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Ledipasvir-Sofosbuvir ( fixed dose combination )

Ledipasvir-Sofosbuvir ( fixed dose combination ). Prepared by: David H. Spach, MD and H. Nina Kim, MD MSc Last Updated: May 20, 2014. Ledipasvir-Sofosbuvir. Background and Dosing. Ledipasvir-Sofosbuvir (fixed dose combination).

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Ledipasvir-Sofosbuvir ( fixed dose combination )

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  1. Ledipasvir-Sofosbuvir(fixed dose combination) Prepared by: David H. Spach, MD and H. Nina Kim, MD MSc Last Updated: May 20, 2014

  2. Ledipasvir-Sofosbuvir Background and Dosing

  3. Ledipasvir-Sofosbuvir(fixed dose combination) • Approval Status: submitted for FDA approval on February 10, 2014 • Proposed Indication for Chronic HCV Monoinfection- GT 1- Duration 8 to 12 weeks depending on prior treatment and fibrosis • Class & Mechanism- Ledipasvir: NS5a inhibitor- Sofosbuvir: Nucleotide analog NS5B polymerase inhibitor • Dosing: Ledipasvir-Sofosbuvir (90 mg/400 mg) PO once daily +/- food • Adverse Effects (AE) attributable to Sofosbuvir: Fatigue, headache • Wholesaler Acquisition Cost in United States: NA

  4. Ledipasvir-SofosbuvirKnown Drug-Drug Interactions Involving Sofosbuvir Sofosbuvir not recommended for coadministration with*: • Anticonvulsants- Carbamazepine- Oxcarbazepine- Phenobarbital- Phenytoin • Antimycobacterials- Rifabutin- Rifampin- Rifapentine • Herbal Supplements- St. John’s wort • HIV Protease Inhibitors- Tipranavir/ritonavir *Not recommended because of potential marked decrease in sofosbuvir levels Source: Sofosbuvir (Sovaldi) Prescribing Information. Gilead Sciences.

  5. Ledipasvir-Sofosbuvir: Summary of Key Phase 2Studies • NIH SYNERGY- Treatment-naïve GT 1- LDV/SOF fixed-dose combination for 12 weeks or SOF/LDV with GS-9669 (NS5B polymerase inhibitor) or GS-9451 (NS3/4A protease inhibitor) for 6 weeks • ELECTRON (Arms 12-17 & 22)- Treatment-naïve and treatment-experienced GT 1- LDV/SOF fixed-dose combination with or without RBV for 6 or 12 weeks • LONESTAR- Treatment-naïve and treatment-experienced GT 1- SOF/LDV fixed-dose combination with or without RBV for 8 or 12 weeks

  6. Ledipasvir-Sofosbuvir: Summary of Key Phase 3Studies • ION-1- Treatment-naïve GT 1- LDV/SOF with or without RBV for 12 or 24 weeks • ION-2- Treatment-experienced GT 1- LDV/SOF with or without RBV for 12 or 24 weeks • ION-3- Treatment-naïve non-cirrhotic GT 1- LDV/SOF +/- RBV for 8 weeks versus LDV/SOF for 12 weeks

  7. Ledipasvir-Sofosbuvir

  8. Phase 3 TreatmentNaïve Ledipasvir-Sofosbuvir +/- Ribavirin in HCV Genotype 1ION-1 Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

  9. Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1ION-1 Study: Features Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

  10. Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1ION-1 Study: Baseline Characteristics Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

  11. Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1ION-1 Study: Study Design 0 12 24 36 Week n =214 SVR12 GT-1Naive LDV-SOF n =217 SVR12 LDV-SOF + RBV n =217 SVR12 GT-1Naive LDV-SOF n =217 SVR12 LDV-SOF + RBV Drug DosingLedipasvir-sofosbuvir (90/400 mg): fixed dose combination; one pill once dailyRibavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg N =14 Abbreviations: LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

  12. Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1ION-1 Study: Results ION-1: SVR 12 by Treatment Duration and Regimen 211/214 211/217 212/217 215/217 12-Week Regimen 24-Week Regimen LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

  13. Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1ION-1 Study: Results ION-1: SVR12 by Treatment Regimen and Liver Disease 179/179 32/33 178/178 33/33 181/182 31/32 179/179 36/36 12-Week Treatment 24-Week Treatment Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

  14. Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1ION-1 Study: Conclusions Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

  15. Phase 3 TreatmentExperienced Ledipasvir-Sofosbuvir +/- Ribavirin in HCV Genotype 1ION-2 Source: Afdhal N, et al. N Engl J Med. 2014;370:1483-93.

  16. Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Experienced HCV GT 1ION-2 Study: Features Source: Afdhal N, et al. N Engl J Med. 2014;370:1483-93.

  17. Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Experienced HCV GT 1ION-2 Study: Study Design 0 12 24 36 Week n =109 SVR12 GT-1Experienced LDV-SOF n =111 SVR12 LDV-SOF + RBV n =109 SVR12 GT-1Experienced LDV-SOF n =111 SVR12 LDV-SOF + RBV Drug DosingLedipasvir-sofosbuvir (90/400 mg): fixed dose combination; one pill once dailyRibavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg N =14 Abbreviations: LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin Source: Afdhal N, et al. N Engl J Med. 2014;370:1483-93.

  18. Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Experienced HCV GT 1ION-2 Study: Baseline Characteristics Source: Afdhal N, et al. N Engl J Med. 2014;370:1483-93.

  19. Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-experienced HCV GT 1ION-2 Study: Results ION-2: SVR 12by Treatment Duration and Regimen 102/109 107/111 108/109 110/111 12-Week Regimen 24-Week Regimen LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin Source: Afdhal N, et al. N Engl J Med. 2014;370:1483-93.

  20. Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-experienced HCV GT 1ION-2 Study: Results ION-2: SVR12 by Treatment Regimen and Liver Disease 83/87 19/22 89/89 18/22 86/87 22/22 88/89 22/22 12-Week Treatment 24-Week Treatment Source: Jacobson I, et al. N Engl J Med. 2013;368:1867-77.

  21. Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-experienced HCV GT 1ION-2 Study: Resistance Data • S282T variants - No resistance detected at baseline • NS5A resistant variants- Baseline resistance in 62 (14%) of 439 patients tested- SVR12 in 55 (89%) of 62 patients with resistance • NS3/4A resistant variants- Baseline resistance in 163 (71%) of 228 patients tested- SVR12 in 159 (98%) of 228 patients with resistance Source: Afdhal N, et al. N Engl J Med. 2014;370:1483-93.

  22. Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Experienced HCV GT 1ION-2 Study: Conclusions Source: Afdhal N, et al. N Engl J Med. 2014;370:1483-93.

  23. Phase 3 TreatmentNaïve Ledipasvir-Sofosbuvir +/- Ribavirin for 8 or 12 weeks in HCV GT1ION-3 Source: Kowdley K, et al. N Engl J Med. 2014;370:1879-88.

  24. Ledipasvir-Sofosbuvir for 8 or 12 Weeks in Treatment-Naïve HCV GT 1ION-3 Study: Features Source: Kowdley, K, et al. N Engl J Med. 2014;370:1879-88.

  25. Ledipasvir-Sofosbuvir for 8 or 12 Weeks in Treatment-Naïve HCV GT 1ION-3 Study: Study Design 12 0 8 20 24 Week n =215 SVR12 GT-1Naive LDV-SOF n =216 SVR12 LDV-SOF + RBV GT-1Naive n =216 SVR12 LDV-SOF Drug DosingLedipasvir-sofosbuvir (90/400 mg): fixed dose combination; one pill once dailyRibavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg N =14 Abbreviations: LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin Source: Kowdley, K, et al. N Engl J Med. 2014;370:1879-88.

  26. Ledipasvir-Sofosbuvir for 8 or 12 Weeks in Treatment-Naïve HCV GT 1ION-3 Study: Baseline Characteristics Source: Kowdley, K, et al. N Engl J Med. 2014;370:1879-88.

  27. Ledipasvir-Sofosbuvir for 8 or 12 Weeks in Treatment-Naïve HCV GT 1ION-3 Study: Results ION-3: SVR 12 by Treatment Duration and Regimen 201/216 206/216 202/215 8-Week Regimen 12-Week Regimen LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin Source: Kowdley, K, et al. N Engl J Med. 2014;370:1879-88.

  28. Ledipasvir-Sofosbuvir for 8 or 12 Weeks in Treatment-Naïve HCV GT 1ION-3 Study: Conclusions Source: Kowdley, K, et al. N Engl J Med. 2014;370:1879-88.

  29. Sofosbuvir-Ledipasvir Fixed-Dose Combination +/- RBVSummary: ION-1, ION-2, and ION-3 *Afdhal N, et al. N Engl J Med. 2014;370:1889-98. +Afdhal N, et al. N Engl J Med. 2014;370:1483-93. ^Kowdley, K, et al. N Engl J Med. 2014;370:1879-88.

  30. Phase 2 TreatmentNaïve (unfavorable baseline treatment characteristics) Ledipasvir-sofosbuvir +/- 3rd DAA in HCV Genotype 1 NIH SYNERGY KohliA, et al. 21st CROI. 2014:Abstract 27LB.

  31. Sofosbuvir-Ledipasvir +/- GS-9669 or GS-9451 in Naïve GT1NIH SYNERGY Trial: Features Source: Kohli A, et al. 21st CROI. 2014:Abstract 27LB.

  32. Sofosbuvir-Ledipasvir +/- GS-9669 or GS-9451 in Naïve GT1NIH SYNERGY Trial: Participants Source: Kohli A, et al. 21st CROI. 2014:Abstract 27LB.

  33. Sofosbuvir-Ledipasvir +/- GS-9669 or GS-9451 in Naïve GT1NIH SYNERGY Trial: Features 0 6 12 Week Treatment NaïveAll stages fibrosis Ledipasvir + Sofosbuvir n =20 SVR12 Treatment NaïveCirrhosis excluded Ledipasvir + Sofosbuvir + GS-9669 n = 20 SVR12 Treatment NaïveCirrhosis excluded Ledipasvir + Sofosbuvir + GS-9451 n = 20 SVR12 Drug Classes/MechanismLedipasvir (investigational): NS5A inhibitorSofosbuvir: nucleotide NS5B polymerase inhibitor GS-9669 (investigational): non-nucleoside NS5B inhibitorGS-9451 (investigational): NS3/4 protease inhibitor Drug DosingLedipasvir-Sofosbuvir: 90/400 mg fixed dose combination one pill once dailyGS-9669: 500 mg once dailyGS-9451: 80 mg once daily Source: Kohli A, et al. 21st CROI. 2014:Abstract 27LB.

  34. Sofosbuvir-Ledipasvir +/- GS-9669 or GS-9451 in Naïve GT1NIH SYNERGY Trial: Features NIH SYNERGY: SVR 12 by Treatment Regimen 20/20 19/20 20/20 Source: Kohli A, et al. 21st CROI. 2014:Abstract 27LB.

  35. Phase 2 Treatment Naïve and Treatment Experienced Sofosbuvir + (Ledipasvir or GS-9669) +/- Ribavirin in GT-1ELECTRON Trial (Arms 12-17 & 22) Source: Gane EJ, et al. Gastroenterogy. 2014:146:746-43.

  36. Sofosbuvir + (Ledipasvir or GS-9669) +/- Ribavirin in GT1ELECTRON Trial (Arms 12-17 & 22): Features Source: Gane EJ, et al. Gastroenterogy. 2014:146:746-43.

  37. Sofosbuvir + (Ledipasvir or GS-9669) +/- Ribavirin in GT1ELECTRON Trial Arms (12-17 & 22): Design 0 6 12 18 24 Week n =25 SVR12 NoncirrhoticTreatment Naive LDV + SOF + RBV n = 25 SVR12 SOF + GS-9669 + RBV n = 25 LDV-SOF + RBV SVR12 n = 9 SVR12 NoncirrhoticNull responder LDV + SOF + RBV n = 10 SVR12 SOF + GS-9669 + RBV n = 10 SVR12 CirrhoticNull responder LDV-SOF n = 9 SVR12 LDV-SOF + RBV Drug DosingSofosbuvir: 400 mg once daily; Ledipasvir: 90 mg; GS-9669 = 500 mg once dailyLedipasvir-sofosbuvir (90/400 mg): fixed dose combination one pill once dailyRibavirin (weight-based and divided bid): 1000 mg/day if < 75kg or 1200 mg/day if ≥ 75kg N =14 Abbreviations: SOF = sofosbuvir; LDV= ledipasvir; RBV = ribavirin Source: Gane EJ, et al. Gastroenterogy. 2014:146:746-43.

  38. Sofosbuvir + (Ledipasvir or GS-9669) +/- Ribavirin in GT1ELECTRON Trial (Arms 12-17 & 22): Results ELECTRON TRIAL, SVR 12 by Treatment Regimen 25/25 23/25 17/25 9/10 10/10 7/10 7/10 NoncirrhoticTreatment-Naive NoncirrhoticPrior Null Responder CirrhoticPrior Null Responder *All regimens 12 weeks except treatment-naïve LDV-SOF + Ribavirin= 6 week regimen Source: Gane EJ, et al. Gastroenterogy. 2014:146:746-43.

  39. Sofosbuvir + (Ledipasvir or GS-9669) +/- Ribavirin in GT1ELECTRON Trial (Arms 12-17 & 22): Conclusion Source: Gane EJ, et al. Gastroenterogy. 2014:146:746-43.

  40. Phase 2 Treatment Naïve and Treatment Experienced Ledipasvir + Sofosbuvir +/- Ribavirin in GT1-3ELECTRON 2 Source: Gane EJ, et al. 49th EASL. 2014: Abstract O6.

  41. Sofosbuvir-Ledipasvir +/- Ribavirin in GT 1 & 3ELECTRON 2 Trial: Features Source: Gane EJ, et al. 49th EASL. 2014: Abstract O6.

  42. Sofosbuvir-Ledipasvir +/- Ribavirin in GT 1 & 3ELECTRON-2: Baseline Characteristics Source: Gane EJ, et al. 49th EASL. 2014: Abstract O6.

  43. Sofosbuvir-Ledipasvir +/- Ribavirin in GT 1 & 3ELECTRON 2: Study Design 0 12 24 Week GT1Prior Sofobuvir n =19 SVR12 LDV-SOF + RBV GT1CTP Class B n = 20 SVR12 LDV-SOF GT3Treatment Naive n = 25 SVR12 LDV-SOF n = 26 SVR12 LDV-SOF + RBV Drug DosingLedipasvir-sofosbuvir (90/400 mg): fixed dose combination; one pill once dailyRibavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg N =14 Abbreviations: LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin Source: Gane EJ, et al. 49th EASL. 2014: Abstract O6.

  44. Sofosbuvir-Ledipasvir +/- Ribavirin in GT 1 & 3ELECTRON 2: Study Design SVR 12, by GT and Treatment Regimen 19/19 13/20 16/25 26/26 SOF-Experienced CTP Class B Treatment Naive LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin Source: Gane EJ, et al. 49th EASL. 2014: Abstract O6.

  45. Phase 2a Treatment Naïve and Treatment Experienced Sofosbuvir-Ledipasvir +/- Ribavirin in GT-1LONESTAR Trial Source: Lawitz E, et al. Lancet. 2014:383:515-23.

  46. Sofosbuvir-Ledipasvir +/- Ribavirin in Naïve & Experienced GT1LONESTAR Trial: Features Source: Lawitz E, et al. Lancet. 2014:383:515-23.

  47. Sofosbuvir-Ledipasvir +/- Ribavirin in Naïve & Experienced GT1LONESTAR: Study Design 0 8 12 16 20 24 Week n =20 SVR12 Cohort ANaïven = 60 SOF-LDV n = 21 SVR12 SOF-LDV + RBV n = 19 SVR12 SOF-LDV n = 19 SVR12 Cohort BExperiencedn = 40 SOF-LDV n = 21 SVR12 SOF-LDV + RBV Drug DosingSofosbuvir-Ledipasvir: 400/90 mg fixed dose combination one pill once dailyRibavirin (weight-based and divided bid): 1000 mg/day if < 75kg or 1200 mg/day if ≥ 75kg N =14 Abbreviations: SOF = sofosbuvir; LDV= ledipasvir; RBV = ribavirin Source: Lawitz E, et al. Lancet. 2014:383:515-23.

  48. Sofosbuvir-Ledipasvir +/- Ribavirin in Naïve & Experienced GT1LONESTAR Trial: Results LONESTAR: SVR 12, by Cohort and Treatment Regimen 19/20 21/21 18*/19 18/19 21/21 Cohort A: Treatment-Naive Cohort B: Experienced (with PI) *One patient lost to follow-up; SOF = sofosbuvir; LDV= ledipasvir; RBV = ribavirin; PI = protease inhibitor Source: Lawitz E, et al. Lancet. 2014:383:515-23.

  49. Sofosbuvir-Ledipasvir +/- Ribavirin in Naïve & Experienced GT1LONESTAR Trial: Adverse Events Source: Lawitz E, et al. Lancet. 2014:383:515-23.

  50. Sofosbuvir-Ledipasvir +/- Ribavirin in Naïve & Experienced GT1LONESTAR Trial: Conclusion Source: Lawitz E, et al. Lancet. 2014:383:515-23.

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