naive patients with hepatitis C virus genotype 1 infection

Journal of Viral Hepatitis, 2015

doi:10.1111/jvh.12464

Grazoprevir plus peginterferon and ribavirin in treatmentnaive patients with hepatitis C virus genotype 1 infection: a randomized trial M. Lagging,1 A. Brown,2 P. S. Mantry,3 A. Ramji,4 F. Weilert,5 J. M. Vierling,6 A. Howe,7 I. N. Gendrano III,7 P. Hwang,7 B. Zhang,7 J. Wahl,7 M. Robertson7 and N. Mobashery7,* 1

Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 2Imperial College Healthcare NHS Trust, St

Mary’s Hospital, London, UK; 3The Liver Institute at Methodist Dallas Medical Center, Dallas, TX, USA; 4University of British Columbia, Vancouver, BC, Canada; 5Waikato District Health Board, Hamilton, New Zealand; 6Baylor College of Medicine, Houston, TX, USA; and 7Merck & Co. Inc., Kenilworth, NJ, USA Received June 2015; accepted for publication August 2015

SUMMARY. Grazoprevir (MK-5172, Merck & Co., Inc.) is a

selective inhibitor of the hepatitis C virus (HCV) NS3/4a protease. The aim of this study was to evaluate the safety and efficacy of grazoprevir at doses of 25–100 mg/day in combination with peginterferon and ribavirin (PEG-IFN/ RBV). In this randomized, dose-ranging, multicentre trial, treatment-naive adults with chronic HCV genotype 1 infection received once-daily grazoprevir 25 mg, 50 mg or 100 mg plus PEG-IFN/RBV for 12 weeks. Patients with quantifiable HCV RNA (≥25 IU/mL) at week 4 received an additional 12 weeks of PEG-IFN/RBV. The primary endpoint was sustained virologic response (HCV RNA 25% of the viral population. Predose plasma samples were evaluated for impact of baseline polymorphisms on treatment outcome. Samples were assayed in patients with virologic failure to determine the development of RAVs. Polymorphisms at amino acid loci prone to resistance selection by protease inhibitors were evaluated (amino acid positions 36, 54, 55, 56, 80, 107, 122, 132, 155, 156, 158, 168, 170 and 175).

Statistical analysis The study aimed to randomly assign approximately 30 patients in each treatment arm. Assuming a protocol violation rate of 10%, the per-protocol population was expected to include 27 patients per arm. If the true SVR12 rate is approximately 89% (24 of 27), the exact 95% confidence interval (CI) is 70.8% to 97.6%. The per-protocol population served as the primary population for the analysis of efficacy and excluded patients because of important deviations from the protocol that may have substantially affected the results. This allows for an assessment of efficacy as specified in the protocol, considered appropriate for a phase 2 trial. The all-subjects-as-treated (ASaT) population was used for safety analyses, and consisted of all randomly assigned patients who received at least one dose of treatment. Patients were included in the ASaT group according to the treatment they actually received. For the primary efficacy analysis to estimate the proportions of patients achieving SVR12, 95% CIs were calculated using the Clopper–Pearson method. For missing data, the observed failure approach was used for the per-protocol population. Patients who (1) discontinued treatment because of lack of efficacy or (2) discontinued following confirmed HCV RNA TD(q) during follow-up were considered as failures thereafter. Otherwise, any patient missing an HCV RNA evaluation was excluded from the analysis at that time point. The key secondary endpoint was analysed

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using summary statistics to characterize the time to first achievement of undetectable (TND) HCV RNA. Summary statistics were provided to describe the rates of virologic failure. The proportion of patients with events of clinical interest [gastrointestinal AEs (vomiting, nausea and diarrhoea) and AEs of elevated transaminases (first instance of ALT or AST >500 IU/L 1; first instance of ALT or AST >3 9 baseline and >100 IU/L 1) or bilirubin] were provided per treatment arm along with corresponding 95% CIs. The percentage of patients with any AE, a drug-related AE, a serious AE, an AE which was both drug-related and serious and patients who discontinued because of an AE were summarized in the same manner. Safety and AEs were assessed on treatment and through to follow-up week 24.

RESULTS Baseline demographics The study was initiated in December 2012 and completed in January 2014. Overall, 136 patients were screened for inclusion, and 87 were randomly assigned (Fig. 1). All 87 patients received at least one dose of therapy (ASaT population), and 85 (98%) completed all protocol-specified study visits. One patient in each treatment arm discontinued therapy because of an AE, and one patient discontinued grazoprevir 100 mg because of breakthrough viraemia. This patient had undetectable serum grazoprevir at the time of failure due to presumed noncompliance and was excluded from the per-protocol population. In total, 12 patients were excluded from the per-protocol population (25 mg, n = 5; 50 mg, n = 3; 100 mg, n = 4; additional details regarding these patients are provided in Table S1). Demographic characteristics were generally similar across treatment groups (Table 1).

Efficacy Patients receiving grazoprevir 100 mg achieved HCV RNA TND at a slightly earlier time than patients in the lower dose arms (median time to first HCV RNA TND of 16 days vs 22 days in both the 25-mg and 50-mg arms) (Table 2). All patients but one had HCV RNA TND or TD(u) at week 4 and received 12 weeks of therapy. The patient who received an extra 12 weeks of PEG-IFN/RBV was in the 25-mg arm and was one of the two patients with endof-treatment failure (both receiving grazoprevir 25 mg). All patients in the grazoprevir 100-mg arm were HCV RNA TND at the end of treatment. SVR12 was highest in patients receiving grazoprevir 100 mg (88%) and lowest in patients receiving grazoprevir 25 mg (54%) (Fig. 2). One patient with GT1a infection receiving grazoprevir 100 mg achieved SVR12 but relapsed after follow-up week 12. SVR 24 weeks after the

© 2015 Merck. Journal of Viral Hepatitis Published by John Wiley & Sons Ltd.

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M. Lagging et al. Screened n = 136 Randomized n = 87

Grazoprevir 25 mg + PEG-IFN/RBV for 12 weeks n = 29



Completed treatment, n = 28 Completed treatment, n = 27 Discontinued, n = 1 Discontinued, n = 1 • AE, n = 1 • AE, n = 1

Completed treatment, n = 28 Discontinued, n = 2 • AE, n = 1 • Lack of efficacy, n = 1

Completed treatment, n = 27 Completed follow-up, n = 28 Discontinued, n = 2 • Lost to follow-up, n = 2

Completed follow-up, n = 30

Fig. 1 Patient disposition. Abbreviations: AE, adverse event; PEGIFN/RBV, peginterferon plus ribavirin.

Table 1 Patient characteristics (ASaT population) Grazoprevir + PEG-IFN + RBV for 12 weeks

Men, n (%) Age, median (range), years Weight, median (range), kg BMI, median (range), kg/m 2 Race,* n (%) Asian Black/African American White Hispanic/Latino IL28B non-CC, n (%) HCV genotype, n (%) GT1a GT1 non-a Baseline HCV RNA >800 000 IU/mL 1, n (%) Hepatic fibrosis stage,† n (%) F0–F2 F3

25 mg (n = 29)

50 mg (n = 28)

100 mg (n = 30)

All (n = 87)

21 53.0 91 29

10 50.5 80 27

15 49.5 69 25

46 51.0 78 27

0 5 22 3 23

(72.4) (37–70) (60–121) (19–39) (0.0) (17.2) (75.9) (10.3) (79.3)

1 4 23 2 22

(35.7) (20–65) (55–114) (19–46) (3.6) (14.3) (82.1) (7.1) (78.6)

1 6 21 4 25

(50.0) (21–66) (51–117) (20–37) (3.3) (20.0) (70.0) (13.5) (83.3)

2 15 66 9 70

(52.9) (20–70) (51–121) (19–46) (2.3) (17.2) (75.9) (10.3) (80.5)

24 (82.8) 5 (17.2)

25 (89.3) 3 (10.7)

22 (73.3) 8 (26.7)

71 (81.6) 16 (18.4)

21 (72.4)

20 (71.4)

19 (63.3)

60 (69.0)

27 (93.1) 2 (6.9)

24 (85.7) 4 (14.3)

28 (93.3) 2 (6.7)

79 (90.8) 8 (9.2)

ASaT, all subjects as treated; BMI, body mass index; GT, genotype; HCV, hepatitis C virus; PEG-IFN, pegylated interferon; RBV, ribavirin. *Two patients receiving grazoprevir 25 mg and two patients receiving grazoprevir 100 mg categorized themselves as multiracial. † Hepatic fibrosis stage was assessed by biopsy for 34 of the 79 patients in the Metavir F0 to F2 category and for all eight patients in the Metavir F3 category. Fibrosis stage was assessed by noninvasive methods for the other patients. end of treatment was therefore achieved by 54%, 84% and 85% of patients receiving 25, 50 and 100 mg of grazoprevir, respectively. SVR12 rates were similar across various selected patient subgroups (Table 3), but it is noteworthy that all 13 patients with IL28B CC genotype

and 10 of 11 patients with HCV GT1 non-a infection achieved SVR12. Rates of virologic failure were 16% (4/25) and 15% (4/26) in the grazoprevir 50-mg and 100-mg arms compared with 46% (11/24) in the 25-mg arm. In total, there


Grazoprevir plus peginterferon/ribavirin Table 2 Time to undetectable HCV RNA

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Grazoprevir + PEG-IFN + RBV for 12 weeks 25 mg (n = 29)

50 mg (n = 27)

Time to undetectable HCV RNA, days Median 22.0 (15.0, 22.0) 22.0 (95% CI) Mean (SE) 21.8 (2.1) 23.0 Patients with undetectable HCV RNA, % Week 2 10/29 (34.5) 8/25 Week 4 23/28 (82.1) 20/26 Week 12 27/28 (96.4) 24/26 EOT 24/26 (92.3) 23/25

100 mg (n = 30)

(15.0, 23.0)

16.0 (15.0, 22.0)

(2.2)

19.2 (1.6)

(32.0) (76.9) (92.3) (92.0)

16/29 26/29 28/28 26/26

(55.2) (89.7) (100) (100)

CI, confidence interval; EOT, end of treatment; HCV, hepatitis C virus; PEG-IFN, pegylated interferon; RBV, ribavirin; SE, standard error.

84.0

SVR12, % of patients

100

75

88.5

54.2

50

25

0

13/24 Grazoprevir 25 mg

21/25

23/26

Grazoprevir 50 mg

Grazoprevir 100 mg

Fig. 2 SVR 12 weeks after the end of all study therapy (PP population). CI, confidence interval. PP, per protocol; SVR, sustained virologic response; SVR12, sustained virologic response HCV RNA 800 000 IU/mL 8/18 Hepatic fibrosis stage, n/N (%) METAVIR F0–F2 12/22 METAVIR F3 1/2

50 mg (n = 25)

Table 3 SVR12 in selected patient subgroups (PP population)

100 mg (n = 26)

(54.2)

21 (84.0)

23 (88.5)*

(47.1) (71.4)

8/9 (88.9) 13/16 (81.3)

12/13 (92.3) 11/13 (84.6)

(100.0) (0) (55.6)

6/6 (100.0) 3/6 (50.0) 12/13 (92.3)

4/4 (100.0) 8/9 (88.9) 11/13 (84.6)

(45.0) (100.0)

19/23 (82.6) 2/2 (100.0)

19/21 (90.5) 4/5 (80.0)

(83.3) (44.4)

6/7 (85.7) 15/18 (83.3)

10/10 (100.0) 13/16 (81.3)

(54.5) (50.0)

20/22 (90.9) 1/3 (33.3)

23/24 (95.8) 0/2 (0.0)

GT, genotype; HCV, hepatitis C virus; PP, per protocol; PEG-IFN, pegylated interferon; RBV, ribavirin; SVR, sustained virologic response; SVR12, HCV RNA 5 9 upper limit of normal (1302 U/L 1), ALT (119 IU/mL 1), AST (210 IU/ mL 1) and total bilirubin >2 9 upper limit of normal (2.43 mg/dL 1). The patient’s urine toxicology was positive for ethanol. Study therapy was discontinued on day 10 and all AEs and laboratory abnormalities resolved in 3 months after the last dose), but none of the three discontinued treatment. One serious AE was considered drug-related (abdominal pain), but was considered by the investigator to be due to PEG-IFN only. Transaminase elevations of clinical interest occurred in two patients. One case was the patient in the 100-mg arm who experienced myositis after 7 days of treatment. In a second patient from the grazoprevir 25-mg arm, laboratory assessments at follow-up week 12 revealed asymptomatic increases in AST of 128 U/L 1 and ALT of 125 U/L 1 (both >3 9 baseline) with no reported increase in bilirubin. This patient had virologic relapse at follow-up week 4, at which time ALT and AST levels were normal (ALT

14 U/L 1 and AST 28 U/L 1). At the virologic failure confirmation visit (approximately follow-up week 8), ALT was 44 U/L 1 and AST was 53 U/L 1. The elevated transaminases had resolved when retested 3 months later and were considered unrelated to study medication.

DISCUSSION Results from the present study indicate that combining grazoprevir (50 or 100 mg/day) with PEG-IFN/RBV results in high rates of SVR. SVR12 was achieved in a majority of patients, with numerically higher SVR rates in patients receiving the grazoprevir 50-mg or 100-mg regimens compared with those treated with grazoprevir 25 mg. There was no association between the presence of baseline RAVs and virologic failure, although >70% of patients with virologic failure had detectable RAVs at the time of failure. D168A/E and A156T were the most commonly reported variants at virologic failure, although in most patients there was a rapid return to wild type, suggesting that these mutants may be relatively unfit for replication. Preliminary in vitro data suggest that D168A/N/E replicates at ≤50% compared with wild type, and that a replicon cell line for A156T cannot be established, possibly because of reduced


Grazoprevir plus peginterferon/ribavirin Table 4 Summary of AEs (ASaT population)

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Grazoprevir + PEG-IFN + RBV for 12 weeks 25 mg (n = 29) Incidence of AEs, n (%) [95% CI]* At least 1 AE 28 (96.6) [82.2–99.9] Drug-related AEs 28 (96.6) [82.2–99.9] Serious AEs 1 (3.4) [0.1–17.8] Serious drug-related AEs 0 (0.0) [0.0–11.9] Discontinued because of AE 1 (3.4) [0.1–17.8] AEs occurring at incidence ≥25% in 1 or more Anaemia 8 (27.6) Arthralgia 5 (17.2) Chills 13 (44.8) Decreased appetite 12 (41.4) Diarrhoea 2 (6.9) Fatigue 18 (62.1) Headache 10 (34.5) Influenza-like illness 6 (20.7) Injection-site erythema 9 (31.0) Irritability 8 (27.6) Myalgia 11 (37.9) Nausea 11 (37.9) Neutropaenia 9 (31.0) Pruritus 5 (17.2) Pyrexia 10 (34.5)

50 mg (n = 28) 28 (100.0) [87.7–100.0] 28 (100.0) [87.7–100.0] 1 (3.6) [0.1–18.3] 1 (3.6) [0.1–18.3] 1 (3.6) [0.1–18.3] treatment groups, 11 (39.3) 8 (28.6) 12 (42.9) 7 (25.0) 7 (25.0) 17 (60.7) 17 (60.7) 7 (25.0) 8 (28.6) 2 (7.1) 6 (21.4) 17 (60.7) 4 (14.3) 8 (28.6) 7 (25.0)

100 mg (n = 30) 28 (93.3) [77.9–99.2] 27 (90.0) [73.5–97.9] 0 (0.0) [0.0–11.6] 0 (0.0) [0.0–11.6] 1 (3.3) [0.1–17.2] n (%) 11 (36.7) 1 (3.3) 13 (43.3) 14 (46.7) 5 (16.7) 18 (60.0) 13 (43.3) 7 (23.3) 7 (23.3) 7 (23.3) 9 (30.0) 9 (30.0) 7 (23.3) 5 (16.7) 11 (36.7)

AE, adverse event; ASaT, all subjects as treated; CI, confidence interval; PEG-IFN, pegylated interferon; RBV, ribavirin. *Based on Clopper–Pearson method. AE relationship to treatment was determined by investigator. replicative fitness of this variant. Overall, grazoprevir was well tolerated: AEs were generally mild/moderate, and there were no unexpected or concerning clinical AEs or laboratory abnormalities. In the United States and Europe, the use of PEG-IFN/ RBV to treat HCV infection is declining, and efforts are increasingly directed at development of IFN- and RBV-free regimens [9,10]. Further clinical development of grazoprevir will be as a component of the fixed-dose combination tablet with the NS5A inhibitor elbasvir, and there are no plans for further development of grazoprevir as a single entity for use in combination with PEG-IFN/RBV. Data from the large C-WORTHY phase 2 trial of grazoprevir plus elbasvir (both with and without RBV) showed high rates of efficacy in previously untreated patients with cirrhosis (12 weeks: 97%) and previous PEG-IFN/RBV null responders with cirrhosis (12 weeks: 92%) and without cirrhosis (12 weeks: 91%) [11]. The rate of virologic failure with grazoprevir plus elbasvir with or without RBV was low, at

4%. The regimen was well tolerated, with only 3% experiencing serious AEs and 1% discontinuing treatment because of AEs. AEs leading to treatment discontinuation were higher in the RBV-treated group (2%), and RBV was concluded to be a major contributor to AEs. Data from ongoing phase 3 studies will provide further insight into the clinical profile of the grazoprevir/elbasvir fixed-dose combination [12,13]. Data from the present study extend the understanding of the clinical profile of grazoprevir, initially assessed at doses of 100–800 mg QD in an earlier phase 2 study [8]. Grazoprevir at 400 or 800 mg QD was associated with transient elevations in transaminase values, and therefore patients assigned to these doses were down-dosed to receive grazoprevir 100 mg/day 1 in combination with PEG-IFN/RBV. Data from the present study show that reducing doses as low as 50 mg/day 1 does not result in a decline in efficacy relative to the 100-mg/day 1 dose and that laboratory abnormalities are rare at these dose levels. Thus, in


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M. Lagging et al.

patients receiving grazoprevir 100 mg/day 1, there exists a relatively wide margin for efficacy, which is important when accounting for internal/external factors that may reduce drug exposure such as adherence, enhanced hepatic metabolism or drug–drug interactions (preclinical and clinical data show grazoprevir to be a substrate of CYP3A4, Pglycoprotein and OATP1B1) [14]. In the United States, first-generation protease inhibitors are no longer recommended, and treatment is currently based on sofosbuvir, simeprevir or sofosbuvir/ledipasvir combinations as well as the combination of ritonavirboosted ABT-450, ombitasvir and dasabuvir [9]. In Europe, the preferred treatment regimens are also all-oral combinations of direct-acting antiviral drugs, although guidelines recognize the necessity for regimens comprising the firstgeneration protease inhibitors plus PEG-IFN/RBV in regions where resource constraints preclude the use of alloral regimens [10]. In conclusion, data from the current study extend the understanding of the clinical profile of grazoprevir and support further study of the 100-mg dose. Phase 3 studies with this dose of grazoprevir in combination with elbasvir are currently ongoing, with the ultimate goal of providing a safe and effective short-duration regimen for patients with HCV infection.

ACKNOWLEDGEMENTS AND DISCLOSURES Medical writing and editorial assistance was provided by Tim Ibbotson, PhD, and Beth McMahon-Wise, PhD, of

ApotheCom, Yardley, Pennsylvania, USA, and this study was funded by Merck & Co., Inc., Kenilworth, NJ, USA.

STATEMENT OF INTERESTS ML has nothing to declare. AB has served on speaker’s bureaus and medical advisory boards and has received sponsorship to attend conferences from AbbVie, Bristol-Myers Squibb, Gilead, Janssen and Merck & Co., Inc. PSM has served on speaker’s bureaus for AbbVie, Gilead, Janssen, Onyx, Salix and Merck & Co., Inc.; has received grant support from Abbvie, Gilead, Bristol-Myers Squibb, Salix, Hyperion, Vital Therapies, Intercept and Merck & Co., Inc.; and has served on advisory boards for AbbVie, Janssen, Gilead and Merck & Co., Inc. AR has served as an investigator and/or consultant for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Idenix, Merck & Co., Inc., Hoffman La Roche, Vertex, Janssen and Novartis and has received speaker’s grants from Gilead, Merck & Co., Inc., Hoffman La Roche, Vertex and Janssen. FW has a relationship with Merck & Co., Inc. relevant to the content of this manuscript. JMV declares relationships with Abbvie, Bristol-Myers Squibb, Eisai Medical Research, Excalenz, Genentech, Gilead, GlaxoSmithKline, Globeimmune, HepQuant, Hyperion, Idenix, Immuron, Intercept, Janssen, Merck, Novartis, Roche, Salix, Sundise, Tranzyme, Vertex, HepaLife Technologies, Herbalife, Ocera and SciGen. ING, PH, BZ, JW and MNR are employees/shareholders of Merck & Co., Inc. NM was an employee of Merck & Co., Inc., at the time of the study and is a current employee of AbbVie.

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N Engl J Med 2014; 370: 1889– 1898. 6 Fried MW, Buti M, Dore GJ et al. Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naive genotype 1 hepatitis C: the randomized PILLAR study. Hepatology 2013; 58: 1918–1929. 7 Summa V, Ludmerer SW, McCauley JA et al. MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrob Agents Chemother 2012; 56: 4161–4167. 8 Manns M, Vierling JM, Bacon BR et al. The combination of MK-5172, peginterferon, and ribavirin is effective in treatment-naive patients with hepatitis C virus genotype 1 infection without cirrhosis. Gastroenterology 2014; 147: 366–376.

9 American Association for the Study of Liver Diseases, Infectious Disease Society of North America. AASLD, IDSA, IAS-USA. Recommendations for testing, managing, and treating hepatitis C. AASLD/IDSA Web Site. Available at: http:// www.hcvguidelines.org. Accessed August 27, 2015. 10 European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2014; 60: 392–420. 11 Lawitz E, Gane E, Pearlman B et al. Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without


Grazoprevir plus peginterferon/ribavirin cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial. Lancet 2014; 385: 1075–1086. 12 Zeuzem S, Ghalib R, Reddy KR et al. Grazoprevir-Elbasvir Combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis C virus

genotype 1, 4, or 6 Infection: A Randomized Trial. Ann Intern Med 2015; 163: 1–13. 13 Forns X, Gordon SC, Zuckerman E et al. Grazoprevir and elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-

acting antiviral agent. J Hepatol 2015; 63: 564–72. 14 Yeh WW, Fraser IP, Reitmann C et al. Pharmacokinetic interaction of HCV protease inhibitor MK-5172 and ritonavir in healthy subjects. Global Antivir J 2013; 9(Suppl. 2): 55–56 [abstract].

SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article:

Table S1. Reasons for exclusion from the per protocol population.


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Figure S1. Study design. Appendix S1. Study protocol.