AASLD 2010 HCV Feedback October 29 - November 2, 2010 Boston, Massachusetts Dr Allister J Grant Consultant Hepatologist Leicester Liver Unit

1.Boceprevir, a potent inhibitor of HCV NS3 protease 2.Telaprevir, a potent inhibitor of HCV NS3/4A protease 3.Both being tested in combination with standard-of- care peginterferon alfa-2/ ribavirin in phase III studies in chronic HCV infection Trials reported at AASLD Boceprevir SPRINT-2: naive GT1 patients RESPOND-2: nonresponder GT1 patients 2.Telaprevir ADVANCE: naive GT1 patients ILLUMINATE: response- guided therapy in naive GT1 patients Boceprevir and Telaprevir

Treatment-naive patients with genotype 1 HCV (2 cohorts: N = 938 nonblack and 159 black) PR* (n = 316, 52) PR* (n = 311 nonblack, 52 black) Wk 72 Wk 48 Follow-up Wk 28 Follow-up Wk 4 BOC + PR* (n = 316 nonblack, 52 black) BOC + PR* (n = 311 nonblack, 55 black) PR* (n = 311, 55) PR* *BOC 800 mg q8h; pegIFN alfa-2b 1.5 µg/kg/wk; weight-based RBV mg/day. † Undetectable HCV RNA at Wk 4 of BOC treatment (ie, at Wk 8) and at all subsequent assays. Poordad F, et al. AASLD Abstract LB-4. Follow-up RVR † No RVR  Phase III, Randomized, placebo-controlled trial SPRINT-2: Boceprevir + PegIFN/RBV in G1 Tx-Naive Patients PR* (n = 311, 52 )

Patients (%) SVR Relapse 4-wk PR + 44 weeks BOC + PR4-wk PR + response-guided BOC + PR48-wk PR Patients (%) SVRRelapse Nonblack Patients Black Patients P <.0001 P =.044 P =.004 Poordad F, et al. AASLD Abstract LB-4. n = SPRINT-2: Response Rates According to Race

SPRINT-2: Response Rates >1 log drop in VL at wk 4: – 82% SVR for both B/PR arms <1log drop in VL at wk 4: – 28% SVR in RGT (response guided therapy) – 38% SVR in 44BOC/PR PCR neg at week 4 and 8 – 97% SVR in RGT (47% of patients) – 98% SVR in 44BOC/PR

RESPOND-2: Boceprevir in G1 Prior Non-responders to PegIFN/RBV Phase III, Randomised PR* (n = 80) PR* (n = 161) BOC + PR* PR* (n = 162) BOC + PR* If detectable at Wk 8 PR* Bacon BR, et al. AASLD Abstract ♯ 216. Treatment- experienced patients with GT1 HCV (N = 403) Wk 48 Wk 8 Wk 36 Follow-up † *BOC 800 mg TID; pegIFN alfa-2b 1.5 µg/kg/wk; weight-based RBV mg/day. † Follow-up for 24 wks after completion of therapy. Wk 4

Overall SVR (%) 4-wk PR + 44-wk BOC + PR (n = 161) 59* Previous Nonresponders Previous Relapsers 48-wk PR (n = 80) 4-wk PR + response-guided BOC + PR (n = 162) P <.0001 vs control (both arms) Bacon BR, et al. AASLD Abstract / / / 80 23/ 57 30/ 58 2/29 72/ / / 51 RESPOND-2: SVR Rates According to Treatment Arm and Prior Response

McHutchison JG, et al. N Engl J Med. 2009;360: Treatment- naive patients infected with genotype 1 HCV (N = 250) 12-Wk Arm TVR* + PegIFN/RBV † (n = 17) PegIFN/RBV* Wk Wk Control Arm PegIFN/RBV † + Placebo (n = 75) 48-Wk Control Arm PegIFN/RBV † + Placebo (n = 75) 24-Wk Arm TVR* + PegIFN/RBV † (n = 79) 48-Wk Arm TVR* + PegIFN/RBV † (n = 79) PegIFN/RBV* Wk 24 Wk wk follow-up *1250 mg loading dose of TVR administered on Day 1, then 750 mg 3 times daily. † PegIFN alfa-2a 180 µg/wk + RBV mg/day. PROVE 1 : Combination of Telaprevir with PegIFN/Ribavirin significantly increases SVR in treatment-naïve patients with HCV Genotype 1

McHutchison JG, et al. N Engl J Med. 2009;360: Patients (%) 12-wk TVR + 48-wk pegIFN/RBV (n = 79) 12-wk TVR + 24-wk pegIFN/RBV (n = 79) 12-wk TVR + pegIFN/RBV (n = 17) Control (n = 75) SVRRelapse † ‡ N/A, not applicable. *P <.001 vs control. † P =.02 vs control. ‡ P =.002 vs control. PROVE 1: Results

Frequency of undetectable HCV RNA levels during and after treatment WeekT12/PR24 N=79 T12/PR48 N=79 T12/PR12 N=17 PR48 N=75 464(81%) 10(59%)8(11%) 1254(68%)63(80%)12(71%)34(45%) 2445(57%)56(71%)NA43(57%) 48NA51(65%)NA35(47%) SVR48(61%)53(67%)6(35%)31(41%) 12% 14% McHutchison JG, et al. N Engl J Med. 2009;360:

T12/PR24 vs T12/PR48 T12/PR24T12/PR48 RVR81% SVR61%67% Relapse2%6% DC 2° to A/E25.3%13.9% Dropouts47%32% McHutchison JG, et al. N Engl J Med. 2009;360:

PROVE 1: Conclusions 1.Coadministration of a 12-week course of TVR with 24 or 48 weeks of pegIFN/RBV significantly increased SVR rates in treatment-naive patients infected with genotype 1 HCV vs 48 weeks of pegIFN/RBV alone 2.Coadministration of TVR also resulted in higher rate of RVR and lower relapse rate compared with pegIFN/RBV 3.TVR coadministration increased rate of treatment discontinuation due to adverse effects, predominantly rash McHutchison JG, et al. N Engl J Med. 2009;360:

Prove 3 McHutchison JG, et al. AASLD Abstract 66, NEJM OutcomeControl Arm (n = 114) 12-Wk TVR + 24-Wk PegIFN/RBV (n = 115) 24-Wk TVR + 48-Wk PegIFN/RBV (n = 113) 24-Wk TVR + PegIFN (n = 111) SVR, %1451*53*24 †  Previous nonresponders, % (n/N) 9 (6/68)39* (26/66)38* (24/64)11 ‡ (7/62)  Previous relapsers, % (n/N) 20 (8/41)69* (29/42)76* (31/41)42 § (16/38)  Cirrhotics % *P <.001 vs control. † P =.024 vs control. ‡ P =.297 vs control. § P =.029 vs control. 24 vs 48wks of T/PR in patients with G1 previously treated with PEG IFN/ RBV- Week 4 non-response - <1log decline in control arm or detectable HCV in TPR arms

ADVANCE: Telaprevir + PegIFN/RBV in G1 Tx-Naive Patients Wk 12 TVR + PR* (n = 364) TVR + PR* (n = 363) PR* (n = 361) eRVR † : PR* Wk 72 Wk 48 Wk 8 Follow-up *TVR 750 mg q8h; pegIFN alfa-2a 180 µg/wk; weight-based RBV mg/day. † eRVR: extended rapid virologic response = undetectable HCV RNA at Wks 4 and 12. Jacobson IM, et al. AASLD Abstract 211. Wk 24 PR* eRVR † : PR* PR* Follow-up  Phase III, Randomized, placebo-controlled trial Treatment-naive patients with genotype1 HCV (N = 1088)

ADVANCE: 1088 Treatment naïve G1 patients randomised: TPV/PEG/RBV x8 weeks then PEG /RBV x16 weeks (T8/PR24) TPV/PEG/RBV x12 weeks then PEG /RBV x12 weeks (T12/PR24) PEG/RBV x48 weeks (PR48) RESULTS: T8/PR24 N=364 T12/PR24 N=363 PR48 N=361 RVR (%)67689 eRVR (%)57588 SVR (%) eRVR-  SVR Completion % PR Viral breakthrough 10.25NA Jacobson I AASLD ♯ 211 Kiefer T AASLD LB-11

ILLUMINATE: Response-Guided Telaprevir + PegIFN/RBV in G1 Naive Pts Treatment- naive patients with GT1 HCV (N = 540) PR* (n = 162) PR* (n = 160) Wk 72Wk 48Wk 24 Follow-up *TVR 750 mg q8h; pegIFN alfa-2a 180 µg/wk; weight-based RBV mg/day. † eRVR: extended rapid virologic response = undetectable HCV RNA at Wks 4 and 12. Sherman KE, et al. AASLD Abstract LB-2. Follow-up  Phase III Open-label, randomized trial, ITT analysis Wk 20 eRVR † No eRVR † PR* (n = 218) TVR + PR* Wk 12 PR*

wk therapy SVR (%) wk therapy 88 Overall 72 Patients With eRVR n/N =388/540149/ /160 Sherman KE, et al. AASLD Abstract LB-2. ILLUMINATE: Overall SVR Rates

ILLUMINATE: Adverse Events – Anaemia <8.5 9% in TPV 2% in PR 0.6% DC – Fatigue (1.1% DC) – Rash Eczematous rash in 37% 7% severe rash – Pruritis – Nausea Overall discontinuation rate 17% In first 12 weeks there was: – 7% DC of all drugs – 12% DC of Telaprevir

Interferon Free Therapy? BMS BMS Alone or With PegIFN/RBV in G1 Null Responders Lok A, et al. AASLD Abstract LB-8. Prior null responders with GT1 HCV (N = 21) BMS mg QD + BMS mg BID (n = 11) Wk 72 Wk 24 Follow-up BMS mg QD + BMS mg BID + PR* (n = 10)  Open-label, randomized, placebo-controlled phase IIa trial  BMS : NS5A polymerase inhibitor  BMS : NS3 protease inhibitor Follow-up *PegIFN alfa-2a 180 µg/wk; weight-based RBV mg/day.

Wk 12 Interim Analysis RVReRVRcEVR BMS BMS BMS BMS PR Patients (%) 7/116/10 4/115/119/10  All viral breakthroughs occurred in patients with GT1a Lok A, et al. AASLD Abstract LB-8.

Other Protease/Polymerase Inhibitors TMC435- NS3/4a Protease inhibitor (PILLAR Trial) – Phase IIa, G1 Naive – Once Daily – weeks Rx +PR48 – SVR 91%-98% (4 vs12 wks ) Daneprovir – RG7227 phase II, in G1 naive patients (ATLAS trial) – 88% to 92% of patients achieved cEVR when combined with pegIFN/RBV vs 43% with SOC Vaniprevir- NS3/4a Protease Inhibitor – MK-7009 phase IIa study G1 naive patients without cirrhosis – Significantly higher when combined with pegIFN/RBV vs SOC RVR: 67% to 84% vs 5% Fried M, et al. AASLD Abstract LB-5. Terrault N, et al. AASLD Abstract 32. Manns MP, et al. AASLD Abstract 82

HCV Pharmacogenetics GWAS used patients from IDEAL and Muir Studies 1137 samples on patients with SVR SNP’s rs on Chr 19 strongly associated with SVR & localised to IL28β SVR % Thomas DL, et al. Nature. 2009;461:

Regional Distribution of IL28B rs CC Genotype

 IL28β polymorphisms associated with – Higher SVR rates [1] – Higher RVR rates [2] – Higher HCV RNA [3] – Higher LDL levels [4] – Higher baseline ALT levels [5] – Higher rate of spontaneous viral clearance [6] 1. Ge D, et al. Nature. 2009;461: Mangia A, et al. AASLD Abstract Liu L, et al. AASLD Abstract Saito H, et al. AASLD Abstract Thompson AJ, et al. AASLD Abstract Thomas DL, et al. Nature. 2009;461: IL28β Associations in Patients With Hepatitis C

And if time

♯ 214:Maintenance PEG IFN to prevent HCC Extended FU from HALT-C trial 1084 patients yr FU 88 HCC (20 clinical HCC) No difference between Rx and Control at 3/5/7yr Subgroup analysis – Cirrhotics who had PEG for >2 years- marginal benefit A Lok et al AASLD 2010, Abstract 214

EXTEND Trial: Long Term FU of PROVE 1-3 patients 3 yr FU of T/PR treated patients 123 patients who had SVR’s from previous studies 122/123 had durable SVR (99%) 79 patients without SVR analysed for resistance and after 22 mo 89% reverted to wild type S Zeuzem et al AASLD 2010, Abstract 227

♯ 213: Effect of SVR on all cause mortality Dept of Veterans Affairs Data Registry patients with post Rx RNA, SVR rate 44% – 52% smokers, 20% DM, 15% COPD, 12% CAD, 26% alcohol, 36% depression – 1535 died (median 3.7yrs) Time Mortality G1,2,3 with SVR G1,2 No SVR G3 No SVR