Grazoprevir/Elbasvir for the treatment of Hepatitis C...replication. Elbasvir is an NS5A inhibitor,...

Grazoprevir/Elbasvir for the treatment of Hepatitis C Application for inclusion on the WHO Model List of Essential Medicines (EML)

1

Contents

Table of Tables ........................................................................................................................................................ 3

Table of Figures ...................................................................................................................................................... 3

General Items ......................................................................................................................................................... 4

Summary statement of the proposal for inclusion, change or deletion ............................................................ 4

Name of the WHO technical department and focal point supporting the application (where relevant) .......... 4

Name of organization(s) consulted and/or supporting the application ............................................................. 4

International Non-proprietary Name (INN) and Anatomical Therapeutic Chemical (ATC) code of the medicine

............................................................................................................................................................................ 5

Formulation(s) and strength(s) proposed for inclusion; including adult and paediatric (if appropriate) .......... 5

Whether listing is requested as an individual medicine or as representative of a pharmacological class ........ 5

Treatment details, public health relevance and evidence appraisal and synthesis ............................................... 6

Grazoprevir/elbasvir treatment details .............................................................................................................. 6

WHO Guidelines ............................................................................................................................................. 6

US Guidelines (AASLD/IDSA) .......................................................................................................................... 6

European Guidelines (EASL) ........................................................................................................................... 7

Summary ........................................................................................................................................................ 8

Additional requirements associated with treatment ......................................................................................... 8

Information supporting the public health relevance ......................................................................................... 9

Review of benefits: summary of comparative effectiveness in a variety of clinical settings ............................... 10

Overview of grazoprevir/elbasvir efficacy........................................................................................................ 10

Genotype 1 ....................................................................................................................................................... 11

Phase 3 trials ................................................................................................................................................ 11

Phase 2 trials ................................................................................................................................................ 13

Genotype 1 summary................................................................................................................................... 14

Genotype 2 ....................................................................................................................................................... 14

Phase 3 trials ................................................................................................................................................ 14

Phase 2 trials ................................................................................................................................................ 14


Genotype 3 ....................................................................................................................................................... 15

Phase 3 trials ................................................................................................................................................ 15

Phase 2 trials ................................................................................................................................................ 15


Genotype 4 ....................................................................................................................................................... 16

Phase 3 trials ................................................................................................................................................ 16

Phase 2 trials ................................................................................................................................................ 17


Genotype 5 ....................................................................................................................................................... 17

2

Phase 3 trials ................................................................................................................................................ 17

Phase 2 trials ................................................................................................................................................ 18


Genotype 6 ....................................................................................................................................................... 18

Phase 3 trials ................................................................................................................................................ 18

Phase 2 trials ................................................................................................................................................ 19


Special populations .......................................................................................................................................... 20

HCV-HIV coinfection..................................................................................................................................... 20

Drug-drug interactions ................................................................................................................................. 20

Severe renal impairment ............................................................................................................................. 20

Intravenous drug users receiving Opioid Agonist Therapy .......................................................................... 21

Efficacy conclusion ........................................................................................................................................... 21

Review of harms and toxicity: summary of evidence on safety ........................................................................... 22

Phase 3 trials .................................................................................................................................................... 22

Phase 2 trials .................................................................................................................................................... 23

Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or

therapeutic group ................................................................................................................................................. 24

United States pricing ........................................................................................................................................ 24

Non-United States pricing ................................................................................................................................ 24

Cost-effectiveness analyses ............................................................................................................................. 24

Regulatory information ........................................................................................................................................ 26

Summary of regulatory status of the medicine ................................................................................................ 26

Availability of pharmacopoeial standards ........................................................................................................ 26

References ............................................................................................................................................................ 27

3

Table of Tables

Table 1 Formulations and strengths proposed for inclusion .................................................................................. 5

Table 2 Product presentation and posology ........................................................................................................... 6

Table 3 AASLD/IDSA grazoprevir/elbasvir treatment recommendations in individuals with or without

compensated cirrhosis ............................................................................................................................................ 7

Table 4 Summary of grazoprevir/elbasvir trials by genotype ............................................................................... 10

Table 5 Completed Phase 3 clinical trials in HCV genotype 1 infected individuals (intent-to-treat analyses) ..... 11





Table 10 Completed Phase 2 clinical trials in HCV genotype 4 infected individuals (intent-to-treat analyses) ... 17




Table 14 Safety data from Phase 3 trials of grazoprevir/elbasvir ......................................................................... 22

Table 15 Safety data from Phase 2 trials of grazoprevir/elbasvir ......................................................................... 23

Table 16 Original US market prices of interferon-free regimens (adapted from Bell et al. 2016) ....................... 24

Table 17 Standard of care regimens for non-cirrhosis, treatment-naive patients with HCV genotype 1, and cost

per SVR (adapted from Rosenthal et al. 2016) ..................................................................................................... 25

Table 18 Regulatory status according to stringent regulatory authorities ........................................................... 26

Table of Figures

Figure 1 Overall proportion of patients achieving SVR when combining trials for each genotype. Confidence

intervals are represented by error bars at 95% confidence ................................................................................. 11

4

General Items

Summary statement of the proposal for inclusion, change or deletion

Grazoprevir with elbasvir is a combination product with US-FDA approved indication for the

treatment of chronic hepatitis C (HCV) genotypes 1 and 4 in adults. [1] Grazoprevir is a

protease inhibitor of HCV NS3/4A that prevents cleavage of the polyprotein necessary for

replication. Elbasvir is an NS5A inhibitor, preventing HCV viral RNA replication and virion

assembly. [2]

The regimen is included in current HCV guidelines as a first-line option for the treatment of

HCV genotype 1 or 4 treatment-naïve and treatment-experienced individuals, with or

without cirrhosis. It is also recommended for individuals with human immunodeficiency

virus (HIV) coinfection and those with severe renal impairment. The regimen is tolerated

well and has a good side effect profile with few individuals discontinuing treatment because

of adverse events.

Given this efficacy and safety data, grazoprevir/elbasvir is a potent regimen in the fight

against chronic HCV and should supplement the current HCV regimens included in the WHO

Essential Medicines List (EML).

Name of the WHO technical department and focal point supporting the application

(where relevant)

WHO Global Hepatitis Programme, Department of HIV/AIDS

Name of organization(s) consulted and/or supporting the application

Department of Pharmacology and Therapeutics

University of Liverpool

70 Pembroke Place

Liverpool

L69 3GF

5

International Non-proprietary Name (INN) and Anatomical Therapeutic Chemical

(ATC) code of the medicine

Grazoprevir (J05AX)

Elbasvir (J05AX)

Formulation(s) and strength(s) proposed for inclusion; including adult and

paediatric (if appropriate)

Grazoprevir/elbasvir (trade name, Zepatier) is available as a fixed-dose film-coated tablet

produced by the manufacturer Merck Sharp & Dohme Corp. Each tablet contains 100 mg of

grazoprevir and 50 mg of elbasvir. The recommended dose of the combination is one tablet

taken orally once daily with or without food.

This information is shown in Table 1. The safety and effectiveness of grazoprevir/elbasvir

have not been established in paediatric patients and as such, no paediatric formulations are

included.

Table 1 Formulations and strengths proposed for inclusion

Medicine Formulation Market availabilitya

Grazoprevir 100 mg -

Elbasvir 50 mg -

Fixed-dose combinations

Grazoprevir + Elbasvir Tablet: 100 mg + 50 mg Zepatier; Merck Sharp & Dohme Corp.

aNo known market availability of individual formulations of grazoprevir and elbasvir

Whether listing is requested as an individual medicine or as representative of a

pharmacological class

The listing is requested as Individuals medicines.

6

Treatment details, public health relevance and evidence appraisal and

synthesis

Grazoprevir/elbasvir treatment details

Grazoprevir 100 mg in combination with elbasvir 50 mg should be provided as per the

recommendations from international/national guidelines as detailed in the sections below.

Grazoprevir/elbasvir is given with or without ribavirin for 12-16 weeks, depending on

genotype, treatment experience, and presence of baseline resistance polymorphisms. [1]

Table 2 Product presentation and posology

Product Presentation Posology

Grazoprevir/elbasvir Tablet containing 100 mg

grazoprevir and 50 mg elbasvir

One tablet one daily

(morning)

WHO Guidelines

Grazoprevir in combination with elbasvir was not considered in the updated 2016 WHO

Guidelines as it had not received stringent regulatory (SRA) approval at the time of writing.

[3] The Guidelines Development Group included that initial available data suggests that the

combination is efficacious in a variety of situations, including in those with HIV coinfection,

and with later stage chronic kidney disease.

US Guidelines (AASLD/IDSA)

The 2016 AASLD/IDSA guidelines for treating HCV have been updated to include

grazoprevir/elbasvir as a recommended regimen in treatment-naïve or experienced patients

with genotype 1 or 4 with or without compensated cirrhosis. [4] AASLD/IDSA treatment

indications and quality of recommendations are shown in Table 3.

In addition, the regimen is recommended in AASLD/IDSA guidelines for individuals co-

infected with HIV, however there are limitations on with which antiretrovirals it can be co-

administered (Class IIa, Level B). Antiretrovirals that cannot be used with

grazoprevir/elbasvir include cobicistat, efavirenz, etravirine, nevirapine, and all HIV protease

inhibitors.

A 12-week regimen of grazoprevir/elbasvir is recommended for use in individuals with

genotype 1a, 1b, or 4 with severe renal impairment (creatinine clearance of <30 mL/min)

7

(Class IIb, Level B). The regimen is not recommended for patients with decompensated

cirrhosis.

Table 3 AASLD/IDSA grazoprevir/elbasvir treatment recommendations in individuals with or without compensated cirrhosis

Patient population Treatment Duration Quality

Genotype 1a: Treatment-

naïve or Peg-IFN/RBV

experienced, no baseline

NS5A RAVs

Grazoprevir/elbasvir 12 weeks Class I, Level

A

Genotype 1a: Treatment-


experienced, baseline

NS5A RAVs

Grazoprevir/elbasvir + WB

ribavirin

16 weeks Class IIa,

Level B (TN);

Class I, Level

B (TE)

Genotype 1b: Treatment-


experienced

Grazoprevir/elbasvir 12 weeks Class I, Level

A

Genotype 1: NS3 inhibitor

experienced

Grazoprevir/elbasvir + WB

ribavirin

12 weeks Class IIa,

Level B

Genotype 4: Treatment-

naïve or relapse after

Peg-IFN/RBV

Grazoprevir/elbasvir 12 weeks Class IIa,

Level B

Genotype 4: Peg-IFN/RBV

experienced

Grazoprevir/elbasvir+ WB

ribavirin

16 weeks Class IIa,

Level B

Abbreviations: WB RBV, weight-based ribavirin; RAV, resistance-associated variants; TN, treatment-naïve; TE, Peg-IFN/RBV exposed

European Guidelines (EASL)

The latest EASL guidelines mirror AASLD guidelines, with grazoprevir/elbasvir recommended

for use in individuals with genotype 1 or 4 infection. [5] Treatment-naïve and treatment-

experienced patients infected with genotype 1 or 4 with or without compensated cirrhosis

should receive grazoprevir/elbasvir for 12 weeks. In genotype 1a infected individuals with a

high baseline HCV RNA level (>800,000 IU/mL) or with baseline RAVs, treatment should

include WB RBV and be extended to 16 weeks.

As with US guidelines, EASL guidelines recommend the use of grazoprevir/elbasvir for 12

weeks in patients with genotype 1 or 4 infection with HIV coinfection or severe renal

impairment/end-stage renal disease.

8

Summary

Not yet included in WHO guidelines but recommended in US and European guidelines;

Recommended for use in patients with genotype 1a, 1b, or 4 infection;

Recommended for use in HIV co-infected individuals although not concomitantly with

several HIV antiretrovirals;

Recommended for use in patients with severe renal impairment;

Not recommended for use in patients with decompensated cirrhosis.

Additional requirements associated with treatment

Prior to administration of HCV treatment, active chronic HCV needs to be confirmed. In

most settings, this is conducted through an initial assay to detect the hepatitis C antibody

(HCVAb). If HCVAb are detected, HCV RNA should be determined by a sensitive molecular

method. [5] In areas where HCV RNA assays are not available or not affordable,

measurement of HCV core antigen levels provides an alternative measure to confirm

infection and whether treatment has been successful. [6, 7]

If feasible, other pre-therapeutic assessments should be conducted, including genotyping,

liver disease severity, and renal function. Contraindications to therapy should be thoroughly

explored, particularly in patients co-infected with HIV on antiretroviral regimens.

Treatment should be initiated and monitored by a physician experienced in the

management of patients with chronic HCV. The safety and effectiveness of task shifting of

HCV treatment to non-specialised providers are currently being explored in various settings.

[8, 9, 10] Specialised treatment facilities are not required for the initiation or monitoring of

treatment.

Monitoring includes assessments of treatment efficacy, of safety and side-effects, and of

drug-drug interactions. Monitoring of treatment efficacy can be simplified by measuring

HCV RNA (or HCV core antigen levels) at baseline and 12 or 24 weeks after the end of

therapy. In terms of safety, grazoprevir/elbasvir are generally well tolerated with low

frequencies of adverse advents.

9

Information supporting the public health relevance

Most recent analyses of the global prevalence of HCV indicate that an estimated 115 million

persons are HCVAb positive of which approximately 80 million are chronically infected. [11]

The prevalence varies greatly by region and population, with the highest burden, in terms of

numbers chronically infected, observed in sub-Saharan Africa and South and East Asia.

Data from the Global Burden of Disease study indicates that the number of deaths

attributable to HCV has been steadily increasing over the past decades from around 330,000

in 1990 to over 700,000 deaths per year in 2013. [12] This reflects the lag time between

infection and the development of complications, such as liver cirrhosis and hepatocellular

carcinoma. The number of deaths is projected to increase through several more decades

unless there is a rapid scale-up in accessibility to treatment. [13]

The availability of direct-acting antivirals (DAAs) for treatment against HCV provide a

realistic opportunity to scale-up treatment, particularly in resource-limited settings, where

public health programmes were previously unfeasible. Scale-up of screening and treatment

using efficacious DAA regimens, inclusive of grazoprevir/elbasvir, has the potential to reduce

the incidence of liver-related complications and mortality in individuals with HCV infection.

[14, 15] In fact, data suggests that an increase in screening rates and treatment with highly

efficacious regimens will be necessary to curb the increased mortality expected over the

coming years. [14] Inclusion of grazoprevir/elbasvir on the WHO EML will help to ensure

timely access to HCV treatment worldwide, alleviating the projected future health and

economic burden. [13]

Further, while several new DAA combinations have shown excellent SVR12 rates, certain

groups, including patients who have previously failed treatment or who have developed

cirrhosis, renal failure, or HIV coinfection remain difficult-to-treat subgroups.

Grazoprevir/elbasvir combination has high efficacy in the treatment of HCV in many of these

subgroups, providing a potent option in the fight against the disease.

10

Review of benefits: summary of comparative effectiveness in a variety of

clinical settings

Several Phase 2 and 3 clinical studies have been carried out evaluating the efficacy of

grazoprevir/elbasvir for treatment of HCV genotypes 1, 2, 3, 4, 5, and 6. These trials include

C-EDGE, C-EDGE CO-INFECTED, C-EDGE CO-STAR, C-EDGE H2H, C-SCAPE, C-SALVAGE, C-

SURFER, C-WORTHY (Lawitz et al. 2015 & Sulkowski et al. 2015), C-SWIFT (Poordad et al.

2015) and C-SWIFT (Lawitz et al. 2016).

Overview of grazoprevir/elbasvir efficacy

Table 4 below shows a summary of the clinical trials conducted and an estimate of

grazoprevir/elbasvir efficacy in each genotype (as measured by sustained virologic response

12 weeks after treatment, SVR12). This information in displayed graphically in Figure 1.

Table 4 Summary of grazoprevir/elbasvir trials by genotype

Geno- type

Trials included Patient Characteristics

Interventions SVR12/Total (%) (95% C.I.)

1 C-SURFER, C-EDGE H2H, C-EDGE TE, C-EDGE TN, C-EDGE CO-INFECTED, C-EDGE CO-STAR, C-SALVAGE, C-WORTHY (Sulkowski et al.), C-WORTHY (Lawitz et al.) & C-SWIFT (Lawitz et al.)

TN & TE, includes HIV/HCV co-infected and patients with severe kidney disease

GZR 100mg/EBR 50mg

or 20mg RBV or SOF, 4-18 wks

1809/1894 (95.5%) (95% C.I.: 94.5% - 96.4%)

2 C-SCAPE TN, non-cirrhotic GZR 100mg/EBR 50mg + RBV, 12 wks

24/30 (80.0%) (95% C.I.: 61.4% - 92.3%)

3 C-SWIFT (Poordad, F. et al. 2015) TN, Non-cirrhotic

& Cirrhotic

GZR 100mg/EBR 50mg + SOF, 8 & 12 wks

38/40 (95.0%) (95% C.I.: 83.1% - 99.4%)

4 C-EDGE H2H, C-EDGE TE, C-EDGE TN, C-EDGE CO-INFECTED, C-EDGE CO-STAR, C-SCAPE

TN & TE, includes HIV/HCV co-infected

GZR 100mg/EBR 50mg

RBV, 12-16 wks

118/126 (93.7%) (95% C.I.: 87.9% - 97.2%)

5 C-SCAPE TN, non-cirrhotic GZR 100mg/EBR 50mg

RBV 12 wks

5/8 (62.5%) (95 C.I.: 24.5% - 91.5%)

6

C-SCAPE, C-EDGE TE, C-EDGE TN, C-EDCGE CO-INFECTED, C-EDGE CO-STAR

TN & TE, includes HIV/HCV co-

infected

GZR 100mg/EBR 50mg

RBV, 12 – 16 wks.

26/35 (74.3%) (95 C.I.: 56.7% - 87.5%)

TOTAL All trials above All above characteristics included

GZR 100mg/EBR 50mg

or 20mg RBV or SOF, 4-18 wks

2,020/2,133 (94.7%) (95% C.I.: 93.7 % - 95.6%)*

Abbreviations: TN, treatment-naïve; TE, treatment-experienced; RBV, ribavirin; GZR, grazoprevir; EBR, elbasvir; PR, pegylated interferon *Not meta-analysis performed, simple addition of trial results

11

Figure 1 Overall proportion of patients achieving SVR when combining trials for each genotype. Confidence intervals are represented by error bars at 95% confidence

Genotype 1

Phase 3 trials

Table 5 Completed Phase 3 clinical trials in HCV genotype 1 infected individuals (intent-to-treat analyses)

Study reference

Study design Patient characteristics

Intervention SVR12, n(%) VF, n(%)

LTFU, n(%)

WC, n(%)

C-SURFER, (Roth et al. 2015)

Multicentre (68 -global) double-blind, placebo-controlled, randomised safety study, observational study of efficacy

Chronic kidney disease (stage 4-5), TN or TE

GZR 100mg/EBR 50mg, 12 weeks

115/116 (99.1%) 1/116(<1%)

0 0

C-EDGE H2H, (Sperl et al. 2016)

Randomised, multisite (EU and Turkey), open-label trial, fixed dose

GT1a (18) GT1b (105), TN or TE


18/18 (100.0%) 0 0 0


104/105 (99.0%) 0 1 (<1%)

0

C-EDGE TE, (Kwo et al. 2015)

Randomised control trial, multisite, open-

GT1a & b, TE


GT1a: 55/61 (90.2%) GT1b: 34/34 (100%) GT1-other:1/1 (100%)

6 (6%)

2 (2%)

0

12

label with parallel group.

GZR 100mg/EBR 50mg + RBV, 12 weeks

GT1a: 56/60 (93.3%) GT1b: 28/29 (96.6%)

6 (7%)

0 0


GT1a:45/48 (93.8%) GT1b:46/48 (95.8%)

7(7%) 1 (<1%)

0

GZR 100mg/EBR 50mg + RBV, 16 weeks

GT1a: 55/58 (94.8%) GT1b: 36/36 (100%) GT1-other:2/2 (100%)

0 3 (3%)

0

C-EDGE TN, (Zeuzem et al. 2015)

Randomized, blinded, placebo-controlled trial, multicentre

TN


GT1a: 144/157 (91.7%) 10 (6%)

3 (1%)

0


GT1b: 129/131 (98.5%) 1 (<1%)

1 (<1%)

0

C-EDGE CO-INFECTED, (Rockstroh et al 2015.)

Open-label, non- randomised, single arm, global multicentre trial,

TN, HIV/HCV co-infection

GZR 100 mg/ EBR 50 mg, 12 wks

GT1a: 135/139 (97.1%) 4 (3%)

5 (4%)

0

GZR 100 mg/ EBR 50 mg, 12 wks

GT1b: 42/42 (100.0%) 0 2 (5%)

0

C-EDGE

CO-STAR,

(Dore et al.

2016)

Randomised,

parallel-group,

placebo-

controlled,

double-blind trial

TN. HIV/HCV

co-infection. On

opioid agonist

therapy (OAT) 3

months or

longer,

Immediate GZR

100mg/EBR

50mg, 12 weeks

GT1a: 147/154 (95.5%) 4

(3%)

1

(<1%)

0

Immediate GZR

100mg/EBR

50mg, 12 weeks

GT1b: 28/30 (93.3%) 1

(3%)

1

(3%)

0

Deferred GZR

100mg/EBR

50mg, 12 weeks

GT1a: 64/71 (90.1%) 1

(1%)

6

(8%)

0

Deferred GZR

100mg/EBR

50mg, 12 weeks

GT1b: 13/14 (92.9%) 0 1

(7%)

0

TOTAL: All Phase 3 trials

- All above characteristics included

GZR 100mg/EBV

50mg RBV, 12 - 16 wks

1,294/1,351 (95.8%) (95% C.I.: 94.6% -96.8%)

41 (3%)

28 (2%)

1 (<1%)

Abbreviations: TN, treatment-naïve; TE, treatment-experienced; GT, genotype; RBV, ribavirin; GZR, grazoprevir; EBR, elbasvir; PR, pegylated interferon; VF, virological failure; LTFU, lost to follow up; WC, withdrawn consent

13

Phase 2 trials


Study Reference Study Design Patient Characteristics

Intervention SVR12, n(%) VF n(%)

LTFU n(%)

W/C n(%)

C-WORTHY, (Lawitz et al. 2015)

International randomised control trial, open-label, multi-centre, with parallel group

Cohort 1: TN, compensated cirrhosis

GZR 100mg/EBR 50mg + RBV, 12 wks

28/31 (90.3%)

3 (10%)

0 0

GZR 100mg/EBR 50mg, 12 wks

28/29 (96.6%)

1 (3%) 0 0


31/32 (96.9%)

0 0


29/31 (93.5%)

2 (6%) 0 0

Cohort 2: TE, non-cirrhotic & compensated cirrhosis,


30/32 (93.8%)

0 2 (6%)

0


30/33 (90.9%)

3 (10%)

0 0


33/33 (100.0%)

0 0 0


31/32 (96.9%)

1 (3%) 0 0

C-WORTHY, (Sulkowski et al. 2015)

Randomised, parallel-group, multi-centre, open-label, international trial.

TN, HIV/HCV co-infection

GZR 100mg/EBR 50mg+ RBV, 8 wks

24/30 (80.0%)

5 (2%) 1 (3%)

0

GZR 100mg/EBR 50mg or 20mg + RBV, 12 wks

79/85 (92.9%)

3 (4%) 3 (4%)

0


43/44 (97.7%)

1 (2%) 0 0


28/29 (96.6%)

1 (2%) 0 0


26/30 (86.7%)

2 (6%) 2 (6%)

0

C-SALVAGE, (Forns et al. 2015)

International, prospective open-label trial

TE GZR 100mg/EBR 50mg + RBV, 12 wks

76/79 (96.2%)

3 (4%) 0 0

C-SWIFT (Poordad,

F. et al. 2015)

Open-label, TN, Non-

cirrhotic

GZR 100mg/EBR 50mg

+ SOF, 4 wks

10/30

(33.3%)

20

(67%)

0 0

GZR 100mg/EBR 50mg

+ SOF, 6 wks

26/30

(86.7%)

4

(13%)

0 0

TN, Cirrhotic GZR 100mg/EBR 50mg

+ SOF, 6 wks

16/20

(80.0%)

4

(20%)

0 0

GZR 100mg/EBR 50mg

+ SOF, 8 wks

17/18

(94.4%)

1 (6%) 0 0

C-SWIFT- FINAL,

(Lawitz, E.J. et al.

2016

Patients

failing 4, 6 or

8 weeks of

Cirrhotic, TE GZR 100mg/EBR 50mg

+ SOF 400mg + RBV, 12

weeks

5/5

(100.0%)

0 0 0

14

GZR/EBR +

SOF are

retreated

Non-cirrhotic, TE

GZR 100mg/EBR 50mg + SOF 400mg + RBV, 12 weeks

18/18 (100.0%)

0 0 0



GZR 100mg/EBR 50mg

or 20mg RBV and SOF, 4-18 wks

608/671 (90.6%) (95% C.I.: 88.2% -92.7%)

25 (5%)

9 (2%)

0


Genotype 1 summary

A total of 1894 individuals infected with HCV genotype 1 were treated in eleven trials (6

Phase 3 and 5 Phase 2) with grazoprevir (100 mg) and elbasvir (50 mg) ± ribavirin and

sofosbuvir. The total cohort includes both treatment-naïve and experienced patients and

those with HIV/HCV co-infection. The C-SURFER trial included patients with chronic kidney

disease. For treatment regimens of 12 weeks or longer the overall SVR12 rate was 95%

(95%CI 94.4-96.4). The results of these trials have led to grazoprevir/elbasvir approval and

recommendation for use in individuals with genotype 1 HCV infection, regardless of

treatment experience or HIV co-infection; treatment is also recommended in individuals

with genotype 1 infection and renal impairment.

Genotype 2

Phase 3 trials

No Phase 3 trials of grazoprevir/elbasvir in HCV genotype 2 have been conducted.

Phase 2 trials


Study Reference

Study Design Patient Characteristics


LTFU n(%)

W/C n(%)

C-SCAPE,

(Brown et

al. 2015)

Open-label,

Randomised

control trial

TN, non-cirrhotic GZR 100mg/EBR 50mg +

RBV, 12 wks

24/30 (80.0%) 4

(13%)

2 (7%) 0


- TN, non-cirrhotic GZR 100mg/EBR 50mg + RBV, 12 wks

24/30 (80.0%) (95% C.I.: 61.4% - 92.3%)

4

(13%)

2 (7%) 0


15

Genotype 2 summary

A total of 30 genotype 2 HCV-infected patients were treated in one Phase 2 trial with

grazoprevir (100 mg) and elbasvir (50 mg) with ribavirin. Patient were treatment-naïve, non-

cirrhotic and mono-infected with HCV. The overall SVR12 rate was 80% (95%CI 61.4-92.3).

Given this low efficacy compared with other treatments, grazoprevir/elbasvir is currently

not approved for use in individuals with genotype 2 HCV infection.

Genotype 3

Phase 3 trials

No Phase 3 trials of grazoprevir/elbasvir have been conducted in patients with genotype 3

infection.

Phase 2 trials


Study Reference



LTFU n(%)

W/C n(%)

C-SWIFT

(Poordad,

F. et al.

2015)

Open-label, TN, Non-cirrhotic GZR 100mg/EBR 50mg +

SOF, 8 wks

14/15 (93.3%) 1

(7%)

0 0

GZR 100mg/EBR 50mg +

SOF, 12 wks

14/14 (100.0%) 0 0 0

TN, Cirrhotic GZR 100mg/EBR 50mg +

SOF, 12 wks

10/11 (90.9%) 1

(9%)

0 0


- TN, Cirrhotic and

Non-cirrhotic

GZR 100mg/EBR 50mg + SOF, 8 & 12 wks

38/40 (95.0%) (95% C.I.: 83.1% - 99.4%)

2 (5%)

0 0


Genotype 3 summary

A total of 40 individuals with HCV genotype 3 were treated in one Phase 2 trial with

grazoprevir (100 mg), elbasvir (50 mg) and sofosbuvir (400 mg). Patients were treatment-

naïve, cirrhotic and non-cirrhotic, and mono-infected with HCV. For treatment regimens 12

weeks or longer the overall SVR12 rate was 96.0% (95%CI 79.7-99.9). Grazoprevir/elbasvir is

currently not recommended for use in individuals with genotype 3 infection, however the in

combination with sofosbuvir, the regimen has demonstrated promising results.

16

Genotype 4

Phase 3 trials


Study Reference


Intervention SVR12, n(%) VF n(%) LTFU n(%)

W/C n(%)

C-EDGE H2H,

(Sperl et al.

2016)

Randomised, multi-site

(EU and Turkey), open-

label trial, fixed dose,

(vs SOF/PR)

TN or TE, GZR 100mg/EBR

50mg, 12 weeks

6/6 (100.0%) 0 0 0

C-EDGE TE,

(Kwo et al.

2015)

Randomised control

trial, multisite, open-

label with parallel

group.

TE, includes

HCV/HIV co-

infected

GZR 100mg/EBR

50mg, 12 weeks

7/9 (77.8%) Failure

data

included in

GT1

- -

GZR 100mg/EBR

50mg + RBV, 12

weeks

14/15 (93.3%) - - -

GZR 100mg/EBR

50mg, 16 weeks

3/5 (60.0%) - - -

GZR 100mg/EBR

50mg + RBV, 16

weeks

8/8 (100.0%) - - -

C-EDGE TN,

(Zeuzem et

al. 2015)

Randomized, blinded,

placebo-controlled

trial, multicentre

TN GZR 100mg/EBR

50mg, 12 weeks

18/18

(100.0%)

0 0 0

C-EDGE CO-

INFECTED,

(Rockstroh

et al 2015.)

Open-label, non

randomised, single

arm, global multicentre

trial

TN, HCV/HIV

co-infected

GZR 100 mg/

EBR 50 mg, 12

wks

26/27 (96.3%) 1 (4%) 1(4%

)

0

C-EDGE CO-

STAR, (Dore

et al. 2016)

Randomised, parallel-

group, placebo-

controlled, double-

blind trial

TN, HIV/HCV

co-infection

On Opioid

agonist

therapy (OAT)

3 months or

longer

Immediate GZR

100mg/EBR

50mg, 12 weeks

11/12 (91.7%) 0 1

(8%)

0

Deferred GZR

100mg/EBR

50mg, 12 weeks

6/6 (100.0%) 0 0 0



GZR 100mg/EBR

50mg RBV, 12-16 wks

99/106 (93.4%) (95% CI: 86.9 - 97.3%)

- - -


17

Phase 2 trials


Study Reference



LTFU n(%)

W/C n(%)

C-SCAPE,

(Brown et

al. 2015)

Open-label,

Randomised

control trial

TN, non-cirrhotic


RBV, 12 wks

10/10 (100.0%) 0 0 0

GZR 100mg/EBR 50mg,

12 wks

9/10 (90.0%) 0 1 (10%) 0


- TN, non-cirrhotic GZR 100mg/EBR 50mg RBV, 12 wks

19/20 (95.0%) (95% C.I.: 75.1% - 99.9%)

0 1 (5%) 0


Genotype 4 summary

A total of 125 individuals with HCV genotype 4 were treated in 6 trials (5 Phase 3 and 1

Phase 2) with grazoprevir (100 mg) and elbasvir (50 mg) with and without ribavirin. Patients

were both treatment-naïve and experience, mono- and co-infected with HIV; 126 patients

were on antiretroviral therapy (ART) and 18 were on opioid agonist therapy (OAT). For

treatment regimens 12 weeks or longer, the overall SVR12 rate was 93.7% (95%CI 87.9-

97.2). These results have led to the approval and recommendation of grazoprevir/elbasvir

for individuals with genotype 4 infection, regardless of treatment experience; individuals

with previous treatment failure require the addition of ribavirin and 16 weeks of treatment.

Genotype 5

Phase 3 trials

No phase 3 trials of grazoprevir/elbasvir have been conducted in patients with genotype 5

infection.

18

Phase 2 trials


Study Reference


Intervention SVR12, n(%) VF n(%) LTFU n(%)

W/C n(%)

C-SCAPE,

(Brown et

al. 2015)

Open-label,

Randomised

control trial

TN, non-cirrhotic


RBV, 12 wks

4/4 (100.0%) 0 0 0

GZR 100mg/EBR 50mg,

12 wks

1/4 (25.0%) 3 (75%) 0 0


- TN, non-cirrhotic

GZR 100mg/EBR 50mg RBV, 12 wks

5/8 (62.5%) (95% C.I.: 24.5% - 91.5%)

3 (38%) 0 0


Genotype 5 summary

A total of eight genotype 5 HCV infected patients were treated in one Phase 2 trial with

grazoprevir (100 mg) and elbasvir (50 mg) with and without ribavirin. Patients were

treatment-naïve, mono-infected with HCV, and non-cirrhotic. For treatment regimens 12

weeks or longer the overall SVR12 rate was 62.5% (95%CI 24.5-91.5). Treatment of genotype

5 infection with grazoprevir/elbasvir is not recommended under treatment guidelines.

Genotype 6

Phase 3 trials


Study Reference



LTFU n(%)

W/C n(%)

C-EDGE TE,

(Kwo et al.

2015)

Randomised control

trial, multisite, open-

label with parallel

group.

HIV co-

infection and

mono-

infection

GZR 100mg/EBR

50mg, 16 weeks

3/4 (75.0%) Failure included in

GT1

GZR 100mg/EBR

50mg + RBV, 16

weeks

2/2 (100.0%)

C-EDGE TN,

(Zeuzem et al.

2015)

Randomized, blinded,

placebo-controlled

trial, multicentre

TN GZR 100mg/EBR

50mg, 12 weeks

8/10 (80.0%) 2 0 0

19

C-EDGE CO-

INFECTED,

(Rockstroh et al

2015.)

Open-label, non-

randomised, single

arm, global

multicentre trial,

TN, HCV/HIV

co-infection

GZR 100 mg/

EBR 50 mg, 12

wks

2/2 (100.0%) 0 0 0

C-EDGE CO-

STAR, (Dore et

al. 2016)

Randomised, parallel-

group, placebo-

controlled, double-

blind trial

On Opioid

agonist

therapy (OAT)

3 months or

longer, some

HIV/HCV co-

infection, TN

Immediate GZR

100mg/EBR

50mg, 12 wks

3/5 (60.0%) 2 0 0

Deferred GZR

100mg/EBR

50mg, 12 wks

2/4 (50.0%) 2 0 0

TOTAL: All phase 3 trials


GZR 100mg/EBR

50mg RBV, 12 – 16 wks

20/27 (74.1%) (95% C.I.: 53.7% - 88.9%)

- - -


Phase 2 trials


Study Reference



LTFU n(%)

W/C n(%)

C-SCAPE,

(Brown et

al. 2015)

Open-label,

Randomised

control trial

TN, Non-cirrhotic

GZR 100mg/EBR

50mg + RBV, 12 wks

3/4 (75.0%) 1 0 0

GZR 100mg/EBR

50mg, 12 wks

3/4 (75.0%) 1 0 0


- TN, Non-cirrhotic

GZR 100mg/EBR

50mg RBV, 12 wks

6/8 (75.0%) (95% C.I.: 34.9% - 96.8%)

2/8 (25%)

0 0


Genotype 6 summary

A total of 35 genotype 6 HCV infected patients were treated in five trials (4 Phase 3 and 1

Phase 2) with grazoprevir (100 mg) and elbasvir (50 mg) with and without ribavirin. This

included treatment-naïve and experienced, HIV/HCV co-infected patients, and both cirrhotic

and non-cirrhotic patients. Two individuals were on ART and nine were on OAT. For

treatment regimens 12 weeks or longer the overall SVR12 rate was 74.3% (95%CI 56.7-

87.5%). Grazoprevir/elbasvir treatment of genotype 6 infection is not approved.

20

Special populations

HCV-HIV coinfection

HCV-HIV coinfection is a significant concern, with over 4 million people worldwide

coinfected with HIV and HCV. [16] Detectable HIV infection accelerates the progression of

HCV and has been associated with higher rates of all-cause, liver-related, and AIDS-related

deaths. [17] Thus, concurrent treatment of HIV and HCV is necessary.

Elbasvir/grazoprevir was tested in coinfected patients in two key trials: C-WORTHY and C-

EDGE coinfection; the results of these studies have been incorporated above. In summary,

over the two trials, 277 patients with HIV and HCV coinfection were treated. Individuals

were treatment-naïve chronic HCV (genotype 1, 4, or 6), both with and without cirrhosis.

Patients received grazoprevir/elbasvir with or without ribavirin for 12 weeks. A total of

264/277 (95.3%) individuals achieved SVR12.

Drug-drug interactions

Grazoprevir/elbasvir is not recommended for use in HIV patients whose ART regimens

contain an HIV-protease inhibitor. Atazanavir, darunavir, lopinavir, saquinavir, and tipranavir

are protease inhibitors whose use is contraindicated with grazoprevir/elbasvir because

elevated concentrations of grazoprevir/elbasvir have been observed, leading to elevated

ALT levels. [17] Conversely, efavirenz is contraindicated due to reductions in the

concentration of grazoprevir/elbasvir. Cobicistat and ritonavir should be used with caution.

Severe renal impairment

Grazoprevir/elbasvir has been evaluated in one study Phase 3 study focusing on patients

with stage 4 or 5 chronic kidney disease, including patients receiving haemodialysis. In the

C-SURFER study, safety and efficacy of grazoprevir/elbasvir (100mg/50mg) for 12 weeks was

evaluated in individuals with HCV genotype 1 infection, treatment-naïve or experienced,

and with or without cirrhosis. In the intent-to-treat analysis, 115/122 (94.3%) individuals

achieved SVR12.

21

Intravenous drug users receiving Opioid Agonist Therapy

Injection drug use is a major risk factor for infection with HCV, accounting for most new HCV

infections. [18] The C-EDGE CO-STAR trial evaluated grazoprevir/elbasvir for 12 weeks in

individuals who inject intravenous drugs currently receiving OAT. Individuals were genotype

1, 4, or 6, with or without HIV coinfection, and with or without cirrhosis. Of the 201

individuals enrolled, 184 (91.5%) achieved SVR12. Several individuals not achieving SVR12

were because of HCV reinfection (5 individuals). Where reinfection was counted as success,

189/201 (94.0%) individuals achieved SVR12 with grazoprevir/elbasvir therapy.

Efficacy conclusion

Grazoprevir/elbasvir is approved in HCV guidelines as a first-line option for the treatment of

treatment-naïve and treatment-experienced individuals with HCV genotype 1a, 1b, or 4,

with or without cirrhosis. Grazoprevir/elbasvir may be used in patients with HIV coinfection

however the regimen has more drug-drug interactions than other treatments.

Grazoprevir/elbasvir may also be used in individuals with severe renal impairment.

22

Review of harms and toxicity: summary of evidence on safety

Safety data from Phase 2 and 3 trials of grazoprevir/elbasvir have shown that the regimen is

well tolerated and safe. A total of 2317 individuals have been treated with the regimen in

Phase 2 and 3 trials; an unknown number of individuals have been treated in real-world

situations since the approval of the regimen.

Data from the Phase 2/3 studies shows few discontinuations because of adverse events

(<1%) and a rate of serious adverse events comparable to other regimens. No deaths have

been observed in clinical trials that were deemed related to grazoprevir/elbasvir treatment.

The most frequently reported adverse effects were headache, nausea, fatigue, decreased

appetite, anaemia, pyrexia, and elevations of ALT. These adverse events are similar to those

observed with other DAA combinations.

Phase 3 trials

Table 14 Safety data from Phase 3 trials of grazoprevir/elbasvir

Study Reference Genotypes Total No. of Patients

D/C due to AE, n (%)

Serious AE n (%)

Deaths, n (%) (causes)

C-SURFER, (Roth et al. 2015) 1 122 0 16 (14%) 1 (<1%)

C-EDGE H2H, (Sperl et al.

2016)

1 & 4 129 0 1 (<1%) 0

C-EDGE CO-STAR, (Dore et al.

2016)

1, 4 & 6 296 1 (<1%) 10 (3%) (1 drug

related)

1 (<1%)

(placebo

group)

C-EDGE TE, (Kwo et al. 2015) 1, 4 & 6 420 7 (2%) 14 (3%) 0

C-EDGE TN, (Zeuzem et al.

2015)

1, 4 & 6 316 3 (<1%)

unrelated

9 (3%)

unrelated

2 (<1%)

C-EDGE CO-INFECTED,

(Rockstroh et al 2015.)

1, 4 & 6 218 0 8 (3%)

unrelated

0

Total 1, 4 & 6 1,501 11 (<1%) 58 (4%) 4 (<1%)

Abbreviations: GT, genotype; AE, adverse event; D/C, discontinuation

There were four deaths observed from a total of 1,501 patients treated in Phase 3 trials

(<1%). In each case the investigators deemed the death to be unrelated to the study drug.

23

Phase 2 trials

Table 15 Safety data from Phase 2 trials of grazoprevir/elbasvir

Study Reference Genotypes Total No. of Patients

D/C due to AE, n (%)

Serious AE n (%) Deaths, n (%) (causes)

C-SCAPE, (Brown et al.

2015)

2,4,5 & 6 98 1 (1%) 3 (3%) 1 drug related 0

C-WORTHY, (Lawitz et

al. 2015)

1 253 2 (<1%) 7 (3%) 1 abdominal pain

related to drug.

1 (<1%)

C-WORTHY,

(Sulkowski et al. 2015)

1 218 0 3 (1%) 2 related to drug 0

C-SALVAGE, (Forns et

al. 2015)

1 79 1 (1%) 5 (6.3%) 0

C-SWIFT- FINAL,

(Lawitz, E.J. et al.

2016

1 25 0 1(4%) 0

C-SWIFT (Poordad, F.

et al. 2015)

1 & 3 143 1 (<1%) 2 (1%) B cell

lymphoma/Pyelonephritis

0

Total All GT’s 816 5 (<1%) 21 (2.6%) 1 (<1%)

Abbreviations: GT, genotype; AE, adverse event; D/C, discontinuation

Of a total of 816 patients enrolled in Phase 2 trials of grazoprevir/elbasvir, one individual

died. Investigators deemed the death unrelated to study drugs.

24

Summary of available data on comparative cost and cost-effectiveness within

the pharmacological class or therapeutic group

United States pricing

The wholesale acquisition cost (WAC) for a 12-week course of therapy with

grazoprevir/elbasvir is estimated at US$54,600 in the US. While this is higher than the cost

of previous, interferon-based treatments, the original US market prices of other new

alternative therapies are significantly higher. [17] This data is shown in Table 16.

Table 16 Original US market prices of interferon-free regimens (adapted from Bell et al. 2016)

Elbasvir-

grazoprevir

(Zepatier)

Simeprevir

(Olysio)-

sofosbuvir

(Sovaldi)

Ledipasvir-

sofosbuvir

(Harvoni)

Daclatasvir

(Daklinza)-

sofosbuvir

(Sovaldi)

12 weeks $54,600 $150,000 $94,500 $147,000

16 weeks $72,800 NA NA NA

24 weeks NA NA $189,000 NA

Non-United States pricing

The cost of pharmaceuticals in the US is disproportionately high, even in comparison to

other high income nations. [19] The total cost of a 12-week treatment course of

grazoprevir/elbasvir in the UK is £36,500. [20] Merck have agreed a nationally available

price reduction with the Commercial Medicines Unit; the contract prices agreed through the

framework are in confidence.

Pharmaceutical companies have several strategies for access in low and middle-income

countries to facilitate access without losing control of the product. No known strategies for

the grazoprevir/elbasvir combination are currently in place.

Cost-effectiveness analyses

Using the US WAC costs, the cost of cure using grazoprevir/elbasvir is lower than that of

interferon-based therapy and other DAA regimens.1 This is shown in Table 17 below. [19]

1 Calculations do not include the costs of diagnostics or other costs related to receiving treatment

25

Table 17 Standard of care regimens for non-cirrhosis, treatment-naive patients with HCV genotype 1, and cost per SVR (adapted from Rosenthal et al. 2016)

Regimena SVR ratea WAC price Cost per SVR

Pegasys + ribavirin x48 weeks 41% $41,758 $101,849

Sofosbuvir + ledipasvir x12 weeks 99% $94,500 $95,454

Grazoprevir + elbasvir x12 weeks 94% $54,600 $58,085

aStandard of care regimen and efficacy data taken from package inserts

Grazoprevir/elbasvir treatment has been shown to be cost-effective in a range of different

scenarios, including in the recent appraisal by the National Institute for Health and Care

Excellence (NICE) for the NHS in England. [19, 20, 21, 17]

26

Regulatory information

Summary of regulatory status of the medicine

Grazoprevir/elbasvir (as Zepatier, Merck Sharp & Dohme Corp.) received US-FDA regulatory

approval in January 2016. The product has also received approval from several other SRA

boards including EMA, Australia, and Health Canada. This data is shown in Table 18.

Table 18 Regulatory status according to stringent regulatory authorities

Product SRA board Approval status

Zepatier (100 mg grazoprevir + 50 mg elbasvir)

US-FDA Approved (28/01/16)

EMA Approved (22/07/16)

Australia Approved (29/08/16)

Japan Not listed

Health Canada Approved (19/01/16)

Availability of pharmacopoeial standards

None of the drugs included in this application are included in the British, International, US,

or European Pharmacopeia’s.

http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004126/human_med_002001.jsp&mid=WC0b01ac058001d124

http://tga-search.clients.funnelback.com/s/search.html?collection=tga-artg&profile=record&meta_i=259928

http://www.hc-sc.gc.ca/dhp-mps/prodpharma/rds-sdr/drug-med/rds-sdr-zepatier-185866-eng.php

27

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Clinical trial references

Brown, A. et al. (2015). C-SCAPE: EFFICACY AND SAFETY OF 12 WEEKS OF GRAZOPREVIR ± ELBASVIR ± RIBAVIRIN IN PATIENTS WITH HCV GT2, 4, 5, OR 6 INFECTION. Retrieved October 12, 2016, from http://www.natap.org/2015/EASL/EASL_06.htm

Dore, G. J. et al. (2016). Elbasvir-Grazoprevir to Treat Hepatitis C Virus Infection in Persons Receiving Opioid Agonist Therapy: A Randomized Trial. Ann Intern Med. http://doi.org/10.7326/m16-0816 [Date accessed 21/10/2016] (C-EDGE CO-STAR)

Forns, X. et al. (2015). Grazoprevir and Elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agent. Journal of Hepatology. 63(3), 564-572. [Date accessed 12/10/2016] (C-SALVAGE)

29

Kwo, P. et al. (2015). C-EDGE TE: EFFICACY AND SAFETY OF GRAZOPREVIR/ELBASVIR +/- RBV FOR 12 OR 16 WEEKS IN PATIENTS WITH HCV G1, G4 OR G6 INFECTION WHO PREVIOUSLY FAILED PEGINTERFERON/RBV: C-EDGE TREATMENT-EXPERIENCED. Retrieved from http://www.natap.org/2015/EASL/EASL_04.htm [Accessed 25/10/2016]

Lawitz, E. et al. (2014). 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 . The Lancet, 385(9973), 1075–1086. http://doi.org/10.1016/S0140-6736(14)61795-5 (C-WORTHY) [Accessed 26/10/2016]

Lawitz, E. J. et al. (2016). C-SWIFT - RETREATMENT FINAL RESULTS: HIGHLY SUCCESSFUL RETREATMENT OF GT1-INFECTED PATIENTS WITH 12 WEEKS OF ELBASVIR/GRAZOPREVIR PLUS SOFOSBUVIR AND RIBAVIRIN AFTER FAILURE OF SHORT-DURATION ALL-ORAL THERAPY. Retrieved November 2, 2016, from http://www.natap.org/2016/EASL/EASL_110.htm

Poordad, F. et al. (2015). C-SWIFT: GRAZOPREVIR/ELBASVIR + SOFOSBUVIR IN CIRRHOTIC AND NONCIRRHOTIC, TREATMENT-NAIVE PATIENTS WITH HEPATITIS C VIRUS GENOTYPE 1 INFECTION, FOR DURATIONS OF 4, 6 OR 8 WEEKS AND GENOTYPE 3 INFECTION FOR DURATIONS OF 8 OR 12 WEEKS. Retrieved October 2, 2016, from http://www.natap.org/2015/EASL/EASL_11.htm

Rockstroh, J.K. et al. (2015). C-EDGE Co-Infected: final results from Phase 3 Study of elbasvir / grazoprevir in Patients with HCV/HIV. Retrieved October 24, 2016 from http://www.natap.org/2015/AASLD/AASLD_61.htm

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Grazoprevir/Elbasvir for the treatment of Hepatitis C...replication. Elbasvir is an NS5A inhibitor,...

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