Updates in the Management of HCV: What Clinicians Who Care for Patients With HCV Need to Know Today

Updates in the Management of HCV: What Clinicians Who Care for Patients With HCV Need to Know Today The treatment paradigm for hepatitis C virus (HCV) is changing very rapidly. In the short time since the publication of our CME/CE-certified activity, Exploring Emerging Treatment Options in the Context of Holistic HCV Treat-Or-Defer Decisions, the Food and Drug Administration (FDA) antiviral drug advisory committees reviewed data on two emerging directacting antiviral agents for the treatment of HCV; additionally, the American Association for the Study of Liver Diseases (AASLD) held its annual conference, at which a substantial volume of new data was presented. Because new therapies have recently become available and others may become available in the near future, much of these recently reported data are immediately relevant. In this focused update, we explore recently reported data that are anticipated to influence HCV treatment decisions in 2014. DC, data were presented from the phase 3 PROMISE trial, which evaluated simeprevir in relapsers.3 Key characteristics of this trial include: N = 393 patients 1 50 mg simeprevir once daily with PegIFN/RBV backbone Treatment duration: 24 or 48 weeks based on response-guided therapy Included treatment-experienced patients and those with cirrhosis Rates of sustained virologic response at 12 weeks post-treatment (SVR12) stratified by level of fibrosis are shown in Figure 1. Simeprevir was well tolerated, and discontinuation rates due to adverse events were low (3%). As previously seen with simeprevir, transient FIGURE 1. PROMISE: SVR12 by Level of Fibrosis Patients With HCV Genotype 1 Simeprevir Simeprevir is an NS3/4a protease inhibitor that has been studied in several large trials. In our CME/ CE-certified activity, we discussed the results of QUEST 1 and QUEST 2, which evaluated simeprevir in only treatment-naïve patients. At the November 2013 annual meeting of the AASLD in Washington, F0-F2 41 82 21 F3-F4 In October 2013, the FDA antiviral advisory panel met on two consecutive days to review the new drug applications for two direct-acting antiviral agents: simeprevir and sofosbuvir. Both agents have now been approved for patients with genotype 1 in combination with peginterferon alfa (PegIFN) and ribavirin (RBV).1,2 Sofosbuvir was also approved for use in genotypes 2 and 3 (discussed in more detail below) and genotype 4 (not included in this focused update). PegIFN/RBV SMV/PegIFN/RBV 73 0 20 40 60 80 100 Derived from Forns X, Lawitz E, Zeuzem S, et al. Simeprevir (TMC435) with peg-interferon α-2a/ribavirin for treatment of chronic HCV genotype 1 infection in patients who relapsed after previous interferon-based therapy: efficacy and safety in patient sub-populations in the PROMISE phase III trial. 64th Annual Meeting of the American Association for the Study of Liver Diseases, November 1-5, 2013, Washington, DC; abstract 1092; US Food and Drug Administration. FDA Antiviral Drugs Advisory Committee meeting, October 24, 2013. Background package for NDA 205123, Simeprevir (TMC435). www.fda.gov/downloads/advisorycommittees/ CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/ UCM371623.pdf. Accessed January 10, 2014. Jointly presented by the Johns Hopkins University School of Medicine and Med-IQ PAGE 1 OF 6

increases in bilirubin were observed, and some patients experienced increased photosensitivity. 3,4 Recently, it has become clear that a critical factor in patient response to simeprevir is the presence of the Q80K polymorphism at baseline; presence of this mutation translates to reduced efficacy of simeprevir in combination with PegIFN/RBV. Results from a pooled analysis of QUEST 1 and 2 reported at the November 2013 AASLD meeting suggest that the Q80K polymorphism appears to be much more prevalent in patients with genotype 1a than in those with genotype 1b. 4 In addition, a regional analysis showed geographic variability in the presence of this polymorphism, with a higher frequency among genotype 1a patients in North America (about 48%) than in Europe (19.4%) or South America (9.1%). 5 Based on the high prevalence of the Q80K polymorphism in North American patients with HCV genotype 1a infection, the prescribing label for simeprevir includes a strong recommendation for screening patients for the presence of the NS3 Q80K polymorphism at baseline. Patients with genotype 1a who are Q80K positive should not be treated with PegIFN/ RBV and simeprevir; other regimens should be considered. 1 Simeprevir/Sofosbuvir The presentation of the first data set from the COSMOS study was a much-anticipated highlight of the 2013 AASLD annual meeting. This trial combines simeprevir with sofosbuvir (the NS5B polymerase inhibitor) in genotype 1 patients for 12 or 24 weeks. Key tenets of this trial design include 6 : Two cohorts: Cohort 1: n = 80; null responders to PegIFN/RBV with METAVIR fibrosis stage 0 to 2 Cohort 2: n = 87; treatment-naïve patients and null responders with METAVIR fibrosis stage 3 or 4 (cirrhosis) Sofosbuvir 400 mg PO QD + simeprevir 150 mg PO QD with or without RBV Treatment duration: 12 or 24 weeks In the cohort 1 data presented in Washington, DC, the SVR12 rates were greater than 95% in prior null responders treated for 12 or 24 weeks; the addition of RBV did not affect the SVR12 rate (Figure 2). Additionally, the Q80K polymorphism was detected in 50% of patients with genotype 1a in cohort 1 and appeared to influence the SVR12 rate. 6,7 No virologic failures were observed in patients with HCV genotype 1a without the Q80K polymorphism or in patients with genotype 1b. However, 3 patients with genotype FIGURE 2. COSMOS: SVR12 24 Weeks 12 Weeks 79.2 n = 24 93.3 n = 14 96.3 n = 27 92.9 n = 14 0 20 40 60 80 100 RBV No RBV Derived from Jacobson IM, Ghalib RH, Rodriguez-Torres M, et al. SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naïve and prior null responder patients: the COSMOS study. 64th Annual Meeting of the American Association for the Study of Liver Diseases, November 1-5, 2013, Washington, DC; abstract LB3; Smith M. HCV combo promising in difficult patients. November 5, 2013. www.medpagetoday.com/ MeetingCoverage/AASLD/42717. Accessed January 7, 2014. 1a and the Q80K polymorphism experienced viral relapse; still, the SVR12 rate among this subgroup was 89%, and most patients with the Q80K polymorphism achieved SVR. 6,7 Early data from cohort 2 (treatmentnaïve patients and null responders with METAVIR fibrosis stage 3 or 4) also show encouraging results with SVR4 rates between 93.3% and 100%. Sofosbuvir At the AASLD meeting, researchers presented exciting data for the traditionally hard-to-treat HCV population of patients who are coinfected with HIV. The genotype 1 results from the PHOTON-1 trial evaluating 24 weeks of sofosbuvir with RBV in patients naïve to HCV treatment showed encouraging results; SVR12 rates were 76% in this group (Figure 3). 8,9 FIGURE 3. PHOTON-1: SVR12 in HIV-Coinfected Patients Receiving Sofosbuvir/RBV Genotype 1 (24 Weeks) Genotype 2 (12 Weeks) Genotype 3 (12 Weeks) 0 10 20 30 40 50 60 70 80 90 100 Derived from Gilead press release. Gilead announces phase 3 results for an all-oral, sofosbuvir-based regimen for the treatment of hepatitis C in patients co-infected with HIV. November 2, 2013. www.gilead.com/news/press-releases/2013/11/ gilead-announces-phase-3-results-for-an-alloral-sofosbuvirbased-regimen-for-thetreatment-of-hepatitis-c-in-patients-coinfected-with-hiv. Accessed January 7, 2014. 67 76 88 PAGE 2 OF 6

Patients With Genotypes 2 and 3 Sofosbuvir/PegIFN/RBV Although genotypes 2 and 3 have often been studied as a single group, it is becoming clear that efficacy rates vary between these genotypes. Results from the LONESTAR-2 study were reported at the AASLD meeting (Figure 4); this trial evaluated 12 weeks of sofosbuvir/pegifn/rbv in patients with genotype 2 or 3 with and without cirrhosis who had failed to respond to prior treatment with PegIFN/RBV. 10 Important considerations when evaluating these data include: N = 47 Sofosbuvir with PegIFN/RBV backbone Treatment duration: 24 weeks All treatment-experienced patients, about 50% with compensated cirrhosis FIGURE 4. LONESTAR-2: SVR12 by Genotype and Cirrhosis Cirrhosis No Cirrhosis Genotype 3 Genotype 2 0 20 40 60 80 100 Derived from Gilead press release. Gilead announces new sustained viral response data for sofosbuvir-based regimens in genotype 3-infected hepatitis C patients. November 2, 2013. www.gilead.com/news/pressreleases/2013/11/gilead-announces-new-sustained-viral-response-datafor-sofosbuvirbased-regimens-in-genotype-3infected-hepatitis-c-patients. Accessed January 7, 2014; Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368(20):1867-1877. Among genotype 3 patients, SVR12 rates did not differ between those with or without cirrhosis, as shown in Figure 4. 10 In addition, the SVR12 rates for sofosbuvir/ PegIFN/RBV are higher than those reported with the 16-week course of sofosbuvir/rbv. 10,11 Sofosbuvir/RBV Without PegIFN Results from the VALENCE trial, which evaluated sofosbuvir/rbv without PegIFN, also show some important outcomes. Key characteristics of this study include 12,13 : Genotype 2, n = 73; genotype 3, n = 250 Sofosbuvir with RBV 83.3 n = 12 83.3 n = 12 92.9 n = 14 100 n = 9 Treatment duration: 12 weeks (genotype 2) or 24 weeks (genotype 3) Among genotype 3 patients, the results of this trial showed high rates of SVR12 in treatment-naïve patients regardless of the presence of cirrhosis, as well as high rates of SVR12 in treatment-experienced patients without cirrhosis (Figure 5). However, the SVR12 rate was lower for treatment-experienced patients with cirrhosis despite 24 weeks of sofosbuvir plus RBV. 12,13 FIGURE 5. VALENCE: Results of Sofosbuvir/RBV for 24 Weeks Among Genotype 3 Patients Cirrhosis No Cirrhosis Treatment Naïve Treatment Experienced 0 20 40 60 80 100 Derived from Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir + ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial. 64th Annual Meeting of the American Association for the Study of Liver Diseases, November 1-5, 2013, Washington, DC; abstract 1085; US Food and Drug Administration. FDA Introductory Remarks: Sofosbuvir. NDA 204671. www.fda.gov/downloads/advisorycommittees/ CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/ UCM375285.pdf. Accessed January 10, 2014. A Pooled Analysis To evaluate the question about duration of treatment for patients with genotype 3, the FDA performed a pooled analysis of the registration trials FISSION, POSITRON, FUSION, and VALENCE, as shown in Figure 6. 13 Sofosbuvir was approved for use in combination with RBV for patients with genotype 2 (12 weeks) or genotype 3 (24 weeks) by the FDA in December of 2013. 2 A Glimpse Into the Future 60 n = 45 92 n = 13 93 n = 92 83 n = 100 Another protease inhibitor, faldaprevir, has been studied in several phase 3 clinical trials. The earlier reported phase 3 studies STARTVerso1 and STARTVerso2 were discussed in our CME/CE-certified activity, Exploring Emerging Treatment Options in the Context of Holistic HCV Treat-Or-Defer Decisions. New information from these data sets, which were reported at the 2013 AASLD annual meeting, showed PAGE 3 OF 6

FIGURE 6. FISSION, POSITRON, FUSION, and VALENCE: FDA Pooled Analysis for Genotype 3 Patients Treated With Sofosbuvir/RBV 100 93 90 80 77 SVR12 Relapse 70 60 50 40 30 56 40 30 66 62 38 20 20 10 5 0 12 Weeks 24 Weeks Treatment Naïve 12 Weeks 16 Weeks 24 Weeks Treatment Experienced Derived from US Food and Drug Administration. FDA Introductory Remarks: Sofosbuvir. NDA 204671. www.fda.gov/downloads/advisorycommittees/ CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM375285.pdf. Accessed January 10, 2014. some geographic variation in response to faldaprevir. Jensen and colleagues showed regional variation in SVR12 rates, with higher cure rates reported in trials completed in Europe and Asia than in those completed in North America. 14 In STARTVerso3, results of which were also reported at AASLD, faldaprevir plus PegIFN/ RBV in treatment-experienced patients showed SVR rates of 70% for relapsed patients but 33% for null responders. 15 Faldaprevir has also been studied with a nonnucleoside polymerase inhibitor (deleobuvir) in a phase 2 trial, which showed a lack of response in genotype 1a patients (SVR12 = 17%) but encouraging response in genotype 1b patients (SVR12 = 95%). 16 Phase 3 trials in patients with genotype 1b are underway based on these data. In addition, researchers are evaluating the impact of the addition of an NS5A inhibitor (PPI-668) to faldaprevir and deleobuvir. Very early results presented at AASLD show encouraging changes in viral kinetics, and more data are expected in the future. 17 STARTVerso4, which is being conducted simultaneously with STARTVerso3, is evaluating faldaprevir/pegifn in patients coinfected with HIV; thus far, this trial has shown overall encouraging results in the coinfected patients. 18 Sofosbuvir plus an NS5A inhibitor is being studied in fixed-dose combinations in several trials. Phase 2 data from the ELECTRON trial of sofosbuvir + ledipasvir with/without RBV or GS-9669 (a nonnucleoside polymerase inhibitor) were reported at the 2013 AASLD meeting. 19 Among genotype 1 treatment-experienced patients in this study, SVR12 rates increased from 70% with sofosbuvir/ ledipasvir to 100% with the addition of either RBV or GS-9669. 19 Another noteworthy trial, the LONESTAR trial, evaluated sofosbuvir/ledipasvir with/without RBV in patients who were treatment naïve or had virologic failure following previous protease inhibitor therapy (boceprevir or telaprevir) for 8 or 12 weeks. 20 This single-center study involved 100 patients in two cohorts. In cohort A, 60 non-cirrhotic treatmentnaïve patients were randomized 1:1:1 to sofosbuvir plus ledipasvir (8 weeks), sofosbuvir plus ledipasvir and RBV (8 weeks), or sofosbuvir plus ledipasvir and RBV (12 weeks). In cohort B, 40 patients with virologic failure following boceprevir or telaprevir were randomized 1:1 to sofosbuvir plus ledipasvir (12 weeks) or sofosbuvir plus ledipasvir and RBV (12 weeks); in this cohort, 55% of patients had compensated cirrhosis. In cohort A, the SVR12 rate for patients PAGE 4 OF 6

treated with sofosbuvir plus ledipasvir (8 weeks) was 95% without the addition of RBV and 100% in patients with the addition of RBV. Among those in cohort A (treatment naïve) who received 12 weeks of sofosbuvir plus ledipasvir and RBV, the SVR12 rate was 95%. Within the previously treated cohort (cohort B), the SVR12 rate was 95% among patients treated with sofosbuvir plus ledipasvir for 12 weeks and 100% among those who received sofosbuvir plus ledipasvir and RBV for 12 weeks. 20 In Exploring Emerging Treatment Options in the Context of Holistic HCV Treat-Or-Defer Decisions, we discussed the AVIATOR trial, which suggested that regimens for patients with genotype 1b might show similar results with a more simplified regimen. At the 2013 AASLD meeting, Lawitz and colleagues presented the data from PEARL-1, which evaluated ABT-450/ritonavir/ABT-267 in treatment-naïve and null- responder patients with genotype 1b. These results showed high SVR rates (90% to 95.2%). 21,22 Finally, a new combination was presented for the first time at the 2013 AASLD meeting: a secondgeneration protease inhibitor with an NS5A inhibitor (MK-5172 + MK-8742) with and without RBV. Data from this study (C-WORTHY) showed SVR12 rates between 89% and 100%, and more studies are planned. 23 These are just a few of the exciting developments in the field of HCV management. Recently there have also been important studies demonstrating the impact of many other developments, including expanding screening and the use of noninvasive strategies to evaluate fibrosis. Although these data are beyond the scope of this discussion, it is clear that clinicians caring for patients with HCV are now better armed and can expect even more advances in the future. PAGE 5 OF 6

References 1. OLYSIO [package insert]. Titusville, NJ: Janssen Products, LP.; 2013. 2. SOVALDI [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2013. 3. Forns X, Lawitz E, Zeuzem S, et al. Simeprevir (TMC435) with peginterferon α-2a/ribavirin for treatment of chronic HCV genotype 1 infection in patients who relapsed after previous interferon-based therapy: efficacy and safety in patient sub-populations in the PROMISE phase III trial. 64th Annual Meeting of the American Washington, DC; abstract 1092. 4. Jacobson IM, Dore GF, Foster GR, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in treatment-naïve patients: efficacy in difficult-to-treat patient sub-populations in the QUEST 1 and 2 phase III trials. 64th Annual Meeting of the American Association for the Study of Liver Diseases, November 1-5, 2013, Washington, DC; abstract 1122. 5. US Food and Drug Administration. Antiviral Drugs Advisory Committee Meeting Briefing Document. Simeprevir (TMC435). Treatment of Patients with Chronic Hepatitis C. NDA 205123. www.fda.gov/downloads/ AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ AntiviralDrugsAdvisoryCommittee/UCM371624.pdf. Accessed January 10, 2014. 6. Jacobson IM, Ghalib RH, Rodriguez-Torres M, et al. SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS- 7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naïve and prior null responder patients: the COSMOS study. 64th Annual Meeting of the American Association for the Study of Liver Diseases, November 1-5, 2013, Washington, DC; abstract LB3. 7. Smith M. HCV combo promising in difficult patients. November 5, 2013. www.medpagetoday.com/meetingcoverage/aasld/42717. Accessed January 7, 2014. 8. Sulkowski MS, Rodriguez-Torres M, Lalezari JP, et al. All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotype 1, 2, and 3 infection in patients co-infected with HIV (PHOTON-1). 64th Annual Meeting of the American Association for the Study of Liver Diseases, November 1-5, 2013, Washington, DC; abstract 212. 9. Gilead press release. Gilead announces phase 3 results for an all-oral, sofosbuvir-based regimen for the treatment of hepatitis C in patients co-infected with HIV. November 2, 2013. www.gilead. com/news/press-releases/2013/11/gilead-announces-phase-3- results-for-an-alloral-sofosbuvirbased-regimen-for-the-treatmentof-hepatitis-c-in-patients-coinfected-with-hiv. Accessed January 7, 2014. 10. Gilead press release. Gilead announces new sustained viral response data for sofosbuvir-based regimens in genotype 3-infected hepatitis C patients. November 2, 2013. www.gilead. com/news/press-releases/2013/11/gilead-announces-newsustained-viral-response-data-for-sofosbuvirbased-regimens-ingenotype-3infected-hepatitis-c-patients. Accessed January 7, 2014. 11. Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368(20):1867-1877. 12. Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir + ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial. 64th Annual Meeting of the American Association for the Study of Liver Diseases, November 1-5, 2013, Washington, DC; abstract 1085. 13. US Food and Drug Administration. FDA Introductory Remarks: Sofosbuvir. NDA 204671. www.fda.gov/downloads/ AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ AntiviralDrugsAdvisoryCommittee/UCM375285.pdf. Accessed January 10, 2014. 14. Jensen DM, Asselah T, Dieterich DT, et al. A pooled analysis of two randomized, double-blind placebo-controlled Phase III trials (STARTVerso 1&2) of faldaprevir plus pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic hepatitis C genotype 1 infection. 64th Annual Meeting of the American Washington, DC; abstract 1088. 15. Jacobson IM, Ferenci P, Foster GR, et al. STARTVerso3: a randomized, double-blind, placebo-controlled Phase III trial of faldaprevir in combination with pegylated interferon alfa-2a and ribavirin in treatment-experienced patients with chronic hepatitis C genotype-1 infection. 64th Annual Meeting of the American Washington, DC; abstract 1100. 16. Dufour J, Soriano V, Buynak R, et al. Interferon-free treatment with faldaprevir, deleobuvir (bi 207127) and ribavirin in SOUND-C3: 95% SVR12 in HCV-GT1b. 64th Annual Meeting of the American Washington, DC; abstract 1102. 17. Lalezari JP, Holland L, Glutzer E, et al. Rapid and consistent virologic responses in a phase 2 trial of a new all-oral combination of faldaprevir, deleobuvir, and PPI-668, with and without ribavirin, in patients with HCV genotype-1a infection. 64th Annual Meeting of the American Association for the Study of Liver Diseases, November 1-5, 2013, Washington, DC; abstract LB-20. 18. Rockstroh JK, Nelson M, Soriano V, et al. STARTVerso 4 Phase III trial of faldaprevir plus peg interferon alfa-2a and ribavirin (PR) in patients with HIV and HCV genotype 1 coinfection: end of treatment response. 64th Annual Meeting of the American Washington, DC; abstract 1099. 19. Gane EJ, Stedman CA, Hyland RH, et al. Once daily sofosbuvir/ ledipasvir fixed dose combination with or without ribavirin: the ELECTRON trial. 64th Annual Meeting of the American Association for the Study of Liver Diseases, November 1-5, 2013, Washington, DC; abstract 73. 20. Lawitz E, Poordad F, Pang PS, et al. Sofosbuvir and ledipasvir fixeddose combination with and without ribavirin in treatment-naïve and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomized, phase 2 trial. Lancet. 2013;Nov 1. [epub ahead of print]. 21. Levin J. Conference reports for NATAP: Interferon- and ribavirinfree regimen of ABT-450/r + ABT-267 in HCV genotype 1b-infected treatment-naïve patients and prior null responders. www.natap. org/2013/aasld/aasld_11.htm. Accessed January 10, 2014. 22. Lawitz E, Hezode C, Varunok P, et al. Interferon- and ribavirin-free regimen of ABT-450/r + ABT-267 in HCV genotype 1b-infected treatment-naïve patients and prior null responders. 64th Annual Meeting of the American Association for the Study of Liver Diseases, November 1-5, 2013, Washington, DC; abstract 75. 23. Lawitz E, Vierling JM, Murillo A, et al. High efficacy and safety of the all-oral combination regimen, MK-5172/MK-8742 +/- RBV for 12 weeks in HCV genotype 1 infected patients: the C-WORTHY study. 64th Annual Meeting of the American Association for the Study of Liver Diseases, November 1-5, 2013, Washington, DC; abstract 76. This activity is supported by educational grants from AbbVie Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Therapeutics, and Merck & Co., Inc. 2014 The Johns Hopkins University School of Medicine and Med-IQ. All rights reserved. PAGE 6 OF 6