Hepatitis C Choices in Care

1. Hepatitis C Choices in Care Future of Western Management of Hepatitis C Robert Gish, MD

2. New Therapy Reality • Pegylated interferon alpha will remain the platform for all hepatitis C therapy for the foreseeable future • No FDA approved small molecule therapy, without interferon base, for at least 3 years and maybe longer

3. HCV: “Drugable” Targets NS5a inhibitors

4. New Therapies Oral drugs (known as direct-acting antivirals, or DAAs) that specifically target certain steps in the hepatitis C virus life cycle are in late-stage development.

5. New Therapies • HCV-specific protease inhibitors will be the first DAA class available. • Protease inhibitors block cleaving of viral proteins

6. New Therapies • Nucleoside and nucleotide polymerase inhibitors • Non-nucleoside polymerase inhibitors • NS5a inhibitors • Novel Interferons • OtherImmune Modulators • Anti-fibrotics • For a complete list of drugs in the HCV pipeline visit: http://www.treatmentactiongroup.org/publication.aspx?id=3798

7. Definitions of Response to Anti-HCV Therapy 8 PEG IFN/RBV 7 Breakthrough Relapse Null Response 6 5 2-Log Decline HCV RNA (IU/mL) 4 Partial Response 3 Limit of Detection 2 SVR 1 0 -6 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Week

8. Definitions of Response to Anti-HCV Therapy • Relapse HCV RNA becomes and remains undetectable during treatment but reappears after treatment is stopped. • Non-response HCV RNA drops by two logs but never becomes undetectable • Null response HCV RNA drops less than one log after four weeks and less than two logs after 12 weeks of treatment • Viral breakthrough HCV RNA reemerges after it becomes undetectablewhile on treatment Adapted from the Treatment Action Group 2010 Pipeline report

9. Definitions of Response to Anti-HCV Therapy • Very rapid virological response (vRVR) HCV RNA becomes undetectable after 14 days of treatment • Rapid virological response (RVR) HCV RNA becomes undetectable after 4 weeks of treatment • Extended rapid virological response (eRVR) HCV RNA becomes undetectable after 4 weeks of treatment and remains undetectable at week 12 • Partial early virological response (pEVR) HCV RNA drops by at least 2 logs at week 12 Adapted from the Treatment Action Group 2010 Pipeline report

10. Definitions of Response to Anti-HCV Therapy • Complete early virological response (cEVR) HCV RNA remains undetectable after 12 weeks of treatment • End-of-treatment response (EOT) HCV RNA remains undetectable at the end of treatment • Slow Virologic response (SR) 2 log drop at week 12 and HCV RNA negative at week 24 • Sustained virological response (SVR) No HCV RNA detectable 6 months after completion of treatment - Cure Adapted from the Treatment Action Group 2010 Pipeline report

11. Looks at: safety & activity Dose (what is maximum tolerated dose) Phamacokinetics(how much drug gets in, & how long it lasts) Small & short-term (monotherapy for 2 days to 2 weeks) Phase Ia - Healthy volunteers Phase Ib - People w/ HCV Clinical Trial PHASE I

12. Looks at: safety & efficacy (capacity to produce a certain effect, such as SVR) 12- 48 weeks of treatment, plus follow up Larger (>100 people) Randomized SVR is primary endpoint; RVR &/ or EVR are co-primary endpoints Often used to choose dose and duration Not a good idea to leap to conclusions about results, as these are too small--but can inform design of phase III (example: 44% SVR rate in African Americans with SOC + an HCV protease inhibitor--based on 10% of study population--or 18/27 people) Clinical Trial PHASE II

13. Looks at: safety & efficacy Effectiveness (a measure of the accuracy or success of a diagnostic or therapeutic technique when carried out in an average clinical environment) Randomized Surrogate (or clinical) endpoints Large (can be 1000’s of people) Used to license medications Clinical Trial PHASE III

14. post-approval; Diverse populations Long-term effectiveness & toxicities Treatment strategies Clinical Trial PHASE IV

15. PHASE I: high-risk(toxicity, risk of incorrect dose/resistance) PHASE II: if you can take a risk, it might be a good idea PHASE III: safer entry point; more is known about the drug & dose Risks & Benefits of Trial Participation

16. PROVE 1 Phase II: Response Rates (ITT) PEG-IFN RBV 48 wk 100 TVR 12 wk PEG-IFN RBV 48 wk 90 † † TVR 12 wk PEG-IFNRBV 24 wk* 81 81 80 TVR 12 wk PEG-IFN RBV 12 wk* ‡ 67 70 † 61 59 60 50 Patients (%) 41 40 35 33 30 23 20 11 10 6 2 0 4 Wk Undetectable SVR Relapse *Patients stopping therapy at 12 and 24 weeks had achieved a RVR; †P=0.001 vs control; ‡P=0.02 vs control McHutchison JG, et al. N Engl J Med. 2009;360(18):1827-1838.

17. Boceprevir: Phase IISustained Virologic Responsea Part 1 Part 2 80 75e 80 60 40 20 0 67d 70 60 56c 54 50 50 38 36 % Patients HCV Negative Patients HCV Negative (%) 40 30 20 10 n= 104 107 103 103 n= 16 59 103 0 P/R(Control)48 wks P/R/B28 wksf P/R 4 wks P/R/B 24 wks P/R/B48 wks P/R 4 wks  P/R/B44 wks P/R/B48 wks P/low-dose R/B48 wks P=PEG-IFN alfa-2b; R=RBV; B=boceprevir aRoche COBAS TaqMan LLD <15 IU/mL; bP=0.013; cP=0.005; dP<0.0001; eP<0.0001 compared to P/R Control; f1 late relapser after follow-up week 24, not included n SVR Kwo PY, et al. (AASLD Abstract 1582). Hepatology. 2009;50(S4):1035A.

18. SVR Influenced by IL28B Genotype 100 75 50 25 0 P<0.0001 P=0.002 P=0.004 P<0.0001 SVR (% of Patients) Genotype: T/T T/C C/C T/T T/C C/C T/T T/C C/C T/T T/C C/C European- Americans African- Americans Hispanics Combined Ge D, et al. Nature. 2009;461(7262):399-401.

19. INFORM-1: No Inteferon !Antiviral Activity in HCV G1 Interferon-Naïve and Null Responders with a BID Regimen of RG7128 + RG7227 100 RG7128 1000 mg BID + RG7227 900 mg BID 88 90 7 80 6 TF - Nulls 70 63 Naïves 5 60 50 EOT HCV RNA <LLOQ or LLOD (%) 50 Median Log10 HCV RNA (IU/mL) 4 40 3 30 25 2 20 Limit of Detection Naïves Naïves Nulls Nulls 10 1 1 3 5 7 9 11 13 0 Days LLOD: Lower limit of detection LLOQ: Lower limit of quantification <LLOD <LLOQ GaneEJ, et al. (Abstract 193). Hepatology. 2009;50(S4):394A-395A.

20. Vitamin D: Impact on virologic response • Randomized Study, 58 patients G1, treatment naïve • PEG-IFN-2b (1.5 mcg/kg) + RBV (1000-1200 mg) + Vit D (1000-4000 IU)(27 patients, median age 47, 50 % male, 55 % > F2) • PEG-IFN-2b (1.5 mcg/kg) + RBV (1000-1200 mg) + placebo(31 patients, median age 49, 60 % male, 18 % > F2) HCV RNA undetectable(< 50 IU) 100 96 % 80 Placebo + PEG-IFN/RBV 60 48 % 44 % % Vitamin D + PEG-IFN/RBV 40 18 % 20 0 S4 S12 AASLD 2009 – Abu-Mouch S, Israël, Abstract LB20 actualisé

21. Graveyard for HCV Compounds is Filling Up Quickly! BILN 2061 (Protease) ISIS 14803 (Antisense) JTK-003 (Polymerase) UT-231B (Imino sugar) Heptazyme (Ribozyme) HCV-796 (Polymerase) VX-497 (IMPDH inhibitor) Viramidine (RBV analogue) NM-283 (Polymerase) R803 (Polymerase) Idenix compounds 2010 ANA975 (TLR agonist) R1626 (polymerase) CPG 10101 (TLR agonist) ACH-806/GS-9132 (NS4a) R7025 (Interferon-alpha) Courtesy of Nelson D.

22. To Treat or not to Treat: A Constellation of Considerations Histologic stage 20%+ life time risk Of cirrhosis Duration of infection Genotype virus Genotype Patient (IL28) Age Family and other support Personal plans (marriage, pregnancy) ALT Occupation Patient "mindset" Extrahepatic Features (Fatigue, EMC, PCT) HIV coinfection Contraindications & comorbidities Insulin Resistance PinKAALSD CME 2009

23. HCV Therapy – the bottom line • No new agent before 2011 • All new therapies will be used in combination with PEG-IFN for the foreseeable future (2015) • Ribavirin will still need to be used • Combination therapyrequired with new DAA due to rapid development of resistance

24. HCV Therapy – the bottom line Adherence is critical! Successful HCV treatment must rapidly—and fully—suppress hepatitis C virus, & keep it completely suppressed throughout the course of treatment (12-72 weeks)

25. For more information Visit us on line at www.HepCChallenge.org 8: Western (Allopathic) Medicine Section 4: Future of Allopathic Hepatitis C Treatment http://www.hepcchallenge.org/choices/pdf/Chapter_08_04_OL.pdf