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Elbasvir-Grazoprevir ( Zepatier )

Comprehensive information on Elbasvir-Grazoprevir (Zepatier) dosage, indications, drug interactions, and clinical trials, including details on efficacy, adverse effects, and results in treatment-naïve HCV patients.

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Elbasvir-Grazoprevir ( Zepatier )

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  1. Elbasvir-Grazoprevir(Zepatier) Prepared by: H. Nina Kim, MD MSc and David Spach, MD Last Updated: January 29, 2016

  2. Elbasvir-Grazoprevir (Zepatier) Background and Dosing

  3. 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 1or 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: ZapatierPrescribing Information. Merck & Co., Inc.

  4. Elbasvir-Grazoprevir (Zepatier)Indications and Usage Source: ZapatierPrescribing Information. Merck & Co., Inc.

  5. Elbasvir-Grazoprevir (Zepatier)Drug-Drug Interactions Source: ZapatierPrescribing Information. Merck & Co., Inc.

  6. Elbasvir-Grazoprevir (Zepatier)Drug-Drug Interactions Source: ZapatierPrescribing Information. Merck & Co., Inc.

  7. Clinical Trials Elbasvir-Grazoprevir

  8. Elbasvir-Grazoprevir (EBR-GZR): Summary of Key Studies • Phase 2 Trials- C-SWIFT: EBR-GZR + Sofosbuvir x 8 or 12 weeks in GT 1 or 3- C-WORTHY: EBR-GZR +/- RBV in TN Cirrhotic or 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

  9. Elbasvir-Grazoprevir (EBR-GZR): Summary of Key Studies • Phase 3 Trials- C-EDGE TN: EBR-GZR x 12 weeks in treatment-naïve 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

  10. Elbasvir-Grazoprevir Treatment-Naïve Patients

  11. Phase 3 TreatmentNaïve Elbasvir-Grazoprevirin Treatment-Naïve HCV Genotype 1, 4 or 6C-EDGE Treatment Naïve (TN) Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.

  12. Elbasvir-Grazoprevirin Treatment-Naïve HCV Genotype 1, 4 or 6C-EDGE TN Study: Features Source: Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.

  13. Elbasvir-Grazoprevir in Treatment-Naïve HCV Genotype 1, 4 or 6C-EDGE TN: Study Design 0 12 16 40 24 28 Week Treatment-naïve GT 1, 4 or 6 (N=421) Elbasvir-Grazoprevir N=316 SVR12 Elbasvir-Grazoprevir Placebo N=105 SVR12 Randomized 3:1 ratio to immediate or deferred arm; stratified by cirrhosis, HCV genotype, subtypeAfter 4 weeks of follow-up, placebo recipients were unblinded and given elbasvir-grazopreviropen label Drug DosingElbasvir-Grazoprevir (50/100 mg): fixed dose combination; one pill once daily Source: Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.

  14. Elbasvir-Grazoprevir in Treatment-Naïve HCV GT 1, 4 or 6C-EDGE TN: Baseline Characteristics Source: Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.

  15. Elbasvir-Grazoprevirin Treatment-Naïve HCV GT 1, 4 or 6C-EDGE TN: Results C-EDGE TN: SVR12 Results by Genotype 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.

  16. Elbasvir-Grazoprevir in Treatment-Naïve HCV GT 1, 4 or 6C-EDGE TN: Results C-EDGE TN: SVR12 by Presence of Cirrhosis or High HCV RNA Level 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.

  17. Elbasvir-Grazoprevir in Treatment-Naïve HCV GT 1, 4 or 6C-EDGE TN: Results Baseline NS5A Resistance-Associated Variants and SVR12 in GT1 11/19 133/135 17/18 112/112 *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.

  18. Elbasvir-Grazoprevir in Treatment-Naïve HCV GT 1, 4 or 6C-EDGE TN: Results Baseline NS3/4A Resistance-Associated Variants and SVR12 in GT1 83/86 58/65 24/25 104/104 Source: Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.

  19. Elbasvir-Grazoprevir in Treatment-Naïve HCV GT 1, 4 or 6C-EDGE TN: Adverse Events § Neither death was considered to be study-related. Source: Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.

  20. Elbasvir-Grazoprevir in Treatment-Naïve HCV GT 1, 4 or 6C-EDGE TN: Conclusions Source: Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.

  21. Phase 2 TreatmentNaïve Elbasvir-Grazoprevir+ Sofosbuvirin Treatment-Naïve HCV Genotype 1 or 3C-SWIFT PoordadF, et al. EASL 2015; Abstract O006.

  22. Elbasvir-Grazoprevir+ Sofosbuvir in Treatment-Naïve GT 1 or 3C-SWIFT Study: Features Source: Poordad F, et al. EASL 2015; Abstract O006.

  23. Elbasvir-Grazoprevir + Sofosbuvir in Treatment-Naïve GT 1 or 3C-SWIFT Study: Study Design for GT 1 8 0 4 6 24 Week n =31 GT-1Non-cirrhotic EBR-GZR + SOF EBR-GZR + SOF n =30 n =20 GT-1Cirrhotic EBR-GZR + SOF EBR-GZR + SOF n =21 Abbreviations: EBR-GZR = elbasvir-grazoprevir; SOF = sofosbuvir Drug DosingElbasvir-grazoprevir(50/100 mg): fixed-dose combination; one pill once dailySofosbuvir: 400 mg once daily Source: Poordad F, et al. EASL 2015; Abstract O006.

  24. Elbasvir-Grazoprevir + Sofosbuvir in Treatment-Naïve GT 1 or 3C-SWIFT Study:Study Design for GT 3 0 8 12 20 24 Week SVR12 N=15 GT-3 Non-cirrhotic EBR-GZR + SOF N=14 SVR12 EBR-GZR + SOF GT-3Cirrhotic N=12 SVR12 EBR-GZR + SOF Abbreviations: EBR-GZR= grazoprevir-elbasvir; SOF = sofosbuvir Drug DosingGrazoprevir/elbasvir (100/50 mg): fixed dose combination; one pill once dailySofosbuvir 400 mg once daily Source: Poordad F, et al. EASL 2015; Abstract O006.

  25. Elbasvir-Grazoprevir + Sofosbuvir in Treatment-Naïve GT 1 or 3C-SWIFT Study: Baseline Characteristics Source: Poordad F, et al. EASL 2015; Abstract O006.

  26. Elbasvir-Grazoprevir + Sofosbuvir in Treatment-Naïve GT 1 or 3C-SWIFT Study: Results for GT 1 C-SWIFT: SVR 12* for GT 1 by Treatment Duration and Cirrhosis 10/30 26/30 16/20 17/18 No Cirrhosis Cirrhosis *Analysis by modified intention-to-treat analysis (excluded patients who discontinued due to reasons other than virologic failure) Source: Poordad F, et al. EASL 2015; Abstract O006.

  27. Elbasvir-Grazoprevir + Sofosbuvir in Treatment-Naïve GT 1 or 3C-SWIFT Study: Results for GT 3 C-SWIFT: SVR 12* for GT 3 by Treatment Duration and Cirrhosis 14/14 10/11 14/15 No Cirrhosis Cirrhosis Analysis by modified intention-to-treat analysis(excluded patients who discontinued due to reasons other than virologic failure) Source: Poordad F, et al. EASL 2015; Abstract O006.

  28. Elbasvir-Grazoprevir + Sofosbuvir in Treatment-Naïve GT 1 or 3C-SWIFT Study: Conclusions Source: Poordad F, et al. EASL 2015; Abstract O006.

  29. Phase 2 TreatmentNaïve Elbasvir + Grazoprevir +/- Ribavirin in Treatment-Naïve HCV GT 2, 4, 5, or 6C-SCAPE Brown A, et al. EASL 2015; Abstract P0771.

  30. Elbasvir + Grazoprevir +/- RBV in Treatment-Naïve GT 2, 4, 5 or 6C-SCAPE Study: Features Source: Brown A, et al. EASL 2015; Abstract P0771.

  31. Elbasvir + Grazoprevir +/- RBV in Treatment-Naïve GT 2, 4, 5 or 6C-SCAPE Study: Study Design for GT 1 24 0 12 Week n =30 GT2Non-cirrhotic EBR-GZR + RBV SVR12 SVR12 GZR + RBV n =30 n =19 SVR12 GT4, 5, or 6Non-cirrhotic EBR-GZR + RBV EBR-GZR n =19 SVR12 Abbreviations: EBR = Elbasvir; GZR = Grazoprevir; RBV = ribavirin Drug DosingElbasvir (50mg)once dailyGrazoprevir (100 mg)once dailyRibavirin (weight-based and divided bid): 800 to 1400 mg/day Source: Brown A, et al. EASL 2015; Abstract P0771.

  32. Elbasvir + Grazoprevir +/- RBV in Treatment-Naïve GT 2, 4, 5 or 6C-SCAPE Study: Baseline Characteristics Source: Brown A, et al. EASL 2015; Abstract P0771.

  33. Elbasvir + Grazoprevir +/- RBV in Treatment-Naïve GT 2, 4, 5 or 6C-SCAPE Study: Results C-SCAPE: SVR12 by Genotype and Regimen EBR + GZR + RBV x 12 weeks EBR + GZR + RBV x 12 weeks 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. EASL 2015; Abstract P0771.

  34. Elbasvir + Grazoprevir +/- RBV in Treatment-Naïve GT 2, 4, 5 or 6C-SCAPE Study: Conclusions Source: Brown A, et al. EASL 2015; Abstract P0771.

  35. Elbasvir-Grazoprevirin Treatment-Experienced Patients

  36. Phase 3 TreatmentExperienced Elbasvir-Grazoprevir+/- Ribavirin in HCV Genotype 1, 4 or 6C-EDGE Treatment Experienced (TE) Kwo P, et al. EASL 2015. Abstract P0886.

  37. Elbasvir-Grazoprevir+/- Ribavirin in HCV Genotype 1, 4 or 6C-EDGE TE Study: Features Source: Kwo P et al. EASL 2015. Abstract P0886.

  38. Elbasvir-Grazoprevir +/- Ribavirin in HCV Genotype 1, 4 or 6C-EDGE TE: Study Design 0 12 16 24 28 36 Week n =105 SVR12 GT1, 4 or 6 Prior Treatment (n = 420) EBR-GZR SVR12 n =104 EBR-GZR + RBV n =105 SVR12 EBR-GZR n =106 SVR12 EBR-GZR + RBV Abbreviations: EBR-GZR = elbasvir-grazoprevir; RBV = ribavirin Drug DosingElbasvir-grazoprevir (50/100 mg): fixed dose combination; one pill once dailyRibavirin (weight-based and divided bid): 800 to 1400 mg/day N =14 Source: Kwo P et al. EASL 2015. Abstract P0886.

  39. Elbasvir-Grazoprevir +/- Ribavirin in HCV Genotype 1, 4 or 6C-EDGE TE: Baseline Characteristics Source: Kwo P et al. EASL 2015. Abstract P0886.

  40. Elbasvir-Grazoprevir +/- Ribavirin in HCV Genotype 1, 4 or 6C-EDGE TE: Results C-EDGE TE: SVR 12* by Treatment Duration and Regimen 97/105 98/104 97/105 103/106 12-Week Regimen 16-Week Regimen * Analysis per protocol: excluding patients who dropped out due to reasons other than virologic failure Source: Kwo P et al. EASL 2015. Abstract P0886.

  41. Elbasvir-Grazoprevir +/- Ribavirin in HCV Genotype 1, 4 or 6C-EDGE TE: Results C-EDGE TE: SVR 12* by Key Subgroups 97/105 98/104 97/105 103/106 * Analysis per protocol: excluding patients who dropped out due to reasons other than virologic failure Source: Kwo P et al. EASL 2015. Abstract P0886.

  42. Elbasvir-Grazoprevir +/- Ribavirin in HCV Genotype 1, 4 or 6C-EDGE TE: Results Source: Kwo P et al. EASL 2015. Abstract P0886.

  43. Phase 2 TreatmentExperienced Elbasvir + Grazoprevir + Ribavirin in PI-experienced HCV GT1C-SALVAGE (1) Buti M, et al. Clin Infect Dis. 2016;62:32-6. (2) Forns X, et al. J Hepatol. 2015;63:564-72.

  44. Elbasvir + Grazoprevir + Ribavirin in PI-experienced HCV GT1C-SALVAGE Study: Features Source: (1) Buti M, et al. Clin Infect Dis. 2016;62:32-6. (2) Forns X, et al. J Hepatol. 2015;63:564-72.

  45. Elbasvir + Grazoprevir + Ribavirin in PI-experienced HCV GT1C-SALVAGE Study: Design 0 12 24 Week PI+PR experienced Genotype 1 Non-cirrhotic (N=45)Cirrhotic (N=34) EBR + GZR + RBV N=79 SVR12 Abbreviations: EBR = elbasvir; GZR = grazoprevir; RBV = ribavirin; PI = protease inhibitor; PR = peginterferon+ribavirin Drug Dosing:Elbasvir: 50 mg once dailyGrazoprevir: 100 mg once dailyRibavirin (weight-based and divided bid): 800 to 1400 mg/day Source: Buti M, et al. Clin Infect Dis. 2016;62:32-6.

  46. Elbasvir + Grazoprevir + Ribavirin in PI-experienced HCV GT1C-SALVAGE Study: Participants Source: Forns X, et al. J Hepatol. 2015;63:564-72.

  47. Elbasvir + Grazoprevir+ Ribavirin in PI-experienced HCV GT1C-SALVAGE Study: Results C-SALVAGE: SVR 24* by Baseline Factors 76/79 63/66 33/36 32/34 * Analysis per protocol: excluding patients who dropped out due to reasons other than virologic failureRAVs = resistance-associated variants (at baseline) Source: Buti M, et al. Clin Infect Dis. 2016;62:32-6.

  48. Elbasvir + Grazoprevir + Ribavirin in PI-experienced HCV GT1C-SALVAGE Study: Results Source: Buti M, et al. Clin Infect Dis. 2016;62:32-6.

  49. Elbasvir + Grazoprevir+ Ribavirin in PI-experienced HCV GT1C-SALVAGE Study: Adverse Events Source: Forns X, et al. J Hepatol. 2015;63:564-72.

  50. Elbasvir + Grazoprevir+ Ribavirin in PI-experienced HCV GT1C-SALVAGE Study: Conclusions Source: Buti M, et al. Clin Infect Dis. 2016;62:32-6.

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