9/21/2014. Sarah Naidoo, PharmD, BCPS September 26, 2014

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1 Sarah Naidoo, PharmD, BCPS September 26, 2014 Be able to discuss changes in hepatitis C treatment Be able to provide recommendations to providers regarding hepatitis C treatment Be able to provide patient education 1

2 Prevalence 2.7 million to 3.9 million persons in the US 45-85% are unaware that they are infected Most prevalent in those born from Most likely infected during the 1970s-1980s Accessed 3/25/2014 Injection drug use Blood transfusions (prior to 1992) Needle stick injuries in health care settings From pregnant mother to child Sex with an infected person Ineffective means of transmission Sharing personal items Ineffective means of transmission Accessed 3/25/2014 2

3 If 100 people become infected with hepatitis C will go on to develop chronic infection will go on to develop chronic liver disease 5 20 will go on to develop cirrhosis over a period of years 1 5 will die from the consequences of chronic infection (liver cancer or cirrhosis) Chronic hepatitis C is the leading indication for liver transplants in the US Accessed 3/25/2014 Genotype 1 US (60-70%) and Europe Genotype 2 US, Europe, Asia, South America, Africa Genotype 3 India, Far East and Australia Genotype 4 Africa and Middle East Genotype 5 South Africa Genotype 6 Hong Kong, Vietnam and Australia Chopra, S. Characteristics of the hepatitis C virus. In: UpToDate, Bloom, A (Ed), UpToDate, Waltham, MA

4 Accessed April 2, Past Present Future 4

5 Past 1957 Discovery of antiviral properties of interferon Discovery of hepatitis c virus FDA approves first alfa interferon for treatment of hepatitis C Injected 3 times weekly x 48 weeks Rebetron approved (alfa interferon and ribavirin) Injected 3 times weekly x weeks given with ribavirin HCV Advocate A Brief History of Hepatitis C. 4/1/2014 5

2001 Peg-Intron approved (pegylated interferon alpha-2b) Peg-Intron plus ribavirin approved Inject 1 time weekly 2002 2011 Pegasys approved (pegylated interferon alpha-2a) Inject 1 time weekly

6 2001 Peg-Intron approved (pegylated interferon alpha-2b) Peg-Intron plus ribavirin approved Inject 1 time weekly Pegasys approved (pegylated interferon alpha-2a) Inject 1 time weekly Protease inhibitors approved (telaprevir and boceprevir) Used in combination with pegylated interferon and ribavirin Approved for genotype 1 only HCV Advocate A Brief History of Hepatitis C. [Last accessed ] Accessed April 3,

7 Yee, HS, et al. (2012) Update on the management and treatment of hepatitis C virus infection: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program Office. Am J Gastroenterol. 107: Present 7

http://img.medscape.com/article/735/757/735757-fig1.jpg Accessed April 3, 2014.

8 Accessed April 3, Recommendations for Testing, Managing, and Treating Hepatitis C hcvguidelines.org AASLD/IDSA This guidance should be considered a living document 8

9 Inhibitors of NS3/4A serine protease Enzyme involved in post-translational processing and replication of hepatitis C virus (HCV) Disrupt HCV by blocking the NS3 catalytic site or the NS3/4A interaction Blocks TRIF-mediated Toll-like receptor signaling and Cardifmediated retinoic acid-inducible gene 1 signaling 1 st Generation Boceprevir Telaprevir 2 nd Generation Simeprevir Pockros, P. Direct acting antivirals for the treatment of hepatitis c virus infection. In: UpToDate, Bloom, A (Ed), UpToDate, Waltham, MA mg TID (available in 200 mg tablets) 12 tablets daily Approved for genotype 1 only Used in combination with peginterferon and ribavirin Treatment guided by an algorithm 9

10 Yee, HS, et al. (2012) Update on the management and treatment of hepatitis C virus infection: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program Office. Am J Gastroenterol. 107: mg BID (available in 375mg tablets) 6 tablets daily Must be taken with 20 grams of fat Approved for genotype 1 only Used in combination with peginterferon and ribavirin Treatment guided by an algorithm 10

11 Yee, HS, et al. (2012) Update on the management and treatment of hepatitis C virus infection: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program Office. Am J Gastroenterol. 107: Approved November 2013 Genotype 1 patients with compensated liver disease (including cirrhosis) In combination with peginterferon alfa and ribavirin 150 mg once daily with food Food increases absorption by ~65% NS3 Q80K polymorphism Specific to genotype 1a subgroup If present, reduces efficacy of simeprevir Contains a sulfonamide moiety Olysio[package insert]. Titusville, NJ: Janssen Therapeutics; December

12 Treatment-naïve and prior relapse patients including those with cirrhosis Prior non-responder patients (including partial and null responders) including thosewith cirrhosis Simeprevir+ peg + ribavirin First 12 weeks First 12 weeks Peg + ribavirin Additional 12 weeks Additional 36 weeks Total Duration 24 weeks 48 weeks Olysio[package insert]. Titusville, NJ: Janssen Therapeutics; December HCV RNA Treatment week 4: Greater than or equal to 25 IU/ml Treatment week 12: Greaterthan or equal to 25 IU/ml Treatment week 24: Greaterthan or equal to 25 IU/ml Action Discontinue simeprevir, peg and ribavirin Discontinue peg and ribavirin -simeprevir is complete at week 12 Discontinue peg and ribavirin *If peg or ribavirin is stopped for any reason simeprevir must be discontinued Olysio[package insert]. Titusville, NJ: Janssen Therapeutics; December

13 Metabolized by CYP3A Mildly inhibits CYP1A2 and intestinal CYP3A4 Effect on simeprevir concentrations Select Examples CYP 3A Inhibitors CYP 3A Inducers INCREASES Increased risk of ADRs DECREASES Risk of reduced efficacy Macrolides, antifungals, milk thistle, ritonavir Anticonvulsants, rifampin, dexamethasone, St Johns wort, efavirenz Pregnancy category C Ribavirin is category X Hepatic Impairment No dose recommendation for patients with moderate or severe hepatic impairment Has not been studied post liver transplant Renal Impairment Not studied in CrCl <30 ml/min Race East Asian ancestry experience increased exposure No dose recommendations Olysio[package insert]. Titusville, NJ: Janssen Therapeutics; December

14 Photosensitivity Most frequently occurs in the first 4 weeks of treatment Exaggerated sunburn in areas exposed to light Use sun protection measures Rash Most frequently occurs in the first 4 weeks of treatment Most are mild to moderate and do not require discontinuation of simeprevir Sulfa allergy No increased incidence of rash or photosensitivity Insufficient evidence Olysio[package insert]. Titusville, NJ: Janssen Therapeutics; December ADR Simeprevir + peg-ifn + ribavirin First 12 weeks N=781 %(n) Rash/photosensitivity 28(218) 20(79) Pruritus 22(168) 15(58) Nausea 22(173) 18(70) Myalgia 16(126) 13(53) Dyspnea 12(92) 8(30) Placebo+ peg-ifn + ribavirin First 12 weeks N=397 %(n) Olysio[package insert]. Titusville, NJ: Janssen Therapeutics; December

15 Should not be taken alone Females and males must use 2 forms of birth control during treatment and 6 months after treatment completed Missed dose Take within 12 hours of missing the dose Photosensitivity Rash Store in original bottle Phase III Genotype 1, treatment naïve, with compensated liver disease including cirrhosis N=785 Simep + peg-ifn+ riba SVR12 Peg-IFN + riba SVR12 Genotype 1 419/521 (80%) 133/264 (50%) Genotype 1a 191/254 (75%) 63/131 (48%) Without Q80K 138/165 (84%) 36/83 (43%) With Q80K 49/84 (58%) 24/44 (55%) Genotype 1b 228/267 (85%) 70/133 (53%) Olysio[package insert]. Titusville, NJ: Janssen Therapeutics; December

16 Subgroup METAVIR Fibrosis Score Subgroup Simep + peg-ifn + riba % (n/n) Peg-IFN + riba % (n/n) F (317/378) 55 (106/192) F (89/130) 36 (26/72) Olysio[package insert]. Titusville, NJ: Janssen Therapeutics; December Phase III, not yet published Genotype 1, relapsed following previous interferon based therapy, with compensated liver disease including cirrhosis N=393 Simep + peg-inf +riba SVR12 Peg-IFN + riba SVR12 Genotype 1 26/260 (79%) 48/133 (36%) Genotype 1a 78/111 (70%) 14/54 (26%) Without Q80K 62/79 (78%) 8/34 (24%) With Q80K 14/30 (47%) 6/20 (30%) Genotype 1b 128/149 (86%) 34/79 (43%) Olysio[package insert]. Titusville, NJ: Janssen Therapeutics; December

17 Subgroup METAVIR Fibrosis Score Subgroup Simep + peg-ifn + riba % (n/n) Peg-IFN + riba % (n/n) F (137/167) 41 (40/98) F (61/83) 24 (8/34) Olysio[package insert]. Titusville, NJ: Janssen Therapeutics; December Phase 2b Genotype 1, failed prior therapy with peg-ifn and ribavirin Simep150 mg x 12 w + PR SVR24 % (n/n) Pooled simep 100 mg and 150 mg x 12w+ PR SVR24 % (n/n) Placebo+ PR SVR24 % (n/n) Prior relapser 77 (20/26) 83 (44/53) 37 (10/27) Prior partial responder 65 (15/23) 67 (31/46) 9 (2/23) Prior null responder 53 (9/17) 45 (15/33) 19 (3/16) Zeuzem S, Berg T, Gane E, et al. Simeprevir Increases Rate of Sustained Virologic Response Among Treatment-Experienced Patients with HCV Genotype-1 Infection: a Phase IIb Trial. Gastroenterology.2013a 17

18 Q80K polymorphism Genotype1a Simep 150mg + PR SVR24 Without Q80K 66.1%(39/59) With Q80K 60.9%(14/23) NS5B is an RNA dependent RNA polymerase involved in post translational processing Necessary for replication of HCV Enzyme has a catalytic site for nucleoside binding Sofosbuvir Pockros, P. Direct acting antivirals for the treatment of hepatitis c virus infection. In: UpToDate, Bloom, A (Ed), UpToDate, Waltham, MA

19 Approved December 2013 Approved for use in genotypes 1, 2, 3, and 4 Nucleotide analog NS5B polymerase inhibitor 400 mg once daily with or without food Dispense in original container Sovaldi[package insert]. Foster City; Gilead Sciences; December Genotype Treatment Duration Genotype1 or 4 sofosbuvir +peg-ifn + ribavirin 12 weeks Genotype 2 sofosbuvir + ribavirin 12 weeks Genotype 3 Sofosbuvir + ribavirin 24 weeks Genotype 1 ineligible for peg-ifn Patients with hepatocellular carcinoma awaiting liver transplant Sofosbuvir + ribavirin Sofosbuvir + ribavirin 24 weeks Upto 48 weeks or untilthe time of liver transplant, whichever occurs first Sovaldi[package insert]. Foster City; Gilead Sciences; December

20 Substrate of P-gp Inducers may decrease sofosbuvir plasma concentrations and decrease its therapeutic effects Do NOT coadminister decreases sofosbuvir concentrations Anticonvulsants Rifampin St. John s wort Tipranavir/ritonavir Drugs WITHOUT clinically significant interactions Cyclosporine Darunavir/ritonavir Efavirenz Emtricitabine Methadone Raltegravir Rilpivirine Tacrolimis Tenofovir Sovaldi[package insert]. Foster City; Gilead Sciences; December Pregnancy category B Ribavirin is category X Hepatic Impairment No dose adjustments needed for patients with mild, moderate or severe hepatic impairment Has not been studied post liver transplant Renal Impairment Not studied in CrCl <30 ml/min Sovaldi[package insert]. Foster City; Gilead Sciences; December

21 Sovaldi[package insert]. Foster City; Gilead Sciences; December Should not be taken alone Females and males must use 2 forms of birth control during treatment and 6 months after treatment completed Keep in original container Take missed dose as soon remembered, but not more than 2 doses in one day Sovaldi[package insert]. Foster City; Gilead Sciences; December

22 12 weeks of sofosbuvir + peg-ifn + ribavirin Treatment naïve subjects with compensated liver disease including cirrhosis Genotypes 1 and 4 Phase 3 trial N=327 Genotype SVR Overall SVR 90% (295/327) 1 89% (261/292) 1a 92% (206/225) 1b 82% (54/66) 4 96% (27/28) Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med.2013b;368(20): Selected subgroups Subgroup SVR Cirrhosis No 92% (252/273) Yes 80% (43/54) Race Black 87%(47/54) Non-black 91% (248/273) Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med.2013b;368(20):

23 Genotypes 2 and 3, treatment naive Sofosbuvir + ribavirin for 12 weeks compared to peg-ifn + ribavirin for 24 weeks Phase 3 Genotype Sof + riba X 12 weeks SVR12 N=253 Peg+ riba x 24 weeks SVR12 N=243 Overall 2 & 3 67% (170/253) 67% (162/243) 2 95% (69/76) 78% (52/67) 3 56% (102/183) 63%(110/176) Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med.2013b;368(20): Selected subgroup Cirrhosis Genotype 2 Genotype 3 Sof + riba X 12 w Peg+ riba X 24 w Sof + riba X 12 w Peg+ riba X 24 w Without 97% (59/61) 81% (44/54) 61% (89/145) 71%(99/139) With 83%(10/12) 62% (8/13) 34% (13/38) 30% (11/37) Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med.2013b;368(20):

24 Sofosbuvir + ribavirin x 12 weeks Genotypes 2 and 3 Patients who are interferon intolerant, ineligible or unwilling with compensated liver disease including cirrhosis Phase 3, placebo controlled 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): Genotype Sofosbuvir+ riba x 12 weeks N=207 Placebo X 12 weeks N=71 Difference [95% CI] Overall 2& 3 78% (161/207) 0/71 78% [71,84] 2 93% (101/109) 0/34 93%[88,98] 3 61% (60/98) 0/37 61% [52,71] 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):

25 Selected subgroups Sofosbuvir + riba x 12 weeks Genotype 2 SVR 12 N=109 Cirrhosis Sofosbuvir + riba x 12 weeks Genotype 3 SVR 12 N=109 No 92% (85/92) 68% (57/84) Yes 94% (16/17) 21% (3/14) Interferon Ineligible 88% (36/41) 70%(33/47) Intolerant 100% (9/9) 50% (4/8) Unwilling 95% (56/59) 53% (23/43) 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): Sofosbuvir and ribavirin for 12 or 16 weeks Phase 3 Genotype 2 or 3 who are treatment experienced with compensated liver disease Genotype including cirrhosis Sofos + riba X 12 weeks N=103 Sofos + riba X 16 weeks N=98 Difference [95% CI] Overall 50%(51/103) 71% (70/98) -22% [-35%,-9%] Genotype 2 82% (32/39) 59%(31/35) -7% [-23%,9%] Genotype 3 30%(19/64) 62% (39/63) -32% [-49%,-16%] 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):

26 Future Not FDA approved Potential treatment for genotype 1, interferon ineligible Jacobson IM, 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. Hepatology: Special Issue: The 64th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting ;58(4):1379A. 26

27 On-going phase II trial Simeprevir150 mg and sofosbuvir400 mg daily with or without ribavirin for 12 or 24 weeks Genotype 1 Published abstract SVR4 Prior nullresponder to peg/riba and metavir score F0-2 Treatment naïve and prior null responders with metavir score F3-4 SVR12 Prior nullresponder to peg/riba and metavir score F0-2 -w/ Q80K mutation Treatment naïve and prior null responders with metavir score F3-4 Sim +sofo w/o ribavirin X 12 weeks Sim + sofo w/ ribavirin X 12 weeks Sim +sofo w/o ribavirin X 24 weeks Sim + sofo w/ ribavirin X 24 weeks 13/14 (92.9%) 26/27 (96.3%) 14/15 (93.3%) 20/24 (83.3%) 14/14 (100%) 26/27 (96.3%) NA NA 13/14 (92.9%) 5/6 (83.3%) 26/27 (96.3%) 8/9/ (88.9%) 14/15 (93.3%) 4/4 (100%) NA NA NA NA 19/24 (79.2%) 8/12 (66.7%) 27

28 NS5A replication complex inhibitor NS5A plays a role in viral replication and assembly of the hepatitis c virus Bristol-Myers Squibb Genotype 1, 2, 3 Previously untreated patients Sofosbuvir for 1 week, then daclatasvir and sofosbuvir for 23 weeks Daclatasvir and sofosbuvir for 24 weeks Daclatasvir, sofosbuvir, and ribavirin for 24 weeks Genotype 1 Previous non responders to treatment with telaprevir or boceprevir Daclatasvir plus sofosbuvir, with or without ribavirin, for 12 weeks Daclatasvir plus sofosbuvir, with or without ribavirin, for 24 weeks Sulkowski, M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014;370:

Genotype 1 Prev untreated Sofo +dac X 12 weeks SVR12 Genotype 1 Failed boc or telap Sofo +dac X 24 weeks SVR12 Genotype 2

29 Sulkowski, M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014;370: Genotype 1 Prev untreated Sofo +dac X 12 weeks SVR12 Genotype 1 Failed boc or telap Sofo +dac X 24 weeks SVR12 Genotype 2 Sofo + dac X 24 weeks SVR12 Genotype 3 Sofo + dac X 24 weeks SVR12 98% 98% 92% 89% Sulkowski, M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014;370:

30 NS3/4A protease inhibitor Phase 2a, open-label, 24-week treatment study Daclatasvir 60 mg once-daily AND Genotype 1b patients received asunaprevir 200mg twice or once-daily Genotype 1a and genotype 1b patients received asunaprevir twice or once-daily plus PegIFN/RBV Genotype 1a and genotype 1b patients received asunaprevir twice-daily plus ribavirin Lok, A. Randomized trial of daclatasvir and asunaprevir with or without PegIFN/RBV for hepatitis C virus genotype 1 null responders. J Hepatol Mar;60(3):

31 Lok, A. Randomized trial of daclatasvir and asunaprevir with or without PegIFN/RBV for hepatitis C virus genotype 1 null responders. J Hepatol Mar;60(3): NS5A inhibitor 31

32 Genotype 1 Treatment naïve and treatment experienced with a protease inhibitor Sofosbuvir 400 mg and ledipasvir 90 mg Cohort A: treatment-naive patients Cohort B: patients previously treated with protease inhibitors Sofosbuvir plus ledipasvir for 8 weeks (n=20) Sofosbuvir plus ledipasvir with ribavirin for 8 weeks (n=21) Sofosbuvir plus ledipasvir for 12 weeks (n=19) Sofosbuvir plus ledipasvir for 12 weeks (n=19) Sofosbuvir plus ledipasvir with ribavirin for 12 weeks (n=21) Treatment week 4 20 (100%; ) 21 (100%; ) 19 (100%; ) 18 (95%; ) 21 (100%; ) End of treatment 20 (100%; ) 21 (100%; ) 19 (100%; ) 19 (100%; ) 21 (100%; ) SVR4 20 (100%; ) 21 (100%; ) 19 (100%; ) 18 (95%; ) 21 (100%; ) SVR12 19 (95%; ) 21 (100%; ) 18 * (95%; ) 18 (95%; ) Lawitz, E. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naïve and previously treatedpatients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised phase 2 trial. Lancet Feb 8;383(9916):

33 Phase 3 Genotype 1, previously untreated Ledipasvir 90 mg and Sofosbuvir 400 mg +/- ribavirin 12 or 24 weeks LDV + SOF X 12 weeks SVR12 LDV + SOF+ RBV X 12 weeks SVR12 LDV +SOF X 24 weeks SVR12 LDV + SOF + RBV X24 weeks SVR12 211/214(99%) 211/217 (97%) 212/217 (98%) 215/217 (99%) Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection ION-1. N Engl J Med May 15;370(20): Phase 3 Genotype 1, previously treated Ledipasvir 90 mg and Sofosbuvir 400 mg +/- ribavirin 12 or 24 weeks LDV + SOF X 12 weeks SVR12 LDV + SOF+ RBV X 12 weeks SVR12 LDV +SOF X 24 weeks SVR12 LDV + SOF + RBV X24 weeks SVR12 102/109(94%) 107/111 (96%) 108/109 (99%) 110/111(99%) Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. ION-2 N Engl J Med Apr 17;370(16):

34 Phase 3 Genotype 1, previously untreated, without cirrhosis Ledipasvir 90 mg and Sofosbuvir 400 mg +/- ribavirin 8 or 12 weeks LDV + SOF 8 Weeks SVR 12 LDV+ SOF + RBV 8 weeks SVR 12 LDV + SOF 12 weeks SVR /215 (94%) 201/216 (93%) 206/216(95%) Kowdley KV, Gordon SC, Reddy KR. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. ION-3. N Engl J Med May 15;370(20):

35 AbbVie Phase 3 Genotype 1, previously untreated, without cirrhosis ABT mg with ritonavir 100 mg, ombitasvir 25 mg, dasabuvir 250 mg and ribavirin 12 weeks Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med Apr 24;370(17): All patients SVR 12 Genotype 1a SVR % 95.3% 98% Genotype 1b SVR 12 Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med Apr 24;370(17):

36 Phase 3 Genotype 1, previously treated, without cirrhosis ABT mg with ritonavir 100 mg, ombitasvir 25 mg, dasabuvir 250 mg and ribavirin 12 weeks Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med Apr 24;370(17): All patients SVR 12 Genotype 1a SVR 12 Genotype 1b SVR /297 (96.3%) 166/173(96%) 119/123 (96.7%) Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med Apr 24;370(17):

37 Phase 3 Genotype 1, previously untreated, with cirrhosis ABT mg with ritonavir 100 mg, ombitasvir 25 mg, dasabuvir 250 mg and ribavirin 12 or 24 weeks Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med May 22;370(21): weeks 24 weeks Genotype 1a No prior treatment 59/64 (92.2%) 52/56 (92.9%) Prior Treatment Null response 10/50 (80%) 39/42(92.9%) Partial response 11/11 (100%) 10/10 (100%) Relapse 14/15 (93.3%) 13/13 (100%) Genotype 1b No prior treatment 22/22 (100%) 18/18(100%) Prior Treatment Null response 25/25(100%) 20/20 (100%) Partial response 6/7 (85.7%) 3/3 (100%) Relapse 14/14 (100%) 10/10 (100%) Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med May 22;370(21):

38 Phase 3 Genotype 1, previously untreated, without cirrhosis ABT mg with ritonavir 100 mg, ombitasvir 25 mg, dasabuvir 250 mg +/-ribavirin 12 weeks Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. PEARL-III Study; PEARL-IV Study.N Engl J Med May 22;370(21): Genotype 1a Genotype 1b With ribavirin 97/100 (97%) 209/210(99.5%) Without ribavirin 185/205 (90.2%) 207/209 (99%) Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. PEARL-III Study; PEARL-IV Study.N Engl J Med May 22;370(21):

39 Simulation model if 50% (270,525) HCV patients in California were treated with new regimens Total Budgetary Impact and Potential Cost Offsets From Use of Newer Drug Regimens in the Population with Chronic Hepatitis C Virus in California Ollendorf DA et al. The Comparative Clinical Effectiveness and Value of Simeprevir and Sofosbuvir for Chronic Hepatitis C Virus Infection. JAMA Intern Med. 2014;():. doi: /jamainternmed Accessed 9/14/2014. NS3 Protease Inhibitors NS5A Replication Complex Inhibitors NS5B NUC Inhibitors NS5B Non- NUC Inhibitors Telaprevir Boceprevir Simeprevir *Asunaprevir (12/2014) ABT-450 (12/2014) MK-5172 Faldaprevir Sovaprevir Danoprevir ACH-2684 Ledipasvir (10/2014) *Daclatasvir (12/2014) Ombitasvir (12/2014) MK-8742 GS-5885 GS-5816 ACH-3102 PPI-668 GSK Samatasvir IDX719 Sofosbuvir IDX20963 ACH-3422 Dasabuvir (12/2014) Deleobuvir BMS PPI-383 GS-9669 TMC Key approach: combine potent agents across classes 39

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UPDATES IN HEPATITIS C

UPDATES IN HEPATITIS C S A R A H N A I D O O, P H A R M, B C P S AP RI L 13, 2014 OBJECTIVES Be able to discuss changes in hepatitis c treatment Be able to provide recommendations to providers regarding