________________; PegIFN, peginterferon; PR, peginterferon 112 therapy to 24 weeks. ClinicalTrials.gov number: NCT01281839. a-2a/ribavirin; RBV, ribavirin; RGT, response-guided treatment; RVR, rapid 113 virologic response; SAE, serious adverse event; SVR, sustained virologic response; SVR12, sustained virologic response at 12 weeks; SVR24, Keywords: PROMISE; Chronic Hepatitis C; Drug; DAA. 114 sustained virologic response at 24 weeks. 115 Q9 116 © 2014 by the AGA Institute Q10 pproximately 150 million individuals worldwide 0016-5085/$36.00 117 Q11 are chronically infected with hepatitis C virus (HCV), http://dx.doi.org/10.1053/j.gastro.2014.02.051 118

Simeprevir With Peginterferon and Ribavirin Leads to High Rates of SVR in Patients With HCV Genotype 1 Who Relapsed After Previous Therapy: A Phase 3 Trial

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daily (6 pills in total).18 Boceprevir and telaprevir also are associated with a high incidence of adverse events (AEs), including anemia, rash, and renal dysfunction.19–22 Recently, the protease inhibitor sofosbuvir also was approved for the treatment of chronic HCV infection in the United States and Europe, representing an improvement on first-generation DAAs.23,24 Simeprevir (TMC435) is administered orally, once daily, as a single pill25; has been approved in the United States, Canada, and Japan; and is under regulatory review in Europe for the treatment of chronic HCV infection. The median simeprevir EC50 and EC90 values against a HCV genotype 1b replicon were 9.4 and 19 nmol/L, respectively.26 Activity of simeprevir against a selection of genotype 1a (N ¼ 78) and 1b (N ¼ 59) chimeric replicons carrying NS3 sequences from HCV NS3/4A protease inhibitor-naive subjects resulted in median fold change in EC50 of 1.4 (interquartile range [IQR], 0.8–11) and 0.4 (IQR, 0.3–0.7), compared with reference genotype 1b replicon. Genotype 1a (N ¼ 33) and 1b (N ¼ 2) isolates with a baseline Q80K polymorphism, a naturally occurring NS3 polymorphism that confers low-level resistance to simeprevir, resulted in a median fold change in simeprevir EC50 of 11 (IQR, 7.4–13) and 8.4, respectively. Simeprevir has antiviral activity in patients infected with HCV genotypes 1, 2, 4, 5, and 6,27–30 and is being evaluated in both PegIFNa/RBV and IFN-free combinations.27,28,31–34 Simeprevir in combination with PegIFNa/RBV showed SVR rates of approximately 80% in phase III trials in treatment-naive patients with HCV genotype 1 infection, with most patients (>84%) able to reduce their treatment duration to 24 weeks.33,34 In these studies, no additional AEs were observed with simeprevir compared with those seen with PegIFNa/RBV alone. Results of the PROtease inhibitor TMC435 In patientS who have previously rElapsed on IFN/RBV study, a randomized, double-blind, placebo-controlled, phase III trial undertaken to assess the efficacy, safety, and tolerability of simeprevir with PegIFNa-2a/RBV (PR) for the treatment of chronic HCV genotype 1 infection in patients who had relapsed after previous IFN-based therapy, are presented.

Materials and Methods Patients Patients were enrolled at study sites in 14 countries across North America, Europe, and the Asia–Pacific region. Eligible patients were adults (18 y) with confirmed genotype 1 HCV infection and screening plasma HCV RNA levels greater than 10,000 IU/mL, who had relapsed after 24 weeks or more of IFN-based therapy (undetectable HCV RNA at end of treatment [EOT] or within 2 months after EOT, with documented relapse within 1 year after therapy). A liver biopsy specimen obtained within 3 years of screening showing histology consistent with chronic HCV infection was required, according to the 2010 Food and Drug Administration (FDA) Guidance for Industry on developing DAAs (available from the FDA). Biopsy specimens indicating a METAVIR score of F0–F3 within 3 years of screening, or a score of F4 at any previous time, were

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acceptable. In total, 68% of patients had a biopsy within a year of screening. Subjects with bridging fibrosis (F3) or cirrhosis (F4) were eligible if they had an ultrasound performed within 6 months before screening (or between the screening and baseline visit) with no findings suspicious for hepatocellular carcinoma. Patients with hepatic decompensation; non–HCV-related liver disease; co-infection with human immunodeficiency virus, hepatitis B virus, or non–genotype 1 HCV; defined laboratory abnormalities (Supplementary Materials and Methods section); any other active disease; or who were either pregnant or planning pregnancy were excluded.

178 179 180 181 182 183 184 Q15 185 186 187 188 189 Study Design 190 This was a randomized, multicenter, double-blind, parallel191 group, placebo-controlled, phase III clinical trial 192 (NCT01281839), conducted between January 2011 and January 193 2013. Institutional review boards of all participating in194 stitutions approved the study and written informed consent 195 was obtained from all participants according to local regula196 tions. All authors had access to the study data, critically 197 reviewed the manuscript at each draft, and approved the final 198 draft for submission. 199 After stratification by HCV 1 subtype (1a, 1b, and other) and 200 IL28B genotype (rs12979860; CC, CT, or TT), participants were 201 randomized centrally in a 2:1 ratio to receive either simeprevir 202 (150 mg once daily) plus PegIFNa-2a/RBV (180 mg/wk and 203 1000 or 1200 mg/day depending on body weight, respectively) 204 (PR) for 12 weeks followed by RGT with PR alone for 12 or 36 205 weeks, or placebo with PR for 12 weeks followed by PR alone 206 for 36 weeks (Supplementary Figure 1). Patients, study 207 personnel, and the sponsor were blinded to the treatment 208 groups. According to RGT criteria, PR therapy was completed at week 24 in simeprevir-treated patients with HCV-RNA levels 209 less than 25 IU/mL at week 4 and undetectable levels at week 210 12. For patients not meeting these criteria and all patients in 211 the placebo group, treatment with PR was continued until week 212 48. Patients in both groups were followed up for 72 weeks after 213 treatment initiation. 214 According to virologic stopping rules, simeprevir/placebo 215 was discontinued if HCV-RNA level was greater than 1000 216 IU/mL at week 4. PR also was discontinued if the reduction in 217 HCV RNA compared with baseline was less than 2 log10 IU/mL 218 at week 12, or if HCV RNA was 25 IU/mL or greater at week 24 219 or 36. Investigators were formally blinded to HCV-RNA data 220 until week 48 and to treatment group until week 72. An 221 external HCV-RNA monitor (who was unblinded to treatment 222 and to HCV-RNA measurements results) informed the investi223 gator if a virologic stopping rule or the RGT criteria were met. 224 225 Assessments 226 Plasma HCV RNA was determined using the Roche COBAS Q16 227 TaqMan HCV/HPS assay version 2.0. Standard population228 based sequencing of the HCV NS3/4A protease domain was 229 performed on baseline samples to determine the presence of 230 naturally occurring baseline polymorphisms, including Q80K, 231 and those from selected time points (based on HCV-RNA 232 changes). 233 Standard HCV genotyping assays, the Siemens Versant HCV Q17 234 LiPA v2 assay or, if that failed, the Trugene 50 NC genotyping 235 assay, were used to determine HCV genotype 1 subtype at 236

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screening. In addition, HCV genotype/subtype was determined at baseline using an NS5B sequence-based assay. The results of the NS5B-based assay were used for study analyses. Determination of the patients’ IL28B genotype (SNP rs12979860) was performed on human genomic DNA by a real-time polymerase chain reaction on the ABI 7900HT platform. AEs were monitored throughout the study. During study visits, patients completed questionnaires to document changes in fatigue severity (Fatigue Severity Scale),35 as well as productivity and daily activity impairment and work absenteeism (Work Productivity and Activity Impairment questionnaire for Hepatitis C).36 Additional details are provided in the Supplementary Materials and Methods section.

Statistical Analysis This primary analysis was performed when all randomized and treated subjects had completed the week 60 visit or discontinued earlier. All analyses were performed on the intent-totreat population, which comprised all subjects who received at least one dose of simeprevir or placebo. The primary study end point was the proportion of patients achieving SVR (HCV RNA <25 IU/mL undetectable at actual EOT and HCV RNA <25 IU/mL) 12 weeks after planned EOT (SVR12). SVR12 rates in the 2 groups were compared using the Cochran–Mantel–Haenszel test controlling for stratification factors (HCV 1 subtype and IL28B genotype). A Breslow–Day test for homogeneity of odds ratios based on this model also was performed and the 95% confidence interval (CI) was constructed around each response rate. Phase III data for telaprevir and boceprevir show a strong correlation between SVR12 and SVR at 24 weeks after planned EOT (SVR24). Similarly, a good correlation also was observed in phase IIb studies with simeprevir. Sample size calculation based on SVR24 rates therefore was regarded as applicable for SVR12. Based on published data,37 the SVR24 rate in the placebo group was expected to be approximately 20%. It was calculated that 250 patients in the simeprevir group and 125 patients in the placebo group were needed to provide more than 90% power to detect a significant difference between the 2 treatment groups with a 5% significance level (2-sided). Secondary end points included comparison of virologic response rates at other time points (SVR24 [data are presented in the Supplementary Materials and Methods section] and rapid virologic response [RVR] rate, defined as the proportion of patients with undetectable HCV RNA at week 4 of treatment) and in different patient subgroups (including METAVIR score, HCV 1 subtype, and IL28B genotype), the proportion of simeprevir-treated patients meeting RGT criteria to complete treatment at week 24, the incidence of viral breakthrough (HCV-RNA increase of >1 log10 IU/mL from the lowest level observed or HCV RNA >100 IU/mL when previously <25 IU/mL), on-treatment failure (confirmed detectable HCV RNA at EOT), or viral relapse (presence of detectable HCV RNA during followup evaluation or at the time of SVR assessments that were undetectable at EOT), the incidence of AEs and laboratory abnormalities, and quality-of-life measures. The 95% CIs were constructed around the observed response rates and for the differences in response rates between treatment groups. Patient-reported fatigue and impairment in productivity, daily activities, and missed work time were analyzed as change from baseline using a piecewise linear model comparing the

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area under the score–time curve from baseline with week 60, allowing slopes to change over time for each treatment arm. These end points were prespecified in the statistical analysis plan in the order presented as part of a closed testing procedure to address multiple testing of secondary end points. All statistical analyses were performed using SAS version 9.1 (SAS Institute, Inc, Cary, NC).

296 297 298 299 300 301 302 303 304 Results 305 Patients 306 A total of 462 patients were screened; of these, 394 were 307 randomized and 393 were treated (260 in the simeprevir/ 308 PR group and 133 in the placebo/PR group) (Supplementary 309 Figure 2). At the time of this primary analysis, all patients had 310 reached the time point at which the primary end point 311 (SVR12) was assessed (ie, week 60), or had discontinued 312 earlier. In addition, 184 patients (46.8%) had completed the 313 final week 72 visit, and 24 (6.1%) had discontinued the study 314 prematurely. The main reasons for study discontinuation 315 were withdrawal of consent (14 patients; 3.6%) and loss to Q19 316 follow-up evaluation (8 patients; 2.0%). 317 Most (93.1%) patients in the simeprevir/PR group 318 completed their assigned treatment regimen (compared 319 with 25.6% in the placebo/PR group). The proportion of 320 patients who discontinued simeprevir/placebo intake early 321 was 3.5% and 72.2% in the simeprevir/PR and placebo/PR 322 groups, respectively. The main reason for discontinuation 323 was meeting the week 4 virologic stopping rule for sime324 previr or placebo in both arms, with a large proportion of 325 patients in the placebo group (69.9%) stopping placebo at 326 week 4. The proportion of patients who completed PR 327 treatment was 93.5% in the simeprevir/PR group (24 or 48 328 weeks) and 72.2% in the placebo/PR group (48 weeks). 329 Baseline demographic and disease characteristics were 330 comparable between groups (Table 1; Supplementary 331 Materials and Methods section). The median times (in 332 months) between the end of previous (Peg)IFN-based 333 therapy and the start of treatment in this study were as 334 follows: 31.0 (4; 141) and 31.0 (5; 115) for the simeprevir Q20 335 and placebo groups. 336 337 338 Efficacy 339 In the simeprevir/PR arm, an SVR12 rate of 79.2% (206 340 of 260) was observed compared with 36.1% (48 of 133) 341 with placebo/PR (Table 2, Figure 1A). The difference be- Q21 342 tween the 2 groups (controlling for HCV 1 subtype and 343 IL28B genotype as stratification factors) was statistically 344 significant at 43.8% (95% CI, 34.6–53.0; P < .001). 345 The majority of simeprevir-treated patients (92.7%; 241 346 of 260) met RGT criteria to complete treatment at week 24, 347 of whom 83.0% (200 of 241) achieved SVR12. Among 348 simeprevir-treated patients who did not meet RGT criteria, 349 40.0% (6 of 15) achieved SVR12. 350 The RVR rate was 77.2% (200 of 259) in the simeprevir/ 351 PR group compared with 3.1% (4 of 129) treated with 352 placebo/PR. Among simeprevir-treated patients who ach353 ieved RVR, 86.5% (173 of 200) subsequently achieved 354

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Table 1.Baseline Demographics and Disease Characteristics

Sex, % Male Female Race, % White Black/African American Native Hawaiian or Other Pacific Islander Asian Multiple Ethnicity, % Hispanic or Latino Median age, y (range) Median body mass index (range) IL28B genotype, % TT CT CC METAVIR fibrosis score, %a F0–F1 F2 F3 F4 Median baseline HCV RNA, log10 IU/mL (range) HCV genotype, % 1 1a 1b Previous HCV therapy, % PegIFNa-2a/RBV PegIFNa-2b/RBV Other FSS score N Mean score (SE) WPAI productivity N Mean score (SE) WPAI daily activity impairment N Mean score (SE) WPAI absenteeism N Mean (SE)

Simeprevir 150 mg 12 weeks þ PR (n ¼ 260)

Placebo þ PR (n ¼ 133)

68.8 31.2

59.4 40.6

93.5 2.7 0.4 3.1 0.4

96.2 3.0 0.0 0.8 0

7.7 52.0 (20–70) 27.2 (14.3–47.7)

4.5 52.0 (21–71) 26.8 (18.5–41.6)

11.9 64.2 23.8

12.0 62.4 25.6

34.8 32.0 17.6 15.6 6.42 (4.6–7.7)

35.6 38.6 11.4 14.4 6.54 (3.1–7.5)

0.4 42.3 57.3

0 40.6 59.4

68.5 26.9 4.6

66.2 27.1 6.8

250 3.6 (0.10)

131 3.3 (0.12)

246 19.0 (1.53)

129 15.6 (1.88)

246 19.4 (1.55)

129 15.4 (1.84)

129 1.2 (0.60)

60 5.8 (2.60)

FSS, Fatigue Severity Scale; WPAI, work productivity and activity impairment: hepatitis C questionnaire. a Liver biopsy obtained within 3 years of screening (or between the screening and baseline visit) with histology consistent with chronic HCV infection.

SVR12. At week 4, 5% (12 of 260) of simeprevir-treated patients had HCV-RNA level of 25 IU/mL or greater. Irrespective of factors such as baseline HCV-RNA level, IL28B genotype, METAVIR score, and HCV subtype, SVR12 rates were significantly higher in the simeprevir/PR group than in the placebo/PR group (all P < .001) (Table 3, Figure 1B). In simeprevir-treated patients with HCV genotype 1a infection, the presence of the Q80K polymorphism at baseline was associated with a lower SVR12 rate compared with those without this polymorphism at baseline

(46.7% [14 of 30] vs 78.5% [62 of 79], respectively). However, the SVR12 rate was high among the 13 simeprevir-treated patients with baseline Q80K polymorphism who achieved RVR (76.9% vs 23.5% among patients without RVR). Only one simeprevir-treated patient with HCV genotype 1b infection had Q80K polymorphism at baseline; this patient achieved SVR12. The possible effect of baseline characteristics and early response parameters on SVR12 in the simeprevir/PR group is presented in Supplementary Table 1.

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Table 2.Virologic Response Over Time (RVR and SVR12), Proportion of Patients Meeting RGT Criteria and Corresponding SVR12 Rate, and Rates of On-Treatment Failure and Relapse

532 533 534 Simeprevir 150 mg þ PR Placebo þ PR 535 (n ¼ 260) (n ¼ 133) 536 RVR 200/259 (77.2) 4/129 (3.1) 537 SVR12 206/260 (79.2) 48/133 (36.1) 538 Met RGT criteria 241/260 (92.7) N/A 539 SVR12 in patients who met RGT criteria 200/241 (83.0) N/A 540 SVR12 in patients who did not meet RGT criteria 6/15 (40.0) N/A a 541 On-treatment failure 8 (3.1) 36 (27.1) 542 Virologic stopping rule met at weeks 12, 24, or 36 5 (1.9) 15 (11.3) Viral relapseb 46/249 (18.5) 45/93 (48.4) 543 544 545 NOTE. All differences between the simeprevir and placebo groups: P < . 001. SVR12 was defined as HCV RNA <25 IU/mL 546 undetectable at the actual EOT and HCV RNA <25 IU/mL 12 weeks after the planned end of treatment. 547 N/A, not applicable. a Confirmed detectable HCV-RNA levels at actual EOT. 548 b Among patients with undetectable HCV-levels RNA at actual EOT. 549 550 551 The rate of on-treatment failure was 3.1% (8 of 260) for (Table 5). AEs were mainly grades 1/2. Grades 3/4 AEs 552 simeprevir/PR and 27.1% (36 of 133) for placebo/PR were reported in 20.0% of patients in the simeprevir/PR 553 (Table 2). Five patients (1.9%) in the simeprevir/PR group group and in 21.1% in the placebo/PR group, with serious 554 and 93 patients (69.9%) in the placebo/PR group met the AEs (SAEs) reported in 1.2% and 2.3% of patients, respec555 virologic stopping rule at week 4, which dictated stopping tively. Grades 2/3 photosensitivity reaction was reported as 556 simeprevir/placebo only and continuing with PR. Respective an SAE in 2 simeprevir-treated patients (0.8%). No other 557 proportions of patients meeting a virologic stopping rule SAE was reported in more than 1 patient in either group. No 558 requiring discontinuation of all treatment at weeks 12, 24, patient discontinued simeprevir or placebo alone owing to 559 or 36 were 1.9% (5 of 260) and 11.4% (15 of 133) in the AEs. During the first 12 weeks of treatment, AEs led to 560 simeprevir/PR and placebo/PR groups. Viral breakthrough permanent discontinuation of all study drugs in 0.4% of 561 occurred in 2.3% (6 of 260) of simeprevir-treated patients; simeprevir-treated and no placebo-treated patients. The 562 this rate was similar in patients infected with genotype same discontinuation rates were reported during the entire 563 1a/other (2.7%) and genotype 1b (2.0%). No placebo- treatment phase for each of the treatment groups. 564 Two deaths have been reported, both after the first 12 treated patients had viral breakthrough. Viral break565 through occurred mainly during the first 12 weeks of weeks of treatment (Table 5). One patient in the simepre566 treatment with simeprevir/PR, and 5 of 6 simeprevir- vir/PR group (METAVIR score F4 at baseline) died 5 days 567 treated patients with viral breakthrough also met a viro- after consent withdrawal owing to SAEs considered unre568 logic stopping rule. Among patients with undetectable HCV lated to simeprevir by the investigator (pancytopenia, 569 RNA at EOT, 18.5% (46 of 249) in the simeprevir/PR group bradycardia, pyrexia, pneumonia, septic shock, confusional 570 and 48.4% (45 of 93) in the placebo/PR group had expe- state, dyspnea, and respiratory acidosis). One patient in the 571 rienced viral relapse. With simeprevir, this occurred less placebo group also died of an SAE considered unrelated to 572 frequently in patients infected with genotype 1b (17 of 144; treatment (primary liver cancer with lung metastasis). 573 Isolated mild and reversible increases in bilirubin 11.8%) than in those with genotype 1a/other (29 of 105; 27.6%). 574 NS3 sequencing data were available for 52 of the (direct, indirect, and total) were observed in the sime575 59 simeprevir-treated patients who did not achieve SVR12 previr/PR group during the first 2 weeks of treatment, but 576 (n ¼ 54) or who relapsed after the SVR12 time point were not accompanied by changes in any other liver pa577 (n ¼ 5). Most of these patients (considering NS3 positions rameters. During the first 12 weeks of treatment, 578 43, 80, 122, 155, 156, and 168) had emerging mutations in increased bilirubin AEs (mainly grades 1/2) were re579 the NS3 protease domain at the time of failure (90.4%). In ported in 5.8% of simeprevir-treated and in 2.3% of 580 genotype 1a–infected patients, this was mainly R155K alone placebo-treated patients. Grades 3 or 4 increased bilirubin 581 or with other amino acid substitutions at positions 80 or AEs occurred in 1.5% and 0.4% of simeprevir-treated 582 168. For genotype 1b, this was mainly D168V or other patients, respectively, but none led to discontinuation of 583 simeprevir. Grades 3/4 hyperbilirubinemia (laboratory mutations at position 168 (Table 4). 584 reported) occurred in 6.2% of simeprevir-treated and in 585 Q22 3.1% of placebo-treated patients. 586 Safety and Tolerability Rash, pruritus, neutropenia, and anemia AEs were 587 During the first 12 weeks of treatment, the most comparable between the simeprevir and placebo groups 588 frequent AEs in the simeprevir/PR group (>25% of pa- (Table 5). For rash and pruritus, all AEs were grades 1/2, 589 tients) were headache, fatigue, and influenza-like illness except for 1 case of grade 3 rash in the simeprevir group 590 CLINICAL LIVER

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Figure 1. (A) SVR12 rates. (B) Differences in SVR12 by patient subgroup. Differences in the proportions and their respective CIs are derived from a logistic regression model including factors for treatment group, baseline HCV RNA (log10 IU/mL), HCV 1 subtype, and IL28B.

(a grade 3 photosensitivity reaction was considered possibly related to simeprevir), and did not lead to treatment discontinuation. Photosensitivity AEs were reported in 3.5% of simeprevir-treated and in no placebo-treated patients. With the exception of the case of grade 3 photosensitivity in the simeprevir group, these were grades 1/2 and did not lead to treatment discontinuation. Most anemia AEs were grades 1/2 and did not lead to treatment discontinuation, with grade 3 anemia occurring in 1.2% of simeprevirtreated and in 2.3% of placebo-treated patients. No cases of grade 4 anemia were reported.

In terms of laboratory abnormalities, decreases in hemoglobin were observed in 16.5% of simeprevir-treated and in 13.0% of placebo-treated patients. These were of grade 3 severity in 0.8% of simeprevir-treated and in 1.5% of placebo-treated patients, with no grade 4 decreases in hemoglobin in either group. No differences were observed for any other laboratory abnormalities between the 2 groups. The only grades 3/4 laboratory abnormality observed in more than 10% of simeprevir-treated patients was a decrease in absolute neutrophil count (14.6% with simeprevir and 17.6% with placebo).

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650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708

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Table 3.SVR12 Rates According to IL28B Genotype, METAVIR Score, and HCV Genotype

768 769 770 771 IL28B genotype, % 772 TT 20/31 (64.5) 3/16 (18.8) 40.0 (27.4–52.7) 773 CT 131/167 (78.4) 28/83 (33.7) 49.1 (38.9–59.4) 774 CC 55/62 (88.7) 18/34 (52.9) 31.0 (18.9–43.1) 775 METAVIR fibrosis score, % 776 F0–F2 137/167 (82.0) 40/98 (40.8) 49.9 (39.6–60.3) 777 F3–F4 61/83 (73.5) 8/34 (23.5) 51.4 (41.5–61.3) 778 F3 32/44 (72.7) 3/15 (20.0) 51.3 (41.4–61.1) F4 29/39 (74.4) 5/19 (26.3) 51.6 (41.5–61.6) 779 HCV genotype, % 780 1a/other 78/111 (70.3) 15/54 (27.8) 49.2 (34.8–63.7) 781 With baseline Q80K 14/30 (46.7) 6/20 (30.0%) 18.6 (-7.5 to 44.7) 782 Without baseline Q80K 62/79 (78.5) 9/34 (26.5%) 60.1 (43.9–76.3) 783 1b 128/149 (85.9) 34/79 (43.0) 44.9 (31.6–58.2) 784 785 a The difference in proportions and respective 95% CIs are derived from a logistic regression model. 786 787 788 Mean scores for patient-reported fatigue, productivity groups. Fatigue, productivity impairment, and activity 789 impairment, and impairment in daily activities increased by impairment improved to levels at or below baseline in the 790 similar amounts from baseline to week 4 in the 2 treatment simeprevir/PR group after week 24, when most simeprevir791 groups, and remained increased through week 24 in both treated patients were able to complete therapy owing to 792 793 794 Q29 Table 4.Emerging Mutations at Time of Failure in Patients Not Achieving SVR 795 796 Proportion of patients with 797 emerging mutations among Emerging mutations at time of Emerging mutations at 798 patients not achieving SVR failure (overview), n/N (%) time of failure 799 Overall 47/52 (90.4) 800 12/14 (85.7) 8/12 (66.7) R155K GT1aa with Q80K 801 3/12 (25.0) D168E 802 1/12 (8.3) Other S122R (n ¼ 1) 803 GT1a without Q80K 18/18 (100) 7/18 (38.9) R155K 804 4/18 (22.2) R155K in combination R155KþD168E (n ¼ 1), 805 with mutations at NS3 R155KþD168A (n ¼ 1, Q80Kþ positions 80 or 168 R155K (n ¼ 2) 806 7/18 (38.9) D168V, A, A/V, E or H D168V (n ¼ 2), D168A (n ¼ 2), 807 D168A/V (n ¼ 1), D168E 808 (n ¼ 1), D168H (n ¼ 1) 809 GT1b 17/20 (85.0) 8/17 (47.1) D168V 810 7/17 (41.2) D168A, E, T or E/V D168A (n ¼ 3), D168E or E/V 811 (n ¼ 3), D168T (n ¼ 1) 2/17 (11.8) Other Q80RþD168E/V(n ¼ 1), 812 Q80RþS122TþD168E (n ¼ 1) 813 814 NOTE. Considering a longer list of 18 NS3 amino acid positions that also includes NS3 positions that have been associated Q30 815 816 with resistance to other HCV NS3/4A protease inhibitors or that were considered of interest based on observations in 817 simeprevir in vitro or in vivo studies (18 NS3 amino acid positions of interest: 36, 41, 43, 54, 55, 80, 107, 122, 132, 138, 155, 156, 158, 168, 169, 170, 174, and 175), 4 patients had additional mutations: 1 HCV genotype 1a patient with Q80K at baseline 818 had a single emerging mutation I170T. I170T also was observed in another HCV genotype 1a patient without baseline Q80K in 819 combination with emerging R155K. One HCV genotype 1b patient had emerging V107I in combination with D168V and another 820 S174F in combination with D168V. Similar mutations were observed at other time points in patients not achieving SVR. 821 Emerging mutations beyond the 18 positions of interest in the NS3 protease domain were infrequent, the same mutation was 822 observed in no more than 1 patient and always in combination with emerging mutations at positions 80, 155, and/or 168. 823 Regarding NS3 positions 43, 80, 122, 155, 156, and 168, specific amino acid changes at 1 or more of these positions are either known to confer reduced susceptibility to simeprevir in vitro or have emerged during in vitro selection experiments. 824 GT1a, HCV genotype 1a; GT1b, HCV genotype 1b. 825 a Genotype 1a might include a few patients with non-1a/1b HCV genotype. 826 Simeprevir 150 mg þ PR (n ¼ 260)

Placebo þ PR (n ¼ 133)

Difference between groups (simeprevir–placebo, 95% CI)a

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Table 5.Adverse Events During the First 12 Weeks of Treatment (Simeprevir/Placebo Plus PR Treatment Phase) Patients, % Simeprevir 150 mg 12 weeks þ PR (n ¼ 260)

Patients, % Placebo þ PR (n ¼ 133)

First 12 weeks Any AE Grade 1 or 2 AE Grade 3 AE Grade 4 AE AE with fatal outcome SAE AE leading to permanent discontinuation of: At least 1 study drug Simeprevir/placebo and PR Simeprevir/placebo only PegIFNa-2a and/or RBV PegIFNa-2a only RBV only Most common AEsa Fatigue Headache Influenza-like illness AEs of clinical interest Rash Pruritus Neutropenia Photosensitivity Anemia

Simeprevir 150 mg 12 weeks þ PR (n ¼ 260)

Placebo þ PR (n ¼ 133)

Entire treatment phase

95.4 75.4 18.1 1.9 0 1.2

92.5 71.4 18.0 3.0 0 2.3

97.3 69.6 24.2 3.5 1 5.4

94.0 63.9 25.6 4.5 1 7.5

1.2 0.4 0 0.8 0 0

1.5 0 0 1.5 0 0

2.3 0.4 0 1.9 0 0

5.3 0 0 5.3 0 0.8

31.9 31.9 29.6

42.1 36.1 20.3

32.3 33.1 30.0

43.6 36.1 20.3

18.5 23.5 14.6 3.5 10.8

14.3 16.5 16.5 0 6.0

23.1 27.7 17.7 3.5 16.9

22.6 27.8 21.8 0 20.3

a AEs occurring in more than 25% of patients in the simeprevir group in the first 12 weeks and during the entire treatment phase.

meeting RGT criteria, but remained increased through week 48 in the placebo/PR group (Figure 2A–C). As a result, significantly lower fatigue, productivity impairment, and activity impairment was observed in simeprevir-treated compared with placebo-treated patients over the entire study period (P < .001). Similar trends were not observed for patient-reported time missed from work. Absenteeism scores for the subset of patients in the labor force at baseline showed no significant difference between groups (P ¼ .701; Figure 2D).

Discussion This study was performed to assess the efficacy and safety of simeprevir in combination with PR in patients with chronic HCV genotype 1 infection who had relapsed after previous IFN-based therapy. Oral, once-daily treatment with simeprevir 150 mg for 12 weeks in combination with PR followed by treatment for 12–36 weeks with PR was associated with a significant improvement in SVR12 in this patient population compared with that seen in the placebo control group. SVR in this study was defined as HCV RNA less than 25 IU/mL undetectable at actual EOT and less than

25 IU/mL detectable/undetectable 12 weeks after planned EOT; all simeprevir-treated patients who achieved SVR12 had undetectable levels at the SVR12 time point. Overall, 79.2% of simeprevir-treated patients achieved SVR12 compared with 36.1% of those who received PR alone. In this study, an RGT strategy was used to allow individualized shortening of PR treatment duration to 24 weeks based on early virologic response. A shorter overall treatment duration is highly desirable in patients with chronic HCV infection because it reduces exposure to PR, resulting in reduced costs and a lower incidence of treatment-related AEs.38–40 Almost all simeprevir-treated patients (92.7%) met RGT criteria and were eligible to stop PR at week 24. The SVR12 rate in these patients was 83.0%, supporting this treatment approach. Among the 77.2% of simeprevir-treated patients with RVR (HCV RNA <25 IU/mL undetectable at week 4), 86.5% achieved SVR12. As expected, the relapse rate in patients treated with simeprevir/PR was lower than in those who received PR alone (18.5% compared with 48.4%). In this study, more than 30% of patients had bridging fibrosis or cirrhosis (given that a 3-year biopsy window was allowed, the proportion of patients with cirrhosis may have

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945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 Q24 983 984 985 986 987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003

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1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 compared with patients without Q80K when treated with 1039 Q25 simeprevir in combination with PR (unpublished data). 1040 Results of this study are consistent with those of previ1041 ous studies of simeprevir in combination with PR in treat1042 ment-experienced30 and treatment-naive patients.27,33,34 1043 SVR24 rates of 75% and 83% have been reported for 1044 boceprevir and telaprevir, respectively, in combination with Q26 1045 PegIFN/RBV in patients who relapsed after prior IFN-based 1046 therapy.11,14 The SVR24 rates in the placebo control groups 1047 in these studies were 24% and 29%, respectively. The 1048 SVR24 rate was 69% in boceprevir-treated patients who 1049 were HCV RNA negative at weeks 8 and 12 and therefore 1050 eligible for a shorter overall duration of PegIFN/RBV (36 1051 weeks).11 No data concerning the potential for RGT with 1052 telaprevir in relapsed patients have been reported. 1053 The safety and tolerability profile of simeprevir/PR in 1054 the present study was generally similar to that of PR 1055 41 alone, with no additional treatment-related AEs reported. 1056 The improved virologic response rates achieved by addition 1057 of simeprevir to PR allowed a reduction in total treatment 1058 duration for most patients, which significantly reduced 1059 exposure to PR and time with treatment-related side effects 1060 overall for simeprevir-treated compared with placebo1061 treated patients. AEs were generally mild and clinically 1062 CLINICAL LIVER

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Figure 2. Change in score from baseline in (A) patient-reported fatigue, (B) productivity impairment, (C) activity impairment, and (D) absenteeism.

been underestimated; however, this approach was based on FDA guidance that was current at the time of patient enrolment in this trial). In patients with baseline METAVIR F3–F4 scores, SVR12 rates were significantly higher in those treated with simeprevir/PR than in those who received placebo/PR (73.5% vs 23.5%, respectively; P <.001). The SVR12 rates in simeprevir-treated patients were also higher than in those who received placebo/PR across IL28B genotypes (88.7% vs 52.9% for CC, 78.4% vs 33.7% for CT, and 64.5% vs 18.8% for TT; all P < .001). The SVR12 rates with simeprevir were lower in HCV genotype 1a patients who had the Q80K polymorphism at baseline compared with those without this polymorphism (46.7% vs 78.5%). The impact of the Q80K polymorphism on SVR varied depending on the presence of baseline characteristics associated with poor treatment outcome. As seen with patients with Q80K, the SVR rates differed based on week 4 virologic response. For example, among simeprevir-treated patients harboring Q80K who had RVR (13 of 29), most achieved SVR12 (76.9%). Although the Q80K variant itself only has limited effect on simeprevir activity, the resistance barrier for Q80K-carrying variants appears to be lower. This potentially facilitates the emergence of additional mutations, resulting in a higher treatment failure rate in Q80K patients

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manageable, with few grades 3/4 AEs or SAEs reported, and no patient discontinued simeprevir because of AEs. No increased incidence for simeprevir/PR compared with PR alone was seen for rash, pruritus, neutropenia, or anemia AEs, despite the fact that use of erythropoiesis-stimulating agents was not allowed in this study. These events were considered of clinical interest because an increased incidence has been reported with boceprevir and telaprevir.11–14,22 Mild and transient bilirubin increases were seen in simeprevir-treated patients; however, no concomitant increases in other laboratory liver parameters were observed. This finding may be associated with inhibition of bilirubin transporters OATP1B1 and MRP2 by simeprevir,42 although RBV-induced hemolysis also may cause bilirubin increases. The addition of simeprevir to PR did not increase patient-reported fatigue, productivity impairment, or activity impairment beyond what was observed in patients who received PR alone, but did shorten the duration of these treatment-related problems. In conclusion, the addition of simeprevir 150 mg once daily to PR substantially improved SVR rates in HCV genotype 1–infected patients who had relapsed after previous IFN-based therapy, irrespective of IL28B genotype, METAVIR score, HCV 1 subtype, or the presence of baseline polymorphisms. The majority of simeprevir-treated patients met RGT criteria, enabling a shorter, 24-week overall duration of PR treatment. The addition of simeprevir to PR generally was well tolerated, with safety and tolerability similar to PR alone. Ongoing studies are investigating simeprevir in both PegIFNa and IFN-free combinations, including all oral regimens.

Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at www.gastrojournal.org, and at http://dx.doi.org/10.1053/ j.gastro.2014.02.051.

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1181 23. 1182 1183 1184 1185 24. 1186 1187 1188 1189 1190 1191 25. 1192 1193 1194 26. 1195 1196 1197 1198 27. 1199 1200 1201 1202 28. 1203 1204 1205 1206 29. 1207 1208 1209 1210 30. 1211 1212 1213 1214 31. 1215 1216 1217 1218 1219 1220 1221 Q28 1222 32. 1223 1224 1225 1226 33. 1227 1228 1229 1230 1231 34. 1232 1233 1234 1235 1236 35. 1237 1238 1239

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36. Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and activity impairment instrument. Pharmacoeconomics 1993; 4:353–365. 37. McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med 2010;362:1292–1303. 38. Kwo PY. Response-guided therapy for HCV. Gastroenterol Hepatol (N Y) 2011;7:43–45. 39. McEwan P, Yuan Y, Litauen G, et al. Cost benefit analysis of response guided therapy: dynamic disease Markov modeling for patients with chronic hepatitis (HCV) by fibrosis stages. J Hepatol 2011;54:S461, abs 1167. 40. Reddy KR, Lin F, Zoulim F. Response-guided and -unguided treatment of chronic hepatitis C. Liver Int 2012;32(Suppl 1):64–73. 41. Sherman M, Yoshida EM, Deschenes M, et al. Peginterferon alfa-2a (40KD) plus ribavirin in chronic hepatitis C patients who failed previous interferon therapy. Gut 2006;55:1631–1638. 42. Huisman MT, Snoeys J, Monbaliu J, et al. In vitro studies investigating the mechanism of interaction between TMC435 and hepatic transporters. Poster 278 presented at the 61st Annual Meeting of the American Association for the Study of Liver Diseases, Boston, MA, October 29-November 2, 2010.

1240 1241 1242 1243 1244 1245 1246 1247 1248 1249 1250 1251 1252 1253 1254 1255 1256 1257 1258 1259 1260 1261 1262 1263 1264 1265 1266 1267 Received August 2, 2013. Accepted February 25, 2014. Q3 1268 Reprint requests Address requests for reprints to: Xavier Forns, MD, Liver Unit, Hospital Clinic, Q4 1269 Institut d’Investigacions Biomèdiques August Pi i Sunyer and Centro de 1270 Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Q5 1271 Barcelona, Spain. e-mail: [email protected]; fax: (xxx) xxx-xxxx. 1272 Q27 Acknowledgments 1273 The authors thank Chrissie Kouremenou of Complete Medical 1274 Communications, funded by Janssen. 1275 Conflicts of interest These authors disclose the following: Xavier Forns has received unrestricted Q6 1276 grant support from Jansen and MSD, and has acted as an advisor for Q7 1277 Jansen, MSD, and Abbott. Eric Lawitz has received research/grant support 1278 from AbbVie, Achillion Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix Pharmaceuticals, Intercept 1279 Pharmaceuticals, Janssen, Medtronic, Merck & Co, Novartis, Presidio, 1280 Roche, Santaris Pharmaceuticals, and Vertex Pharmaceuticals; has acted as 1281 a speaker for Gilead, Kadmon, Merck, and Vertex; and has participated in Advisory Boards for AbbVie, Achillion Pharmaceuticals, BioCryst, Biotica, 1282 Enanta, Idenix Pharmaceuticals, Janssen, Merck & Co, Novartis, Santaris 1283 Pharmaceuticals, Theravance, and Vertex Pharmaceuticals. Stefan Zeuzem has acted as a consultant for Abbvie, Achillion, BMS, Boehringer Ingelheim, 1284 Gilead, Idenix, Janssen, Merck, Novartis, Presidio, Roche, Santaris, and 1285 Vertex. Ed Gane has acted as an advisor for Janssen, Gilead, AbbVie, Novartis, Tibotec, Achillion, and Roche; and as a speaker for Gilead, Roche, 1286 and Novartis. Jean Pierre Bronowicki has been a clinical investigator, 1287 speaker, and/or consultant for Boehringer Ingelheim, Bristol-Myers Squibb, 1288 Gilead Sciences, Janssen Pharmaceuticals, Merck Sharp & Dohme, Novartis, and Roche. Pietro Andreone has received research grants from Gilead, MSD, 1289 and Roche, and has acted as an advisor for Janssen, MSD, and Roche; and 1290 as a consultant for BMS and MSD. Ashley Brown has acted as an advisor and/or speaker for Abbvie, Achillion, BMS, Boehringer Ingelheim, Gilead, 1291 Janssen, Merck, Novartis, Presidio, and Roche. Monika Peeters, Oliver Lenz, 1292 Rekha Sinha, and Maria Beumont–Mauviel are employees of Janssen Infectious Diseases. Sivi Ouwerkerk–Mahadevan is an employee of Janssen 1293 Research & Development. Jane Scott, Guy De La Rosa, and Ronald 1294 Kalmeijer are employees of Janssen Global Services, LLC. The remaining author discloses no conflicts. 1295 1296 Funding Q8 1297 Supported by Janssen. 1298

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1299 Supplementary Materials 1300 and Methods 1301 1302 Patients 1303 Patients with the following defined laboratory abnor1304 malities were excluded from the trial: platelets less than 1305 90,000/mm3, absolute neutrophil count less than 1500/ 1306 mm3, white blood cell count less than 3000/mL, hemoglobin 1307 level less than 12 g/dL for women and less than 13 g/dL for 1308 men, creatinine level greater than 1.5 mg/dL, alanine 1309 aminotransferase and/or aspartate aminotransferase level 1310 greater than 10 times the upper limit of laboratory normal 1311 range, total serum bilirubin level 1.5 times or more the 1312 upper limit of laboratory normal range, and a-fetoprotein 1313 level greater than 50 ng/mL in subjects with cirrhosis 1314 (METAVIR fibrosis score, F4). 1315 1316 Assessments 1317 Blood samples were collected at screening, on days 1, 3, 1318 Q31 7, 14, and 28, at 4-week intervals thereafter until week 28, 1319 at weeks 36, 42 and 48, and during follow-up evaluation 1320 (weeks 52, 60, and 72). 1321 Blood samples for biochemical and hematologic analyses 1322 were obtained at screening and during scheduled visits, 1323 when electrocardiogram, vital signs, and physical examina1324 tion assessments also were performed. 1325 1326 1327 1328 Results 1329 Patients 1330 Approximately 70% of patients were enrolled in Europe, 1331 22% in North America, and 8% in Australia and New 1332 1333 1334 1335 1336 1337 1338 1339 1340 1341 1342 1343 1344 1345 1346 1347 1348 1349 1350 1351 1352 1353 1354 1355 1356 1357

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Zealand. The majority of patients were male (65.6%), 94.4% were white, their median age was 52 years, and their median body mass index was 27.0 kg/m2. A significant proportion of patients had bridging fibrosis (METAVIR F3 [15.4%]) or cirrhosis (METAVIR F4 [15.2%]). All patients were infected with HCV genotype 1 (41.7% with HCV genotype 1a, and 58.0% with HCV genotype 1b). In terms of IL28B genotype, 24.4% had CC, 63.6% had CT, and 12.0% had TT. Most patients had received prior PegIFN-based therapy (67.7% had received PegIFNa-2a/RBV and 27.0% had received PegIFNa-2b/RBV). The median baseline HCV-RNA level was 6.5 log10 IU/mL (range, 3.1–7.7 log10 IU/mL), with 83.7% of patients having baseline HCV-RNA levels greater than 800,000 IU/mL. The Q80K polymorphism was present at baseline in 13.1% of patients (12.1% [31 of 257] in the simeprevir/PR group and 15.0% [20 of 133] in the placebo/PR group). Among the 51 patients with Q80K at baseline, only 1 was infected with HCV genotype 1b (enrolled in the simeprevir arm). The prevalence of Q80K at baseline among patients infected with HCV genotype 1a was 30.7% (50 of 163).

1358 1359 1360 1361 1362 1363 1364 1365 1366 1367 1368 1369 1370 1371 1372 1373 1374 1375 1376 1377 1378 1379 1380 Efficacy 1381 At the time of this primary week 60 analysis, the SVR24 assessment time point had been reached by 254 of Q32 1382 1383 260 patients in the simeprevir/PR group and by 64 of 1384 133 patients in the placebo/PR group. The SVR24 rate 1385 was higher among simeprevir-treated patients (78.3% 1386 [199 of 254] vs 31.3% [20 of 64]; adjusted difference, 1387 47.1%; 95% CI, 34.8–59.5; P < .001). All simeprevir1388 treated patients who achieved SVR24 had HCV-RNA 1389 levels less than 25 IU/mL undetectable at the SVR24 1390 time point. 1391 1392 1393 1394 1395 1396 1397 1398 1399 1400 1401 1402 1403 1404 1405 1406 1407 1408 1409 1410 1411 1412 1413 1414 1415 1416

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Supplementary Figure 1. Study design. Response-guided treatment in simeprevir (SMV) arm: if HCV-RNA level was less than 25 IU/mL at week 4 and undetectable at week 12, complete treatment at week 24. Stopping rules: if HCV-RNA level was greater than 1000 IU/mL at week 4, stop SMV/ placebo; if HCV-RNA level was less than 2 log10 IU/mL reduction at week 12, or confirmed 25 IU/mL or greater at week 24 or 36, stop all treatment. PR, peginterferon a-2a 180 mg/week þ ribavirin 1000–1200 mg/day; QD, once daily; SMV, simeprevir.

Supplementary Figure 2. Patient disposition.

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1535 Supplementary Table 1.Univariate Analyses of Baseline Characteristics, Pharmacokinetic Exposure Measures, and Early 1594 Response Parameters on SVR12 in the Simeprevir/PR Treatment Arm (Intent-to-Treat Population) 1536 1595 a 1537 1596 P value (likelihood ratio test) Significance level 1538 1597 .455 1539 Age, y 1598 level, U/L (nonlinear) .731 1540 Baseline ALT 1599 BMI, kg/m2 (nonlinear) .002 ** 1600 1541 Baseline HCV-RNA level, log10 IU/mL .080 1601 1542 Height, cm (nonlinear) .633 1543 Weight, kg (nonlinear) 1602 .052 1544 HCV genotype/subtype 1603 .002 ** <.001 *** 1545 Baseline Q80K 1604 .345 1546 Sex 1605 <.001 *** 1547 HCV genotype/subtype, baseline Q80K 1606 IL28B .023 * 1548 METAVIR score 1607 .299 1549 Race 1608 .583 1550 Region 1609 <.001 *** 1551 AUC24h (log10 ng$h/mL) 1610 .070 .081 1552 Q33 C0h (log10 ng/mL) 1611 <.001 *** 1612 1553 cEVR <.001 *** 1554 eRVR 1613 RVR <.001 *** 1555 HCV RNA <25 IU/mL at week 4 1614 <.001 *** 1556 1615 1557 1616 1558 NOTE. Generalized additive modeling methodology using cubic spline functions was applied in the analysis. Nonlinear 1617 1559 indicates that a cubic spline function with 2 degrees of freedom was used to model SVR12. 1618 ALT, alanine transaminase; AUC, area under the concentration-time curve; BMI, body mass index; cEVR, complete early Q34 1560 virologic response; eRVR, extended rapid virologic response. 1619 1561 aStatistical significance level of likelihood ratio test: *<.05, **<.01, ***<.001. 1620 1562 1621 1563 1622 1623 1564 1565 1624 1566 1625 1567 1626 1568 1627 1569 1628 1570 1629 1571 1630 1572 1631 1573 1632 1574 1633 1634 1575 1576 1635 1577 1636 1578 1637 1579 1638 1580 1639 1581 1640 1582 1641 1583 1642 1584 1643 1585 1644 1645 1586 1587 1646 1588 1647 1589 1648 1590 1649 1591 1650 1592 1651 1593 1652 FLA 5.2.0 DTD
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