Update on Real-World Experience With A RESOURCE FOR PAYERS This information is intended for payers only. The HCV-TARGET and TRIO studies were supported by Gilead Sciences, Inc. Real-world experience data were derived from patient medical records and specialty pharmacy databases. Such data are retrospective and observational in nature, and are not based on controlled clinical studies. Results from these cohorts may differ from results seen in the membership of a particular payer. INDICATIONS AND USAGE Harvoni is indicated with or without ribavirin for the treatment of patients with chronic hepatitis C virus (HCV) genotype 1, 4, 5, or 6 infection.
1 TABLET ONCE A DAY Pill not actual size Ledipasvir (9 mg) An HCV NS5A inhibitor Sofosbuvir (4 mg) A nucleotide analog inhibitor of HCV NS5B polymerase is indicated with or without ribavirin for the treatment of patients with chronic hepatitis C virus (HCV) genotype 1, 4, 5, or 6 infection. Contraindications If is used in combination with ribavirin (RBV), all contraindications, warnings and precautions, in particular pregnancy avoidance, and adverse reactions to RBV also apply. Refer to RBV prescribing information. 1
RECOMMENDED TREATMENT DURATION FOR HCV GT 1, 4, 5, OR 6 PATIENTS, INCLUDING THOSE WITH HCV/HIV-1 COINFECTION 1 1 TABLET DAILY 8 WEEKS Can be considered in treatment-naïve (TN) GT 1 patients without cirrhosis and with pre-treatment HCV RNA <6 million IU/mL 12 WEEKS TN GT 1 patients without cirrhosis or with compensated cirrhosis (Child-Pugh A) Treatment-experienced (TE) a GT 1 patients without cirrhosis TN or TE a GT 4, GT 5 or GT 6 patients without cirrhosis or with compensated cirrhosis (Child-Pugh A) NO FOOD REQUIREMENT + RBV 12 WEEKS TN and TE a GT 1 patients with decompensated cirrhosis (Child-Pugh B or C) b TN and TE a GT 1 or GT 4 liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh A) c 24 WEEKS TE a GT 1 patients with compensated cirrhosis (Child- Pugh A) d a TE patients include those who have failed a peginterferon alfa + ribavirin (RBV)-based regimen with or without an HCV protease inhibitor. b In patients with decompensated cirrhosis (Child-Pugh B or C), the starting dosage of RBV is 6 mg and can be titrated up to 1 mg for patients <75 kg and 12 mg for those 75 kg in two divided doses with food. If the starting dosage of RBV is not well tolerated, the dosage should be reduced as clinically indicated based on hemoglobin levels. c The daily dosage of RBV is weight-based (1 mg for patients <75 kg and 12 mg for those 75 kg) administered orally in two divided doses with food. Refer to the RBV prescribing information. d + RBV for 12 weeks can be considered in TE GT 1 patients with cirrhosis who are eligible for RBV. See footnote c for RBV dosage recommendations. For patients with HCV/HIV-1 coinfection, refer to the Drug Interactions section of the Prescribing Information for dosage recommendations for concomitant HIV-1 antiretroviral drugs No dose recommendation can be given for patients with severe renal impairment (estimated Glomerular Filtration Rate [egfr] <3 ml/min/1.73m 2 ) or with end-stage renal disease (ESRD) due to higher exposures (up to 2-fold) of the predominant sofosbuvir metabolite Warnings and Precautions Risk of Serious Symptomatic Bradycardia When Coadministered with Amiodarone: Amiodarone is not recommended for use with due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. In patients without alternative, viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia. 2
CLINICAL STUDIES IN PATIENTS WITHOUT CIRRHOSIS OR WITH COMPENSATED CIRRHOSIS (CHILD-PUGH A) 1 Study Weeks 8 12 24 ION-1 and ION-2 ION-3 ION-4 SIRIUS + RBV a + RBV a Primary endpoint: sustained virologic response (SVR12), defined as HCV RNA <25 IU/mL at 12 weeks after the cessation of treatment 1, b SVR12 is considered a virologic cure 2 + RBV a Baseline demographics ION-1 1 ION-2 1 ION-3 1 ION-4 1,3 SIRIUS 1 N 865 44 647 335 155 Design Randomized, open-label Randomized, open-label Randomized, open-label Single-arm, open-label Randomized, placebo-controlled c Cirrhotics 16% (n = 136) 2% (n = 88) None 2% (n = 67) 1% (n = 155) Prior treatment TN Peg-IFNa + RBV or Peg-IFNa + RBV + HCV PI TN TN or RBV +/- PegIFN +/- HCV DAA Peg-IFNa + RBV followed by Peg-IFNa + RBV + HCV PI HCV GT GT 1 GT 1 GT 1 GT 1 or GT 4 d GT 1 HCV/HIV-1 coinfection No No No Yes No DAA = direct-acting antiviral agent; Peg-IFNa = peginterferon alfa. a RBV 1-12 mg/day. b Relapse was a secondary endpoint. c In the 12-week arm, subjects received placebo for 12 weeks followed by + RBV for 12 weeks. d GT 1, n = 327; GT 4, n = 8. Warnings and Precautions (cont.) Risk of Reduced Therapeutic Effect of Due to P-gp Inducers: Rifampin and St. John s wort are not recommended for use with as they may significantly decrease ledipasvir and sofosbuvir plasma concentrations. Related Products Not Recommended: is not recommended for use with other products containing sofosbuvir. 3
CLINICAL STUDIES IN PATIENTS WITHOUT CIRRHOSIS OR WITH COMPENSATED CIRRHOSIS (CHILD-PUGH A) 1 (cont.) Patients achieving SVR12 with ± RBV Patients (%) 1 8 6 4 97% 96% 99% 96% 95% 96% 97% 1% 8 Weeks + RBV 24 Weeks 2 n = 215 n = 216 n = 214 n = 335 n = 87 n = 77 n = 77 n = 22 ION-3 a ION-3 ION-1 ION-4 b ION-2 SIRIUS SIRIUS ION-2 TN, NC TN, NC/CC TN/TE, NC/CC TE, NC TE, CC CC = compensated cirrhosis (Child-Pugh A); NC = noncirrhotic. Adverse reactions (all grades) reported in 5% of GT 1 patients receiving for 8, 12, or 24 weeks: ION-1, ION-2, and ION-3 8 Weeks (N = 215) (N = 539) 24 Weeks (N = 326) Fatigue 16% 13% 18% Headache 11% 14% 17% Nausea 6% 7% 9% Diarrhea 4% 3% 7% Insomnia 3% 5% 6% The safety profile in HCV/HIV-1 coinfected subjects (ION-4) was similar to that observed in HCV monoinfected subjects The most common adverse reactions occurring in at least 1% of subjects were headache (2%) and fatigue (17%) Direct comparisons across studies should not be made due to differing study designs Adverse reactions reported in 5% of TE, CC, GT 1 patients receiving for 24 weeks or + RBV for 12 weeks versus placebo: SIRIUS 24 Weeks (N = 78) + RBV (N = 76) Placebo (N = 77) Asthenia 31% 36% 23% Headache 29% 13% 16% Fatigue 18% 4% 1% Cough 5% 11% 1% Myalgia 9% 4% Dyspnea 3% 9% 1% Irritability 8% 7% 1% Dizziness 5% 1% Footnotes for all figures: a Subgroup of TN, NC, GT 1 HCV patients with baseline HCV RNA <6 million IU/mL. In ION-3, relapse rates for for 8 weeks were 2% (n = 2/123) in patients with baseline HCV RNA <6 million IU/mL and 1% (n = 9/92) in patients with baseline HCV RNA 6 million IU/mL. b Patients with GT 1 or 4 HCV with HIV coinfection. Adverse Reactions Most common ( 1%, all grades) adverse reactions were fatigue, headache and asthenia. 4
REAL-WORLD EXPERIENCE: HCV-TARGET 4 Baseline demographics 8 Weeks (N = 154) (N = 627) 24 Weeks (N = 161) Male, n (%) 7 (46) 367 (59) 12 (63) Median age, years (range) 58 (19-84) 6 (21-87) 6 (3-8) White, n (%) 116 (75) 441 (7) 131 (81) Black, n (%) 34 (22) 136 (22) 22 (14) Prior HCV treatment, n (%) Experienced DAA experienced HCV genotype, n (%) 1a 1b 6 (4) 2 (1) 11 (66) 45 (29) 252 (4) 63 (1) 46 (65) 176 (28) 156 (97) 51 (32) 11 (68) 33 (21) Cirrhosis, n (%) 3 (2) 183 (29) 126 (78) Mean HCV RNA (log 1 ) 6. 6.2 6.1 HIV, n (%) 1 (1) 19 (3) 5 (3) PPI use, n (%) 3 (2) 163 (26) 54 (34) DAA = direct-acting antiviral; PPI = proton pump inhibitor. HCV-TARGET is a consortium of healthcare providers from academic (n = 44) and community (n = 17) medical centers in the United States (US) (primarily) and Europe conducting a longitudinal, observational study of HCV management in clinical practice All data throughout treatment and during posttreatment follow-up were collected from medical records and entered into a centralized database Data were independently reviewed for completeness and accuracy HCV treatment regimen was selected and administered at clinicians discretion according to local standards of care Patients in this analysis completed treatment before July 1, 215 Patients achieving SVR12 with Patients (%) 1 8 6 4 2 97% 97% 95% n = 127/131 n = 67/627 n = 153/161 8 a 12 24 Treatment Duration (Weeks) a Subgroup of patients treated with 8 weeks according to label (ie, GT 1 TN, noncirrhotic, pretreatment HCV RNA <6 million IU/mL). Treatment with for 8, 12, or 24 weeks resulted in SVR12 rates of 95% Across all treatment arms: 2% of patients discontinued treatment (n = 31) 1% (n = 17) were lost to follow-up posttreatment.5% (n = 11) died for 12 weeks is recommended for TN GT 1 patients without cirrhosis or with compensated cirrhosis (Child-Pugh A) and for TE GT 1 patients without cirrhosis. for 8 weeks can be considered in TN GT 1 patients without cirrhosis who have pre-treatment HCV RNA <6 million IU/mL. for 24 weeks is recommended for TE GT 1 patients with compensated cirrhosis (Child-Pugh A). + RBV for 12 weeks can be considered in TE GT 1 patients with compensated cirrhosis (Child-Pugh A) who are eligible for RBV. 1 Drug Interactions In addition to rifampin and St. John s wort, coadministration of is also not recommended with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, and tipranavir/ritonavir. Such coadministration is expected to decrease the concentration of ledipasvir and sofosbuvir, reducing the therapeutic effect of. 5
REAL-WORLD EXPERIENCE: HCV-TARGET 4 (cont.) The overall SVR12 rate with treatment was 97% Patients achieving SVR12 with a 1 8 97% 98% 93% b 96% 98% Patients (%) 6 4 2 Overall Yes Cirrhosis No Naïve Experienced Prior Treatment a For 8 (n = 154), 12 (n = 627), or 24 (n = 161) weeks. b P<.5. Adverse events reported in 5% of patients receiving in HCV-TARGET 4 (n = 1435) 4 (n = 1435) Any adverse event, n (%) 9 (63) Insomnia 89 (6) Fatigue 32 (22) Diarrhea 86 (6) Headache 37 (21) Influenza-like illness 65 (5) Nausea 19 (8) Across the ION-1, ION-2, and ION-3 clinical trials, adverse reactions (all grades) reported in 5% of subjects receiving 8, 12, or 24 weeks of treatment with were fatigue (13%-18%), headache (11% 17%), nausea (6%-9%), diarrhea (3%-7%), and insomnia (3%-6%) 1 Patients who may be considered for 8 weeks of are those with GT 1 HCV who are treatment-naïve without cirrhosis and have a baseline HCV RNA <6 million IU/mL. In ION-3, relapse rates for for 8 weeks were 2% (n = 2/123). in patients with baseline HCV RNA <6 million IU/mL and 1% (n = 9/92) in patients with baseline HCV RNA 6 million IU/mL. 1 Drug Interactions (cont.) Coadministration of is not recommended with simeprevir due to increased concentrations of ledipasvir and simeprevir. Coadministration is also not recommended with rosuvastatin or co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate due to increased concentrations of rosuvastatin and tenofovir, respectively. Consult the full Prescribing Information for for more information on potentially significant drug interactions, including clinical comments. 6
REAL-WORLD EXPERIENCE: TRIO NETWORK 5,6 In the TRIO Network study, data were collected directly from US specialty pharmacies through the Trio Health cloud-based disease management platform In this analysis, all patients were treated between October 214 and March 215 Of TN, noncirrhotic patients (n = 895), 62% were treated in community centers, and the remainder were treated in academic centers In contrast, 45% of TE, cirrhotic patients (n = 476) were treated in community centers, and the remainder in academic centers Baseline demographics TN, Noncirrhotic TE, Cirrhotic 8 Weeks (n = 263) a (n = 632) + RBV (n = 26) a 24 Weeks (n = 329) Age, mean (range) 57 (18-84) 6 (19-89) 58 (4-71) 61 (26-84) Male, n (%) 121 (46) 353 (56) 16 (62) 23 (7) Patient ethnicity, n (%) Black White 39 (15) 152 (58) 118 (19) 36 (48) 1 (4) 19 (73) 28 (8) 29 (64) Severe fibrosis (F3), n (%) 32 (12) 151 (24) N/A N/A HCV genotype, n (%) 1a 1b Baseline viral load, n (%) <6 million IU/mL 6 million IU/mL Prior HCV treatment, n Peg-IFN + RBV DAA 18 (69) 72 (27) 254 (97) 8 (3) 429 (68) 175 (27) 456 (72) 17 (27) 18 (69) 7 (27) 21 (81) 5 (19) N/A N/A 9 15 226 (69) 82 (25) 283 (86) 41 (12) 181 124 a 3% (n = 21) of TN, NC patients were treated with + RBV for 12 weeks, and 2% (n = 8) of TE, cirrhotic patients were treated with + RBV for 24 weeks. In the ION-1, ION-2, and ION-3 clinical trials, the addition of RBV was not shown to increase SVR12 rates observed with treatment. 1 for 8 weeks can be considered in TN, NC, GT 1 patients with a baseline viral load <6 million IU/mL. Contraindications If is used in combination with ribavirin (RBV), all contraindications, warnings and precautions, in particular pregnancy avoidance, and adverse reactions to RBV also apply. Refer to RBV prescribing information. 7
REAL-WORLD EXPERIENCE: TRIO NETWORK 5,6 Treatment with with or without RBV for 8, 12, or 24 weeks resulted in SVR12 rates of 92% Patients achieving SVR12 with ± RBV Patients (%) 1 8 6 4 95% 96% 96% 92% TN noncirrhotic TE cirrhotic 2 n = 242/254 n = 64/632 n = 25/26 n = 33/329 a 8 Weeks Baseline viral load <6 million IU/mL b + RBV Treatment Regimen and Duration b 24 Weeks for 12 weeks is recommended for TN GT 1 patients without cirrhosis or with compensated cirrhosis (Child-Pugh A) and for TE GT 1 patients without cirrhosis. for 8 weeks can be considered in TN GT 1 patients without cirrhosis who have pre-treatment HCV RNA <6 million IU/mL. for 24 weeks is recommended for TE GT 1 patients with compensated cirrhosis (Child-Pugh A). + RBV for 12 weeks can be considered in TE GT 1 patients with compensated cirrhosis (Child-Pugh A) who are eligible for RBV. 1 Treatment discontinuation rates in the TRIO Network study TRIO Network 5,6 8 Weeks +/- RBV b b 24 Weeks TN, noncirrhotic 1% <1% N/A TE, cirrhotic N/A % b 1.5% Footnotes for both figures: a 3% (n = 9) of TN, noncirrhotic patients treated with for 8 weeks had a baseline viral load that was either unknown or 6 million IU/mL. b 3% (n = 21) of TN, noncirrhotic patients were treated with + RBV for 12 weeks, and 2% (n = 8) of TE, cirrhotic patients were treated with + RBV for 24 weeks. 5,6 In the ION-1, ION-2, and ION-3 clinical trials, the addition of RBV was not shown to increase SVR12 rates observed with treatment. 1 The overall discontinuation rate for both TRIO cohorts combined was ~1% (n = 12/1371) In the clinical trials (ION-1, ION-2, and ION-3), the discontinuation rate due to adverse events was % for patients receiving for 8 weeks, <1% for patients receiving for 12 weeks, and 1% for patients receiving for 24 weeks Warnings and Precautions Risk of Serious Symptomatic Bradycardia When Coadministered with Amiodarone: Amiodarone is not recommended for use with due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. In patients without alternative, viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia. 8
REAL-WORLD EXPERIENCE Efficacy in patients who can be considered for 8 weeks of SVR12 rates in GT 1, TN, noncirrhotic patients with baseline HCV RNA <6 million IU/mL 5,6,a Patients (%) 1 8 6 4 97% 97% 95% 96% 8 weeks 12 weeks 2 HCV-TARGET TRIO Network in HCV GT 1: Real-world experience from HCV-TARGET and TRIO Network studies Patients achieving SVR12 with ± RBV 1 8 97% 95% 96% 96% 96% 92% Patients (%) 6 4 8 Weeks + RBV 24 Weeks 2 n = 131 n = 254 n = 632 n = 627 n = 26 n = 329 HCV-TARGET TRIO TRIO b HCV-TARGET TRIO TRIO b <6 million IU/mL TN, NC TN, NC TN, NC/CC TE, CC Patients who may be considered for 8 weeks of are those with GT 1 HCV who are treatment-naïve without cirrhosis and have a baseline HCV RNA <6 million IU/mL. In ION-3, relapse rates for for 8 weeks were 2% (n = 2/123). in patients with baseline HCV RNA <6 million IU/mL and 1% (n = 9/92) in patients with baseline HCV RNA 6 million IU/mL. 1 Footnotes for both figures: a In the TRIO Network study, 3% (n = 9) of TN, noncirrhotic patients treated with for 8 weeks had a baseline viral load that was either unknown or 6 million IU/mL. b 3% (n = 21) of TN, noncirrhotic patients were treated with + RBV for 12 weeks, and 2% (n = 8) of TE, cirrhotic patients were treated with + RBV for 24 weeks. 5,6 In the ION-1 and ION-2 clinical trial, the addition of RBV was not shown to increase SVR12 rates observed with treatment. 1 Warnings and Precautions (cont.) Risk of Reduced Therapeutic Effect of Due to P-gp Inducers: Rifampin and St. John s wort are not recommended for use with as they may significantly decrease ledipasvir and sofosbuvir plasma concentrations. Related Products Not Recommended: is not recommended for use with other products containing sofosbuvir. 9
REAL-WORLD EXPERIENCE: SUMMARY The HCV-TARGET and TRIO Network studies were supported by Gilead Sciences, Inc. Real-world experience data were derived from patient medical records and specialty pharmacy databases. Such data are retrospective and observational in nature, and are not based on controlled clinical studies. Results from these cohorts may differ from results seen in the membership of a particular payer. High SVR12 rates were achieved regardless of duration of (8, 12, or 24 weeks) a HCV-TARGET: 95% TRIO Network: 92% Among patients who may be considered for the 8-week regimen, SVR12 rates for those who actually received it were similar to SVR12 rates for those who received for 12 weeks instead Patients who may be considered for 8 weeks of are those with GT 1 HCV who are treatmentnaive without cirrhosis and have a baseline HCV RNA <6 million IU/mL. In ION-3, relapse rates for for 8 weeks were 2% (n = 2/123) in patients with baseline HCV RNA <6 million and 1% (n = 9/92) in patients with baseline RNA 6 million IU/mL a Note: not head-to-head comparisons. Contraindications If is used in combination with ribavirin (RBV), all contraindications, warnings and precautions, in particular pregnancy avoidance, and adverse reactions to RBV also apply. Refer to RBV prescribing information. Warnings and Precautions Risk of Serious Symptomatic Bradycardia When Coadministered with Amiodarone: Amiodarone is not recommended for use with due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. In patients without alternative, viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia. Risk of Reduced Therapeutic Effect of Due to P-gp Inducers: Rifampin and St. John s wort are not recommended for use with as they may significantly decrease ledipasvir and sofosbuvir plasma concentrations. Related Products Not Recommended: is not recommended for use with other products containing sofosbuvir. Adverse Reactions Most common ( 1%, all grades) adverse reactions were fatigue, headache and asthenia. Drug Interactions In addition to rifampin and St. John s wort, coadministration of is also not recommended with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, and tipranavir/ritonavir. Such coadministration is expected to decrease the concentration of ledipasvir and sofosbuvir, reducing the therapeutic effect of. Coadministration of is not recommended with simeprevir due to increased concentrations of ledipasvir and simeprevir. Coadministration is also not recommended with rosuvastatin or co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate due to increased concentrations of rosuvastatin and tenofovir, respectively. Consult the full Prescribing Information for for more information on potentially significant drug interactions, including clinical comments. 1
References. 1. [package insert]. Foster City, CA: Gilead Sciences, Inc.; February 216. 2. US Food and Drug Administration. Draft guidance for industry. Chronic hepatitis C virus infection: developing direct-acting antiviral drugs for treatment. October 213. 3. Naggie S, et al. N Engl J Med. 215;373:75-713. 4. Terrault N, et al. Presented at: The Liver Meeting American Association for the Study of Liver Diseases. AASLD; November 13-17, 215; San Francisco, CA. Presentation 94. 5. Curry M, et al. Presented at: The Liver Meeting American Association for the Study of Liver Diseases. AASLD; November 13-17, 215; San Francisco, CA. Poster 146. 6. Curry M, et al. Presented at: The Liver Meeting American Association for the Study of Liver Diseases. AASLD; November 13-17, 215; San Francisco, CA. Poster 118., the Logo, GILEAD, and the GILEAD Logo are trademarks of Gilead Sciences, Inc., or its related companies. 216 Gilead Sciences, Inc. All rights reserved. HVNP832 5/16