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Ledipasvir-Sofosbuvir ( Harvoni )

Ledipasvir-Sofosbuvir ( Harvoni ). Prepared by: David H. Spach, MD and H. Nina Kim, MD MSc Last Updated: December 15, 2015. Ledipasvir-Sofosbuvir ( Harvoni ). Background and Dosing. Ledipasvir-Sofosbuvir ( Harvoni ).

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Ledipasvir-Sofosbuvir ( Harvoni )

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  1. Ledipasvir-Sofosbuvir (Harvoni) Prepared by: David H. Spach, MD and H. Nina Kim, MD MSc Last Updated: December 15, 2015

  2. Ledipasvir-Sofosbuvir (Harvoni) Background and Dosing

  3. Ledipasvir-Sofosbuvir (Harvoni) • Approval Status- Initial approval by United States FDA October 10, 2014- Expanded indications approved by FDA November 12, 2015 • Indications and Usage - Indicated for the treatment of chronic HCV genotypes 1, 4, 5, and 6 in adults- Indicated for the treatment of chronic HCV in patients co-infected with HIV • Class & Mechanism- Ledipasvir: NS5A inhibitor- Sofosbuvir: Nucleotide analog NS5B polymerase inhibitor • Dosing: Ledipasvir-Sofosbuvir (fixed dose 90 mg/400 mg) One tablet orally once daily with or without food • Adverse Effects (AE): Fatigue, headache Source: Harvoni Prescribing Information. Gilead Sciences

  4. Ledipasvir-Sofosbuvir (Harvoni)Indications and Usage Source: Harvoni Prescribing Information. Gilead Sciences

  5. Ledipasvir-Sofosbuvir (Harvoni)Estimated Cost of Therapy

  6. Ledipasvir-Sofosbuvir(Harvoni)Drug-Drug Interactions • Not recommended for coadministration with:- P-gp inducers(eg. rifampin, St. John’s Wort)- Amiodarone • Consult Prescribing Information Regarding Interactions with: - Acid reducing agents- Antiarrhythmics- Anticonvulsants- Antimycobacterials- HIV antiretrovirals Source: Harvoni Prescribing Information. Gilead Sciences

  7. Ledipasvir-Sofosbuvir (Harvoni)Adverse Effects Source: Harvoni Prescribing Information. Gilead Sciences

  8. Clinical Trials Ledipasvir-Sofosbuvir

  9. Ledipasvir-Sofosbuvir (LDV-SOF): Summary of Key Studies • Treatment Naïve (Phase 3)- ION-1: GT-1 / LDV-SOF +/- RBV x 12 or 24 weeks- ION-3: GT-1 / LDV-SOF +/- RBV x 8 weeks vs LDV/SOF x 12 weeks • Treatment Naïve(Phase 2)- NIAID SYNERGY (GT-1): GT-1 LDV-SOF +/- [GS-9669 or GS-9451] • Treatment Experienced (Phase 3)- ION-2: GT-1 / LDV-SOF +/- RBV x 12 or 24 weeks • Treatment Experienced with Compensated Cirrhosis (Phase 2)- SIRIUS: GT-1 / LDV-SOF + RBV x 12 weeks or LSV-SOF x 24 weeks

  10. Ledipasvir-Sofosbuvir (LDV-SOF): Summary of Key Studies • Treatment Naïve or Treatment Experienced (Phase 2)- LONESTAR: GT-1 / LDV-SOF +/- RBV x 8 or 12 weeks- ELECTRON (Arms 12-17 & 22): LDV-SOF +/- RBV x 6 or 12 weeks- ELECTRON-2: experienced GT-1 & naïve GT-3/ LDV-SOF +/- RBV x 12 weeks- New Zealand: GT 3,6 / LDV-SOF +/- RBV x 12 weeks- NIAID SYNERGY (GT-4): GT 4 / LDV/SOF x 12 weeks • Prior Sofosbuvir Failure (Phase 2)- NIAID: GT-1 / LDV-SOF +/- RBV x 12 weeks- PRIOR Failure in Sofosbuvir Trials: GT-1 / LDV-SOF +/- RBV x 12 weeks

  11. Ledipasvir-Sofosbuvir (LDV-SOF): Summary of Key Studies • HIV Coinfection: Treatment Naïve (Phase 2)- NIAID ERADICATE: GT 1 / LDV-SOF x 12 weeks +/- HIV antiretrovirals • HIV Coinfection: Treatment Naïve or Treatment Experienced- ION-4: GT 1 or 4 / LDV-SOF x 12 weeks +/- HIV antiretrovirals • Advanced Liver Disease: Pre and Post Transplant (Phase 2)- SOLAR-1: GT 1,4 / LDV-SOF + RBV x 12 or 24 wks

  12. Ledipasvir-Sofosbuvir in Treatment-Naïve Patients

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

  14. 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.

  15. Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1ION-1 Study: Study Design 0 12 24 36 Week GT-1Naive n =214 SVR12 LDV-SOF n =217 SVR12 LDV-SOF + RBV n =217 SVR12 GT-1Naive LDV-SOF n =217 SVR12 LDV-SOF + RBV Abbreviations: LDV-SOF= ledipasvir-sofosbuvir; RBV = ribavirin 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 Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

  16. 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.

  17. 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 Abbreviations: LDV-SOF= ledipasvir-sofosbuvir; RBV = ribavirin*Primary end-point by intention-to-treat analysis Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

  18. 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 Note: subgroup results do not include patients who withdrew consent or were lost to follow-up Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

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

  20. Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1ION-1 Study: Resistance Data • NS5A resistant variants- Baseline resistance in 140 (16%) of 861 patients tested- SVR12 in 135 (96%) of 140 patients with NS5A resistance- 2 of the 3 patients with virologic failure had baseline NS5A resistance Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

  21. 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.

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

  23. 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.

  24. Ledipasvir-Sofosbuvir for 8 or 12 Weeks in Treatment-Naïve HCV GT 1ION-3 Study: Study Design 0 8 12 20 24 Week SVR12 n =215 GT-1 Naïve Non-cirrhotic LDV-SOF n =216 SVR12 LDV-SOF + RBV GT-1Naive n =216 SVR12 LDV-SOF Abbreviations: LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin 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 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: Baseline Characteristics 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: Results ION-3: SVR 12* by Treatment Duration and Regimen 201/216 206/216 202/215 8-Week Regimen 12-Week Regimen Abbreviations: LDV-SOF= ledipasvir-sofosbuvir; RBV = ribavirin*Primary end-point by intention-to-treat analysis 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 Source: Harvoni Prescribing Information. Gilead Sciences

  28. Ledipasvir-Sofosbuvir for 8 or 12 Weeks in Treatment-Naïve HCV GT 1ION-3 Study: Resistance Data • NS5B S282T variant (reduces susceptibility to sofosbuvir) - Not observed in any patients at baseline or after treatment by deep sequencing • NS5A resistant variants- Baseline resistance in 116 (18%) of 647 patients- SVR12 in 104 (90%) of 116 patients with NS5A resistance- Of the 23 patients who had viral relapse, 15 (65%) had NS5A-resistant variants at time of relapse Source: Kowdley, K, et al. N Engl J Med. 2014;370:1879-88.

  29. 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.

  30. Title changed on results slide Phase 2 TreatmentNaïve (unfavorable baseline treatment characteristics) Ledipasvir-Sofosbuvir +/- 3rd DAA in HCV Genotype 1 NIAID SYNERGY: Genotype 1 KohliA, et al. Lancet. 2015:385:1107-13.

  31. Ledipasvir-Sofosbuvir +/- [GS-9669 or GS-9451] in Naïve GT1NIAID SYNERGY GT-1 Trial: Features Source: Kohli A, et al. Lancet. 2015:385:1107-13.

  32. Ledipasvir-Sofosbuvir +/- [GS-9669 or GS-9451] in Naïve GT1NIAID SYNERGY GT-1 Trial: Features 0 6 12 18 24 Week Treatment NaïveAll stages fibrosis LDV-SOF n =20 SVR12 Treatment NaïveCirrhosis excluded LDV-SOF+ GS-9669 n = 20 SVR12 Treatment NaïveCirrhosis excluded LDV-SOF + GS-9451 n = 20 SVR12 Abbreviations: LDV-SOF= ledipasvir-sofosbuvir 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. Lancet. 2015:385:1107-13.

  33. Ledipasvir-Sofosbuvir +/- [GS-9669 or GS-9451] in Naïve GT1NIAID SYNERGY GT-1 Trial: Participants Source: Kohli A, et al. Lancet. 2015:385:1107-13.

  34. Ledipasvir-Sofosbuvir +/- [GS-9669 or GS-9451] in Naïve GT1NIAID SYNERGY GT-1 Trial: Viral Kinetics 7 Sofosbuvir + Ledipasvir 6 Sofosbuvir + Ledipasvir + GS-9669 Sofosbuvir + Ledipasvir + GS-9451 5 4 Log10 Median HCV RNA (IU/ml) 3 *p<0.05 *p<0.05 *p<0.05 2 0 7 14 21 28 Time (days) Source: Kohli A, et al. Lancet. 2015:385:1107-13.

  35. Ledipasvir-Sofosbuvir +/- [GS-9669 or GS-9451] in Naïve GT1NIAID SYNERGY GT-1 Trial: Results NIH SYNERGY: SVR 12 by Treatment Regimen 20/20 19/20* 19/20^ *1 patient relapsed 2 weeks after completion of treatment^1 patient lost to follow-up after reaching SVR at 4 weeks Source: Kohli A, et al. Lancet. 2015:385:1107-13.

  36. Ledipasvir-Sofosbuvir +/- [GS-9669 or GS-9451] in Naïve GT1NIAID SYNERGY GT-1 Trial: Interpretation Source: Kohli A, et al. Lancet. 2015:385:1107-13.

  37. Ledipasvir-Sofosbuvir in Treatment-Experienced Patients

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

  39. 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.

  40. Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Experienced HCV GT 1ION-2 Study: Study Design 0 12 24 36 Week GT-1Experienced n =109 SVR12 LDV-SOF n =111 SVR12 LDV-SOF + RBV GT-1Experienced n =109 SVR12 LDV-SOF n =111 SVR12 LDV-SOF + RBV Abbreviations: LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin 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 Source: Afdhal N, et al. N Engl J Med. 2014;370:1483-93.

  41. 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.

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

  43. 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: Afdhal N, et al. N Engl J Med. 2014;370:1483-93.

  44. Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-experienced HCV GT 1ION-2 Study: Results for Ledipasvir-Sofosbuvir ION-2: SVR12 by Treatment Regimen and Liver Disease 83/87 19/22 86/87 22/22 Note: subgroup results do not include patients who withdrew consent or were lost to follow-up Source: Afdhal N, et al. N Engl J Med. 2014;370:1483-93.

  45. Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-experienced HCV GT 1ION-2 Study: Results ION-2: SVR12 by Prior Treatment Regimen 40/43 62/66 45/47 62/64 58/58 49/50 58/59 51/51 12-Week Treatment 24-Week Treatment Source: Afdhal N, et al. N Engl J Med. 2014;370:1483-93.

  46. Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-experienced HCV GT 1ION-2 Study: Resistance Data • NS5B S282T variant (reduces susceptibility to sofosbuvir) - Not observed in any patients at baseline or after treatment • NS5A resistant variants- Baseline resistance in 62 (14%) of 439 patients tested- SVR12 in 55 (89%) of 62 patients with NS5A resistance- All 11 patients who had viral relapse had detectable NS5Aresistant variants at the time of relapse • NS3/4A resistant variants- Baseline resistance in 163 (71%) of 228 patients tested- SVR12 in 159 (98%) of 163 patients with resistance Source: Afdhal N, et al. N Engl J Med. 2014;370:1483-93.

  47. 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.

  48. Phase 2 TreatmentExperienced Ledipasvir-Sofosbuvir in Treatment-Experienced GT1 with Cirrhosis SIRIUS Bourliere M, et al. Lancet Infect Dis. 2015;15:397-404.

  49. Ledipasvir-Sofosbuvir in Treatment-Experienced GT1 with Cirrhosis SIRIUS Trial: Features Source: BourliereM, et al. Lancet Infect Dis. 2015;15:397-404.

  50. Ledipasvir-Sofosbuvir in Treatment-Experienced GT1 with Cirrhosis SIRIUS Trial: Study Design 0 12 24 36 Week n =77 Placebo LDV-SOF + RBV SVR12 n =78 LDV-SOF SVR12 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: BourliereM, et al. Lancet Infect Dis. 2015;15:397-404.

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