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Presented by. Jointly sponsored by the Duke University School of Medicine and The Chronic Liver Disease Foundation. Supported by:. Educational Objectives.

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  1. Presented by Jointly sponsored by the Duke University School of Medicine and The Chronic Liver Disease Foundation Supported by:

  2. Educational Objectives • Describe the differences for each of the treatment regimens newly approved or likely to be approved in 2014 in order to optimize patient outcomes. • Identify the most important baseline characteristics when assessing benefit/risk of individual patients in order to make the decision to treat now or wait.

  3. Boceprevir and Telaprevir: Therapies Approved in 2011

  4. First Direct Acting Antivirals (DAAs) with an Indication for the Treatment of GT 1 Chronic Hepatitis C Both compounds act by inhibiting HCV nonstructural NS3/4A protease and are referred to as direct acting antivirals Telaprevir (INCIVEK™) Prescribing Information. Vertex Pharmaceuticals Incorporated, Cambridge, MA. October, 2013.Boceprevir(VICTRELIS™) Prescribing Information. Merck Sharp & Dohme Corp., Whitehouse Station, NJ, September 2013.

  5. Limitations of Boceprevirand Telaprevir Telaprevir and boceprevir only approved for Genotype 1 Interferon and ribavirin backbone required Twice per day dosing (BID) for telaprevir and three times per day (TID) dosing for boceprevir Response guided therapy (both) and lead-in (boceprevir) complicated 24-48 week treatment Limited efficacy in difficult to cure patients (e.g., patients with cirrhosis, prior null responders, African-Americans) Hematologic (both) and rash/dermatological (telaprevir) adverse events Drug-drug interactions Telaprevir (INCIVEK™) Prescribing Information. Vertex Pharmaceuticals Incorporated, Cambridge, MA. October, 2013.Boceprevir(VICTRELIS™) Prescribing Information. Merck Sharp & Dohme Corp., Whitehouse Station, NJ, September 2013.

  6. Many Direct Acting Antiviralsin Development • NS5A Inhibitors • Daclatasvir • Ledipasvir • ABT-267 • GS-5816 • ACH-3102 • PPI-668 • GSK2336805 • Samatasvir • MK-8742 • Protease inhibitors • Faldaprevir • Asunaprevir • ABT-450 • MK-5172 • Sovaprevir • ACH-2684

  7. Many Direct Acting Antiviralsin Development • NS5B Non-nuc • ABT-333 • Deleobuvir • BMS 791325 • PPI-383 • GS 9669 • TMC 647055 • NS5B Nuc • VX-135 • IDX20963 • ACH-3422

  8. Simeprevir (SMV) (protease inhibitor) +PEG-IFN/RBV APPROVED REGIMEN FOR GT 1

  9. Simeprevir (SMV) (TMC 435) FDA approval: November 22, 2013 NS3/4A protease inhibitor One capsule taken once daily with food Must be used in combination with PEG/RBV Approved for GT 1 infected subjects with compensated liver disease (including cirrhosis) Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

  10. QUEST 1, QUEST 2 and PROMISEStudy Designs Response Guided Treatment SMV 150mg/ PEG/RBV* Placebo/ PEG/RBV PEG/RBV PEG/RBV PEG/RBV PEG/RBV Post-Therapy Follow-Up Post-Therapy Follow-Up Post-Therapy Follow-Up Weeks 0 24 12 48 72 Response Guided Therapy: if HCV RNA <25 International Units/mL at Week 4 and undetectable at Week 12, complete treatment at Week 24 QUEST 1 and QUEST 2: GT 1, Treatment Naïve PROMISE: GT 1, Prior Relapsers *PEG/RBV=Peginterferon/Ribavirin

  11. SVR12 Rates in Treatment Naive Patients (QUEST 1 and QUEST 2 Combined) 49/ 84 23/ 44 191/ 254 138/ 165 36/ 83 62/ 131 70/ 133 419/ 521 132/ 264 228/ 267 *Observed prevalence of Q80K variants at baseline in US population in the Phase 2b/3 trials: 48% of GT 1a and 0% of GT 1b patientsSimeprevir(OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

  12. SVR12 Rates by METAVIR Fibrosis Score in Treatment Naive Patients With GT 1 Infection (Pooled Data QUEST 1 and QUEST 2) 317/ 378 106/ 192 89/ 130 26/ 72 Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

  13. SVR12 Rates in Patients Who Relapsed AfterPrior IFN-Based Therapy (PROMISE) 6/ 20 49/ 133 14/ 30 128/ 149 34/ 79 78/ 111 62/ 79 9/ 34 206/ 260 15/ 54 Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

  14. SVR12 Rates by METAVIR Fibrosis Score in Patients Who Relapsed After Prior IFN-Based Therapy (PROMISE) 137/ 167 40/ 98 61/ 83 8/ 34 Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

  15. SVR24 Rates in Patients Who Failed PriorIFN-Based Therapy (ASPIRE) 20/ 26 10/ 27 15/ 23 9/ 17 3/ 16 2/23 12 weeks SMV/PEG/RBV followed by 36 weeks of PEG/RBV vs 48 weeks Placebo/PEG/RBV Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

  16. Simeprevir: Impact of the Q80K Polymorphism Efficacy of SMV/PEG/RBV is substantially reduced in patients infected with GT 1a with an NS3 Q80K polymorphism at baseline compared to patients without this polymorphism. Screening GT 1a patients for Q80K polymorphism at baseline is strongly recommended. Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

  17. Simeprevir: Dosage and Administration *Recommended duration of treatment if patient does not meet stopping rule.Simeprevir(OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

  18. Futility Rules If PEG or RBV is discontinued for any reason, SMV must also be discontinued. TW=treatment week, SMV=simeprevir, PEG=peginterferon, RBV=ribavirinSimeprevir(OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

  19. Higher SMV Concentrations Likely in Patientswith Hepatic Impairment • SMV primarily metabolized by the liver • Phase 1 study conducted in HCV-uninfected subjects • Compared to subjects with normal hepatic function • 2.4-fold higher concentrations in subjects with moderate hepatic impairment (Child-Pugh Class B) • 5.2-fold higher concentrations in subjects with severe hepatic impairment (Child-Pugh Class C) • Higher SMV exposures have been associated with increased frequency of adverse events • No SMV dose recommendation given Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

  20. SMV Concentrations Based on Race • Compared to Caucasians • Higher SMV concentrations in East Asians • Comparable SMV concentrations in Black/African Americans • Higher SMV exposures have been associated with increased frequency of adverse events • No SMV dose recommendation given for patients of East Asian ancestry Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

  21. Drug: Drug Interaction Potential:SMV As An Inhibitor • Potential for increased plasma concentrations of drugs that are substrates • CYP1A2 • Intestinal CYP3A4 (not hepatic CYP3A4) • OATP1B1/3 • P-gp transporters • No adjustment required when co-administered with cyclosporine or tacrolimus Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

  22. Drug: Drug Interaction Potential:SMV As A Substrate Co-administration of SMV with substances that are moderate or strong inducers or inhibitors of CYP3A is not recommended as this may lead to significantly lower or higher exposure of SMV, respectively Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

  23. Adverse Reactions (All Grades): ≥3% Higher Frequency Among Subjects Receiving 150 mg SMV/PEG/RBV vs Placebo/PEG/RBV* *During the first 12 weeks of treatment (pooled phase 3 trials)**Grouped term ‘rash’ includes 26 preferred terms***Grouped term ‘pruritus’ includes the preferred terms ‘pruritus’ and ‘pruritus generalized’****Grouped term ‘dyspnea’ includes the preferred terms ‘dyspnea’ and ‘dyspnea generalized’Simeprevir(OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

  24. Treatment-Emergent Lab Abnormalities (WHO Worst Toxicity Grades 1 to 4) Observed at a Higher Incidence in SMV-Treated Subjects* *During the first 12 weeks of treatment (pooled phase 3 trials)**No Grade 3 or 4 changes in alkaline phosphatase were observed. ***ULN=Upper Limit of NormalSimeprevir(OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

  25. Laboratory Abnormalities Mild to moderate elevations in bilirubin Included elevation of both direct andindirect bilirubin Elevations occurred early after treatment initiation, peaked by Week 2 and were rapidly reversible upon cessation of SMV Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

  26. Conclusions • Simeprevir + PEG/RBV is a newly approved HCV protease inhibitor for GT 1-infected patients • Total treatment duration (including patients with cirrhosis) • Treatment naive and prior relapsers: 24 weeks (12 weeks SMV/PEG/RBV + 12 weeks PEG/RBV) • Prior non-responder patients: 48 weeks (12 weeks SMV/PEG/RBV + 36 weeks PEG/RBV) • Rash, pruritus, nausea, myalgia and dyspnea only adverse reactions reported at a >3% higher frequency in SMV/PEG/RBV patients compared to PEG/RBV patients Simeprevir (OLYSIO™) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

  27. Sofosbuvir (SOF) APPROVED FOR GT 1, 2, 3 and 4(REGIMENS DIFFER BY GENOTYPE AND PATIENT TYPE)

  28. Sofosbuvir (SOF) (GS-7977) FDA approval: December 6, 2013 Nucleotide analog NS5B polymerase inhibitor One oral 400 mg tablet once daily with orwithout food Must be used in combination with RBV or in combination with PEG/RBV Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.

  29. Sofosbuvir (SOF) (GS-7977) Approved for treatment of GT 1, 2, 3 and 4 including patients with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 coinfection Treatment regimen and duration dependent on both viral genotype and patient population Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.

  30. SOF: Dosage and Administration *HCV mono-infected and HCV/HIV-1 co-infected patients**If the other agents used in combination with SOF are permanently discontinued, SOF should also be discontinued.Sofosbuvir(SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.

  31. SOF: Dosage and Administration SOF + RBV for 24 weeks can be considered as a therapeutic option for chronic hepatitis C patients with GT 1 infection who are ineligible to receive an interferon-based regimen SOF + RBV is recommended up to 48 weeks or until the time of liver transplantation, whichever occurs first, to prevent post-transplant HCV reinfection Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.

  32. Potential for Drug Interactions • SOF rapidly converted to predominant circulating metabolite GS-331007 (>90% of drug related material systemic exposure) • SOF is P-gp and breast cancer resistance protein (BCRP) substrate • Potent P-gp inducers in the intestine (rifampin, St. John’s wort) may decrease SOF concentrations and should not be used with SOF Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.

  33. Drugs Without Clinically SignificantInteractions with SOF • No adjustment required when co-administered with • Cyclosporine or tacrolimus • Methadone • Darunavir/ritonavir, efavirenz, emtricitabine, raltegravir, rilpivirine or tenofovirdisoproxilfumarate Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.

  34. SOF Concentrations In Specific Populations • Race has no clinically relevant effect on the exposure of SOF or the active metabolite. • No SOF dose adjustment is recommended for patients with mild, moderate and severe hepatic impairment. • Renal impairment • No dose adjustment is required for patients with mild to moderate renal impairment • Safety and efficacy has not been established in patients with severe renal impairment or end stage renal disease. Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.

  35. Sofosbuvir:GT 1 and GT 4 Data

  36. NEUTRINO: Study Design Week 0 12 24 Sofosbuvir/PEG/RBV, n=327 SVR12 • Open label • SOF+PEG+RBV for 12 weeks (no response-guided therapy) E. Lawitz et al, Abstract 1411. EASL, April 2013; Lawitz et al., N Engl J Med2013, 368: 1878-1887.

  37. SVR12 Rates in Treatment-Naive GT 1 and GT 4 Patients (NEUTRINO) 295/ 327 261/ 292 54/ 66 27/ 28 Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.

  38. SVR Rates in Selected Subgroups (NEUTRINO) 252/ 273 43/54 47/ 54 248/ 273 37/ 52 No Cirrhosis Cirrhosis Black Non-Black *Patients with GT 1, METAVIR F3/F4, IL28B non-CC, HCV RNA >800,000 IU/mL (factors traditionally associated with a lower response to interferon-based treatment.Sofosbuvir(SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.

  39. Sofosbuvir:GT 2 and GT 3 Data

  40. SVR12 Rates in GT 2 and GT 3 Treatment Naive Patients (FISSION) 110/ 176 102/ 183 171/ 256 69/ 73 52/ 67 162/243 Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.

  41. Impact of Cirrhosis on SVR12 Rates in Treatment-Naive Patients (FISSION) 13 38 10/ 12 59/ 61 44/ 54 13/ 38 8/ 13 11/ 37 89/ 145 99/ 139 Genotype 2 Genotype 3 Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.

  42. SOF + RBV for 12 Weeks: Impact of Cirrhosis on SVR12 Rates in Interferon-Intolerant, Ineligible or Unwilling Adults (POSITRON) 85/ 92 3/ 14 57/ 84 16/ 17 Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.

  43. FUSION: Impact of Cirrhosis and Duration on SVR Rates (Prior Relapsersor Nonresponders) 6/ 10 7/ 9 26/ 29 14/ 23 14/ 38 25/ 40 24/ 26 5/ 26 Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.

  44. VALENCE: Evaluating Impact of Duration on SVR With SOF/RBV (GT 2 and GT 3) Wk 0 Wk 12 Wk 24 SVR4, SVR12, SVR24 Placebo*(n = 85) Sofosbuvir + Ribavirin(n = 84)* Sofosbuvir + Ribavirin (n = 250) *Protocol amended to eliminate placebo arm. 12-wk arm predominantly GT2 patients (N = 73); 11 GT3 patients completed 12 wks SOF + RBV prior to amendment to extend treatment duration. ZeuzemS, et al. AASLD 2013. Abstract 1085.

  45. SVR12 Rates in GT 3 Patients: SOF + RBV for 24 weeks (VALENCE) 210/ 250 85/ 100 98/ 105 112/ 145 86/ 92 27/ 45 12/ 13 Sofosbuvir (SOVALDI™) Prescribing Information. Gilead Sciences, Inc. December, 2013.

  46. Group Discussion • Patient • GT 3-infected with cirrhosis who is prior nonresponder to PEG/RBV • Approved regimen: 24 weeks SOF + RBV • SVR rate ~60% • Would you treat? • Other options?

  47. LONESTAR-2: Study Design Wk 0 Wk 12 Wk24 Wk36 SOF + PEG/RBV GT 2/3(N=47) SVR12 • Study population • HCV GT 2 or 3 • Failed treatment with pegylated interferon and ribavirin • Approximately 50% with compensated cirrhosis • HIV and HBV coinfected patients excluded Lawitz E, et al. Abstract #LB-4, AASLD 2013

  48. SVR12 Rates in GT 3 Patients: SOF + PEG/RBV for 12 weeks (LONESTAR-2) 10/12 10/12 Lawitz E, et al. Abstract #LB-4, AASLD 2013

  49. Sofosbuvir:HCV/HIV-1 Coinfection Data

  50. PHOTON-1: Study Design Wk 0 Wk 12 Wk 24 Wk 36 • GT 1 TN SOF + RBV, n=114 • GT 2/3 TN SOF + RBV, n=68 SVR12 SVR12 SVR12 • GT 2/3 TE SOF + RBV, n=41 • Broad inclusion criteria • Cirrhosis permitted with no platelet cutoff • Hemoglobin: ≥12 mg/dL (males); ≥11 mg/dL (females) • Wide range of ART regimens allowed • Undetectable HIV RNA for >8 weeks on stable ART regimen • Baseline CD4 count • ART treated: CD4 T-cell count >200 cells/mm3 • ART untreated: CD4 T-cell count >500 cells/mm3 Sulkowski MS, et al. Abstract #212, AASLD 2013

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