1 supported by: jointly sponsored by the duke university school of medicine and the chronic liver...

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

2 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.

4 Generic NameTrade Name boceprevir telaprevir Victrelis Incivek 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 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 Protease inhibitors Faldaprevir Asunaprevir ABT-450 MK-5172 Sovaprevir ACH-2684 NS5A Inhibitors Daclatasvir Ledipasvir ABT-267 GS-5816 ACH-3102 PPI-668 GSK2336805 Samatasvir MK-8742

7 NS5B Nuc VX-135 IDX20963 ACH-3422 NS5B Non-nuc ABT-333 Deleobuvir BMS 791325 PPI-383 GS 9669 TMC 647055

8 APPROVED REGIMEN FOR GT 1

9 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 SMV 150mg/ PEG/RBV* PEG/RBV Post-Therapy Follow-Up Response Guided Treatment Placebo/ PEG/RBV Post-Therapy Follow-Up 0 12 24 48 72 Weeks *PEG/RBV=Peginterferon/Ribavirin Response Guided Therapy: if HCV RNA

11 419/ 521 132/ 264 191/ 254 62/ 131 138/ 165 36/ 83 49/ 84 23/ 44 228/ 267 70/ 133 *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 patients Simeprevir (OLYSIO) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

12 Simeprevir (OLYSIO) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013. 317/ 378 106/ 192 89/ 130 26/ 72

13 206/ 260 49/ 133 78/ 111 15/ 54 62/ 79 9/ 34 14/ 30 6/ 20 128/ 149 34/ 79 Simeprevir (OLYSIO) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

14 Simeprevir (OLYSIO) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013. 137/ 167 40/ 98 61/ 83 8/ 34

15 Simeprevir (OLYSIO) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013. 20/ 26 10/ 27 15/ 23 2/23 9/ 17 3/ 16 12 weeks SMV/PEG/RBV followed by 36 weeks of PEG/RBV vs 48 weeks Placebo/PEG/RBV

16 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 Triple Therapy SMV/PEG/RBV* Dual Therapy PEG/RBV Total Treatment Duration* Treatment-naive and prior relapse patients including those with cirrhosis First 12 weeksAdditional 12 weeks24 weeks Prior non-responder patients (including partial and null responders) including those with cirrhosis First 12 weeksAdditional 36 weeks48 weeks *Recommended duration of treatment if patient does not meet stopping rule. Simeprevir (OLYSIO) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

18 If PEG or RBV is discontinued for any reason, SMV must also be discontinued. HCV-RNAAction TW4,12 and 24: >25 IU/mL TW4: Discontinue SMV/PEG/RBV TW12: Discontinue PEG/RBV (SMV treatment complete at 12 weeks) TW24: Discontinue PEG/RBV TW=treatment week, SMV=simeprevir, PEG=peginterferon, RBV=ribavirin Simeprevir (OLYSIO) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

19 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 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 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 Simeprevir (OLYSIO) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013. 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

23 Preferred Term or Grouped Term SMV/PEG/RBV (First 12 Weeks) N=781 Placebo/PEG/RBV (First 12 Weeks) N=397 Rash (including photosensitivity)**28%20% Pruritus***22%15% Nausea22%18% Myalgia16%13% Dyspnea****12%8% *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 Laboratory ParameterWHO Toxicity Grade SMV/PEG/RBV (First 12 Weeks) N=781 Placebo/PEG/RBV (First 12 Weeks) N=397 Alkaline Phosphatase* Grade 1>1.25 to 2.50 to 3% higher frequency in SMV/PEG/RBV patients compared to PEG/RBV patients Simeprevir (OLYSIO) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

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

28 FDA approval: December 6, 2013 Nucleotide analog NS5B polymerase inhibitor One oral 400 mg tablet once daily with or without food Must be used in combination with RBV or in combination with PEG/RBV Sofosbuvir (SOVALDI) Prescribing Information. Gilead Sciences, Inc. December, 2013.

29 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 Patient Population*Treatment**Treatment Duration GT 1 or 4SOF + PEG/RBV12 weeks GT 2SOF + RBV12 weeks GT 3SOF + RBV24 weeks *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 + 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 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. Johns wort) may decrease SOF concentrations and should not be used with SOF Sofosbuvir (SOVALDI) Prescribing Information. Gilead Sciences, Inc. December, 2013.

33 Sofosbuvir (SOVALDI) Prescribing Information. Gilead Sciences, Inc. December, 2013. No adjustment required when co-administered with Cyclosporine or tacrolimus Methadone Darunavir/ritonavir, efavirenz, emtricitabine, raltegravir, rilpivirine or tenofovir disoproxil fumarate

34 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.

36 SVR12Sofosbuvir/PEG/RBV, n=327 Week 0 12 24 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 Med 2013, 368: 1878-1887.

37 295/ 327 261/ 292 54/ 66 27/ 28 Sofosbuvir (SOVALDI) Prescribing Information. Gilead Sciences, Inc. December, 2013.

38 *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. Black Non-Black No Cirrhosis Cirrhosis 252/ 273 47/ 54 248/ 273 37/ 52 43/ 54

40 69/ 73 52/ 67 102/ 183 110/ 176 171/ 256 162/ 243 Sofosbuvir (SOVALDI) Prescribing Information. Gilead Sciences, Inc. December, 2013.

41 59/ 61 13 38 Genotype 2 44/ 54 10/ 12 8/ 13 89/ 145 99/ 139 13/ 38 11/ 37 Genotype 3 Sofosbuvir (SOVALDI) Prescribing Information. Gilead Sciences, Inc. December, 2013.

42 Sofosbuvir (SOVALDI) Prescribing Information. Gilead Sciences, Inc. December, 2013. 85/ 92 16/ 17 57/ 84 3/ 14

43 Sofosbuvir (SOVALDI) Prescribing Information. Gilead Sciences, Inc. December, 2013. 6/ 10 5/ 26 26/ 29 7/ 9 24/ 26 14/ 38 14/ 23 25/ 40

44 Wk 0Wk 24SVR4, SVR12, SVR24 Placebo* (n = 85) Sofosbuvir + Ribavirin (n = 250) Sofosbuvir + Ribavirin (n = 84)* Wk 12 *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. Zeuzem S, et al. AASLD 2013. Abstract 1085.

45 Sofosbuvir (SOVALDI) Prescribing Information. Gilead Sciences, Inc. December, 2013. 210/ 250 98/ 105 86/ 92 12/ 13 112/ 145 85/ 100 27/ 45

46 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 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 SOF + PEG/RBV SVR12 GT 2/3 (N=47) Wk 0Wk 12 Wk 24 Wk 36 Lawitz E, et al. Abstract #LB-4, AASLD 2013

48 10/12 Lawitz E, et al. Abstract #LB-4, AASLD 2013

50 Wk 0Wk 12Wk 24Wk 36 SOF + RBV, n=114 GT 1 TN SVR12 SOF + RBV, n=41 GT 2/3 TE SVR12 SOF + RBV, n=68 GT 2/3 TN SVR12 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

51 87/1 14 23/ 26 12/ 13 *GT 2 patients treated for 24 weeks and GT 3 patients treated for 12 weeks were not included Sofosbuvir (SOVALDI) Prescribing Information. Gilead Sciences, Inc. December, 2013. SVR12 (%)

52 Patient Population*Treatment** Treatment Duration GT 1 or 4SOF + PEG/RBV12 weeks GT 2SOF + RBV12 weeks GT 3SOF + RBV24 weeks *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.

53 INVESTIGATIONAL COMBO FOR GT 1

54 Simeprevir and sofosbuvir are both approved by the US FDA GT 1: Approved labeling is for use of either agent with PEG/RBV backbone Neither package insert/label contains information regarding using the 2 newly approved agents concomitantly COSMOS is a Phase IIa, randomized, open-label study investigating simeprevir + sofosbuvir +/- ribavirin

55 SMV + SOF + RBVPost-treatment follow-up 0412243648 Arm 1 Week SMV + SOF SMV + SOF + RBV SMV + SOF Post-treatment follow-up Arm 2 Arm 3 Arm 4 Enrollment ratio 2:1:2:1 Jacobson IM, et al. Abstract #LB-3, AASLD 2013 Cohort 1: Prior null responders (METAVIR F0-F2) Final SVR12 for all arms Cohort 2: Treatment-nave and prior null responders (METAVIR F3-F4) Interim SVR4 for Arms 3 and 4

56 Jacobson IM, et al. Abstract #LB-3, AASLD 2013 14/15 19/24 13/14 26/27

57 Jacobson IM, et al. Abstract #LB-3, AASLD 2013 7/712/127/714/15 26/27 14/14

58 24 weeks12 weeks Adverse Event, % SMV + SOF + RBV (n=54) SMV + SOF (n=31) SMV + SOF + RBV (n=54) SMV + SOF (n=28) Fatigue37%32.3%24.1%25% Headache20.4%22.6%16.7%21.4% Nausea11.1%12.9%14.8%21.4% Insomnia16.7%6.5%9.3%14.3% Rash13.0%9.7%14.8%3.6% Pruritus16.7%3.2%9.3%10.7% Photosensitivity/sunburn a 3.7%3.2%5.6%7.1% Anemia20.4%3.2%11.1%0 a No sun-protective measures were in place for this trial RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir Jacobson IM, et al. Abstract #LB-3, AASLD 2013

59 Treatment with SMV + SOF RBV results in: High SVR12 rates in HCV GT 1 null responder patients High SVR4 rates in naive and null responder patients with METAVIR F3-F4 Addition of RBV to SMV + SOF may not be needed to achieve high rates of SVR in this patient population 12 weeks of treatment may confer similar SVR rates compared with 24 weeks of treatment SMV + SOF RBV was generally well tolerated Jacobson IM, et al. Abstract #LB-3, AASLD 2013

60 Do you anticipate using simeprevir + sofosbuvir in combination based on Phase 2 data even though both have only been approved for use with PEG/RBV backbone? If so, in which patient populations? Would you include RBV? Safety concerns? Concerns regarding patient reimbursement?

61 What options are currently available for GT 1 patients who previously failed boceprevir or telaprevir containing regimens due to resistance? Simeprevir/PEG/RBV for 24 weeks if relapser? 48 weeks? Sofosbuvir/PEG/RBV for 12 weeks? What may be on the horizon?

63 Patients GT 1, non-cirrhotic Prior nonresponse, relapse, or breakthrough during treatment with PEG/RBV+TVR or BOC Patients who discontinued TVR or BOC due to an adverse event were excluded Week 24 Prior TVR/BOC Failures, GT 1a/1b (N = 41) n = 21 Follow-up n = 20 DCV once daily + SOF once daily DCV once daily + SOF once daily + RBV Follow-up SVR 4 SVR 12 M.S. Sulkowski et al, Abstract 1417. EASL, April 2013

64 *1 patient missing at follow up week 12: HCV RNA was undetectable at follow up week 4 and follow up week 24 M.S. Sulkowski et al, Abstract 1417. EASL, April 2013 21/41 patients have reached follow up week 24; all have achieved SVR24 EOT Week 2SVR4 N = Week 4 21 20 SVR12 21 20

66 Randomized 1:1 SOF/LDV SOF/LDV + RBV SOF/LDV Treatment Naive (No cirrhosis) PI Failures (50% cirrhosis) SOF/LDV + RBV COHORT 1 (n=60) COHORT 2 (n=40) Wk 0 Wk 8Wk 12 Randomized 1:1:1 Wk 24Wk 20 SVR12 Single center study of GT 1 patients Broad inclusion criteria No upper limit to age or BMI Platelets 50,000/mm3 Lawitz E, et al. Abstract #215, AASLD 2013

67 PI Failures n=40 Prior treatment with boceprevir22/40 (55) Prior treatment with telaprevir18/40 (45) Cirrhosis, n (%)22/40 (55) Mean platelet count, x 10 3 /L107 Mean albumin, g/dL3.8 Lawitz E, et al. Abstract #215, AASLD 2013 All patients were required to have experienced virologic failure Patients who stopped prior therapy due to an AE were excluded

68 Treatment Nave (No Cirrhosis) PI Failures (50% Cirrhosis) ++ 812 8 19/2021/2118/19 21/21 RBV Duration (week) Lawitz E, et al. Abstract #215, AASLD 2013

69 Based on Phase 2 data, would you retreat BOC or TVR failures with SMV+SOF? If so, would there be certain patient characteristics that would affect your decision? Do you believe RBV is necessary?

70 209/ 214 Gilead press release, December 18, 2013. GT 1 Treatment- Experienced (20% cirrhotics) GT 1 Treatment- Nave (No cirrhotics) GT 1 Treatment- Nave (15.7% cirrhotics) -RBV +RBV 12 weeks 24 weeks 8 weeks 211/ 217 102/ 109 107/ 111 108/ 109 110/ 111 202/ 215 201/ 216 206/ 216

72 DCV 30 mg BID + ASV 200 mg BID + BMS-791325 75 mg BID DCV 30 mg BID + ASV 200 mg BID + BMS-791325 150 mg BID 12-week follow-up Additional follow-up to SVR 48 0 1224 N = 80 N = 86 Week Primary endpoint: SVR 12 Treatment-naive patients stratified by GT 1a/1b and presence of biopsy-confirmed cirrhosis (82% GT1a and 9% cirrhotics) Everson GT, et al. Abstract #LB-1, AASLD 2013

73 *Modified Intent to Treat (mITT): missing, breakthrough, relapse or addition of PEG/RBV=failure **Observed: breakthrough, relapse, or addition of PEG/RBV=failure Everson GT, et al. Abstract #LB-1, AASLD 2013 71/ 77 77/ 84

75 Phase 3, global, multi-center, randomized, double-blind, placebo-controlled studies 12 week treatment 3D regimen Fixed-dose combination of ABT-450/ritonavir co-formulated with ABT-267: Once daily ABT-333: Twice daily RBV: Twice daily AbbVie press releases, November 18, 2013 and December 10, 2013.

76 AbbVie press releases, November 18, 2013 and December 10, 2013. SAPPHIRE-I N=631 GT 1, non-cirrhotic Treatment-naive SAPPHIRE-II N=394 GT 1, non-cirrhotic Prior PEG/RBV treatment failures (49% prior null responders)

77 TN=treatment-naive; TE=treatment-experienced AbbVie press releases, November 18, 2013 and December 10, 2013. 286/ 297 166/ 173 119/ 123 455/ 473 307/ 322 148/ 151 TNTETNTETNTE OverallGT1aGT1b

78 Most commonly reported adverse events in both the 3D and placebo arms Headache Fatigue Nausea AbbVie press releases, November 18, 2013 and December 10, 2013.

80 Telaprevir and boceprevir only approved for GT 1 SOF approved for GT 1, 2, 3 and 4 Interferon and ribavirin backbone required GT 1 and GT 4: IFN/RBV still required GT 2 and GT 3: IFN free (SOF+RBV)

81 Twice per day dosing (BID) for telaprevir and three times per day (TID) dosing for boceprevir SOF and SMV both once daily dosing Response guided therapy (both) and lead-in (boceprevir) complicated SOF and SMV do not require response guided therapy or lead-in

82 24-48 week treatment GT 1: SOF+PEG/RBV for 12 weeks GT 1: SMV+PEG/RBV for 24-48 weeks GT 2: SOF+RBV for 12 weeks GT 3: SOF+RBV for 24 weeks GT 4: SOF+PEG/RBV for 12 weeks

83 Limited efficacy in difficult to cure patients (e.g., patients with cirrhosis, prior null responders, African-Americans) GT 1: SMV and SOF demonstrate improved efficacy in difficult to treat populations GT 2: SOF+RBV strong efficacy GT 3: SOF+RBV less efficacious in null responders with cirrhosis

84 Hematologic (both) and rash/dermatological (telaprevir) adverse events No hematologic signal with SMV or SOF monotherapy GT 1: SMV and SOF both require PEG/RBV backbone and hematologic adverse events comparable to PEG/RBV control arm GT 2 and 3: Interferon free regimens have no hematologic signal beyond anemia associated with RBV

85 Drug-drug interactions SMV has DDIs with many of the same drug classes as boceprevir and telaprevir SMV use with cyclosporine or tacrolimus does not require dose adjustments SOF does not have any significant drug:drug interactions

1 supported by: jointly sponsored by the duke university school of medicine and the chronic liver...

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