Vaniprevir Plus Peginterferon Alfa-2B and Ribavirin in Treatment-Experienced Japanese Patients with Hepatitis C Virus Genotype 1 (Gt1b) Infection: Phase 3 Studies

Vaniprevir plus peginterferon alfa-2b and ribavirin in treatment-experienced Japanese patients with hepatitis C virus genotype 1 (GT1b) infection: phase 3 studies

Hiromitsu Kumada,* Satoshi Mochida,† Fumitaka Suzuki,* Kazuaki Chayama,‡ Yoshiyasu

Karino,§ Keisuke Nakamura,¶ Go Fujimoto,¶ Anita Y. M. Howea,** Steve W. Ludmerer** and

Niloufar Mobasherya,**

*Department of Hepatology, Toranomon Hospital, Kanagawa, †Department of

Gastroenterology & Hepatology, Saitama Medical University, Saitama, †Department of

Gastroenterology and Metabolism, Hiroshima University, Hiroshima, §Department of

Gastroenterology, Sapporo-Kosei General Hospital, Sapporo, and ¶MSD K.K., Tokyo, Japan;

**Merck & Co., Inc., Kenilworth, New Jersey USA aFormer employee of Merck & Co., Inc.

Correspondence

Dr. Fumitaka Suzuki, Department of Hepatology, Toranomon Hospital, 1-3-1 Kajigaya,

Takatsu-ku, Kawasaki, Kanagawa 213-8587, Japan

Telephone: +81-44-877-5111

Email: [email protected]

Abstract

Background and Aim: Vaniprevir is a macrocyclic hepatitis C virus (HCV) non-structural

(NS)3/4A protease inhibitor. The objective of these phase 3 multicenter, open-label trials was to evaluate the safety and efficacy of vaniprevir + peginterferon alfa-2b + ribavirin (PR) in

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/jgh.13328

Japanese patients with HCV genotype (GT)1 infection who had previously failed treatment with interferon-based regimens.

Methods: Japanese patients with chronic HCV GT1 were enrolled. In PN044, patients with previous relapse or virologic breakthrough were randomized to vaniprevir (300 mg twice daily) + PR for 12 weeks followed by PR for another 12 weeks (12-week arm) or vaniprevir

+ PR for 24 weeks (24-week arm). In PN045, patients with previous partial/null response received vaniprevir + PR for 24 weeks. The primary endpoint was sustained virologic response at 24 weeks after completing treatment (SVR24).

Results: In PN044 (n = 51), SVR24 was 92.0% and 96.2% in the 12- and 24-week arms, respectively. In PN045 (n = 42), SVR24 was 61.9% in all patients and 55.2% in previous null responders. In both studies, vaniprevir + PR was generally safe and well tolerated; the majority of adverse events were mild/moderate and included pyrexia, decreased hemoglobin, headache, nausea, pruritus, and decreased platelet count. Polymorphisms in the HCV NS3 gene at baseline (Y56, Q80, and V170) did not impact treatment outcome. Virologic failure was principally associated with the on-treatment emergence of R155 or D168 mutations.

Conclusions: Vaniprevir + PR is an effective, well-tolerated treatment for Japanese patients with HCV GT1 infection who failed previous interferon-based treatment.

ClinicalTrials.gov Identifier NCT01405937 and NCT01405560 (Protocols PN044 and

PN045)

Key words vaniprevir, hepatitis C virus, peginterferon, ribavirin, Japan

Introduction

Hepatitis C virus (HCV) affects approximately 2 million individuals in Japan, with an annual mortality of more than 30,000 owing to the development of hepatocellular carcinoma

(HCC).1 Development of highly effective treatment regimens for patients with HCV infection who have previously failed therapy represents a major global unmet need. In Japan, the direct-acting antiviral agents (DAAs) telaprevir and simeprevir, each in combination with pegylated interferon (peg-IFN) and ribavirin, are approved for the treatment of patients with

HCV genotype (GT)1 infection who have previously failed to achieve sustained virologic response (SVR). Recently, all oral treatment therapies for HCV GT1 infection have been approved in Japan (daclatasvir + asunaprevir; ledipasvir + sofosbuvir).2,3 Due to various limitations with these regimens, the need for additional effective regimens is warranted.

Vaniprevir is a macrocyclic HCV NS3/4A protease inhibitor with potent antiviral efficacy in vitro and in patients with HCV infection.4–7 A phase 3 study of vaniprevir + peginterferon alfa-2b + ribavirin (PR) in treatment-naïve Japanese patients with HCV GT1 infection showed that vaniprevir + PR was associated with SVR24 rates of 83.7% (12-week arm) and 84.5% (24-week arm), compared with 55.1% in patients receiving PR alone (P <

0.001).8 Herein, we report the results of two phase 3 studies of vaniprevir in previously relapsed and non-responder Japanese patients with HCV GT1 infection.

Methods

These studies were conducted in accordance with principles of Good Clinical Practice, approved by the appropriate institutional review boards and regulatory agencies, and are registered with ClinicalTrials.gov (NCT01405937 and NCT01405560; protocols: P044 and

P045).

Japanese patients aged 20 to 70 years with chronic, compensated, HCV GT1 infection who had previously failed treatment for HCV infection with an IFN-based therapy with or without ribavirin (≥60% adherence at 12 weeks) were enrolled. Patients were required to have HCV RNA levels ≥5.0 log10 IU/mL at screening and no evidence of cirrhosis or other

signs of advanced liver disease. Major exclusion criteria were previous treatment with investigational therapy or vaccine for HCV, coinfection with HIV or hepatitis B virus, or evidence of chronic hepatitis due to a non-HCV–related etiology.

Study design. These were phase 3, multicenter, open-label studies. Study PN044 enrolled patients with prior relapse or virologic breakthrough, and study PN045 enrolled patients with a prior partial or null response. Response to previous treatment was defined as: relapse

(undetectable HCV RNA at the end of treatment and subsequent detectable HCV RNA during follow-up); breakthrough (detectable HCV RNA on treatment after initially achieving undetectable HCV RNA); partial response (detectable but ≥2-log10 decrease in HCV RNA after 12 weeks of therapy); or null response (detectable and <2-log10 decrease in HCV RNA after 12 weeks of therapy).

In study PN044, patients were randomized to receive vaniprevir (300 mg BID) + peg-

IFN alfa-2b (1.5 µg/kg/wk) and ribavirin (600–1000 mg/d) (PR) for 12 weeks followed by

PR for 12 weeks (total treatment duration 24 weeks) or vaniprevir (300 mg BID) + PR for 24 weeks. Randomization (1:1) was stratified according to age (<65/≥65 years), site, and IL28B

(rs12979860) genotype (major: CC/minor: CT + TT). In study PN045, all patients received vaniprevir (300 mg BID) + PR for 24 weeks.

In both studies, post-treatment assessments were conducted at follow-up weeks 4, 12,

20, and 24. Dose reduction and interruption of PR were permitted as detailed in the protocol.

Vaniprevir dose adjustment was not permitted. Adherence was calculated as: (total administered dose for each medication/[defined dose by protocol × defined treatment days])

× 100 (%).

End points: In both studies, the primary efficacy end point was SVR24 (undetectable HCV

RNA 24 weeks after completing treatment). Secondary virologic end points included the

proportion of patients with undetectable HCV RNA at treatment week [TW]4 and 12, end-of- treatment response, and SVR at follow-up week 12. Virologic failure was defined as breakthrough (undetectable HCV RNA followed by HCV RNA >1000 IU/mL on therapy), incomplete virologic response/rebound (>1 log10 increase in HCV RNA from nadir with an

HCV RNA >1000 IU/mL), or relapse (detectable HCV RNA at two consecutive visits following the end of treatment after having undetectable HCV RNA at end of treatment).

Safety evaluations included adverse events (AEs), laboratory tests, physical examinations, electrocardiography (ECG), and vital sign assessments. AEs of special interest were: rash categorized as a serious AE (SAE); anemia; neutropenia; increased bilirubin; and gastrointestinal AEs (vomiting, nausea, and diarrhea). Baseline samples were tested for variants in HCV NS3 gene in all patients. Additional samples from patients who met the criteria for virologic failure were tested for resistance-associated variants (RAVs) at the time of failure and for an additional follow-up period as defined in the protocol. Additional testing for variants in the HCV NS5A gene was retrospectively conducted as part of exploratory research, using plasma samples collected at baseline, at the time of virologic failure, and through follow-up from GT1b-infected patients who consented to optional specimen collection for future biomedical research.

Assays. Serum HCV RNA concentrations. Serum HCV RNA levels were measured using

Roche COBAS® TaqMan® (Roche Diagnostics K.K., Tokyo, Japan) HCV auto assay. The limit of quantification (LoQ) was 1.2 log10 IU/mL (15 IU/mL) and the limit of detection

(LoD) was <1.2 log10 IU/mL, but with no specific value.

Resistance-associated variants. RAVs were assessed using the direct/population sequencing method in samples with a viral titer >1000 IU/mL. The HCV NS3/4A gene was amplified and

population sequenced and compared with the reference sequence GT1b_Con1 (Genbank

AJ238799). Resistance analysis focused on polymorphisms reported in patients who failed treatment with HCV protease inhibitors, including vaniprevir (V36, Q41, F43, T54, V55,

Y56, Q80, R155, A156, D168, and V170). In addition, L23, Q24, L28, R30, L31, P32, F37,

Q54, P58, Q62, A92, and Y93 were included in the analysis of variants within the NS5A gene.

NS3/4A and NS5A evaluations were performed independently, and the sensitivities of the assays are such that a given polymorphism must be present in at least 25% (NS3/4A) or 10%

(NS5A) of the total viral population to be detected. In vitro potency measurements were made using the replicon system as previously described.5 Mutants within the NS3 or NS5A genes were engineered into the GT1a_H77 or GT1b_Con1 replicons with stable cell lines generated using standard molecular biology techniques.

Statistics. In study PN044, target enrollment was approximately 25 patients per treatment arm to ensure that a response rate of 70% would result in 99% power to demonstrate that the proportion of patients achieving SVR24 in at least one treatment arm would exceed 20% at an overall two-sided, 5% alpha-level. In study PN045, target enrollment was approximately 40 patients, allowing estimation of SVR24 with a 95% confidence interval (CI) with a half-width of 15 percentage points.

In both studies, the full analysis set (FAS) population served as the primary population for efficacy analyses (all randomized patients who received ≥1 dose of study treatment). Patients were included in the treatment group to which they were randomized.

The All Patients-as-Treated (APaT) population was used for safety analyses (all randomized patients who received ≥1 dose of study treatment and had ≥1 safety assessment); however, unlike the FAS population, patients were included according to the treatment they actually received.

For the primary end points in study PN044, the response rates in treatment arms were compared to a reference rate using the exact test for a binomial proportion. In study PN045, the primary efficacy end point was estimated based on the proportion of patients achieving

SVR24 using a Clopper-Pearson exact 95% CI. The proportion of patients with AEs of special interest and corresponding 95% CIs were provided by treatment arm.

Results

Study PN044 was performed at 22 study sites in Japan between September 2011 and March

2013. In total, 62 patients with previous relapse or breakthrough were screened, and 51 were randomly assigned to receive vaniprevir for 12 (n=25) or 24 weeks (n=26). All patients but one completed treatment; one patient discontinued because of an AE of depression (Fig. 1).

Study PN045 was performed at 10 study sites in Japan between October 2011 and March

2013. Overall, of 43 patients with prior partial response/null response were screened, 42 were allocated to 24 weeks of vaniprevir + PR (one patient withdrew informed consent). Three patients failed to complete treatment (on-treatment virologic failure, n=2; discontinued because of an AE, n=1). All patients were Japanese with HCV GT1b infection (Table 1).

Virologic response. In both studies, there was a rapid decline in HCV RNA following start of treatment (Fig. S1). In study PN044, SVR24 was 92.0% (23/25) and 96.2% (25/26) in the 12- and 24-week treatment arms. The three patients who failed to attain SVR24 had undetectable

HCV RNA at the end of treatment and relapsed during follow-up (12-week arm, n=2; 24- week arm, n=1). In the 12- and 24-week arms, the proportions of patients with undetectable

HCV RNA at TW4 were 88.0% and 88.5%; all patients had undetectable HCV RNA at

TW12.

In study PN045, 61.9% (26/42) of patients achieved SVR24. Two patients had on- treatment virologic failure (breakthrough, n=1; incomplete virologic response/rebound, n=1), and 14 relapsed. Overall, 24 patients (57.1%) had undetectable HCV RNA at TW4 and 40

(95.2%) had undetectable HCV RNA at TW12.

Subgroup analyses indicate higher SVR24 in both studies with ≥80% adherence, younger age, and IL28B CC genotype (Table 2 and Table S1). In PN045, SVR24 was also lower in partial/null responders than in previous relapse/breakthrough patients.

Resistance-associated variants. Variants in HCV NS3 gene. Baseline sequences were available for all patients in study PN044: 31 of 51 patients (60.8%) had baseline RAVs

(Table 3). The most common variants at baseline were Y56F, Q80K/L, and V170I. All patients with baseline RAVs achieved SVR24. Three of 51 patients (5.9%) relapsed with

D168V virus detected at the time of failure (Table 4). None of these patients had RAVs at baseline. Virus from one of these patients also encoded an R155Q mutation at failure, but neither R155Q nor D168V were detected in a sample collected at an unscheduled visit 154 days later. D168V virus persisted through follow-up week 24 in the other two patients.

Baseline sequences were available for all 42 patients enrolled in study PN045.

Twenty-five patients (59.5%) had baseline RAVs, with mutations at Y56F (n=12, including three patients with a Y56F/Y mixed population), Q80L (n=5), and V170I (n=17, including three patients with a V170I/V mixed population) most commonly observed (Table 3). These variants conferred at most a modest shift in vaniprevir in vitro potency (1.0- to 8.2-fold)

(Table S2). In total, 14 of 26 patients with baseline RAVs (53.8%) achieved SVR24. With the exception of one patient, mutations at these positions did not emerge during vaniprevir-based treatment among patients who failed therapy.

Sixteen of 42 patients (38.1%) met the criteria for virologic failure in PN045 (relapse n=14; virologic breakthrough n=1; incomplete virologic response/rebound n=1; Table 4).

Mutations at D168 were detected at failure in 13 of these patients (81.3%), including 11 relapsers, one breakthrough, and one incomplete virologic response/rebound (Table 4).

Treatment-emergent D168A/I/N/S/T/V/Y mutations were observed, including several patients with mixed populations (D168D/V, n=1; D168A/I/T/V, n=1; and D168N/S/T/Y, n=1). No other RAVs emerged during treatment, with the exception of one patient with Q80L and D168H at failure. This patient was subsequently found to encode a low level of Q80L virus at baseline as measured by clonal sequencing (data on file, Merck & Co., Inc.), and the

D168H mutation emerged in the background of this baseline Q80L variant. A follow-up week

24 sequence was available for 12 of these patients, with wild-type D168 virus observed in seven patients at the final visit. Virus from three patients who relapsed did not encode mutations at either R155 or D168. One of these patients had Y56F polymorphism at baseline, but it is unlikely that this polymorphism contributed to failure as it does not confer a potency loss to vaniprevir (Table S2) and was commonly observed at baseline among patients who achieved SVR24. Neither of the other two patients had known RAVs at failure. One of these patients displayed a V170I/V polymorphism at baseline which resolved to V170 at failure, and the other had no known RAVs at either baseline or failure (Table 4).

Variants in HCV NS5A gene. Baseline samples from 46 patients were sequenced through the

HCV NS5A gene and showed the presence of RAVs in 39 patients (84.8%) (Table 5). The most commonly observed variant at baseline was F37L (22/39, 56.4%, including F37F/L or

F37F/I/L mixed populations). Generally, no apparent difference was observed in the prevalence of NS5A variants between SVR and non-SVR populations. An L31V variant was reported at baseline in 1/39 patient (2.6%); this patient achieved SVR24. Three patients

(7.7%) had a Y93Y/H mutation at baseline, two of whom achieved SVR24. There were no treatment-emerging mutations within NS5A (Table S3). Furthermore, no mutations emerged in the NS5A gene after treatment failure.

Safety. In both studies, the majority of AEs were mild/moderate in severity, with the most commonly reported AEs being pyrexia, decreased hemoglobin and headache in PN044, and pyrexia, nausea, pruritus, and decreased platelet count in PN045 (Table 6). Gastrointestinal

AEs, including nausea (33.3–38.5%); diarrhea (16.7–40.0%), and vomiting (16.7–28.0%), were common in both studies.

The frequencies of AEs of special interest were generally similar between patients with previous relapse and patients with previous non-response; all occurrences of AEs of special interest were mild or moderate in severity, and none resulted in treatment discontinuation (Table 6). There were no reports of serious rash in either study, and bilirubin elevations were uncommon (3.8–8.0%). In total, 52.4% to 65.4% of patients reported gastrointestinal AEs (vomiting, nausea, and diarrhea) of special interest. Two patients discontinued treatment because of an AE (depression and ALT/AST elevations); both were considered treatment related and recovered or became around normal after discontinuation.

Eight patients reported SAEs (Table 6). In PN044, 13 SAEs were reported in five patients

(12-week arm, n=2; 24-week arm, n=3). The SAEs included appendicitis, pneumonia aspiration, and depression in the 12-week arm, and diffuse large B-cell lymphoma, ankle fracture, contusion, rib fracture, spinal compression fracture, sternal fracture, back pain, chills, pallor, and vomiting in the 24-week arm. Of these, SAEs considered related to vaniprevir were depression (12-week arm) and back pain, chills, pallor, and vomiting (24- week arm). Back pain, chills, pallor, and vomiting were attributed to an overdose of vaniprevir 900 mg (above the total daily dose of 600 mg/day). All events were mild in

intensity and resolved within 1 hour without any further intervention. In PN045, there were three patients with SAEs (bacterial pneumonia, cervical vertebral fracture and loss of consciousness). Of these, bacterial pneumonia was related to peg-IFN, and except for the event of cervical vertebral fracture, all events resolved. There were no deaths, no SAEs leading to the discontinuation of vaniprevir, and no clinically meaningful differences in vital signs or ECG parameters from baseline.

Discussion

Data from these phase 3 studies indicate that addition of vaniprevir to PR represents a safe and effective therapeutic option for Japanese patients with HCV GT1 (GT1b) infection and previous treatment failure. These findings are consistent with high SVR rates previously shown with vaniprevir + PR in Western populations with HCV GT1 infection.9,10 In study

PN044, SVR24 rates were high in both treatment arms, indicating no incremental benefit associated with extending the duration of vaniprevir therapy from 12 to 24 weeks. Consistent with these outcomes, most patients had baseline characteristics associated with a favorable response to peg-IFN + ribavirin-based therapy, such as IL28B CC genotype and age <65 years. Conversely, most patients in study PN045 were aged ≥50 years with IL28B non-CC genotype. SVR24 in this study was 61.9%, with 16 patients failing to attain SVR. As in other studies with vaniprevir + PR, few patients experienced failure while receiving treatment.

We assessed polymorphisms at 11 amino acid positions in the NS3 region which have been previously reported as RAVs to the class of NS3 protease inhibitor including VAN and other PIs. In both studies, virologic failure was principally associated with the emergence of mutations at D168. These mutations were not detected at baseline and were rapidly lost during the follow-up period. All patients in study PN044 and 13 of 16 patients in study

PN045 who failed with a D168 mutation showed diminished levels of mutant virus in parallel

with an increase in levels of wild-type virus by the end of the follow-up period. The presence of other baseline variants including Y56F, Q80L and V170I that have been associated with failure in DAA regimens did not appear to impact outcome to vaniprevir-based treatment.

This is evidenced by their similar baseline prevalence among patients who achieved SVR and those who failed treatment. These observations are also supported by in vitro data confirming that mutations at residues other than R155, A156, or D168 have minimal impact on vaniprevir potency.5 Variants in the HCV NS5A gene are not anticipated to impact efficacy to vaniprevir because NS3 protease, not the NS5A gene product, is the drug target. Consistent with this, mutations within NS5A at loci linked to NS5A drug resistance do not impact vaniprevir potency in vitro (Table S2). However, the testing for NS5A gene was conducted to confirm that clinical outcome to vaniprevir-based treatment was not influenced by baseline

NS5A RAVs.

Safety observations were consistent with the known safety profile of vaniprevir + PR.

The incidence of gastrointestinal AEs (vomiting, nausea, and diarrhea) was generally high, although all were mild to moderate in severity. No gastrointestinal AEs or SAEs led to treatment discontinuation. There was no serious rash, and reports of other AEs of special interest were few.

In conclusion, results of these phase 3 studies indicate that addition of vaniprevir to

PR is an effective therapeutic option for Japanese patients with previous treatment failure.

Based on the results of these studies and a study in treatment-naïve patients,8 vaniprevir + PR has recently received approval for the treatment of Japanese treatment-naïve and treatment- experienced patients with HCV GT1 infection. In Japan, treatment-naïve patients and previously relapsed patients receive vaniprevir + PR for 12 weeks followed by PR for another

12 weeks (total treatment duration 24 weeks), and previous partial/null responder patients receive vaniprevir + PR for 24 weeks. Vaniprevir, therefore, provides a valuable addition to

the therapeutic options for Japanese HCV GT1-infected patients who are eligible for IFN- based treatment according to the JSH Guidelines for the Management of Hepatitis C Virus

Infection.11

Acknowledgements

We thank all patients, their families, investigators, and staff at the participating sites.

Investigators at the following 22 (PN044) and 10 (PN045) study sites in Japan participated in this study (ordered according to the site number assigned in the studies [study sites of PN045 are followed by study sites of PN044]): Yoshiyasu Karino (Sapporo Kosei-General Hospital),

Yasushi Matsuzaki (Tokyo Medical University Ibaraki Medical Center), Satoshi Mochida

(Saitama Medical University Hospital), Kazuhiko Koike (The University of Tokyo Hospital),

Hiromitsu Kumada (Toranomon Hospital Branch Hospital), Kenji Ikeda (Toranomon

Hospital), Satoko Suzuki (Juntendo University Hospital), Namiki Izumi (Musashino Red

Cross Hospital), Takeji Umemura (Shinshu University Hospital), Minoru Sakamoto

(University of Yamanashi Hospital), Masatoshi Ishigami (Nagoya University Hospital),

Yoichi Nishigaki (Gifu Municipal Hospital), Hidenori Toyoda (Ogaki Municipal Hospital),

Tetsuo Takehara (Osaka University Hospital), Toshihide Shima (Saiseikai Suita Hospital),

Hideki Hagiwara (Kansai Rosai Hospital), Masatoshi Kudo (Kinki University Hospital,

Faculty of Medicine), Yoshiiku Kawakami (Hiroshima University Hospital), Hideyuki

Nomura (Shin-Kokura Hospital), Makoto Nakamuta (National Hospital Organization Kyushu

Medical Center), Yutaka Sasaki (Kumamoto University Hospital), Osamu Yokosuka (Chiba

University Hospital), and Takayoshi Ito (Showa University Hospital).

We also thank Lisa Lupinacci, Stuart Black, Akiko Takase, Norio Abe, Tomona

Hirano, Takahiro Fukuhara, and Yoshiyuki Tanaka of Merck & Co., Inc., and MSD K.K. for their support in data analysis and/or preparation of this manuscript. This study was funded by

MSD K.K., a subsidiary of Merck & Co., Inc. Medical writing and editorial assistance were provided by Tim Ibbotson, PhD, and Beth McMahon-Wise, PhD, of ApotheCom, Yardley,

Pennsylvania, USA. This assistance was funded by Merck & Co., Inc..

Compliance with ethical requirements

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki

Declaration of 1975, as revised in 2008 (5). Informed consent was obtained from all patients for being included in the study.

Disclosures

Hiromitsu Kumada received lecture fees from MSD K.K., Sumitomo Dainippon Pharma,

Toray, Mitsubishi Tanabe Pharma, Glaxo Smith Kline K.K., Bristol-Myers Squibb, and

Janssen Pharmaceutical K.K. Satoshi Mochida received lecture fees from Bristol-Myers

Squibb, MSD K.K., Ajinomoto Pharmaceuticals, and Toray Medical; consigned/joint research expenses from Bristol-Myers Squibb, and Mitsubishi Tanabe Pharma; and scholarship donations from Bristol-Myers Squibb, MSD K.K., Eisai, Toray Medical, Chugai

Pharmaceutical, and Mitsubishi Tanabe Pharma. Fumitaka Suzuki received lecture fees from

MSD K.K and Bristol-Myers Squibb. Kazuaki Chayama received lecture fees from MSD

K.K., Sumitomo Dainippon Pharma, Toray Medical, and Chugai Pharmaceuticals; and scholarship donations from MSD K.K., Sumitomo Dainippon Pharma, Toray Medical, and

Chugai Pharmaceuticals. Yoshiyasu Karino received lecture fees from Bristol-Myers Squibb.

Keisuke Nakamura is an employee of MSD K.K. and has stock ownership in Merck. Go

Fujimoto is an employee of MSD K.K. Anita Y.M. Howe is a former employee of Merck and a current employee of British Columbia Center for Excellence in HIV/AIDS, a non-profit

organization. She has no conflict of interest. Steven W. Ludmerer is an employee of Merck.

Niloufar Mobashery is an employee of AbbVie, a former employee of Merck, and has stock ownership in Merck and AbbVie.

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Table 1 Patient demographics

Relapse study Null responder

study

Vaniprevir Vaniprevir Vaniprevir

12-week arm 24-week arm 24-week arm

n = 25 n = 26 n = 42

Sex, n (%)

Men 12 (48.0) 12 (46.2) 25 (59.5)

Women 13 (52.0) 14 (53.8) 17 (40.5)

Age, years

Median (range) 60.0 (30–68) 62.5 (46–70) 60.5 (26–69)

≥65, n (%) 6 (24.0) 7 (26.9) 10 (23.8)

HCV genotype, n (%)

GT1b 25 (100) 26 (100) 42 (100)

Baseline HCV RNA, mean 6.6 ± 0.5 6.5 ± 0.7 6.6 ± 0.6

(log10 IU/mL ± SD)

IL28B (rs12979860), n (%)

CC 18 (72.0) 20 (76.9) 5 (11.9)

CT 7 (28.0) 6 (23.1) 36 (85.7)

TT 0 (0.0) 0 (0.0) 1 (2.4)

IL28B (rs8099917), n (%)

TT 19 (76.0) 20 (76.9) 6 (14.3)

TG 6 (24.0) 6 (23.1) 35 (83.3)

GG 0 (0.0) 0 (0.0) 1 (2.4)

Response to prior treatment, n (%)

Relapse 19 (76.0) 24 (92.3) 0 (0.0)

Breakthrough 6 (24.0) 2 (7.7) 0 (0.0)

Partial response 0 (0.0) 0 (0.0) 13 (31.0)

Null response 0 (0.0) 0 (0.0) 29 (69.0)

Prior treatment, n (%)

IFN only 0 (0.0) 2 (7.7) 1 (2.4)

IFN + RBV 0 (0.0) 2 (7.7) 4 (9.5)

Peg-IFN only 2 (8.0) 1 (3.8) 1 (2.4)

Peg-IFN + RBV 23 (92.0) 21 (80.8) 36 (85.7)

Neutrophils (/µL)

Mean ± SD 2976.4 ± 1313.5 2529.9 ± 751.9 2780.1 ± 1167.5

Median (range) 2747.0 (1560.0– 2390.7 (1560.0– 2456.8 (1541.0–

7710.0) 3994.0) 7627.7)

Hemoglobin (g/dL)

Mean ± SD 14.5 ± 1.6 14.2 ± 1.2 14.6 ± 1.2

Median (range) 13.9 (12.0–17.6) 14.3 (12.1–16.1) 14.8 (12.0–16.8)

Platelets (104/µL)

Mean ± SD 18.3 ± 4.5 18.2 ± 4.5 17.4 ± 4.3

Median (range) 17.1 (11.6– 27.2) 17.4 (10.9– 32.1) 16.9 (10.4– 31.9)

HCV, hepatitis C virus; IFN, interferon; Peg-IFN, pegylated interferon; RBV, ribavirin; SD standard deviation.

Table 2 Virologic response rates

Relapse study Null responder

study

Vaniprevir Vaniprevir Vaniprevir

12-week arm 24-week arm 24-week arm

(n = 25) (n = 26) (n = 42)

SVR24, n/N (%)

All 23/25 (92.0) 25/26 (96.2) 26/42 (61.9)

SVR24 by subgroup, n/N (%)

Age, years

< 65 18/19 (94.7) 18/19 (94.7) 22/32 (68.8)

≥ 65 5/6 (83.3) 7/7 (100) 4/10 (40.0)

Sex

Men 12/12 (100) 11/12 (91.7) 14/25 (56.0)

Women 11/13 (84.6) 14/14 (100) 12/17 (70.6)

IL28B (rs12979860)

CC 17/18 (94.4) 19/20 (95.0) 5/5 (100)

CT/TT 6/7 (85.7) 6/6 (100) 21/37 (56.8)

Adherence, vaniprevir (% dosage received)

< 80% adherent — 1/1 (100) 0/3 (0.0)

≥ 80% adherent 23/25 (92.0) 24/25 (96.0) 26/39 (66.7)

Adherence, peg-IFN (% dosage received)

<80% adherent 1/1 (100) — 3/8 (37.5)

≥80% adherent 22/24 (91.7) 25/26 (96.2) 23/34 (67.6)

Adherence, ribavirin (% dosage received)

<80 % adherent 4/4 (100) 3/3 (100) 4/8 (50.0)

≥80 % adherent 19/21 (90.5) 22/23 (95.7) 22/34 (64.7)

Response to previous treatment

Relapse 19/19 (100.0) 23/24 (95.8) Not applicable

Breakthrough 4/6 (66.7) 2/2 (100.0) Not applicable

Partial response Not applicable Not 10/13 (76.9)

applicable

Null response Not applicable Not 16/29 (55.2)

applicable

Undetectable HCV RNA at TW4

Yes 20/22 (90.9) 22/23 (95.7) 18/24 (75.0)

No 3/3 (100) 3/3 (100) 8/18 (44.4)

Undetectable HCV RNA at TW12

Yes 23/25 (92.0) 25/26 (96.2) 26/40 (65.0)

No — — 0/1 (0.0)

Virologic failure, n/N (%)

Virologic breakthrough 0/25 (0.0) 0/26 (0.0) 1/42 (2.4)

Incomplete virologic 0/25 (0.0) 0/26 (0.0) 1/42 (2.4) response/rebound

Relapse 2/25 (8.0) 1/26 (3.8) 14/42 (33.3)

Virologic response, n/N (%)

Undetectable HCV RNA at TW4 22/25 (88.0) 23/26 (88.5) 24/42 (57.1)

Undetectable HCV RNA at TW12 25/25 (100.0) 26/26 (100.0) 40/42 (95.2)

End of treatment response 25/25 (100.0) 26/26 (100.0) 40/42 (95.2)

SVR at follow-up week 12 22/25 (88.0) 24/26 (92.3) 26/42 (61.9)

Relapse rate after treatment completion, n/N (%)

Relapse rate 2/25 (8.0) 1/26 (3.8) 14/40 (35.0)

Virologic breakthrough was defined as any patient who achieved undetectable HCV RNA and subsequently had an HCV RNA > 1000 IU/mL. Incomplete virologic response/rebound was defined as any patient who had a 1-log10 increase in HCV RNA from their nadir with an

HCV RNA > 1000 IU/mL. Relapse was defined as any patient who had two consecutive visits with detectable HCV RNA following end of all study treatment, after becoming undetectable on treatment. The second visit would be an unscheduled visit within 2 weeks of the first visit.

SVR24 sustained virologic response 24 weeks after completing treatment, peg-IFN pegylated interferon, HCV, hepatitis C virus; peg-IFN, pegylated interferon; SVR24, sustained virologic response 24 weeks after completing treatment; TW treatment week.

Table 3 Distribution of baseline RAVs in HCV NS3 gene among patients receiving vaniprevir-based treatment

Patients with SVR24 Patients with virologic failure

Relapse Relapse Null Relapse Relapse Null

study study responder study study responder

study study

Vaniprevir Vaniprevir Vaniprevir Vaniprevir Vaniprevir Vaniprevir

12-week 24-week 24-week 12-week 24-week 24-week

arm arm arm arm arm arm

(n = 23) (n = 25) (n = 26) (n = 2) (n = 1) (n = 16)

Patients 23 25 26 2 1 16 with sample sequenced, n

Patients 16/23 15/25 14/26 0 0 11/16 with (69.6) (60.0) (53.8) (68.8) specific

RAVs, n/N

(%)†

V36I 0 (0.0) 1 (6.7) 0 (0.0) — — 0 (0.0)

T54S 0 (0.0) 1 (6.7) 1 (7.1) — — 0 (0.0)

Y56F 5 (31.3) 7 (46.7) 6 (42.9) — — 3 (27.3)

Y56F/Y 1 (6.3) 0 (0.0) 2 (14.3) — — 1 (9.1)

Q80K 0 (0.0) 1 (6.7) 0 (0.0) — — 0 (0.0)

Q80L 5 (31.3) 2 (13.3) 4 (28.6) — — 1 (9.1)

D168D/E 0 (0.0) 1 (6.7) 0 (0.0) — — 0 (0.0)

V170I 9 (56.3) 10 (66.7) 9 (64.3) — — 5 (45.5)

V170I/V 0 (0.0) 2 (13.3) 0 (0.0) — — 3 (27.3)

V170T 1 (6.3) 0 (0.0) 0 (0.0) — — 0 (0.0)

†Expressed as a % of the total number of patients with any baseline NS3 RAV.

HCV, hepatitis C virus; NS, non-structural; RAVs, resistance-associated variants; SVR24, sustained virologic response 24 weeks after completing treatment.

Table 4 Listing of patients in vaniprevir arms who met virologic failure criteria and RAVs in

HCV NS3 gene detected at baseline, at failure, and during follow-up period

Treat Treat Geno IL2 Age Sex Treatm RAV Sample RAVs in NS3 ment ment type 8B (y) ent s in collection ~FU4 FU12 FU FU group failure (rs1 failure NS3 date for 20 24 catego 297 confir at RAVs in

ry 986 med base NS3 at

0) (study line failure‡

day)†

Rel Relaps 1b CC 66 F 260 No 335 Not Not D1 D1

apse e§ ne (FU20) applica applica 68 68

stud ble ble V V

Rel Relaps 1b CT 58 F 253 No 281 Not R155Q, Not Not

apse e§ ne (FU12) applica D168V coll coll

stud ble ecte ect

y 12 d ed

Rel Relaps 1b CC 64 M 260 No 272 Not D168V D1 D1

apse e§ ne (FU12) applica 68 68

stud ble V V

y 24

Treat Treat Geno IL2 Age Sex Treatm RAV Sample RAVs in NS3 ment ment type 8B (y) ent s in collection ~FU4 FU12 FU FU group failure (rs1 failure NS3 date for 20 24 catego 297 confir at RAVs in

ry 986 med base NS3 at

0) (study line failure‡

day)†

Null Relaps 1b CT 56 M 253 Q8 274 Not Q80L, Q8 Q8

resp e§ 0L (FU12) applica D168D/ 0L, 0L,

ond , ble V, D1 D1

er V1 V170I 68 68

stud 70I D/ D/

y 24 V, V,

wk V1 V1

70I 70I

Null Relaps 1b CT 67 M 253 Y5 262 Not Q80L, Q8 Q8

resp e§ 6F (FU12) applica D168H 0L 0L

ond ble

stud

y 24

Null Relaps 1b CT 67 M 197 V1 211 D168T D168T D1 D1

resp e§ 70I (FU4) 68T 68

ond /V T

Treat Treat Geno IL2 Age Sex Treatm RAV Sample RAVs in NS3 ment ment type 8B (y) ent s in collection ~FU4 FU12 FU FU group failure (rs1 failure NS3 date for 20 24 catego 297 confir at RAVs in

ry 986 med base NS3 at

0) (study line failure‡

day)†

stud

y 24

Null Relaps 1b CT 63 F 201 V1 212 D168V, D168D/ V1 V1

resp e§ 70I (FU4) V170I H/L/V, 70I 70I

ond V170I

stud

y 24

Null Relaps 1b CT 58 F 197 V1 205 D168V, V170I V1 V1

resp e§ 70I (FU4) V170I 70I 70I

ond

stud

y 24

Treat Treat Geno IL2 Age Sex Treatm RAV Sample RAVs in NS3 ment ment type 8B (y) ent s in collection ~FU4 FU12 FU FU group failure (rs1 failure NS3 date for 20 24 catego 297 confir at RAVs in

ry 986 med base NS3 at

0) (study line failure‡

day)†

Null Relaps 1b CT 65 F 204 Y5 211 Y56F, Not Not Not

resp e§ 6F (FU4) D168V collecte coll coll

ond d ecte ect

er d ed

stud

y 24

Null Relaps 1b CT 43 M 254 V1 310 Not Not No No

resp e§ 70I (FU20) applica applica ne ne

ond /V ble ble

stud

y 24

Null Relaps 1b CT 48 M 253 V1 267 Not D168V, D1 V1

resp e§ 70I (FU12) applica V170I 68 70I

ond ble D/

er V,

Treat Treat Geno IL2 Age Sex Treatm RAV Sample RAVs in NS3 ment ment type 8B (y) ent s in collection ~FU4 FU12 FU FU group failure (rs1 failure NS3 date for 20 24 catego 297 confir at RAVs in

ry 986 med base NS3 at

0) (study line failure‡

day)†

stud V1

y 24 70I

Null Relaps 1b CT 47 M 253 Y5 274 Not Y56F Y5 Y5

resp e§ 6F/ (FU12) applica 6F 6F

ond Y ble

stud

y 24

Null Relaps 1b CT 51 M 113 Y5 127 Y56F, Y56F, Y5 Y5

resp e§ 6F, (FU4) D168V, D168V, 6F, 6F,

ond V1 V170I V170I V1 V1

er 70I 70I 70I

stud

y 24

Null Relaps 1b CT 67 F 197 No 225 D168A D168A/ D1 No

Treat Treat Geno IL2 Age Sex Treatm RAV Sample RAVs in NS3 ment ment type 8B (y) ent s in collection ~FU4 FU12 FU FU group failure (rs1 failure NS3 date for 20 24 catego 297 confir at RAVs in

ry 986 med base NS3 at

0) (study line failure‡

day)†

resp e§ ne (FU4) /I/T/V I/T/V 68 ne

ond X

stud

y 24

Null Relaps 1b CT 67 M 197 No 204 D168T D168A/ D1 D1

resp e§ ne (FU4) T 68 68

ond A/I/ A/I

er T/V /T/

stud V

y 24

Null Incom 1b CT 68 F 85 No 92 (On D168N D168T D1 D1

resp plete ne treatme ‡‡/S‡‡/T 68T 68

ond virolo nt) /Y† N/

er gic T

stud respon

Treat Treat Geno IL2 Age Sex Treatm RAV Sample RAVs in NS3 ment ment type 8B (y) ent s in collection ~FU4 FU12 FU FU group failure (rs1 failure NS3 date for 20 24 catego 297 confir at RAVs in

ry 986 med base NS3 at

0) (study line failure‡

day)†

y 24 se/reb

wk ound¶

Null Relaps 1b CT 26 M 260 No 330 Not Not No No

resp e§ ne (FU20) applica applica ne ne

ond ble ble

stud

y 24

Null Virolo 1b CT 61 M 113 V1 134 D168V, D168V, D1 D1

resp gic 70I (On V170I V170I 68 68

ond breakt /V treatme V, D/

er hroug nt) V1 V,

stud h†† 70I V1

y 24 70I

Null Relaps 1b CT 63 M 197 No 206 D168Y D168D/ No No

resp e§ ne (FU4) Y ne ne

Treat Treat Geno IL2 Age Sex Treatm RAV Sample RAVs in NS3 ment ment type 8B (y) ent s in collection ~FU4 FU12 FU FU group failure (rs1 failure NS3 date for 20 24 catego 297 confir at RAVs in

ry 986 med base NS3 at

0) (study line failure‡

day)†

ond

stud

y 24

These variants encompass amino acid residues 36, 41, 43, 54, 55, 56, 80, 155, 156, 168, and

170 in NS3 gene.

†Confirmed study day was the time of the first visit in two consecutive visits.

‡At failure includes the testing result obtained with the samples collected at failure, or if they

were unavailable the next available sample.

§Any patient who had two consecutive visits with detectable HCV RNA following end of all

study treatment, after becoming undetectable on treatment. The second visit would be an

unscheduled visit within 2 weeks of the first visit.

¶At failure included the testing result using the samples collected at failure, or if unavailable

the next available sample.

††Any patient who achieved undetectable HCV RNA and subsequently had an HCV RNA

>1,000 IU/mL while on therapy.

‡‡The amino acid was detected only at the failure point.

FU, follow-up week; HCV, hepatitis C virus; NS, non-structural; RAVs, resistance-associated variants.

Table 5 Distribution of baseline RAVs in HCV NS5A gene among patients receiving

vaniprevir-based treatment

Patients with SVR24 Patient with virologic failure

Relapse Relapse Non- Relapse Relapse Non-

study study responder study study responder

study study

Vaniprevir Vaniprevir Vaniprevir Vaniprevir Vaniprevir Vaniprevir

12-week 24-week 24-week 12-week 24-week 24-week

arm arm arm arm arm arm

(n = 23) (n = 25) (n = 26) (n = 2) (n = 1) (n = 16)

Patients 12 15 12 1 0 6 with sample sequenced

Patients 11/12 10/15 11/12 1/1 (100) — 6/6 (100) with (91.2) (66.7) (91.7) specific

RAVs, n/N

(%)†

Q24K 2 (18.2) 0 1 (9.1) 0 — 0

Q24R 1 (9.1) 1 (10.0) 1 (9.1) 0 — 0

L28M 2 (18.2) 1 (10.0) 1 (9.1) 0 — 0

R30L 0 1 (10.0) 0 0 — 0

R30Q, 3 (27.3) 0 3 (27.3) 0 — 0

R30Q/R

L31V 1 (9.1) 0 0 0 — 0

F37L, 6 (54.5) 7 (70.0) 4 (36.4) 1 (100) — 4 (66.7)

F37F/L,

F37F/I/L

F37I 1 (9.1) 0 1 (9.1) 0 — 0

F37Y 0 1 (10.0) 0 0 — 0

Q54H, 1 (9.1) 4 (40.0) 5 (45.5) 0 — 3 (50.0)

Q54H/Q,

Q54H/L/Q,

Q54H/N/Y

Q54N 1 (9.1) 0 0 0 — 0

Q54Y 1 (9.1) 0 1 (9.1) 0 — 0

P58A 0 0 0 0 — 1 (16.7)

P58S, 2 (18.2) 1 (10.0) 2 (18.2) 0 — 0

P58P/S

Q62E/Q 0 1 (10.0) 0 0 — 0

Q62H 0 1 (10.0) 0 0 — 0

Q62R 0 0 1 (9.1) 0 — 0

A92A/T, 1 (9.1) 1 (10.0) 0 0 — 0

A92T

Y93H/Y 1 (9.1) 1 (10.0) 0 0 — 1 (16.7)

†Expressed as a % of the total number of patients with any baseline NS5A RAV.

HCV, hepatitis C virus; NS, non-structural; RAVs, resistance-associated variants; SVR24,

sustained virologic response 24 weeks after completing treatment.

Table 6 Adverse events (occurring at an incidence of ≥ 20% in any treatment arm)

Adverse events, n (%) Relapse study Null responder study

Vaniprevir Vaniprevir Vaniprevir

12-week arm 24-week arm 24-week arm

(n = 25) (n = 26) (n = 42)

Any AE 24 (96.0) 26 (100) 42 (100)

Serious AE 2 (8.0) 3 (11.5) 3 (7.1)

Deaths 0 (0.0) 0 (0.0) 0 (0.0)

Discontinued due to an AE 1 (4.0)† 0 (0.0) 1 (2.4)‡

Discontinued due to a serious AE 1 (4.0)† 0 (0.0) 0 (0.0)

AEs, n (%)

Pyrexia 20 (80.0) 19 (73.1) 25 (59.5)

Hemoglobin decreased 12 (48.0) 12 (46.2) 5 (11.9)

Headache 11 (44.0) 11 (42.3) 12 (28.6)

Malaise 10 (40.0) 7 (26.9) 12 (28.6)

Diarrhea 10 (40.0) 7 (26.9) 7 (16.7)

Nausea 9 (36.0) 10 (38.5) 14 (33.3)

White blood cell decreased 8 (32.0) 10 (38.5) 7 (16.7)

Vomiting 7 (28.0) 5 (19.2) 7 (16.7)

Neutrophil count decreased 7 (28.0) 10 (38.5) 13 (31.0)

Alopecia 7 (28.0) 10 (38.5) 13 (31.0)

Decreased appetite 7 (28.0) 8 (30.8) 4 (9.5)

Nasopharyngitis 7 (28.0) 6 (23.1) 10 (23.8)

Stomatitis 7 (28.0) 4 (15.4) 6 (14.3)

Rash 6 (24.0) 6 (23.1) 10 (23.8)

Pruritus 6 (24.0) 11 (42.3) 14 (33.3)

Insomnia 6 (24.0) 5 (19.2) 3 (7.1)

Platelet count decreased 5 (20.0) 5 (19.2) 14 (33.3)

Abdominal discomfort 5 (20.0) 7 (26.9) 3 (7.1)

Cough 5 (20.0) 1 (3.8) 3 (7.1)

Injection site reaction 3 (12.0) 7 (26.9) 12 (28.6)

Anemia 3 (12.0) 4 (15.4) 12 (28.6)

Fatigue 2 (8.0) 3 (11.5) 6 (14.3)

Abdominal pain upper 2 (8.0) 2 (7.7) 9 (21.4)

Dysgeusia 1 (4.0) 4 (15.4) 10 (23.8)

AEs of special interest, n (%)

Any event 22 (88.0) 22 (84.6) 33 (78.6)

Anemia/hemoglobin decreased 14 (56.0) 16 (61.5) 17 (40.5)

Bilirubin increased 2 (8.0) 1 (3.8) 3 (7.1)

Gastrointestinal AEs 16 (64.0) 17 (65.4) 22 (52.4)

Neutropenia/neutrophil count 10 (40.0) 11 (42.3) 17 (40.5)

decreased

†Depression.

‡Increased ALT and AST.

AEs, adverse events; ALT, alanine transaminase; AST, aspartate aminotransferase.

Figure Legend

Figure 1 Patient disposition. IVR, incomplete virologic response; PR, peginterferon alfa-2b

+ ribavirin.