How Will New HCV Therapies Overcome the Challenges of Current Regimens?

1. How Will New HCV Therapies Overcome the Challenges of Current Regimens? Jordan J. Feld, MD, MPH Assistant Professor of Medicine University of Toronto Hepatologist Toronto Western Hospital Liver Centre McLaughlin-Rotman Centre for Global Health Toronto, Ontario, Canada Supported by an educational grant from Gilead Sciences Supported by an educational grant from Janssen Therapeutics

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3. Faculty Disclosures Jordan J. Feld, MD, MPH, has disclosed that he has received consulting fees from Abbott, Boehringer Ingelheim, Gilead Sciences, Merck, Roche, and Vertex and fees for non-CME services from Abbott and Merck.

4. A Major Advance DAAs 100 2011 PegIFN 2001 RBV 80 70+ Standard IFN 1998 55 60 1991 SVR (%) 42 39 40 34 16 20 6 0 IFN 12 mos IFN/RBV 6 mos IFN/RBV 12 mos PegIFN 12 mos PegIFN/ RBV 12 mos IFN 6 mos PegIFN/ RBV/ DAA Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring, MD.

5. A Major Step Forward: SVR Rates With BOC or TVR in GT1 Treatment-Naive Patients 100 80 63-75 60 SVR (%) 38-44 40 20 0 PegIFN/RBV BOC or TVR + PegIFN/RBV Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

6. SVR Rates With BOC or TVR in GT1 Treatment-Experienced Patients 100 PegIFN/RBV 69-83 BOC or TVR + pegIFN/RBV 80 40-59 60 SVR (%) 29-40 40 24-29 20 7-15 5 0 Relapsers[1,2] Partial Responders[1,2] NullResponders[2,3] 1. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 2. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 3. Bronowicki JP, et al. EASL 2012. Abstract 11.

7. Challenges of Current PI-Based Therapy • Efficacy • Very dependent on the IFN response • Tolerability • Additional AEs beyond pegIFN/RBV • Regimens • Complicated (lead-in, RGT)/pill burden • DDIs • Many with both agents to common drugs • Genotype/special populations • Limited activity in non-GT1, limited data HIV/OLTx, ESRD

8. Likelihood of SVR and Risk of Resistance Related to IFN Responsiveness HCV RNA Reduction After 4-Wk Lead-in ≥ 1 log decline < 1 log decline 100 100 82 80 76 80 60 60 SVR (%) SVR (%) 40 33 40 33 20 20 0 0 REALIZE (TVR)[2] RESPOND-2* (BOC)[1] *Pooled data from RGT and 48-wk therapy. 1. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 2. Foster G, et al. EASL 2011. Abstract 6.

9. IL28B Genotype Predicts Likelihood of Achieving SVR in Treatment-Naive Patients ADVANCE: T12PR48*[2] SPRINT-2: BOC + PR48[1] 100 100 SVR (%) SVR (%) 90 80 80 80 73 71 71 59 60 60 40 40 20 20 n/N = n/N = 45/50 48/68 16/22 44/55 82/115 26/44 0 0 CC CT TT CC CT TT *IL28B testing in ADVANCE was in whites only. 1. Poordad F, et al. Gastroenterology. 2012;143:608-618. 2. Jacobson IM, et al. EASL 2011. Abstract 1369.

10. Limited Data and Lower SVR Rates With Advanced Fibrosis F0-2 F3/4 100 100 SVR (%) SVR (%) 80 80 67 67 60 60 52 41 38 38 40 40 20 20 n/N = n/N = 9/ 24 14/ 34 22/ 42 123/ 328 213/ 319 211/ 313 0 0 BOC48 BOCRGT BOC48 BOCRGT 48 PR 48 PR Poordad F, et al. N Engl J Med. 2011;364:1195-1206.

11. REALIZE: Very Low SVR in Cirrhotic Previous Null Responders REALIZE: TVR + PegIFN/RBV in GT1 Previous Relapsers and Nonresponders Previous Relapsers Previous Partial Responders Previous Null Responders 100 86 85 Pooled T12/PR48 84 Pbo/PR48 80 72 56 60 SVR (%) 41 39 40 34 32 10 20 6 18 20 14 1/10 13 13 1/18 0 0 144/167 12/38 53/62 15/38 2/15 48/57 2/15 34/47 3/17 10/18 11/32 1/5 24/59 7/50 n/N = 0/5 0/9 0 No, Minimal, or Portal Fibrosis BridgingFibrosis Cirrhosis No, Minimal, or Portal Fibrosis BridgingFibrosis Cirrhosis No, Minimal, or Portal Fibrosis BridgingFibrosis Cirrhosis Stage Zeuzem S, et al. EASL 2011. Abstract 5.

12. Efficacy Limitations • Dependent on response to pegIFN/RBV • Limited efficacy in poor IFN responders • Cirrhosis, IL28B non-CC, black patients • Prior nonresponders, particularly nulls • Treatment failure—high rate of resistance • May affect future treatment options

13. Challenges of Current PI-Based Therapy • Efficacy • Very dependent on the IFN response • Tolerability • Additional AEs beyond pegIFN/RBV • Regimens • Complicated (lead-in, RGT)/pill burden • DDIs • Many with both agents to common drugs • Genotype/special populations • Limited activity in non-GT1, limited data HIV/OLTx, ESRD

14. Adverse Effects

15. Preliminary Real-World Safety Findings: CUPIC—PIs in Patients With Cirrhosis *Causes of death in patients treated with TVR: septicemia, septic shock, pneumopathy, esophageal varices bleeding, endocarditis; causes of death in patients treated with BOC: pneumopathy. Hezode C, et al. EASL 2012. Abstract 8.

16. Higher Discontinuation Rates in Real-World Settings Than in Clinical Trials 40 30 498 GT1 Patients Evaluated[1] 174 GT1 Patients StartedTVR-Based Triple Therapy[2] 21 50 20 40 33[2] 10 30 21 Patients (%) 22 0 18 17 20 D/CBeforeWk 12 11 10 91/ 498 69/ 407 89/ 407 43/ 407 58/ 174 36/ 174 n/N = 0 D/C TVR < 12 wks Due to AEs Started Therapy PatientChoice Wait forBetterTherapies MildDisease Did Not Start 1. Chen EY, et al. AASLD 2012. Abstract 133. 2. Bichoupan K, et al. AASLD 2012. Abstract 1755.

17. Tolerability • Multiple AEs • Some severe, but mostly manageable • Creates issues with capacity and experience • “Discouraging” to some low volume treaters

18. Challenges of Current PI-Based Therapy • Efficacy • Very dependent on the IFN response • Tolerability • Additional AEs beyond pegIFN/RBV • Regimens • Complicated (lead-in, RGT)/pill burden • DDIs • Many with both agents to common drugs • Genotype/special populations • Limited activity in non-GT1, limited data HIV/OLTx, ESRD

19. Regimens—Many Challenges For us—lead-in, response-guided therapy . . . For our patients . . . Pill Burden Food Requirement BOC = 12/day RBV = 4-7/day TVR = 6/day RBV = 4-7/day

20. Challenges of Current PI-Based Therapy • Efficacy • Very dependent on the IFN response • Tolerability • Additional AEs beyond pegIFN/RBV • Regimens • Complicated (lead-in, RGT)/pill burden • DDIs • Many with both agents to common drugs • Genotype/special populations • Limited activity in non-GT1, limited data HIV/OLTx, ESRD

21. Drug–Drug Interactions Substrates and Inhibitors of CYP3A4 Interactions with many common drugs • Statins • OCP • SSRI • Sildenafil • Many more PI Metabolites CYP3A4 www.hep-druginteractions.org

22. Challenges of Current PI-Based Therapy • Efficacy • Very dependent on the IFN response • Tolerability • Additional AEs beyond pegIFN/RBV • Regimens • Complicated (lead-in, RGT)/pill burden • DDIs • Many with both agents to common drugs • Genotype/special populations • Limited activity in non-GT1, limited data HIV/OLTx, ESRD

23. The future looks bright,but some challenges remain . . .

24. Potent IFN-Free DAA Regimens in Treatment-Naive Genotype 1 ABT-450/r (PI) + ABT-333 (NNI) + ABT-267 (NS5A) + RBV x 12 wks Sofosbuvir (Nuc) + daclatasvir (NS5A) + RBV x 24 wks Sofosbuvir (Nuc) + daclatasvir (NS5A) x 24 wks Sofosbuvir (Nuc) + GS-5885 (NS5A) + RBV x 12 wks Daclatasvir (NS5A) + asunaprevir (PI) + BMS 791325 (NNI) x 12 wks 100[2] 100[1] 98[3] 97[1] 100 94[4] 80 60 SVR4, 12, or 24 (%) 40 20 n/N = 15/15 77/79 28/29 15/16 25/25 0 2-3 DAAs + RBV 2-3 DAAs, No RBV • Major caveats: small n, no/few patients with cirrhosis 1. Sulkowski M, et al. AASLD 2012. Abstract LB-2. 2. Gane E, et al. AASLD 2012. Abstract 229.3. Kowdley KV, et al. AASLD 2012. Abstract LB-1. 4. Everson G, et al. AASLD 2012. Abstract LB-3.

25. Cirrhosis

26. Cirrhosis—Still Very Limited Data ASPIRE: Treatment-Experienced[1] Simeprevir 150 mg QD + PR* SOUND-C2: IFN-Free, Naive[2] Faldaprevir 120 mg QD + BI 207127 600 mg TID/BID + RBV x 16-40 wks All cirrhotics in trial: n = 39 All cirrhotics in trial: n = 33 100 Cirrhosis 100 No cirrhosis 82 80 80 73 70 67 57 60 60 52 SVR12 (%) SVR24 (%) 40 40 31 20 20 n/N = 11/ 15 9/ 11 4/ 13 n/N = 11/ 21 124/ 217 6/ 9 48/ 69 0 0 TID* Relapser Partial Null BID *Treatment arms with different durations combined. • Very limited data in patients with cirrhosis • Limited safety profile looks promising 1. Zeuzem S, et al. EASL 2012. Abstract 2. 2. Soriano V, et al. AASLD 2012. Abstract 84.

27. Previous Null Responders

28. Previous Null Responders: Triple Therapy ASPIRE: Simeprevir (PI) + PegIFN alfa-2a + RBV[1] SILEN-C2: Faldaprevir (PI) + PegIFN alfa-2a + RBV[2] Simeprevir 150 mg QD + PR* PR48 Faldaprevir 240 mg QD 24 wks + PR 48 wks 100 100 85 76 80 80 60 60 51 50 SVR24 (%) SVR (%) 37 40 40 35 31 19 20 20 13/ 26 14/ 40 n/N = 9 67/ 79 52/ 69 26/ 51 4/ 13 n/N = 10/ 27 3/ 16 2/23 0 0 Null F4 Null Relapser Partial Null Partial *Treatment arms with different durations combined. Modest benefit in efficacy—but once-daily dosing/fewer AEs 1. Jacobson IM, et al. IDSA 2012. 2. Sulkowski M, et al. EASL 2011. Abstract 66.

29. Previous Null Responders: Quad Therapy Daclatasvir (NS5A) + Asunaprevir (PI) + PegIFN/RBV x 24 wks (Quad) Danoprevir/r (PI) + Mericitabine (Nuc) + PegIFN/RBV x 24 wks (Quad)[3] 88% GT1a 61% GT1a 100 100 93*[2] 90[1] 80 84 80 60 60 SVR12 (%) SVR12 or 24 (%) 40 40 20 20 n/N = n/N = 9/10 38/41 0 62/74 0 *Asunaprevir QD and BID combined. • Quad therapy may be a good option for null responders • Well tolerated BUT cirrhotics excluded 1. Lok AS, et al. N Engl J Med. 2012;366:216-224. 2. Lok AS, et al. AASLD 2012. Abstract 79. 3. Feld JJ, et al. AASLD 2012. Abstract 81.

30. Previous Null Responders: IFN Free Daclatasvir (NS5A) + Asunaprevir (PI) x 24 wks Japan[2] 100 90 AASLD 2012*[3] 78 80 US Study 9/11 GT1a Japanese Study 10/10 GT1b AASLD 2012 GT1b only United States[1] 60 SVR4, 12, or 24 (%) 36 40 20 n/ N = 14/18 4/11 9/10 0 • First IFN-free SVRs in null responders • Likely adequate for GT1b but not for GT1a • No data in cirrhotics *Includes only asunaprevir BID dosing arm. 1. Lok AS, et al. N Engl J Med. 2012;366:216-224. 2. Chayama K, et al. AASLD 2011. Abstract LB-4. 3. Lok AS, et al. AASLD 2012. Abstract 79.

31. Past Treatment May Affect Future Response… ABT450/r (PI) + ABT-333 (NNI) + RBV x 12 wks[1] ABT-450/r (PI) + ABT-333 (NNI) +ABT-267 (NS5A) + RBV x 12 wks[2] SVR NR Relapse 98 100 94* 100 93 Statistical fluke or due to previous NR, RBV resistance? 80 80 3/6 null 5/11 partial 60 60 SVR (%) 47 SVR (%) 40 35 40 27 20 20 7 1 6 n/N = n/N = 0 0 0 77/79 42/45 3/45 1/79 31/34 3/34 8/17 6/17 3/11 0 0 Naive Nulls Naive Nonresponders • Very high SVR rates in 12 wks • Potent combination may overcome null response to PR *Different doses of ABT450/r combined. 1. Poordad, et al. EASL 2012. Abstract. 2.Kowdley KV, et al. AASLD 2012. Abstract LB-1.

32. IFN Ineligible/Intolerantor Unwilling

33. IFN Ineligible/Intolerant or Unwilling Daclatasvir (NS5A) + Asunaprevir (PI) x 24 Wks (IFN Free) 100 PegIFN/RBV Ineligible/Intolerant 91 Null Responders Daclatasvir + Asunaprevir Follow-up Daclatasvir + Asunaprevir Follow-up 80 8 8 64 N = 22 N = 21 7 7 6 6 60 5 5 SVR 24 (%) 4 4 HCV RNA (log10 IU/mL) 3 3 40 2 2 Below LLOQ Undetectable 1 1 20 0 0 0 2 4 6 8 10 12 16 20 24 28 36 48 0 2 4 6 8 10 12 16 20 24 28 36 48 n/N = 19/21 14/22 EOT SVR24 EOT SVR24 0 Time (wks) LLOQ = 15 IU/mL PreviousNulls IFN Intolerant/ Ineligible Breakthrough correlated with low plasma drug concentrations • Challenges beyond AEs of IFN • Therapy only works if you take your medications Suzuki F, et al. EASL 2012. Abstract 14.

34. Non–Genotype 1 HCV

35. Non-GT1: Options Increasing Sofosbuvir (Nuc) + RBV + pegIFN x 24 wks Sofosbuvir (Nuc) + RBV x 12 wks + pegIFN x 4-12 wks Danoprevir (PI)/ritonavir + pegIFN + RBV x 12-24 wks Sofosbuvir (Nuc) + RBV x 12 wks Sofosbuvir (Nuc) + Daclatasvir (NS5A) ± RBV x 24 wks 100[1] 100[1] 97[4] 100 96[2] 88[3] 80 68[1] 60 SVR12 or 24 (%) 40 20 n/N = 29/29 11/11 27/28 17/25 14/16 29/30 0 GT2/3 Naive GT2/3 Experienced GT4/6 Naive GT4 Naive • Major caveat: no patients with cirrhosis included 1. Gane EJ, et al. AASLD 2012. Abstract 229. 2. Sulkowski M, et al. AASLD 2012. Abstract LB-2. 3. Hassanein T, et al. AASLD 2012. Abstract 230. 4. Hezode C, et al. AASLD 2012. Abstract 760.

36. Advantages of Future Therapies • Once-daily dosing • Shorter duration • Simpler regimens—no RGT • Fewer AEs • IFN free • High efficacy

37. Caveats to Future Therapies • Very small studies • Potential for toxicity remains • Agents from multiple classes (nucs, nonnucs, PI, alisporivir) pulled for toxicity • Efficacy and safety in cirrhosis largely unknown • Minimal data—DDIs, special populations (OLTx, HIV, ESRD) • Timelines uncertain • Not just approval, but availability and reimbursement • Costs uncertain, but likely an issue in many regions

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