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Daclatasvir ( Daklinza )

Daclatasvir ( Daklinza ). Prepared by: H. Nina Kim, MD MSc and David Spach, MD Last Updated: March 10, 2017. Daclatasvir ( Daklinza ). Background Information. Daclatasvir ( Daklinza ). Approval Status : Approved by United States FDA July 24, 2015

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Daclatasvir ( Daklinza )

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  1. Daclatasvir (Daklinza) Prepared by: H. Nina Kim, MD MSc and David Spach, MD Last Updated: March 10, 2017

  2. Daclatasvir (Daklinza) Background Information

  3. Daclatasvir (Daklinza) • Approval Status: Approved by United States FDA July 24, 2015 • Indications and Usage - Indicated with sofosbuvir, with or without ribavirin for the treatment of chronic HCV genotype 1 and 3 in adults • Class & Mechanism- NS5A inhibitor • DosingPreparations and Adjustments- Daclatasvir 60 mg and 30 mg tablets- No dosage adjustment with any degree of renal impairment - No dosage adjustment with mild, moderate, or severe hepatic impairment • Most Common Adverse Effects- Headache, fatigue, nausea, diarrhea Source: Daklinza Prescribing Information. Bristol Myers Squibb

  4. Daclatasvir (Daklinza)Indications and Usage Source: Daklinza Prescribing Information. Bristol Myers Squibb

  5. Daclatasvir (Daklinza)Estimated Cost of Therapy

  6. Daclatasvir (Daklinza)Adverse Effects Source: Daklinza Prescribing Information. Bristol Myers Squibb

  7. Daclatasvir (Daklinza)Drug-Drug Interactions Source: Daklinza Prescribing Information. Bristol Myers Squibb

  8. Clinical Trials Daclatasvir

  9. Daclatasvir: Summary of Key Studies • Phase 2b Trial in Treatment-Naïve GT 1 or 4- COMMAND-1: Daclatasvir+ PEG/RBV • Phase 3 Trial in Treatment-Naïve GT 4- COMMAND-4: Daclatasvir + PEG/RBV versus Placebo + PEG/RBV • Phase 3 Trial in Treatment-Experienced GT 1 or 4- HALLMARK-QUAD: Daclatasvir + Asunaprevir + PEG/RBV • Phase 3 Trial in Treatment-Naïve and Experienced GT 1-4 and HIV - ALLY-2: Daclatasvir + Sofosbuvir • hase 3 Trial in Treatment-Naïve and Experienced GT 3- ALLY-3: Daclatasvir + Sofosbuvir • Phase 3 Trial in Treatment-Naïve and Experienced GT 3- ALLY-3+: Daclatasvir + Sofosbuvir

  10. Daclatasvir: Summary of Key Studies • Phase 2 Trial of Treatment-Naïve or Experienced GT 1,2,3- AI444040: Daclatasvir + Sofosbuvir +/- Ribavirin • Phase 3 Trial in Treatment-Naïve or Experienced GT 1 without cirrhosis- UNITY-1: Daclatasvir + Asunaprevir + Beclabuvir • Phase 3 Trial in Treatment-Naïve or Experienced GT 1 cirrhotics- UNITY-2: Daclatasvir + Asunaprevir + Beclabuvir +/- Ribavirin • Phase 3 Trial in Treatment-Naïve or Experienced GT 1B- HALLMARK-DUAL: Daclatasvir + Asunaprevir • Phase 3 Trial in Treatment-Naïve and Experienced GT 1-4 and HIV - ALLY-2: Daclatasvir + Sofosbuvir • Phase 3 Trial in Advanced Cirrhosis and Post-Liver Transplant GT 1-6 - ALLY-1: Daclatasvir + Sofosbuvir + Ribavirin

  11. Daclatasvir-Based Regimens in Treatment-Naïve Patients

  12. Phase 2b Treatment-Naïve Daclatasvir + Peg/RBV in Treatment-Naïve Genotype 1 or 4COMMAND-1 Study Hézode C, et. al. Gut. 2015;64:948-56.

  13. Daclatasvir + Peginterferon/RBV for HCV GT 1 or 4COMMAND-1 Trial: Study Features Source: Hézode C, et. al. Gut. 2015;64:948-56.

  14. Daclatasvir + Peginterferon/RBV for HCV GT 1 or 4COMMAND-1 Trial: Design Weeks 1-12 Weeks 13-24 Weeks 25-48 DCV 20 mg + PR Follow-up Protocol-Defined Response Yes DCV 20 mg + PR(N = 159) Placebo + PR Follow-up No PR Placebo + PR DCV 60 mg + PR Follow-up Yes DCV 60 mg + PR(N = 158) Placebo + PR Follow-up No Placebo + PR PR Placebo + PR(n = 78) Placebo + PR PR Week 4 RNA Week 10 RNA PDR = Protocol-Defined Response (HCV RNA <lower limit of quantitation at week 4 & undetectable at week 10) DCV = daclatasvir; PEG = peginterferon; RBV = ribavirin Source: Hézode C, et. al. Gut. 2015;64:948-56.

  15. Daclatasvir + Peginterferon/RBV for HCV GT 1 or 4COMMAND-1 Trial: Patient Characteristics Source: Hézode C, et. al. Gut. 2015;64:948-56.

  16. Daclatasvir + Peginterferon/RBV for HCV GT 1 or 4COMMAND-1 Trial: Results SVR12, by Genotype 88/146 26/72 9/12 12/12 3/6 95/147 DCV=daclatasvir; PR=peginterferon plus ribavirin Source: Hézode C, et. al. Gut. 2015;64:948-56.

  17. Daclatasvir + Peginterferon/RBV for HCV GT 1 or 4COMMAND-1: Conclusions Source: Hézode C, et. al. Gut. 2015;64:948-56.

  18. Phase 3 Treatment-Naïve Daclatasvir + Peg/RBV in Treatment-Naïve Genotype 4COMMAND-4 Study Hézode C, et. al. Antivir Ther. 2015;21:195-205.

  19. Daclatasvir + Peginterferon/RBV for HCV GT 4COMMAND-4 Trial: Study Features Source: Hézode C, et. al. Antivir Ther. 2015;21:195-205.

  20. Daclatasvir + Peginterferon/RBV for HCV GT 4COMMAND-4 Trial: Design 0 24 48 Week Treatment Arm(n=82) Daclatasvir 60 mg once daily PEG + RBV If no eRVR continue PEG + RBV Placebo Arm (n=42) Placebo PEG + RBV eRVR = HCV RNA < 25 IU/mL at weeks 4 and 12PEG = peginterferon; RBV = ribavirin Source: Hézode C, et. al. Antivir Ther. 2015;21:195-205.

  21. Daclatasvir + Peginterferon/RBV for HCV GT 4COMMAND-4 Trial: Patient Characteristics Source: Hézode C, et. al. Antivir Ther. 2015;21:195-205.

  22. Daclatasvir + Peginterferon/RBV for HCV GT 4COMMAND-4Trial: Results COMMAND-4: SVR12 by Analysis 60/82 16/42 67/82 18/42 Modified ITT, intent-to-treat: patients with missing data at post-treatment week 12 were considered treatment failures. Source: Hézode C, et. al. Antivir Ther. 2015;21:195-205.

  23. Daclatasvir + Peginterferon/RBV for HCV GT 4COMMAND-4: Results in Daclatasvir Arm COMMAND-4: SVR12 by eRVR in Patients Receiving DCV 56/62 4/17 In DCV group, most (79%) patients achieved an eRVR and were eligible for shortened (24 week) duration Source: Hézode C, et. al. Antivir Ther. 2015;21:195-205.

  24. Daclatasvir + Peginterferon/RBV for HCV GT 4COMMAND-4: Conclusions Source: Hézode C, et. al. Antivir Ther. 2015;21:195-205.

  25. Daclatasvir in Treatment-Experienced Patients

  26. Phase 3 Treatment-Experienced Daclatasvir + Asunaprevir + Peg/RBV in Genotype 1and 4HALLMARK-QUAD Study Jensen D, et. al. J Hepatol. 2015;63:30-7.

  27. Daclatasvir + Asunaprevir + P/R for HCVGT 1,4HALLMARK-QUAD Trial: Study Features Source: Jensen D, et. al. J Hepatol. 2015;63:30-7.

  28. Daclatasvir + Asunaprevir + P/R for HCV GT 1,4HALLMARK-QUAD Trial: Design 0 12 24 Week Treatment-Experienced GT 1a or 1b N = 354 Daclatasvir + Asunaprevir +Peginterferon + Ribavirin SVR12 Treatment-Experienced GT 4 N = 44 Daclatasvir + Asunaprevir +Peginterferon + Ribavirin SVR12 Drug DosingDaclatasvir: 60 mg once dailyAsunaprevir: 100 mg twice dailyPeginterferon alfa-2a: 180 mcg once weeklyRibavirin, weight-based dosing, twice daily: 1000 mg/day if < 75kg or 1200 mg/day if ≥ 75kg Source: Jensen D, et. al. J Hepatol. 2015;63:30-7.

  29. Daclatasvir + Asunaprevir + P/R for HCV GT 1,4HALLMARK-QUAD Trial: Patient Characteristics Source: Jensen D, et. al. J Hepatol. 2015;63:30-7.

  30. Daclatasvir + Asunaprevir + P/R for HCV GT 1,4HALLMARK-QUAD Trial: Results HALLMARK-QUAD: SVR 12 by Genotypea 329/354 153/176 176/178 43/44 a Modified intention-to-treat analysis; GT = genotype Source: Jensen D, et. al. J Hepatol. 2015;63:30-7.

  31. Daclatasvir + Asunaprevir + P/R for HCV GT 1,4HALLMARK-QUAD Trial: Results HALLMARK-QUAD: SVR12, by Cirrhosis Status 66/73 263/281 19/20 24/24 Source: Jensen D, et. al. J Hepatol. 2015;63:30-7.

  32. Daclatasvir + Asunaprevir + P/R for HCV GT 1,4HALLMARK-QUAD Trial: Adverse Events Source: Jensen D, et. al. J Hepatol. 2015;63:30-7.

  33. Daclatasvir + Asunaprevir + P/R for HCV GT 1,4HALLMARK-QUAD Trial: Conclusions Source: Jensen D, et. al. J Hepatol. 2015;63:30-7.

  34. Daclatasvir-Based Regimens in Treatment-Naïve and Treatment-Experienced Patients

  35. Phase 3 Treatment-Naïve and Treatment-Experienced Daclatasvir + Sofosbuvir in Genotype 3ALLY-3 Study Nelson DR, et al. Hepatology 2015;61:1127-35.

  36. Daclatasvir + Sofosbuvir for HCVGT 3ALLY-3 Trial: Study Features Source: Nelson DR, et al. Hepatology2015;61:1127-35.

  37. Daclatasvir + Sofosbuvir for HCV GT 3ALLY-3 Trial: Design 0 12 24 Week Daclatasvir + Sofosbuvir Treatment-Naïve n=101 SVR12 Treatment-Experienced n=51 Daclatasvir + Sofosbuvir SVR12 Drug DosingDaclatasvir: 60 mg once dailySofosbuvir: 400 mg once daily Source: Nelson DR, et al. Hepatology 2015;61:1127-35.

  38. Daclatasvir + Sofosbuvir for HCV GT 3ALLY-3 Trial: Patient Characteristics a Intolerant of therapy (n=6), virologic breakthrough (n=2), HCV never undetectable on treatment (n=2) Source: Nelson DR, et al. Hepatology 2015;61:1127-35.

  39. Daclatasvir + Sofosbuvir for HCV GT 3ALLY-3 Trial: Results ALLY-3: SVR12, by Baseline Characteristics Status 58/62 128/142 7/10 40/44 95/108 55/60 80/92 77/90 Male Female <65 ≥65 <800K ≥800K CC Non-CC Note: SVR 12 based on HCV RNA less than lower limit of quantitation (25 IU/mL), detectable or undetectable Source: Nelson DR, et al. Hepatology 2015;61:1127-35.

  40. Daclatasvir + Sofosbuvir for HCV GT 3ALLY-3 Trial: Results ALLY-3: SVR12, by Cirrhosis Status 91/101 44/51 135/152 Source: Nelson DR, et al. Hepatology 2015;61:1127-35.

  41. Daclatasvir + Sofosbuvir for HCV GT 3ALLY-3 Trial: Results ALLY-3: SVR12, by Cirrhosis Status 73/75 32/34 11/19 9/13 20/32 73/75 11/19 32/34 9/13 105/109 Note:11 had missing or inconclusive findings for cirrhosis and not included in denominators Source: Nelson DR, et al. Hepatology 2015;61:1127-35.

  42. Daclatasvir + Sofosbuvir for HCV GT 3ALLY-3 Trial: Adverse Events Source: Nelson DR, et al. Hepatology 2015;61:1127-35.

  43. Daclatasvir + Sofosbuvir for HCV GT 3ALLY-3 Trial: Conclusion Source: Nelson DR, et al. Hepatology 2015;61:1127-35.

  44. Phase 3 Treatment-Naïve and Treatment-Experienced Daclatasvir + Sofosbuvir + RBV in GT3with Advanced Liver DiseaseALLY-3+ Study Leroy V, et al. Hepatology 2016;63:1430-41.

  45. Daclatasvir + Sofosbuvir + RBV for HCVGT 3 Advanced Liver DiseaseALLY-3+ Trial: Study Features Source: Leroy V, et al. Hepatology 2016;63:1430-41.

  46. Daclatasvir + Sofosbuvir + RBV for HCV GT 3 Advanced Liver DiseaseALLY-3+ Trial: Design 0 12 24 16 28 Week DCV + SOF + RBV N = 24 SVR12 DCV + SOF + RBV N = 26 SVR12 Drug DosingDaclatasvir (DCV): 60 mg once dailySofosbuvir (SOF: 400 mg once dailyRibavirin (RBV): GT1, given weight-based and divided bid (1000 mg/day if < 75kg or 1200 mg/day if ≥ 75kg) Source: Leroy V, et al. Hepatology 2016;63:1430-41.

  47. Daclatasvir + Sofosbuvir + RBV for HCV GT 3 Advanced Liver Disease ALLY-3+ Trial: Patient Characteristics IFN=peginterferon, SOF=sofosbuvir, DCV=daclatasvir, RAVs=resistance-associated variants Source: Leroy V, et al. Hepatology 2016;63:1430-41.

  48. Daclatasvir + Sofosbuvir + RBV for HCV GT 3 Advanced Liver DiseaseALLY-3+ Trial: Results ALLY-3+: SVR12by Treatment Arm 21/24 24/26 45/50 SVR12 rates determined by intent-to-treat analysis Source: Leroy V, et al. Hepatology 2016;63:1430-41.

  49. Daclatasvir + Sofosbuvir + RBV for HCV GT 3 Advanced Liver DiseaseALLY-3+ Trial: Results ALLY-3+: SVR12 by Cirrhosis Status 73/75 32/34 11/19 9/13 31/36 26/30 6/6 15/18 14/16 8/8 16/18 12/14 14/14 SVR12 rates determined by intent-to-treat analysis Source: Leroy V, et al. Hepatology 2016;63:1430-41.

  50. Daclatasvir + Sofosbuvir + RBV for HCV GT 3 Advanced Liver Disease ALLY-3+ Trial: Safety Source: Leroy V, et al. Hepatology 2016;63:1430-41.

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