Elbasvir-Grazoprevir ( Zepatier ) Prepared by: H. Nina Kim, MD, MSc - - PowerPoint PPT Presentation

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Elbasvir-Grazoprevir (Zepatier)

Prepared by:

• H. Nina Kim, MD, MSc

David H. Spach, MD

Last Updated: July 15, 2020

Background and Dosing

ELBASVIR-GRAZOPREVIR (ZEPATIER)

Elbasvir-Grazoprevir (Zepatier)

• Approval Status
• Approval by United States FDA on January 28, 2016
• Indications and Usage
• Indicated for the treatment of chronic HCV genotypes 1 or 4 in adults
• Indicated for treatment of patients with HIV coinfection
• Class & Mechanism
• Elbasvir: HCV NS5A inhibitor
• Grazoprevir: HCV NS3/4A inhibitor
• Dosing: Elbasvir-Grazoprevir (fixed dose 50 mg/100 mg)

One tablet orally once daily, with or without food

• Adverse Effects (AE):
• Fatigue, headache, and nausea
• Increase in ALT > 5x normal in 1% of subjects

Source: Zapatier Prescribing Information. Merck & Co., Inc.

Source: Zapatier Prescribing Information. Merck & Co., Inc.

Elbasvir-Grazoprevir (Zepatier) Indications and Usage

Elbasvir-Grazoprevir (EBR-GZR) HCV Treatment in Patients with or without Cirrhosis Patient Population Treatment Duration

GT 1a: Treatment-naïve or PegIFN/RBV-experienced (without baseline NS5A polymorphisms*) Elbasvir-Grazoprevir 12 weeks GT 1a: Treatment-naïve or PegIFN/RBV-experienced (with baseline NS5A polymorphisms*) Elbasvir-Grazoprevir + RBV 16 weeks GT 1b: Treatment-naïve or PegIFN/RBV-experienced Elbasvir-Grazoprevir 12 weeks GT 1a or 1b: PegIFN/RBV/PI-experienced Elbasvir-Grazoprevir + RBV 12 weeks GT 4: Treatment-naïve Elbasvir-Grazoprevir 12 weeks GT 4: PegIFN/RBV-Experienced Elbasvir-Grazoprevir + RBV 16 weeks

Abbreviations: PegIFN = peginterferon; RBV = ribavirin; PI = protease inhibitor; EBR-GZR = elbasvir-grazoprevir *Polymorphisms at amino acid positions 28, 30, 31, or 93

Source: Zapatier Prescribing Information. Merck & Co., Inc.

Elbasvir-Grazoprevir (Zepatier) Drug-Drug Interactions

HCV GT1a and Impact of Baseline NS5A Polymorphisms on SVR12

NS5A Polymorphism Status EBR-GZR x 12 weeks SVR12% (n/N) EBR-GZR + RBV x 16 weeks SVR12% (n/N) Without baseline NS5A polymorphism (M28, Q30, L31, or Y93) 98% (441/450) 100% (49/49) With baseline NS5A polymorphism (M28*, Q30*, L31*, or Y93*) 70% (39/56) 100% (6/6) Abbreviations: GT = genotype; EBR = elbasvir; GZR = grazoprevir *Any change from GT1a reference

Source: Zapatier Prescribing Information. Merck & Co., Inc.

Elbasvir-Grazoprevir (Zepatier) Drug-Drug Interactions

Drugs that are Contraindicated for Use with Elbasvir-Grazoprevir* Organic ion transporter polypeptide 1B (OATP1B) inhibitors Antimycobacterials Rifampin HIV medications Atazanavir Darunavir Lopinavir Saquinavir Tipranavir Immunosuppressants Cyclosporine Strong CYP3A Inducers Anticonvulsants Phenytoin Carbamazepine Herbal products

• St. John’s Wort (Hypericum perforatum)

HIV medications Efavirenz+

*This is not a complete list of all drugs that inhibit OAT1B or strongly induce CYP3A

+Efavirenz is listed as a strong CYP3A inducer because it reduced grazoprevir exposure by ≥80%

Elbasvir-Grazoprevir

CLINICAL TRIALS

• Phase 2 Trials
• C-SWIFT: EBR-GZR + SOF x 8 or 12 weeks in TN, GT1 or GT3
• C-WORTHY: EBR-GZR +/- RBV in TN Cirrhotic or TE null responders
• C-WORTHY Coinfection: EBR-GZR +/- RBV in HIV coinfection
• C-SALVAGE: EBR-GZR + RBV in PI-experienced patients
• C-SCAPE: EBR +/- GZR +/- RBV in GT 2, 4, 5, or 6 without cirrhosis

Elbasvir-Grazoprevir (EBR-GZR): Summary of Key Studies

Abbreviations: EBR-GZR = elbasvir-grazoprevir; SOF = sofosbuvir; TN = treatment-naïve; GT = genotype; TE = treatment experienced; RBV = ribavirin

• Phase 3 Trials
• C-EDGE TN: EBR-GZR x 12 weeks in TN, GT 1, 4, or 6
• C-EDGE TE: EBR-GZR +/- RBV x 12 or 16 weeks in TE, GT 1, 4 or 6
• C-EDGE Coinfection: EBR-GZR x 12 weeks in HIV-HCV coinfected
• C-EDGE CO-STAR: EBR-GZR x 12 weeks in persons who inject drugs
• C-SURFER: EBR-GZR x 12 weeks in GT1 and Chronic kidney disease

Elbasvir-Grazoprevir (EBR-GZR): Summary of Key Studies

Abbreviations: EBR-GZR = elbasvir-grazoprevir; TN = treatment-naïve; GT = genotype; TE = treatment experienced; RBV = ribavirin

Elbasvir-Grazoprevir in Treatment-Naïve Patients

Elbasvir-Grazoprevir + Sofosbuvir in Treatment-Naïve HCV Genotype 1 or 3

C-SWIFT

Phase 2

Treatment Naïve Source: Lawitz E, et al. Hepatology. 2017;65:439-50.

Source: Lawitz E, et al. Hepatology. 2017;65:439-50.

Elbasvir-Grazoprevir + Sofosbuvir in Treatment-Naïve GT 1 or 3

C-SWIFT Study: Features

C-SWIFT Trial

• Design: Open-label phase 2 trial to evaluate the efficacy and safety of

short duration therapy with elbasvir-grazoprevir + sofosbuvir in treatment- naïve GT 1 or 3 infection, with or without cirrhosis

• Entry Criteria
• Chronic HCV genotype 1 (n = 102) or genotype 3 (n = 41)
• Age 18 years or older
• No prior HCV treatment
• HCV RNA ≥10,000 IU/mL
• ALT and AST <350 IU/L
• Cirrhosis allowed
• Primary End-Point: SVR12

Source: Lawitz E, et al. Hepatology. 2017;65:439-50.

Elbasvir-Grazoprevir + Sofosbuvir in Treatment-Naïve GT 1 or 3

C-SWIFT Study: Study Design for GT 1

EBR-GZR + SOF GT-1 Non-cirrhotic n = 31 EBR-GZR + SOF EBR-GZR + SOF EBR-GZR + SOF GT-1 Cirrhotic n = 30 n = 20 n = 21 Week 24 4 6 Abbreviations: EBR-GZR = elbasvir-grazoprevir; SOF = sofosbuvir Drug Dosing Elbasvir-grazoprevir (50/100 mg): fixed-dose combination; one pill once daily Sofosbuvir: 400 mg once daily 8

Source: Lawitz E, et al. Hepatology. 2017;65:439-50.

Elbasvir-Grazoprevir + Sofosbuvir in Treatment-Naïve GT 1 or 3

C-SWIFT Study: Study Design for GT 3

EBR-GZR + SOF SVR12

GT-3

Non-cirrhotic n = 15 EBR-GZR + SOF SVR12 EBR-GZR + SOF SVR12

GT-3

Cirrhotic n = 14 n = 12 Week 24 8 12 20 Abbreviations: EBR-GZR= grazoprevir-elbasvir; SOF = sofosbuvir Drug Dosing Grazoprevir/elbasvir (100/50 mg): fixed dose combination; one pill once daily Sofosbuvir 400 mg once daily

Source: Lawitz E, et al. Hepatology. 2017;65:439-50.

Elbasvir-Grazoprevir + Sofosbuvir in Treatment-Naïve GT 1 or 3 C-SWIFT Study: Baseline Characteristics

Baseline Characteristic

Genotype 1 Genotype 3 No cirrhosis Cirrhosis No Cirrhosis Cirrhosis 4 weeks

(n = 31)

6 weeks

(n = 30)

6 weeks

(n = 20)

8 weeks

(n = 21)

8 weeks

(n = 15)

12 weeks

(n = 14)

12 weeks

(n = 12)

Mean age, years 52 51 56 57 51 42 55 Male sex, % 65 63 65 62 73 57 83 Race, % White 97 93 100 95 100 100 100 Hispanic/Latino 29 47 65 48 40 57 50 HCV Genotype, % 1a 84 87 80 76

• 1b

16 13 20 24

• 3
• 100

100 100 IL28B CC, % 36 27 30 24 40 21 50 Cirrhosis, % 100 100 100 HCV RNA, 106 IU/mL (mean) 3.7 3.1 1.7 2.4 3.3 2.6 2.3

Source: Lawitz E, et al. Hepatology. 2017;65:439-50.

Elbasvir-Grazoprevir + Sofosbuvir in Treatment-Naïve GT 1 or 3 C-SWIFT Study: Results for GT 1

C-SWIFT: SVR 12* for GT 1 by Treatment Duration and Cirrhosis

32.0 86.7 80.0 81.0 20 40 60 80 100

4 weeks 6 weeks 6 weeks 8 weeks

Patients with SVR 12 (%)

10/30 No Cirrhosis 26/30 16/20 17/21 Cirrhosis

Source: Lawitz E, et al. Hepatology. 2017;65:439-50.

Elbasvir-Grazoprevir + Sofosbuvir in Treatment-Naïve GT 1 or 3 C-SWIFT Study: Results for GT 3 C-SWIFT: SVR 12* for GT 3 by Treatment Duration and Cirrhosis

93.0 100.0 83.3 20 40 60 80 100

8 weeks 12 weeks 12 weeks

Patients with SVR 12 (%)

14/15 No Cirrhosis 14/14 10/12 Cirrhosis

Source: Lawitz E, et al. Hepatology. 2017;65:439-50.

Elbasvir-Grazoprevir + Sofosbuvir in Treatment-Naïve GT 1 or 3 C-SWIFT Study: Conclusions

Conclusions: “Data from this study support the use of 8-week treatment regimens that maintain high efficacy, even for patients with HCV GT3 infection. Retreatment of patients who failed short-duration therapy was achieved through extended treatment duration and addition of ribavirin.

Elbasvir-Grazoprevir in Treatment-Naïve HCV Genotype 1, 4, or 6

C-EDGE Treatment Naïve

Phase 3

Treatment Naïve Source: Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.

Source: Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.

Elbasvir-Grazoprevir in Treatment-Naïve HCV Genotype 1, 4, or 6

C-EDGE TN Study: Features

C-EDGE TN Trial

• Design: Randomized, placebo-controlled, parallel-group, phase 3 trial

using a fixed-dose combination of elbasvir-grazoprevir for 12 weeks in treatment-naïve patients with GT 1, 4, or 6 chronic HCV

• Setting: 60 sites in United States, Europe, Australia, Scandinavia, & Asia
• Entry Criteria
• Chronic HCV: GT1 = 91%, GT4 = 6%, or GT6 = 3%
• Age 18 years or older
• HCV RNA ≥10,000 IU/mL
• No prior HCV treatment
• Patients with compensated cirrhosis accepted
• Primary End-Point: SVR12

Source: Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.

Elbasvir-Grazoprevir in Treatment-Naïve HCV Genotype 1, 4, or 6 C-EDGE TN: Study Design

Elbasvir-Grazoprevir SVR12 Drug Dosing Elbasvir-Grazoprevir (50/100 mg): fixed dose combination; one pill once daily Treatment-naïve GT 1, 4 or 6 (n = 421) n =316 Placebo SVR12 n =105 Week 40 12 16 28 Elbasvir-Grazoprevir Randomized 3:1 ratio to immediate or deferred arm; stratified by cirrhosis, HCV genotype, subtype After 4 weeks of follow-up, placebo recipients were unblinded and given elbasvir-grazoprevir open label 24

Delayed Immediate

Source: Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.

Elbasvir-Grazoprevir in Treatment-Naïve HCV GT 1, 4, or 6 C-EDGE TN: Baseline Characteristics

Baseline Characteristic Immediate Arm (n = 316) Delayed Arm (n = 105) All Patients (n = 421) Age, mean 52 54 53 Male, % 54 53 54 Race, % Asian Black White 17 19 60 12 17 70 16 18 63 HCV genotype, n (%) 1a 1b 4 6 157 (50) 131 (42) 18 (6) 10 (3) 54 (51) 40 (38) 8 (8) 3 (3) 211 (50) 171 (41) 26 (6) 13 (3) HCV RNA >800,000 IU/ml, % 222 (70) 66 (63) 288 (68) IL28B non-CC, % 66 64 65 Fibrosis stage, % F0-2 F3 F4 67 11 22 66 13 21 66 12 22

Source: Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.

Elbasvir-Grazoprevir in Treatment-Naïve HCV GT 1, 4, or 6 C-EDGE TN: Results for Immediate Group

C-EDGE TN: SVR12 Results by Genotype

95 92 99 100 80 20 40 60 80 100 All GT 1a GT 1b GT 4 GT 6

Patients with SVR12 (%)

299/316 144/157 129/131 18/18 8/10 Primary efficacy analysis included all patients who received ≥1 dose of drug.

Source: Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.

Elbasvir-Grazoprevir in Treatment-Naïve HCV GT 1, 4, or 6 C-EDGE TN: Results for Immediate Group

C-EDGE TN: SVR12 by Presence of Cirrhosis or High HCV RNA Level

94 97 100 92

20 40 60 80 100 No Cirrhosis Cirrhosis ≤800K IU/mL >800K IU/mL Patients (%) with SVR 12

231/246 68/70 94/94 205/222

Presence of Cirrhosis Baseline HCV RNA

Source: Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.

Elbasvir-Grazoprevir in Treatment-Naïve HCV GT 1, 4, or 6 C-EDGE TN: Results

Baseline NS5A Resistance-Associated Variants and SVR12 in GT1

58 94 99 100

20 40 60 80 100 Genotype 1a Genotype 1b Patients (%) with SVR 12

Baseline NS5A RAVs* No Baseline NS5A RAVs

133/135 11/19 112/112 17/18 *Patients with baseline GT1a RAVs with a ≤5-fold shift to elbasvir: SVR12=90% (9 of 10) *Patients with baseline GT1a RAVs with a >5-fold shift to elbasvir: SVR12=22% (2 of 9)

Source: Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.

Elbasvir-Grazoprevir in Treatment-Naïve HCV GT 1, 4, or 6 C-EDGE TN: Results

Baseline NS3/4A Resistance-Associated Variants and SVR12 in GT1

97 96 89 100

20 40 60 80 100 Genotype 1a Genotype 1b Patients (%) with SVR 12

Baseline NS3/4A RAVs No Baseline NS3/4A RAVs

58/65 83/86 104/104 24/25

Source: Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.

Elbasvir-Grazoprevir in Treatment-Naïve HCV GT 1, 4 or 6 C-EDGE TN: Adverse Events

Adverse Event (AE) Elbasvir-Grazoprevir Immediate (n = 316) Delayed (Placebo) (n = 105) Discontinuation due to AE 3 (0.9%) 1 (1%) Serious AEs 9 (3%) 3 (3%) Deaths 2 (0.6%)§ Any AE in ≥10% of patients Headache Fatigue 52 (17%) 49 (16%) 19 (18%) 18 (17%) Laboratory AEs ALT >5 x baseline AST >5 x baseline Total bilirubin elevation >5 x baseline Grade 3 or 4 hemoglobin Grade 3 or 4 neutrophils Grade 3 or 4 creatinine 3 (0.9%) 1 (0.3%) 1 (0.3%) 1 (0.3%) 1 (1%)

§Neither death was considered to be study-related.

Source: Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.

Elbasvir-Grazoprevir in Treatment-Naïve HCV GT 1, 4, or 6 C-EDGE TN: Conclusions

Conclusions: “Grazoprevir-elbasvir achieved high SVR12 rates in treatment-naive cirrhotic and noncirrhotic patients with genotype 1, 4,

• r 6 infection. This once-daily, all-oral, fixed-combination regimen

represents a potent new therapeutic option for chronic HCV infection.”

Elbasvir + Grazoprevir +/- Ribavirin in Treatment-Naïve HCV GT 2, 4, 5, or 6

C-SCAPE

Phase 2

Treatment Naïve Source: Brown A, et al. J Viral Hepat. 2018;25:457-64.

Source: Brown A, et al. J Viral Hepat. 2018;25:457-64.

Elbasvir + Grazoprevir +/- RBV in Treatment-Naïve GT 2, 4, 5 or 6

C-SCAPE Study: Features

C-SCAPE Trial

• Design: Open-label, phase 2 trial to evaluate the efficacy and safety of

elbasvir + grazoprevir + ribavirin versus elbasvir + grazoprevir versus grazoprevir + ribavirin in non-cirrhotic, treatment-naïve patients with GT 2, 4, 5, or 6 chronic hepatitis C infection

• Entry Criteria
• Chronic HCV GT2 (n = 60), GT4 (n = 20), GT5 (n = 8), or GT6 (n = 10)
• Age 18 years or older
• No prior HCV treatment
• HCV RNA ≥10,000 IU/mL
• No evidence of cirrhosis
• Primary End-Point: SVR12

Source: Brown A, et al. J Viral Hepat. 2018;25:457-64.

Elbasvir + Grazoprevir +/- RBV in Treatment-Naïve GT 2, 4, 5 or 6

C-SCAPE Study: Study Design for GT 1

EBR-GZR + RBV GT 2 Non-cirrhotic n = 30 EBR-GZR + RBV EBR-GZR GZR + RBV GT 4, 5, or 6 Non-cirrhotic n = 30 n = 19 n = 19 Week 12 Abbreviations: EBR = Elbasvir; GZR = Grazoprevir; RBV = ribavirin Drug Dosing Elbasvir (50 mg) once daily Grazoprevir (100 mg) once daily Ribavirin (weight-based and divided bid): 800 to 1400 mg/day 24 SVR12 SVR12 SVR12 SVR12

Source: Brown A, et al. J Viral Hepat. 2018;25:457-64.

Elbasvir + Grazoprevir +/- RBV in Treatment-Naïve GT 2, 4, 5 or 6

C-SCAPE Study: Baseline Characteristics

Baseline Characteristic

Genotype 2 Genotype 4, 5, 6 EBR + GZR + RBV (n = 30) GZR + RBV (n = 30) EBR + GZR + RBV (n = 19) EBR-GZR (n = 19) Mean age, y (range) 47.3 48.3 52.2 52.8 Male sex, % 63.3 56.7 42.1 63.2 Race, % White Other 100 86.7 13.3 73.7 26.3 68.4 31.6 HCV Genotype, n 2 4 5 6 1 30

• 26

4 10 4 4

• 10

4 4

• HCV RNA

≤ 2 million >2 million 36.7 63.3 36.7 63.3 57.9 42.1 36.8 63.2 *Excluded from modified intent-to-treat analysis due to discordant genotype

Source: Brown A, et al. J Viral Hepat. 2018;25:457-64.

Elbasvir + Grazoprevir +/- RBV in Treatment-Naïve GT 2, 4, 5, or 6

C-SCAPE Study: Results

C-SCAPE: SVR12 by Genotype and Regimen

80 100 100 75 73 90 25 75

20 40 60 80 100 GT2 GT4 GT5 GT6 Patients (%) with SVR 12

EBR + GZR + RBV x 12 weeks GZR + RBV x 12 weeks EBR + GZR + RBV x 12 weeks EBR + GZR x 12 weeks 24/30 19/26 10/10 9/10 4/4 1/4 3/4 3/4

Source: Brown A, et al. J Viral Hepat. 2018;25:457-64.

Elbasvir + Grazoprevir +/- RBV in Treatment-Naïve GT 2, 4, 5 or 6

C-SCAPE Study: Conclusions

Conclusions: “These data support the inclusion of participants with genotype 4 or 6 infection in the elbasvir-grazoprevir phase 3 studies. Elbasvir-grazoprevir ± ribavirin was unsatisfactory for participants with genotype 2 or 5 infection.”

Elbasvir-Grazoprevir in Treatment-Experienced Patients

Elbasvir-Grazoprevir +/- Ribavirin in HCV Genotype 1, 4 or 6

C-EDGE Treatment Experienced (TE)

Phase 3

Treatment Experienced Source: Kwo P, et al. Gastroenterology. 2017;152:164-75.

Source: Kwo P, et al. Gastroenterology. 2017;152:164-75.

Elbasvir-Grazoprevir +/- Ribavirin in HCV Genotype 1, 4 or 6

C-EDGE TE Study: Features

C-EDGE TE Trial

• Design: Randomized, open label, parallel-group, phase 3 trial examining

the safety and efficacy of a fixed-dose combination of elbasvir-grazoprevir with or without ribavirin for 12 or 16 weeks in treatment-experienced adults with GT 1, 4, or 6 HCV and previous failure of peginterferon plus ribavirin

• Entry Criteria
• Chronic HCV Genotype 1, 4 or 6
• 18 years or older
• HCV RNA ≥10,000 IU/mL
• History of peginterferon plus ribavirin treatment failure
• Patients with compensated cirrhosis accepted
• Some patients with HIV infection accepted
• Primary End-Point: SVR12

Source: Kwo P, et al. Gastroenterology. 2017;152:164-75.

Elbasvir-Grazoprevir +/- Ribavirin in HCV Genotype 1, 4 or 6 C-EDGE TE: Study Design

EBR-GRZ SVR12 N =14 Abbreviations: EBR-GZR = elbasvir-grazoprevir; RBV = ribavirin Drug Dosing Elbasvir-grazoprevir (50/100 mg): fixed dose combination; one pill once daily Ribavirin (weight-based and divided bid): 800 to 1400 mg/day GT 1, 4 or 6 Prior Treatment (n = 420) n = 105 EBR-GRZ SVR12 EBR-GRZ + RBV SVR12 EBR-GRZ + RBV SVR12 n = 104 n = 105 n = 106 Week 36 12 16 24 28

Source: Kwo P, et al. Gastroenterology. 2017;152:164-75.

Elbasvir-Grazoprevir +/- Ribavirin in HCV Genotype 1, 4 or 6 C-EDGE TE: Baseline Characteristics

Baseline Characteristic

12-Week Treatment 16-Week Treatment EBR-GRZ (n = 105) EBR-GRZ + RBV (n = 104) EBR-GRZ (n = 105) EBR-GRZ + RBV (n = 106) Age, yrs median (range) 56 (25–76) 56 (23–75) 55 (31–73) 55 (19–77) Male sex, % 63 69 66 60 Race, n (%) Caucasian African American Asian 66 (63) 23 (22) 15 (14) 70 (67) 24 (23) 9 (9) 72 (69) 9 (9) 22 (21) 78 (74) 15 (14) 10 (9) HCV Genotype, % 1a 1b 4 6 61 (58) 34 (32) 9 (9) 0 (0) 60 (58) 29 (28) 15 (14) 0 (0) 48 (46) 48 (46) 5 (5) 4 (4) 58 (55) 36 (34) 8 (8) 2 (2) Cirrhosis, % 37 (35) 35 (34) 38 (36) 37 (35) HIV coinfection, % 6 (6) 5 (5) 6 (6) 4 (4) Prior treatment response Relapse, % Partial response, % Prior null, % 35 (33) 21 (20) 49 (47) 38 (37) 22 (21) 44 (42) 38 (36) 21 (20) 46 (44) 40 (38) 23 (22) 43 (41)

Source: Kwo P, et al. Gastroenterology. 2017;152:164-75.

Elbasvir-Grazoprevir +/- Ribavirin in HCV Genotype 1, 4 or 6 C-EDGE TE: Results

C-EDGE TE: SVR 12*, by Genotype

96 89 100 20 40 60 80 100

Genotype 1 Genotype 4 Genotype 6

Patients with SVR 12 (%)

356/370 32/36 4/4 * Analysis per protocol: excluding patients who dropped out due to reasons other than virologic failure

Source: Kwo P, et al. Gastroenterology. 2017;152:164-75.

Elbasvir-Grazoprevir +/- Ribavirin in HCV Genotype 1, 4 or 6 C-EDGE TE: Results

C-EDGE TE: SVR 12* by Regimen and Treatment Duration (GT 1, 4, or 6)

92 94 92 98 20 40 60 80 100

EBR-GRZ EBR-GRZ + RBV EBR-GRZ EBR-GRZ + RBV

Patients with SVR 12 (%)

97/105 12-Week Regimen 98/104 97/105 104/106 16-Week Regimen * Analysis per intent to treat

Source: Kwo P, et al. Gastroenterology. 2017;152:164-75.

Elbasvir-Grazoprevir +/- Ribavirin in HCV Genotype 1, 4 or 6 C-EDGE TE: Results

C-EDGE TE: SVR 12 by Regimen, Treatment Duration, and GT1 Subtype

91.7 93.3 93.8 100 100 96.6 97.9 100

20 40 60 80 100

EBR-GRZ EBR-GRZ + RBV EBR-GRZ EBR-GRZ + RBV

Patients with SVR 12 (%) Genotype 1a Genotype 1b

55/60 12-Week Regimen 16-Week Regimen 34/34 56/60 28/29 45/48 46/47 55/55 37/37

Source: Kwo P, et al. Gastroenterology. 2017;152:164-75.

Elbasvir-Grazoprevir +/- Ribavirin in HCV Genotype 1, 4 or 6 C-EDGE TE: Results

C-EDGE TE: SVR 12 in Patients with Baseline NS5A RAVs

60.0 66.7 50.0 100 100 80.0 91.7 100

20 40 60 80 100

EBR-GRZ EBR-GRZ + RBV EBR-GRZ EBR-GRZ + RBV

Patients with SVR 12 (%) Genotype 1a Genotype 1b

6/10 12-Week Regimen 16-Week Regimen 4/4 6/9 4/5 3/6 11/12 6/6 9/9

Source: Kwo P, et al. Gastroenterology. 2017;152:164-75.

Elbasvir-Grazoprevir +/- Ribavirin in HCV Genotype 1, 4 or 6 C-EDGE TE: Results

Conclusions: “The combination tablet of elbasvir and grazoprevir, with

• r without ribavirin, was highly efficacious in inducing an SVR12 in

patients with HCV genotype 1, 4, or 6 infection failed by previous treatment with peg-interferon and ribavirin, including patients with cirrhosis and/or a prior null response. The treatment was generally well tolerated.”

Elbasvir + Grazoprevir + Ribavirin in PI-experienced HCV GT1

C-SALVAGE

Phase 2

Treatment Experienced Source: (1) Buti M, et al. Clin Infect Dis. 2016;62:32-6. (2) Forns X, et al. J Hepatol. 2015;63:564-72.

Source: (1) Buti M, et al. Clin Infect Dis. 2016;62:32-6. (2) Forns X, et al. J Hepatol. 2015;63:564-72.

Elbasvir + Grazoprevir + Ribavirin in PI-experienced HCV GT1 C-SALVAGE Study: Features

C-SALVAGE Trial

• Design: Prospective, open-label, single-arm, phase 2 trial of elbasvir plus

grazoprevir plus ribavirin for 12 weeks in treatment-experienced patients with HCV GT1, with or without cirrhosis, and previous failure of peginterferon and ribavirin plus an early-generation HCV protease inhibitor (boceprevir, simeprevir, or telaprevir)

• Entry Criteria
• Chronic HCV genotype 1
• Age 18 years or older
• HCV RNA ≥10,000 IU/mL
• Prior treatment failure with ≥4 weeks of peginterferon + ribavirin + PI
• Patients with compensated cirrhosis accepted
• Primary End-Points:

SVR12 data analysis: Buti M, et al. Clin Infect Dis. 2016;62:32-6. SVR24 data analysis: Forns X, et al. J Hepatol. 2015;63:564-72.

Source: Buti M, et al. Clin Infect Dis. 2016;62:32-6.

Elbasvir + Grazoprevir + Ribavirin in PI-experienced HCV GT1 C-SALVAGE Study: Design

PI+PR experienced Genotype 1 Non-cirrhotic (N=45) Cirrhotic (N=34)

N=79

EBR + GZR + RBV

Week 24 12 SVR12 Abbreviations: EBR = elbasvir; GZR = grazoprevir; RBV = ribavirin; PI = protease inhibitor; PR = peginterferon+ribavirin Drug Dosing: Elbasvir: 50 mg once daily Grazoprevir: 100 mg once daily Ribavirin (weight-based and divided bid): 800 to 1400 mg/day

Source: Forns X, et al. J Hepatol. 2015;63:564-72.

Elbasvir + Grazoprevir + Ribavirin in PI-experienced HCV GT1 C-SALVAGE Study: Participants

Baseline Characteristic

All Patients

(n = 79)

Baseline NS3 RAVs*

(n = 34)

No Baseline NS3 RAVs*

(n = 44)

Mean age, years 54.4 53.9 54.6 Male/Female, % 58.2/41.8 61.8/38.2 54.5/45.5 HCV genotype, % 1a 1b 38.0 62.0 67.6 32.4 15.9 84.1 Cirrhosis, % 43.0 44.1 43.2 Previous PI, % Boceprevir Telaprevir Simeprevir 35.4 54.4 10.1 29.4 55.9 14.7 38.6 54.5 6.8 Non-virologic failure+, % 16.5 5.9 25.0

* Among evaluable patients

+ Reasons for the 13 non-virologic failure included adverse events/drug intolerance (n=12) and short course

regimen in a clinical trial (n=1)

Source: Buti M, et al. Clin Infect Dis. 2016;62:32-6.

Elbasvir + Grazoprevir + Ribavirin in PI-experienced HCV GT1 C-SALVAGE Study: Results

C-SALVAGE: SVR 24* by Baseline Factors

96.2 95.5 91.7 94.1

20 40 60 80 100

All patients Prior virologic failure NS3 +/- NS5 RAVs Cirrhosis Patients (%) with SVR24 76/79 63/66 32/34

* Analysis per intent to treat

33/36

Source: Buti M, et al. Clin Infect Dis. 2016;62:32-6.

Elbasvir + Grazoprevir + Ribavirin in PI-experienced HCV GT1 C-SALVAGE Study: Results

SVR24 Related to Baseline RAVs in 79 Patients with Prior Virologic Failure Categories of RAVs Baseline RAV SVR24 in Patients with Baseline RAVs

NS3 RAV 34/79 (43%) 31/34 (91%) NS5A RAV 9/79 (11%) 8/9 (89%) Total 43/79 (54%) 39/43 (91%) RAV = Resistance Associated Variants

Source: Forns X, et al. J Hepatol. 2015;63:564-72.

Elbasvir + Grazoprevir + Ribavirin in PI-experienced HCV GT1 C-SALVAGE Study: Adverse Events

Adverse Event (AE), n (%) Grazoprevir + Elbasvir + Ribavirin (n = 79) Discontinuation due to AE 1 (1.3%) Serious AEs 4 (5.1%) Deaths Specific AE in ≥10% of patients Fatigue Headache Asthenia Nausea 22 (28%) 15 (19%) 12 (15%) 9 (12%) Grade 3 or 4 laboratory abnormality Total bilirubin Direct bilirubin AST or ALT Lipase Hemoglobin Grade 3 4 (5.1%) 2 (2.5%) 4 (5.1%) 2 (2.5%) Grade 4 1 (1.3%)

Source: Buti M, et al. Clin Infect Dis. 2016;62:32-6.

Elbasvir + Grazoprevir + Ribavirin in PI-experienced HCV GT1 C-SALVAGE Study: Conclusions

Conclusions: “Grazoprevir and elbasvir with ribavirin for 12 weeks

maintained HCV suppression for at least 24 weeks posttherapy without late

• relapses. Baseline resistance-associated variants (RAVs) stably reappeared at

relapse in all 3 patients with virologic failure. NS5A RAVs emerging at relapse persisted for the full 24-week follow-up period. If confirmed, this finding could complicate retreatment of the small number of patients failing regimens containing an NS5A inhibitor.”

Elbasvir-Grazoprevir + Sofosbuvir +/- RBV in GT 3

C-ISLE

Phase 2

Treatment Naïve and Treatment Experienced Source: Foster GR, et al. Hepatology. 2018;67:2113-26.

Source: Foster GR, et al. Hepatology. 2018;67:2113-26.

Elbasvir + Grazoprevir +/- Ribavirin in HCV GT3

C-ISLE Study: Features

C-ISLE Trial

• Design: Randomized, open label, phase 2 trial examining the safety and

efficacy of elbasvir-grazoprevir plus sofosbuvir, with or without ribavirin, for 8

• r 12 weeks in treatment-naïve adults with HCV GT3 and compensated

cirrhosis, or for 12 or 16 weeks in adults with HCV GT3 and prior with treatment failure with peginterferon plus ribavirin (PR)

• Entry Criteria
• Chronic HCV genotype 3
• 18 years or older
• Compensated cirrhosis (Child-Pugh class A) and HIV allowed
• Exclusions: prior DAA therapy, HBV, Child-Pugh class B or C cirrhosis
• Primary End-Point: SVR12

Source: Foster G, et al. Hepatology 2018;67:2113-6.

Elbasvir-Grazoprevir + Sofosbuvir +/- RBV in HCV GT3 Cirrhosis

C-ISLE Study: Study Design

Week 12

EBR-GZR + SOF + RBV

SVR24 Treatment- Naive n = 24 n = 23 EBR-GZR + SOF n = 17 EBR-GZR + SOF SVR24 SVR24 EBR-GZR + SOF SVR24 n = 18 Abbreviations: EBR = elbasvir; GRZ = grazoprevir; SOF = sofosbuvir; RBV = ribavirin Drug Dosing Elbasvir: 50 mg once daily, Grazoprevir: 100 mg once daily, Sofosbuvir: 400 mg once daily Ribavirin (weight-based and divided bid): 800 to 1400 mg/day Treatment- Experienced 8 n = 18 EBR-GZR + SOF + RBV SVR24

//

16

// // // //

Source: Foster GR, et al. Hepatology. 2018;67:2113-26.

Elbasvir-Grazoprevir + Sofosbuvir +/- Ribavirin in HCV GT3

C-ISLE: Study Design

Week 24 8 16 12 EBR-GZR + SOF + RBV SVR12 n = 24 n = 23 EBR-GZR + SOF n = 17 EBR-GZR + SOF SVR12 SVR12 EBR-GZR + SOF SVR12 Abbreviations: EBR-GZR = elbasvir-grazoprevir; RBV = ribavirin: SOF = sofosbuvir Drug Dosing Elbasvir: 50 mg once daily; Grazoprevir: 100 mg once daily; Sofosbuvir: 400 mg once daily Ribavirin (weight-based and divided bid): 800 to 1400 mg/day n = 18 28

HCV GT3: Treatment-Naïve Participants HCV GT3: Peginterferon + Ribavirin Treatment Experienced Participants

n = 18 EBR-GZR + SOF + RBV SVR12

Source: Foster GR, et al. Hepatology. 2018;67:2113-26.

Elbasvir-Grazoprevir + Sofosbuvir +/- Ribavirin in HCV GT3

C-ISLE Study: Baseline Characteristics

Baseline Characteristic Treatment-Naïve Treatment-Experienced

EBR-GZR + SOF + RBV 8 weeks (n = 23 EBR-GZR + SOF 12 weeks (n = 24) EBR-GZR + SOF 12 weeks (n = 17) EBR-GZR + SOF + RBV 12 weeks (n = 18) EBR-GZR + SOF 16 weeks (n = 18)

Median age, y (range) 51 (37-68) 48 (32-64) 58 (48-68) 56 (38-70) 53 (43-66) Male, % Female, % 56.5 43.5 70.8 29.2 64.7 35.3 66.7 33.3 83.3 16.7 Race White, % Asian, % 69.6 26.1 79.2 16.7 76.5 23.5 50.0 50.0 66.7 33.3 BMI, % <30 kg/m2 ≥30 kg/m2 73.9 26.1 75.0 25.0 76.5 23.5 72.2 27.8 61.1 38.9 Baseline HCV RNA ≤2 million IU/mL, % >2 million IU/mL, % 52.2 47.8 41.7 58.3 58.8 41.2 44.4 55.6 61.1 38.9

Source: Foster GR, et al. Hepatology. 2018;67:2113-26.

Elbasvir-Grazoprevir + Sofosbuvir +/- Ribavirin in HCV GT3

C-ISLE Study: Results

91 96 100 94 94

20 40 60 80 100

EBR-GZR + SOF + RBV x 8 Weeks EBR-GZR + SOF + RBV x 12 Weeks EBR-GZR + SOF x 12 weeks EBR-GZR + SOF + RBV x 12 weeks EBR-GZR + SOF x 16 weeks

Patients with SVR 12 (%)

21/23 Treatment-Naive Treatment-Experienced Abbreviations: EBR-GZR = elbasvir-grazoprevir; SOF = sofosbuvir; RBV = ribavirin 23/24 17/17 17/18 17/18

Source: Foster GR, et al. Hepatology. 2018;67:2113-26.

Elbasvir-Grazoprevir + Sofosbuvir +/- Ribavirin in HCV GT3

C-ISLE Study: Results

91 96 100 94 94

20 40 60 80 100

EBR-GZR + SOF + RBV x 8 Weeks EBR-GZR + SOF + RBV x 12 Weeks EBR-GZR + SOF x 12 weeks EBR-GZR + SOF + RBV x 12 weeks EBR-GZR + SOF x 16 weeks

Patients with SVR 12 (%)

21/23 Treatment-Naive Treatment-Experienced Abbreviations: EBR-GZR = elbasvir-grazoprevir; SOF = sofosbuvir; RBV = ribavirin 23/24 17/17 17/18 17/18

2 relapses 1 LTFU 1 withdrew consent 1 DC due to AE

Elbasvir-Grazoprevir + Sofosbuvir +/- RBV in HCV GT3 Cirrhosis

C-ISLE Study: Results by Presence of RAS

C-ISLE: SVR12 Rates by Presence of RAS

Source: Foster G, et al. Hepatology 2018;67:2113-6. 97 98 100 98

20 40 60 80 100 NS3 NS5A Patients (%) with SVR 12

RAS No RAS

3/3 85/87 46/47 49/50

RAS = resistance-associated substitution. 97 patients contributed to RAS analysis. Of these, 90 had sequences available for NS3 analysis and all 97 for NS5A analysis.

Source: Foster G, et al. Hepatology 2018;67:2113-6.

Elbasvir-Grazoprevir + Sofosbuvir +/- RBV in HCV GT3 Cirrhosis

C-ISLE Study: Adverse Events

Adverse Event (AE), n (%) Treatment-naïve Treatment-Experienced

EBR-GZR + SOF + RBV 8 weeks (n = 23) EBR-GZR + SOF 12 weeks (n = 24) EBR-GZR + SOF + RBV 12 weeks (n = 17) EBR-GZR + SOF 12 weeks (n = 18) EBR-GZR + SOF 16 weeks (n = 18) Drug-related AE 14 (61) 13 (54) 5 (29) 15 (83) 11 (61) Any AE Fatigue Nausea Headache Rash 20 (87) 6 (26) 4 (17) 5 (22) 3 (13) 21 (88) 8 (33) 3 (13) 7 (29) 1 (4) 14 (82) 6 (35) 3 (18) 5 (29) 1 (6) 17 (94) 10 (56) 6 (33) 11 (61) 3 (17) 17 (94) 6 (33) 3 (17) 7 (39) 1 (6) Serious AE 1 (6) 3 (17) 1 (6) Discontinuation due to AE 1 (6) Deaths Hemoglobin <10 mg/dL 1 (6) 2 (11) Bilirubin <5x baseline ALT/AST >5x baseline

Source: Foster GR, et al. Hepatology. 2018;67:2113-26.

Elbasvir-Grazoprevir + Sofosbuvir +/- Ribavirin in HCV GT3

C-ISLE Study: Conclusions

Conclusion: “Data from this study support the use of elbasvir-grazoprevir plus sofosbuvir for 12 weeks without reibavirin for treatment-naive and peginterferon/ribavirin- experienced people with GT3 infection and cirrhosis.”

Elbasvir-Grazoprevir + Sofosbuvir +/- RBV in GT 3 Patients with Compensated Cirrhosis

C-ISLE

Phase 2

Treatment Naïve and Treatment Experienced Source: Foster G, et al. Hepatology 2018;67:2113-6.

Source: Foster G, et al. Hepatology 2018;67:2113-6.

Elbasvir-Grazoprevir + Sofosbuvir +/- RBV in HCV GT3 Cirrhosis

C-ISLE Study: Baseline Characteristics

Baseline Characteristic Treatment-naïve Treatment-Experienced

EBR-GZR + SOF + RBV 8 wks (n = 23) EBR-GZR + SOF 12 wks (n = 24) EBR-GZR + SOF + RBV 12 wks (n = 17) EBR-GZR + SOF 12 wks (n = 18 EBR-GZR + SOF 16 wks n = 18) Median age, yrs (range) 51 (37-68) 48 (32-64) 58 (48-68) 56 (38-70) 53 (43-66) Male, % 56.5 70.8 64.7 66.7 83.3 Race White Asian Other 69.6 26.1 4.3 79.2 16.7 4.2 76.5 23.5 50 50 66.7 33.3 BMI ≥30 kg/m2, % 26.1 25 23,5 27.8 38.9 Prior PR history, % Intolerant Null responder Relapser n/a n/a 100 5.6 94.4 5.6 94.4 IL28B non-CC, % 39.1 33.3 64.7 61.1 61.1 HCV RNA >2 million IU/mL, % 47.8 58.3 41.2 55.6 38.9

Source: Foster G, et al. Hepatology 2018;67:2113-6.

Elbasvir-Grazoprevir + Sofosbuvir +/- RBV in HCV GT3 Cirrhosis

C-ISLE Study: Conclusions

Conclusion: “In conclusion, high efficacy was demonstrated in treatment-naive and peginterferon/ribavirin treatment–experienced participants with HCV GT3 infection and cirrhosis, with SVR12 rates of 100% achieved in participants receiving elbasvir-grazoprevir plus sofosbuvir with or without ribavirin for 12 weeks.”

Elbasvir + Grazoprevir +/- RBV in GT 1 Cirrhotics & Null Responders

C-WORTHY

Phase 2b

Treatment Naïve and Treatment Experienced Source: Lawitz E, et al. Lancet 2015;385:1075-86.

Source: Lawitz E, et al. Lancet 2015;385:1075-86.

Elbasvir + Grazoprevir +/- Ribavirin in HCV GT1

C-WORTHY Study: Features

C-WORTHY (Protocol 035) Trial

• Design: Randomized, open label phase 2 trial examining the safety and

efficacy of elbasvir plus grazoprevir, with or without ribavirin, for 12 or 18 weeks in treatment-naïve patients with cirrhosis (cohort 1) or patients with a previous null response to peginterferon/ribavirin (PR) (cohort 2)

• Entry Criteria
• Chronic HCV Genotype 1
• Age 18 years or older
• HCV RNA ≥10,000 IU/mL
• ALT and AST <350 IU/L
• Cohort 1: compensated cirrhosis (Child-Pugh class A)
• Cohort 2: prior PR null response (<2 log10 HCV RNA decline at week 12)
• Primary End-Point: SVR12

Source: Lawitz E, et al. Lancet 2015;385:1075-86.

Elbasvir + Grazoprevir +/- Ribavirin in HCV GT1 C-WORTHY: Study Design Cohort 1 (Cirrhosis)

Week 30 12 18 24 EBR + GZR + RBV SVR12 Cohort 1 Treatment-Naive Cirrhosis (n = 123) n = 29 n = 31 EBR + GZR n = 32 EBR + GZR + RBV SVR12 SVR12 EBR + GZR SVR12 Abbreviations: EBR = elbasvir; GZR = grazoprevir; RBV = ribavirin Drug Dosing Elbasvir: 50 mg once daily Grazoprevir: 100 mg once daily Ribavirin (weight-based and divided bid): 800 to 1400 mg/day n = 31

Source: Lawitz E, et al. Lancet 2015;385:1075-86.

Elbasvir + Grazoprevir +/- Ribavirin in HCV GT1 C-WORTHY: Study Design Cohort 2 (Null Responders)

Week 30 12 18 24 EBR + GZR + RBV SVR12 Cohort 2 Null Responders (n = 130) n = 33 n = 32 EBR + GZR n = 33 EBR + GZR + RBV SVR12 SVR12 EBR + GZR SVR12 n = 32 Abbreviations: EBR = elbasvir; GZR = grazoprevir; RBV = ribavirin Drug Dosing Elbasvir: 50 mg once daily Grazoprevir: 100 mg once daily Ribavirin (weight-based and divided bid): 800 to 1400 mg/day

Source: Lawitz E, et al. Lancet 2015;385:1075-86.

Elbasvir + Grazoprevir +/- Ribavirin in HCV GT1

C-WORTHY: Baseline Characteristics

Baseline Characteristic Treatment-naïve + cirrhosis Null responders

EBR + GZR + RBV (n = 63) EBR + GZR (n = 60) EBR + GZR + RBV (n = 65) EBR + GZR (n = 65) Mean age, y (range) 58 (41-79) 59 (42-82) 54 (24-76) 54 (18-77) Male, % 54 67 55 58 Race White Non-white 90 10 92 8 92 8 94 6 Hispanic/Latino, % 11 7 2 HCV Genotype, % 1a 1b Unclassified 70 29 2 72 25 3 57 43 60 40 IL28B CC, % 27 35 3 Cirrhosis, % 100 98 35 38 HCV RNA >2 million IU/mL, % 65 73 78 86

Source: Lawitz E, et al. Lancet 2015;385:1075-86.

Elbasvir + Grazoprevir +/- Ribavirin in HCV GT1 C-WORTHY: Results for Naïve Cirrhotics (Cohort 1)

C-WORTHY: SVR 12* by Treatment Duration and Regimen

90 97 97 94 20 40 60 80 100

EBR + GZR + RBV EBR + GZR EBR + GZR + RBV EBR + GZR

Patients with SVR 12 (%)

28/31 12-Week Regimen 28/29 31/32 29/31 18-Week Regimen Abbreviations: EBR = elbasvir; GZR = grazoprevir; RBV = ribavirin *Analysis per intent to treat

Source: Lawitz E, et al. Lancet 2015;385:1075-86.

Elbasvir + Grazoprevir +/- Ribavirin in HCV GT1 C-WORTHY: Results for Null Responders (Cohort 2)

C-WORTHY: SVR 12* by Treatment Duration and Regimen

94 91 100 97 20 40 60 80 100

EBR + GZR + RBV EBR + GZR EBR + GZR + RBV EBR + GZR

Patients with SVR 12 (%)

30/32 12-Week Regimen 30/33 33/33 31/32 18-Week Regimen Abbreviations: EBR = elbasvir; GZR = grazoprevir; RBV = ribavirin *Analysis per intent to treat

Source: Lawitz E, et al. Lancet 2015;385:1075-86.

Elbasvir + Grazoprevir +/- Ribavirin in HCV GT1 C-WORTHY: Adverse Events

Adverse event (AE), % Treatment-naïve with cirrhosis Null Responders EBR + GZR + RBV

(n = 63)

EBR + GZR

(n = 60)

EBR + GZR + RBV

(n = 65)

EBR + GZR

(n = 65)

Serious AE 2 3 3 3 Discontinuation due to AE 2 2 Death 2 AEs in ≥10% of patients Fatigue Headache Asthenia 22 11 5 23 35 12 23 23 18 35 23 20 Laboratory events Hemoglobin <10 g/dL Hemoglobin <8.5 g/dL Total bilirubin >5 x baseline ALT or AST >2 to ≤5 x ULN* ALT or AST >5 x ULN* 13 2 3 3 6 2 2 5 *ULN = upper limit of normal

Source: Lawitz E, et al. Lancet 2015;385:1075-86.

Elbasvir + Grazoprevir +/- Ribavirin in HCV GT1

C-WORTHY Study: Conclusions

Interpretation: “Treatment with grazoprevir plus elbasvir, both with and without ribavirin and for both 12 and 18 weeks' treatment duration, showed high rates of efficacy in previously untreated patients with cirrhosis and previous PR-null responders with and without cirrhosis. These results support the phase 3 development of grazoprevir plus elbasvir.”

Elbasvir-Grazoprevir in HIV Coinfection

Elbasvir-Grazoprevir in HCV and HIV Coinfection, GT 1, 4 or 6

C-EDGE CO-INFECTION

Phase 3

Treatment Naïve Source: Rockstroh JK, et al. Lancet HIV. 2015;2:e319-27. HIV Coinfection

Source: Rockstroh JK, et al. Lancet HIV. 2015;2:e319-27.

Elbasvir-Grazoprevir in HCV-HIV Coinfection GT 1, 4 or 6 C-EDGE CO-INFECTION: Study Features

C-EDGE Trial

• Design: Prospective, open-label, single-arm study examining the safety

and efficacy of a fixed-dose combination of elbasvir-grazoprevir for 12 weeks in treatment-naïve patients with chronic HCV genotype 1, 4, or 6 and HIV coinfection.

• Entry Criteria
• Chronic HCV Genotype 1, 4, or 6
• Age 18 years or older
• HCV RNA ≥10,000 IU/mL
• No prior treatment
• Compensated cirrhosis permitted
• HIV infection
• Primary End-Point: SVR12

Source: Rockstroh JK, et al. Lancet HIV. 2015;2:e319-27.

Elbasvir-Grazoprevir in HCV-HIV Coinfection GT 1, 4 or 6 C-EDGE CO-INFECTION: Study Design

HIV-HCV Coinfected Treatment-naïve GT 1, 4, or 6

n = 218

Elbasvir-Grazoprevir

Week 24 12 SVR12 Drug Dosing Elbasvir-grazoprevir (50/100 mg): fixed dose combination; one pill once daily

Source: Rockstroh JK, et al. Lancet HIV. 2015;2:e319-27.

Elbasvir-Grazoprevir in HCV-HIV Coinfection GT 1, 4 or 6 C-EDGE CO-INFECTION: Participants

Baseline Characteristic Elbasvir-Grazoprevir (n = 218) Age, mean 49 Male, n (%) 183 (84%) Race, n (%) White Black or African-American Other 167 (77%) 38 (17%) 13 (6%) HCV genotype, n (%) 1a 1b 4 6 144 (66%) 44 (20%) 28 (13%) 2 (1%) Fibrosis stage, n (%) F0-2 F3 F4 160 (73%) 23 (11%) 35 (16%) Mean baseline HCV RNA, log10 IU/ml 6.03

Source: Rockstroh JK, et al. Lancet HIV. 2015;2:e319-27.

Elbasvir-Grazoprevir in HCV-HIV Coinfection GT 1, 4 or 6 C-EDGE CO-INFECTION: Participants

HIV Characteristics Elbasvir-Grazoprevir (n = 218) Median CD4 cell count, (IQR) 568 (424-766) ART Status On ART with undetectable HIV RNA ART naïve 211 (97%) 7 (3%) ART nucleos(t)ide pair Abacavir-containing Tenofovir-containing None 47 (22%) 164 (75%) 7 (3%) ART Third Agent Raltegravir Dolutegravir Rilpivirine None 113 (52%) 59 (27%) 38 (17%) 8 (4%)

IQR = interquartile range; ART = antiretroviral therapy

Source: Rockstroh JK, et al. Lancet HIV. 2015;2:e319-27.

Elbasvir-Grazoprevir in HCV-HIV Coinfection GT 1, 4 or 6 C-EDGE CO-INFECTION: Results

C-EDGE CO-INFECTION: SVR12 Results by Genotype

96 97 96 96 20 40 60 80 100 All GT1a GT1b GT4 Patients with SVR12 (%) Genotype

210/218 139/144 42/44 27/28 Overall SVR12 results includes the 2 patients with GT 6, who both achieved SVR12.

Source: Rockstroh JK, et al. Lancet HIV. 2015;2:e319-27.

Elbasvir-Grazoprevir in HCV-HIV Coinfection GT 1, 4 or 6 C-EDGE CO-INFECTION: Adverse Events

Adverse Event (AE), n (%) Elbasvir-Grazoprevir (n = 218) Discontinuation due to AE Serious AEs 2 (1%) Deaths Any AE in >5% of patients Fatigue Headache Nausea Upper respiratory tract infection Diarrhea Insomnia 29 (13%) 27 (12%) 20 (9%) 18 (8%) 16 (7%) 15 (7%) Grade 3 or 4 laboratory abnormality Total bilirubin ALT elevation AST elevation Hemoglobin Grade 3 1 (<1%) 3 (1%) Grade 4 2 (1%) 1 (<1%)

Source: Rockstroh JK, et al. Lancet HIV. 2015;2:e319-27.

Elbasvir-Grazoprevir in HCV-HIV Coinfection GT 1, 4 or 6 C-EDGE CO-INFECTION: Conclusions

Conclusions: “This HCV treatment regimen seems to be effective and well tolerated for patients co-infected with HIV with or without cirrhosis. These data are consistent with previous trials of this regimen in the monoinfected population. This regimen continues to be studied in phase 3 trials.”

Elbasvir + Grazoprevir +/- RBV: HCV GT1 +/- HIV Coinfection

C-WORTHY Coinfection

Phase 2

Treatment Naïve Source: Sulkowski M, et al. Lancet. 2015;385:1087-97. HIV Coinfection

Source: Sulkowski M, et al. Lancet. 2015;385:1087-97.

Elbasvir + Grazoprevir +/- RBV in HCV GT1 +/- HIV Coinfection

C-WORTHY Coinfection: Study Features

C-WORTHY (Protocol 035) Trial

• Design: Randomized, open-label phase 2 trial examining the safety and

efficacy of a fixed-dose combination of elbasvir-grazoprevir, with or without ribavirin, in treatment-naïve HCV-monoinfected (part A) or HCV-HIV coinfected (part B) patients without cirrhosis

• Entry Criteria
• Chronic HCV genotype 1
• Age 18 years or older
• HCV RNA ≥10,000 IU/mL
• No prior treatment
• No cirrhosis
• Part B: well-controlled HIV infection (on antiretroviral therapy ≥8 weeks,

HIV RNA undetectable x ≥24 weeks and CD4 count ≥300 cells/mm3

• Primary End-Point: SVR12

Source: Sulkowski M, et al. Lancet. 2015;385:1087-97.

Elbasvir + Grazoprevir +/- RBV in HCV GT1 +/- HIV Coinfection C-WORTHY Coinfection: Study: Study Design Part A

Week 12 24 EBR (20 mg) + GZR + RBV SVR12 Group A Treatment-Naive HCV Monoinfected n = 25 EBR (50 mg) + GZR + RBV EBR (50 mg) + GZR Abbreviations: EBR = elbasvir; GZR = grazoprevir; RBV = ribavirin Drug Dosing Elbasvir (20 mg or 50 mg) once daily Grazoprevir (100 mg) once daily Ribavirin (weight-based and divided bid): 800 to 1400 mg/day SVR12 SVR12 A2 A3 A1 GT 1a + 1b GT 1a + 1b GT 1b n = 27 n = 13

Source: Sulkowski M, et al. Lancet. 2015;385:1087-97.

Elbasvir+ Grazoprevir +/- RBV in HCV GT1 +/- HIV Coinfection C-WORTHY Coinfection: Study: Study Design Part B

Week 12 24

EBR + GZR (50 mg) + RBV SVR12

Group B Treatment-Naive HCV Monoinfected

n = 30

Abbreviations: EBR = elbasvir; GZR = grazoprevir; RBV = ribavirin Drug Dosing Elbasvir (50 mg) once daily Grazoprevir (100 mg) once daily Ribavirin (weight-based and divided bid): 800 to 1400 mg/day

SVR12 SVR12 B2 B3 B1 GT 1a GT 1a + 1b GT 1a n = 33 n = 31

Group B Treatment-Naive HIV Coinfected

SVR12 SVR12 B12 B13 GT 1a + 1b GT 1a + 1b n = 29 n = 30 EBR + GZR (50 mg) + RBV EBR + GZR (50 mg) EBR + GZR EBR + GZR

8 20

Source: Sulkowski M, et al. Lancet. 2015;385:1087-97.

Elbasvir + Grazoprevir +/- RBV in HCV GT1 +/- HIV Coinfection C-WORTHY Coinfection: Results

C-WORTHY: SVR12 Results by Treatment and HIV Coinfection Status

80 93 98 97 87 20 40 60 80 100

8 weeks (+ Ribavirin) Arm B1 12 weeks (+ Ribavirin) Arms A1, A2, B2 12 weeks (- Ribavirin) Arms A3, B3 12 weeks (+ Ribavirin) Arm B12 12 weeks (- Ribavirin) Arm B13

Patients with SVR12 (%)

HCV Monoinfected HCV-HIV Coinfected 24/30 79/85 43/44 28/29 26/30

Source: Sulkowski M, et al. Lancet. 2015;385:1087-97.

Elbasvir + Grazoprevir +/- RBV in HCV GT1 +/- HIV Coinfection

C-WORTHY Coinfection: Study: Results

C-WORTHY: SVR12 Rates by HCV GT1 Subtype and Use of Ribavirin

95 92 92 95

20 40 60 80 100

Genotype 1a Genotype 1b

Patients (%) with SVR 12 Elbasvir + Grazoprevir + Ribavirin Elbasvir + Grazoprevir

48/52 72/76 21/22 33/36

Source: Sulkowski M, et al. Lancet. 2015;385:1087-97.

Elbasvir + Grazoprevir +/- RBV in HCV GT1 +/- HIV Coinfection

C-WORTHY Coinfection: Study Features

Interpretation: “Once-daily grazoprevir plus elbasvir with or without ribavirin for 12 weeks in previously untreated HCV-mono-infected and HIV/HCV-co-infected patients without cirrhosis achieved SVR12 rates

• f 87-98%. These results support the ongoing phase 3 development of

grazoprevir plus elbasvir.”

Elbasvir-Grazoprevir in Patients with Renal Disease

Elbasvir + Grazoprevir in GT 1 and Chronic Renal Disease

C-SURFER

Phase 3

Treatment Naïve and Treatment Experienced Source: Roth D, et al. Lancet 2015;386:1537-45.

Source: Roth D, et al. Lancet 2015;386:1537-45.

Elbasvir + Grazoprevir in HCV GT1 and Renal Disease C-SURFER Study: Features

C-SURFER

• Design: Randomized, phase 3, double-blind trial examining the safety and

efficacy of elbasvir plus grazoprevir for 12 weeks in treatment-naïve or treatment-experienced patients genotype 1 chronic HCV and stage 4 or 5 chronic renal disease, including patients on hemodialysis.

• Setting: 68 international sites
• Entry Criteria
• Chronic HCV genotype 1
• Chronic kidney disease (Stage 4 or 5) +/- hemodialysis
• Age 18 years or older
• Treatment naïve or treatment-experienced
• Cirrhosis allowed
• Primary End-Point: SVR12

Source: Roth D, et al. Lancet 2015;386:1537-45.

Elbasvir + Grazoprevir in HCV GT1 and Renal Disease C-SURFER Study: Study Design

Drug Dosing Grazoprevir 100 mg once daily and Elbasvir 50 mg once daily; given as separate medications in Immediate treatment and Intensive PK arms; given as fixed dose combination in Deferred arm

Immediate Treatment

EBZ + GRZ SVR12 TN TE GT 1 Stage 4 or 5 CKD N=111

Deferred Therapy

Placebo SVR12 N=113 Week 40 12 16 28

Deferred Therapy

EBZ + GRZ 24

Intensive PK

EBZ + GRZ N=11 SVR12

Source: Roth D, et al. Lancet 2015;386:1537-45.

Elbasvir + Grazoprevir in HCV GT1 and Renal Disease C-SURFER Study: Participants

Baseline Characteristic

EBR + GZR Immediate (n =111) EBR + GZR Deferred (n =113) EBR + GZR PK (n =11) Total (n =235) Mean age, years (SD) 56.5 (9.1) 55.2 (10.1) 58.2 (6.8) 56 (9.5) Male sex, % 73 71 100 73 Race, % White Black Asian 50 45 5 43 47 8 54 45 47 46 6 HCV Genotype, % 1a 1b 1 other 48 52 52 47 1 91 9 52 48 Cirrhosis, % 6 6 6 Treatment-naïve, % 82 78 91 80 Diabetes, % 34 32 55 34 Kidney disease severity Stage 4, % Stage 5, % On dialysis, % 16 84 78 20 80 77 36 64 55 19 81 76

99 94

20 40 60 80 100

Modifed Full Analysis Set Full Analysis Set SVR12 (%)

115/116 115/122

Source: Roth D, et al. Lancet 2015;386:1537-45.

Elbasvir + Grazoprevir in HCV GT1 and Renal Disease C-SURFER Study: Results

C-SURFER: SVR12 Results

Modified analysis excluded patients who did not receive ≥1 dose of drug or who died or discontinued early for reasons unrelated to HCV treatment.

Source: Roth D, et al. Lancet 2015;386:1537-45.

Elbasvir + Grazoprevir in HCV GT1 and Renal Disease C-SURFER Study: Safety

Adverse Event (AE), n (%) Elbasvir + Grazoprevir Immediate (n = 111) Deferred (Placebo) (n = 113) Discontinuation due to AE 5 (4.4) Serious AEs 16 (14.4) 19 (16.8) Deaths 1 (0.8) 3 (2.7) Any AE in ≥10% of patients Headache Nausea Fatigue Insomnia Dizziness Diarrhea 84 (75.7) 19 (17.1) 17 (15.3) 11 (9.9) 7 (6.3) 6 (5.4) 6 (5.4) 95 (84.1) 19 (16.8) 18 (15.9) 17 (15.9) 12 (10.6) 18 (15.9) 15 (13.3) Laboratory AEs Hemoglobin <8.5 g/dl ALT 1.1-2.5 x baseline Creatinine§ >2.5 x baseline 5 (4.5) 2 (1.8) 1 (1.2) 5 (4.4) 36 (31.9)

§ Among patients not on dialysis at baseline.

Source: Roth D, et al. Lancet 2015;386:1537-45.

Elbasvir + Grazoprevir in HCV GT1 and Renal Disease C-SURFER Study: Conclusions Interpretation: “Once-daily grazoprevir and elbasvir for 12 weeks had a low rate of adverse events and was effective in patients infected with HCV genotype 1 and stage 4-5 chronic kidney disease.”

Elbasvir-Grazoprevir +/- Ribavirin in HCV GT 4

Pooled Analysis

Phase 2/3

Treatment Naïve and Treatment Experienced Source: Asselah T, et al. Liver Int. 2018;38:1583-91.

Source: Asselah T, et al. Liver Int. 2018;38:1583-91.

Elbasvir-Grazoprevir +/- RBV in HCV GT4

Pooled Analysis: Study Features

C-EDGE Trial

• Design: Pooled analysis of treatment naïve and treatment experienced

adults with HCV genotype 4 who participated in phase 2 and 3 clinical trials involving treatment with elbasvir-grazoprevir for 12-16 weeks, with or without ribavirin.

• Entry Criteria
• Chronic HCV genotype 4 (n = 155)
• 18 years or older
• Baseline HCV RNA ≥10,000 IU/mL
• Treatment naïve & Treatment experienced (prior PEG-INF-based failure)
• Persons with compensated cirrhosis permitted
• Persons with HIV infection permitted
• Primary End-Point: SVR12

Source: Asselah T, et al. Liver Int. 2018;38:1583-91.

Elbasvir-Grazoprevir +/- RBV in HCV GT4

Pooled Analysis: Results in Treatment Naive

96.4 96.0 100.0

20 40 60 80 100

EBR-GZR ± RBV x 12 Weeks EBR-GZR x 12 Weeks EBR-GZR + RBV x 12 weeks

Patients with SVR 12 (%) ALL 107/111

Abbreviations: EBR-GZR = elbasvir-grazoprevir; RBV = ribavirin

97/101 10/10

Source: Asselah T, et al. Liver Int. 2018;38:1583-91.

Elbasvir-Grazoprevir +/- RBV in HCV GT4

Pooled Analysis: Results in Treatment Experienced

88.6 87.5 93.3 60.0 100.0

20 40 60 80 100

EBR-GZR ± RBV x 12 or 16 Weeks EBR-GZR x 12 Weeks EBR-GZR + RBV x 12 weeks EBR-GZR x 16 weeks EBR-GZR + RBV x 16 weeks

Patients with SVR 12 (%)

ALL 39/44 Abbreviations: EBR-GZR = elbasvir-grazoprevir; RBV = ribavirin 14/16 14/15 3/5 8/8

Source: Asselah T, et al. Liver Int. 2018;38:1583-91.

Elbasvir-Grazoprevir +/- RBV in HCV GT4

Pooled Analysis: Conclusions

Conclusion: “The regimens of 12 weeks of elbasvir/grazoprevir without ribavirin, and 16 weeks of elbasvir/grazoprevir plus ribavirin, were efficacious in HCV GT4‐infected treatment‐naïve and treatment‐experienced participants respectively. Baseline NS5A resistance‐associated substitutions did not impact the efficacy of elbasvir/grazoprevir in GT4‐infected participants.”

Elbasvir-Grazoprevir in Persons who Inject Drugs

Elbasvir-Grazoprevir in HCV GT 1,4, or 6 in PWID* on Opiate Agonist Therapy

C-EDGE CO-STAR

Phase 3

Treatment Naïve Source: Dore GJ, et al. Ann Intern Med. 2016;165:625-34. Injection Drug Use

*PWID = Persons Who Inject Drugs

Source: Dore GJ, et al. Ann Intern Med. 2016;165:625-34.

Elbasvir-Grazoprevir in HCV GT 1, 4, or 6 in PWID on Opiate Agonist Therapy

C-EDGE CO-STAR: Study Features

C-EDGE CO-STAR

• Design: Randomized, phase 3, placebo-controlled, double-blind, multi-site

trial using a fixed-dose combination of elbasvir-grazoprevir in treatment- naïve chronic HCV genotype 1, 4, or 6 in persons who inject drugs who are receiving opiate agonist therapy

• Entry Criteria
• Chronic HCV Genotype 1, 4, or 6
• No prior treatment
• 18 years or older
• Opiate Agonist Therapy for ≥3 months and kept ≥ 80% of appointments
• HCV RNA ≥10,000 IU/mL
• Cirrhosis allowed with goal 20% of subjects with cirrhosis
• HIV infection allowed
• Primary End-Point: SVR12

Source: Dore GJ, et al. Ann Intern Med. 2016;165:625-34.

Elbasvir-Grazoprevir in HCV GT 1, 4, or 6 in PWID on Opiate Agonist Therapy

C-EDGE CO-STAR: Study Features

Elbasvir-Grazoprevir SVR12 Drug Dosing Grazoprevir-elbasvir (100/50 mg): fixed dose combination; one pill once daily Treatment-naïve GT 1, 4 or 6 (N=301) N=201 Placebo SVR12 N=100 Week 40 12 16 28 Elbasvir-Grazoprevir 24

Source: Dore GJ, et al. Ann Intern Med. 2016;165:625-34.

Elbasvir-Grazoprevir in HCV GT 1, 4, or 6 in PWID on Opiate Agonist Therapy

C-EDGE CO-STAR: Results in Immediate-Treatment Group

C-EDGE CO-STAR: SVR12 Results (Assumes Reinfections are Failures)

91.5 93.5 93.3 91.7 20.0 20 40 60 80 100 All GT GT1a* GT1b GT4 GT6

Patients with SVR12 (%)

184/201 144/154 28/30 11/12 1/5

Source: Dore GJ, et al. Ann Intern Med. 2016;165:625-34.

Elbasvir-Grazoprevir in HCV GT 1, 4, or 6 in PWID on Opiate Agonist Therapy

C-EDGE CO-STAR: Results in Immediate-Treatment Group

C-EDGE CO-STAR: SVR12 Results (Assumes Reinfections are Responses)

94.0 95.5 93.3 91.7 60.0 20 40 60 80 100 All GT GT1a* GT1b GT4 GT6

Patients with SVR12 (%)

189/201 147/154 28/30 11/12 3/5

Source: Dore GJ, et al. Ann Intern Med. 2016;165:625-34.

Elbasvir-Grazoprevir in HCV GT 1, 4, or 6 in PWID on Opiate Agonist Therapy

C-EDGE CO-STAR: Results in Deferred-Treatment Group

C-EDGE CO-STAR: SVR12 Results (Assumes Reinfections are Failures)

89.5 90.1 92.9 100.0 50.0 20 40 60 80 100 All GT GT1a* GT1b GT4 GT6

Patients with SVR12 (%)

85/95 64/71 13/14 6/6 2/4

Source: Dore GJ, et al. Ann Intern Med. 2016;165:625-34.

Elbasvir-Grazoprevir in HCV GT 1, 4, or 6 in PWID on Opiate Agonist Therapy

C-EDGE CO-STAR: Results

C-EDGE CO-STAR: SVR12 Results Subgroup Analysis

91.3 92.5 92.0 91.2 93.8 90.4

20 40 60 80 100

No Yes ≤2 million > 2 million Negative Positive

Patients (%) with SVR 12 Cirrhosis HCV RNA IU/mL Drug Screen

147/161 37/40 81/88 103/113 61/65 123/136

Source: Dore GJ, et al. Ann Intern Med. 2016;165:625-34.

Elbasvir-Grazoprevir in HCV GT 1, 4, or 6 in PWID on Opiate Agonist Therapy

C-EDGE CO-STAR: Safety

Adverse Event (AE), n (%) Elbasvir-Grazoprevir Immediate (n = 201) Deferred (Placebo) (n = 100) Discontinuation due to AE 1 (0.5) 1 (1.0) Serious AEs 7 (3.5) 4 (4.0) Deaths 1 (1.0) Any AE in ≥10% of patients Fatigue Headache Nausea 166 (82.6) 32 (15.9) 25 (12.4) 22 (10.9) 83 (83.0) 20 (20.0) 13 (13.0) 9 (9.0) Laboratory AEs Hemoglobin <8.5 g/dl Bilirubin >2.6 times upper limit of normal Creatinine >2.5 times baseline level 1 (0.5) 1 (1.0)

Source: Dore GJ, et al. Ann Intern Med. 2016;165:625-34.

Elbasvir-Grazoprevir in HCV GT 1, 4, or 6 in PWID on Opiate Agonist Therapy

C-EDGE CO-STAR: Conclusions Conclusions: “Patients with HCV infection who were receiving OAT and treated with elbasvir-grazoprevir had high rates of SVR12, regardless of ongoing drug use. These results support the removal of drug use as a barrier to interferon-free HCV treatment for patients receiving Opiate Agonist Therapy (OAT).”

Questions?

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