BOCEPREVIR (BOC): EVIDENCE FROM TRIALS

BOCEPREVIR (BOC): EVIDENCE FROM TRIALS ROME, FEBRUARY 22 nd -25 th, 212 Savino Bruno, MD Department of Internal Medicine A.O. Fatebenefratelli e Oftalmico Milan, Italy

Savino Bruno, MD Director of InternalMedicine, Gastroenterologyand Liver Units A.O. Fatebenefratelli e Oftalmico Milan, Italy Il sottoscritto dichiara di aver avuto negli ultimi 12 mesi conflitto d interesse in relazione a questa presentazione Speaking Bureau and advisory Board MSD e che la presentazione contiene discussione di farmaciin studio o ad usooff-label Boceprevir

On-treatment response markers according to BOC use: the new lexicon BOC RVR Responsive Poorly responsive Early Late HCV RNA undetectable at wk 4 after Lead-in (LI) HCV RNA drop from baseline >1 log 1 after LI HCV RNA drop from baseline < 1 log 1 after LI HCV RNA undetectable at Wk 8 after BOC addition HCV RNA detectable at Wk 8 after BOC addiction * *LLD = 9 IU/ml, LLQ= 25 IU/ml

SPRINT-2 Treatment naive patients

SVR rates according to three different arms 1 9 8 SVR % 7 6 5 4 66 63 38 3 2 1 242/366 233/368 137/363 BOC PR 48 BOC RGT PR Poordad F, et al. NEJM 211

SVR rates by week 4 response 1 9 8 7 >1 log decline/undetectable <1 log decline undetectable 97 89 81 79 9 SVR % 6 5 4 3 51 28 38 2 1 4 PR 48 BOC RGT BOC PR 48 Poordad F, et al. NEJM 211

SVR rates by EARLY (week 8 HCV-RNA undetectable) and LATE (week 8 HCV-RNA detectable) response % Patients eligible for short therapy with PR /BOC due to HCV-RNA undetectable at week 8 SPRINT-2 Early Resp Late Resp 1 9 89 91 8 7 6 44 56 SVR % 5 4 3 2 37 43 1 17 19 36 14 166 182 44 12 Early Resp Late Resp Early Resp Late Resp BOC RGT BOC PR48 Poordad F, et al. NEJM 211

SVR rates according to IL-28B* SVR % 1 9 8 7 6 5 4 3 2 1 78 82 8 5/64 63/77 44/55 CC CT TT 28 33 113 65 67 13 PR48 BOC RGT BOC44/PR48 PR48 BOC RGT BOC44/PR48 PR48 BOC RGT BOC44/PR48 71 27 55 59 82 115 1/37 23/42 23/64 *6% of included patients Poordad F, et al. EASL 211

SVR rates according to Genotype (1a vs 1b) SVR % 1 9 8 7 6 5 4 3 2 1 36 66 177 41 51 126 59 16 179 PR BOC RGT BOC/PR 48 Gen 1a 66 89 134 Gen 1b 62 147 237 73 85 117

Anemia as predictor of SVR 1 9 SVR % 8 7 6 5 4 3 31 56 58 72 2 1 77 147 PR 48 6 18 212 363 BOC/PR 263 363 Hb 1 g/dl Hb<1 g/dl Sulkowski M, et al. EASL 211

IL-28B CC Polymorphism as a Predictor of SVR (Multiple Stepwise Logistic Regression Model) Genotype: 1b/Other vs 1a Age 4 vs>4 IL28B Genotype: CC vs. Non-CC BOC/RGT vs PR48 BOC/PR48 vs PR48 P <.1 P =.2 P <.1 P <.1 P <.1 IL28 (CC vs non-cc) was also predictive of SVR in full model with limited covariates (OR = 4.5, p <.1) Baseline HCV-RNA: 4, vs. >4, Only 7-9% of patients had VL 4, P <.1 23 Only covariates remaining significant at α=.5 after adjustment for the other variables were retained in the model as shown in the figure. Factors entered but not retained in the model were, region, race, gender, weight, BMI, steatosis, platelets, ALT, statin use, and fibrosis

IL28B and fibrosis are no longer an important predictor of SVR when Lead-in Response is considered SPRINT-2 (effect) Odds Ratio (95% CI) p-value BOC/PR48 vs PR48 7. (4.1, 12.) <.1 BOC/RGT vs PR48 6. (3.5, 1.2) <.1 Baseline HCV-RNA: 4, vs. >4, IU/mL 5.8 (1.9, 17.5).2 Log decline in HCV-RNA at TW 4 (continuous variable) 2.6 (2.1, 3.) <.1 Genotype: 1b/others vs 1a 2.3 (1.5, 3.6) <.1 BMI: 25-3 kg/m 2 vs. >3 kg/m 2 2.3 (1.4, 3.9).2 BMI: 25 kg/m 2 vs. >3 kg/m 2 1.9 (1.1, 3.3).2 Only covariates remaining significant at α=.5 after adjustment for the other variables were retained in the model as shown in the table.

Impact of severe Fibrosison SVR SVR % 1 9 8 7 6 5 4 3 2 1 67 67 52 38 38 41 328 319 313 24 34 42 F/1/2 F3/4 PR 48 BOC RGT BOC/PR48 Bruno S, et al. EASL 211

RESPOND-2 and PROVIDE Treatment experienced patients

SVR rates according to three different arms SVR % 1 9 8 7 6 5 4 3 2 1 66 59 21 17/161 95/162 17/8 BOC PR 48 BOC RGT PR Bacon BR, et al. NEJM 211

SVR rates in prior Relapser, Partial and Null Responders SVR % 1 9 8 7 6 5 4 3 2 1 72 36 38 149/28 53/145 16/42 Relapse Partial Null * Bacon BR, et al. NEJM 211 *Vierling J, et al. AASLD 211

SVR rates by EARLY (week 8 HCV-RNA undectable) and LATE (week 8 HCV-RNA detectable) response % Patients eligible for short therapy with PR /BOC due to HCV-RNA undetectable at week 8 Early Resp Late Resp 1 9 86 RESPOND-2 88 8 7 51 49 SVR % 6 5 4 3 4 43 2 1 64 74 29 74 74 84 3 7 Early Resp Late Resp Early Resp Late Resp BOC RGT BOC PR48 Bacon BR, et al. NEJM 211

SVR rates according to IL-28B* SVR % 1 9 8 7 6 5 4 3 2 1 CC CT TT 79 77 73 72 61 55 5 46 17 PR 48 BOC RGT BOC PR 48 PR 48 BOC RGT BOC PR 48 PR 48 BOC RGT BOC PR 48 *6% of included patients Poordad F, et al. EASL 211

SVR rates according to Genotype (1a vs 1b) SVR % 1 9 8 7 6 5 4 3 2 1 24 11 46 18 6 34 53 5 94 PR BOC RGT BOC/PR 48 Gen 1a 67 44 66 Gen 1b 64 61 96 71 43 61

Anemia as predictor of SVR 1 9 8 76 7 SVR % 6 5 5 4 3 2 1 2 12 6 PR 48 25 5 2 83 165 BOC/PR 119 157 Hb 1 g/dl Hb<1 g/dl Sulkowski M, et al. EASL 211

IL-28B CC Polymorphism as a Predictor of SVR (Multiple Stepwise Logistic Regression Model) BMI: 25 kg/m2 vs >3 kg/m2 Previous Response: Relapser vs Nonresponder.4 P <.1 P <.1 IL28 (CC vs non-cc) was predictive of SVR in full model with limited covariates (OR = 2.2, p=.25) BOC/RGT vs PR48 P <.1 BOC/PR48 vs PR48 <.1 P <.1 Only covariates remaining significant at α=.5 after adjustment for the other variables were retained in the model as shown in the figure. Factors entered but not retained in the model were IL28 polymorphism, HCV 1 subtype, race, gender, age, weight, platelets, fibrosis, steatosis, previous treatment (peginterferon alfa-2a vs peginterferon alfa-2b), ALT, baseline viral load, statin use and region

IL28B is no longer an important predictor of SVR when Lead-in Response is considered RESPOND-2 (effect) Odds Ratio (95% CI) p-value BOC/PR48 vs PR48 12.3 (6. to 24.9) <.1 BOC/RGT vs PR48 9.8 (4.9 to 19.7) <.1 Previous Response: Relapser vs Nonresponder Log decline in HCV-RNA at TW 4 (continuous variable) 2.3 (1.4 to 3.8).15 5.2 (3. to 9.2) <.1 Model fit using historical treatment response (relapser vs non responder), week 4 response and baseline characteristics Week 4 response (>1 log vs < 1 log decrease in HCV-RNA from baseline) was stronger predictor of SVR than historical treatment response Only covariates remaining significant at α=.5 after adjustment for the other variables were retained in the model as shown in the table.

Impact of severe Fibrosison SVR 1 9 8 7 66 68 68 SVR % 6 5 4 3 2 1 44 23 13 61 117 119 15 21 31 PR 48 BOC RGT BOC/PR48 PR 48 BOC RGT BOC/PR48 F /1/2 F 3/4 Bruno S, et al. EASL 211

SVR rates according to fibrosis stages and historical response 1 Relapser Partial responder 9 8 7 75 75 83 SVR % 6 5 5 47 55 46 4 3 2 1 31 12 38 59 79 PR 48 BOC RGT 58 77 BOC PR 48 2 2 1 11 22 PR 48 BOC RGT 15 18 BOC PR 48 9 PR 48 BOC RGT BOC PR 48 3 PR 48 BOC RGT F -2 F 3-4 F -2 F 3-4 2 23 18 38 23 42 6 13 3 1 6 13 BOC PR 48 Bruno S, et al. EASL 211

The paradigmoflead-inphase Potential biological and clinical usefulness of 4 week P/R lead-in period before the addition of BOC Achievement of steady-state drug levels (full biological actions) for Peginterferon/ribavirin Prevention of exposure to DAA agents in patients who cannot tolerate P/R therapy Accurate evaluation of real-time IFN responsiveness AssessmentofriskvsbenefitwhendecisiontoaddDAAisunclear NoroleinimprovingSVR

The paradigm of lead-in phase Undetectable Peg-interferon + Ribavirin for 4 weeks (Lead-in) before adding DAA HCV-RNA at week 4 RVR 1 log decay Responsive to IFN <1 log decay Poorly responsive to IFN

What is the role of lead-in period? Is lead-in period useful at identifying patients who can spare the addition of DAA? Is lead-in period useful at identifying patients at higher risk of developing resistance? May lead-in phase more accurately redefine the historical response in real-time?

SVR rates by HCV RNA undetectable (RVR) at TW 4 SVR % 1 9 8 7 6 5 4 3 2 1 97 89 9 PR 48 BOC RGT BOC PR 48 Poordad F, et al. NEJM 211

Resistance-Associated Variants (RAVs) SPRINT-2 RESPOND-2 1 1 9 9 8 8 7 7 RAV % 6 5 4 3 2 1 18 16 BOC RGT BOC PR48 6 5 4 3 2 1 7 BOC RGT 31 BOC PR48

Rate of resistant associated variants according to HCV-RNA decline at week 4 SPRINT-2 RESPOND-2 1 1 9 9 8 8 7 7 RAV % 6 5 4 3 52 4 6 5 4 3 28 34 2 1 4 <1 log >1 log decline decline RGT arm 6 <1 log >1 log decline decline Standard arm 2 1 9 <1 log >1 log decline decline RGT arm 6 <1 log >1 log decline decline Standard arm Poordad F, et al. NEJM 211 Bacon BR, et al. NEJM 211

1 9 SVR and RAV rates according to TW4 response* SPRINT-2 % % 8 8 7 7 6 52 6 5 5 38 4 4 4 33 28 28 3 3 34 34 2 2 1 1 SVR RAV SVR RAV SVR RAV SVR RAV 1 9 RESPOND-2 76 24 * * < 1log decline >1 log decline 76 26 < 1log decline >1 log decline

SVR % 1 9 8 7 6 5 4 3 2 1 7 SVR rates according to Historical response Partial responder 2 29 4 23 57 52 3 58 PR 48 BOC RGT BOC PR 48 1 9 8 7 6 5 4 3 2 1 TW 4 response 12 < 1 log decline 33 34 15 64 15 44 PR 48 BOC RGT BOC PR 48 SVR % 1 9 8 7 6 5 4 3 2 1 29 15 51 Relapser 69 72 15 75 77 13 PR 48 BOC RGT BOC PR 48 1 9 8 7 6 5 4 3 2 1 25 17 67 > 1 log decline 73 8 11 79 9 114 PR 48 BOC RGT BOC PR 48 Bacon BR, et al. NEJM 211

RESPOND-2: SVR according to historical and TW4 response Historical response 18% Historical response 1 9 1 9 6% 8 8 7 7 SVR % 6 5 4 3 6 5 4 3 61 81 2 1 37 31 36,5 72 Partial Relapse 2 1 36,5 72 Partial Relapse < 1 log decline at wk 4 > 1 log decline at wk 4

Poorly responsiveness to IFN patients

Predictors of SVR in Poor IFN Responders (SPRINT-2 and RESPOND-2 studies combined) Pre-treatment factors predictive of SVR Genotype 1b F/1/2 BL viral load <2,, IU/mL TW8 virologic response No patient with <3 log decline at TW8 achieved SVR Bacon BR, Bruno S, et al. AASLD 211

1 Combined Studies SVR in Patients with < or >1. log 1 Week 4 HCV-RNA Decline Patients With F3/F4 Score 9 8 82 7 SVR % 6 5 4 54 38 BOC/PR48 BOC RGT PR 3 2 1 22 13 < 1 log decline > 1 log decline

ADVERSE EVENTS Adverse Event, % BOC+PR PR Treatment naive patients n=1225 n=467 1) Anemia 5 3 EPO use 43 24 2) Dysgeusia 35 16 3) Neutropenia 25 19 Treatment experienced patients n=323 n=8 1) Anemia 45 2 2) Dysgeusia 44 11 Discontinuations due to adverse events, % 14 16 Anemia 2 1 Poordad F, et al. NEJM 211

No Difference in SVR in Patients With Hb<1 g/dl with ESA or Dose Reduction of Ribavirin 1 SPRINT-2: BOC/PR 9 8 7 71 78 74 68 SVR (%) 6 5 4 3 2 1 19 153 29 37 95 129 Both RBV DR EPO Neither 3 44 Sulkowski M et al. EASL 211

DRUG-DRUG interation 1. Major metabolic pathway of BOC is aldokenoreductase (AKR) 2. Changes in exposure of sensitive CYP3A substrate drugs with concomitant BOC expected BOC inhibits CYP3A4 only 3. BOC was safely tolerated when taken with many commonly prescribed medications including methadone and antidepressants 4. No apparent differences in SVR in patients treated with BOC/PR and concomitant medications Poordad F et al. AASLD 211

Treating G1 patients with BOC Triple tx Overall SVR rates encouraging in both naives and treatment experienced patients including well-certified null-responders. Roughly half of all patients will be eligible for shortened course of therapy Successful treatment arrests progression of liver disease LI enables predictability of response, resistance, and individualized care *DUAL tx/ Defer tx * RVR after LI/IL28B CC at BL, Low rate of SVR in poorly IFN responsive patients with advanced fibrosis and cirrhosis (either naives or treatment experienced ones) Potential for better treatment options in future, eg, better response rates, fewer adverse events, shorter duration Risk of resistance if therapy fails; impact on future options?

Futility Rules Differ for Boceprevir Boceprevir If HCV RNA is 1 IU/mL at Wk 12, all 3 medications should be discontinued If HCV RNA is confirmed detectableat Wk 24, all 3 medications should be discontinued

Suggested algorithm in clinical practice of BOC treatment

Suggested algorithm in clinical practice of BOC treatment in either RVR or responsiveto IFN Lead-in TW 4 RNA RVR (Naives) 1 log decay No BOC Add BOC TW 8 RNA Neg Pos 24/48 wks based on BL viralload 28 (Naives)/36 wks(nr) 48 wks(cirrhosis) 48 wks

Suggested algorithm in clinical practice of BOC treatment in poorly responsive to IFN (both naive and treatment experienced patient) Lead-in TW 4 RNA Add BOC < 1 log decline Favourable baseline predictive factors Genotype 1b, F-2, LVL Unfavourable baseline predictive factors BothGenotypes, F3-4, HVL TW 8 RNA NEG or 3 log decay <3 log decay Stop 48 weeks Stop

Avoid False Start

BACK UP

SVR rates (%) in PATIENTS POORLY RESPONSIVENESS TO IFN according to GENOTYPE in F3-4 STAGE and baseline VL >2.. COMBINED SPRINT 2 AND RESPOND 2 STUDIES SVR % 1 9 8 7 6 5 4 3 2 1 14 4 G1 a G1 b N=26 N=7 Bruno S, et al manuscript in progress

SVR rates (%) according to GENOTYPE, FIBROSIS STAGE and baseline VL in PATIENTS WITH POOR IFN RESPONSE (<1 log decline at TW4) COMBINED SPRINT 2 AND RESPOND 2 STUDIES Viral load Fibrosis G1a G1b HCV RNA (IU/ml) METAVIR % Patient number % Patient number 2.. F -2 44 27 65 26 F 3-4 25 8 1 4 >2.. F -2 27 13 4 58 F 3-4 4 26 14 7

SVR rates (%) according to GENOTYPE, FIBROSIS STAGE and baseline VL in PATIENTS WITH POOR IFN RESPONSE (<1 log decline at TW4) COMBINED SPRINT 2 AND RESPOND 2 STUDIES Viral load/fibrosis G1a G1b HCV RNA 2. / METAVIR F -2 44 (27paz) 65 (26 paz) HCV RNA 2. / METAVIR F 3-4 25 (8) 1 (4) HCV RNA >2. / METAVIR F -2 27 (13) 4 (58) HCV RNA >2. / METAVIR F 3-4 4 (26) 14 (7)

Quarto Stato, Giuseppe Pellizza da Volpedo

IL28B is no longer an important predictor of SVR when Lead-in Response is considered RESPOND-2 (effect) Odds Ratio (95% CI) p-value BOC/PR48 vs PR48 11.4 (4.6 to 28.) <.1 BOC/RGT vs PR48 7.9 (3.3 to 18.9) <.1 Previous Response: Relapser vs Nonresponder 2.2 (1.2 to 4.3).1 Log decline in HCV-RNA at TW 4 (continuous variable) 1.8 (1.3 to 2.4) <.1 BMI: 25 kg/m 2 vs >3 kg/m 2 3.4 (1.4 to 8.2).1 Only covariates remaining significant at α=.5 after adjustment for the other variables were retained in the model as shown in the table.

Anemia as predictor of SVR SPRINT-2 RESPOND-2 1 1 9 9 SVR (%) 8 7 6 5 4 3 2 31 56 58 72 8 7 6 5 4 3 2 2 25 5 76 1 77 147 PR 48 6 18 212 363 263 363 BOC/PR 1 12 6 PR 48 5 2 83 165 119 157 BOC/PR Hb 1 g/dl Hb<1 g/dl Hb 1 g/dl Hb<1 g/dl Sulkowski M et al, EASL 211

Next Stop

1 9 8 7 6 5 4 3 2 1 Early Interferon Response (Lead-In) Further Defines Likelihood of Success For Non-CC Patients 2 67 5 75 81 81 4 2 3 2 4 56 75 SPRINT-2 and RESPOND-2 combined 83 12 PR48 BOC RGT BOC/PR48 58 72 1 27 37 44 <1 log >1log <1log >1log <1log >1log CC CT TT Poordad, et al. Presented at the European Association for the Study of the Liver Annual Meeting; March 3 April 3, 211; Berlin, Germany. Abstract 12. 19 51 2 45 32 37 117 75 83 111 82 19 133 1 2 5 24 6 25 4 1 25 5 13 26 82 23 28 76 26 34

%Patients with RAVs detected 1 9 8 7 6 5 4 3 2 1 RAVs (All BOC treatment) 19% SPRINT-2 16% 1% 11% 87/468 24/232 Gen 1a RESPOND-2 Gen 1b 1 9 8 7 6 5 4 3 2 1 RAVs (NON-SVR Patients Only 58% 48% SPRINT-2 Gen 1a 48% 42% 31/188 14/127 87/151 24/5 31/66 17/41 RESPOND-2 Gen 1b

SPRINT-2 RESPOND-2 1 1 9 9 SVR% 8 7 6 5 4 36 41 59 66 62 73 8 7 6 5 4 53 67 64 71 3 2 3 2 24 18 1 66/177 51/126 16/179 89/134 147/237 85/117 11/46 6/34 5/94 44/66 61/96 43/61 1 PR BOC RGT BOC/PR 48 PR BOC RGT BOC/PR 48 Gen 1a Gen 1b Gen 1a Gen 1b

RESPOND-2: SVR by week 4 lead in response 1 1 8 8 73 79 SVR (%) 6 4 2 33 34 SVR (%) 6 4 2 25 12 15 46 15 44 17 67 8 11 9 114 PR 48 BOC RGT BOC/PR48 PR 48 BOC RGT BOC/PR48 Poorly Responsive to IFN Responsive to IFN <1 log 1 viral load decline at treatment week 4 1 log 1 viral load decline at treatment week 4 Bacon R et al., NEJM 211

Boceprevir in treatment experienced patients: Sub-analysis according to prior response 1 9 8 7 75 69 SVR % 6 5 4 52 4 3 2 1 77 13 72 15 BOC PR 48 BOC RGT BOC PR 48 BOC RGT 3 58 23 87 Relapse Partial

Boceprevir-response guided therapy guideline dosing regimen and duration of therapy Patient treatment status Naive to treatment with no cirrhosis Previous partial responder or relapser with no cirrhosis Patients with cirrhosis Week 1-4 (LI) Add at Week 5 Peg IFN and Ribavirin Peg IFN and Ribavirin Peg IFN and Ribavirin Boceprevir 8 mg 3 times daily Boceprevir 8 mg 3 times daily Boceprevir 8 mg 3 times daily Assessment HCV-RNA results Week 8 viral count Week 24 viral count Undetectable Undetectable Detectable Undetectable Undetectable Undetectable Detectable Undetectable Undetectable Undetectable Detectable Undetectable Treatment reccommendation Complete therapy with BPR up to treatment Week 28 Continue BPR up to treatment Week 36 then Give PR only from Week 37 to 48 Complete therapy with BPR up to treatment Week 36 Continue BPR up to treatment Week 36 then Give PR only from Week 37 to 48 Complete therapy with BPR up to treatment

SVR rate by EARLY (week 8 HCV-RNA negative) and LATE (week 8 HCV-RNA positive) response SPRINT-2 RESPOND-2 1 9 89 91 1 9 86 88 8 8 7 7 6 6 SVR 5 4 3 2 1 43 37 Early Resp Late Resp Early Resp Late Resp 5 4 3 2 1 4 43 Early Resp Late Resp Early Resp Late Resp BOC RGT BOC PR48 BOC RGT BOC PR48 Poordad F, et al NEJM 211

Advancesin HCV treatment: Genotype1 towards the end the disease? 1 1 9 8 75 SVR % 7 6 5 4 4 3 28 2 1 16 7 2 IFN 24 IFN 48 IFN/RBV24 IFN/RBV 48 PEG/RBV 48 DAA RGT QUAD 1991 211? Since the year of FDA approval

Next stop Very potent DAA therapy will make predictors of treatment outcome useless Eg: PSI-7977 (NS5B NI) + RBV +/-PegIFN - G1 SVR = 91% (98% per protocol) - G2/3 SVR = 1% Lawitz E, AASLD, 211 Gane EJ, AASLD, 211

Response markers associated with SVR in the era of DAA Baseline IL28B Fibrosis/Cirrhosis stage Viral load Genotype Statins in Boceprevir (BOC) Race On treatment Lead-in Early-late response at week 8 in BOC

SVR rates in prior Relapser and Partial responder SVR % 1 9 8 7 6 5 4 3 2 1 72 36 149/28 53/145 Relapse Partial

% 1 9 8 7 6 5 4 3 2 1 PROVIDE Study (SVR rates in prior NULL responders) 47 38 16 2/43 16/42 3/19 EOT SVR Relapse

Boceprevir in treatment naïvepatients: SVR rates by week 4 response >1 log decline/undetectable <1 log decline undetectable 1 9 8 97 81 89 79 9 7 SVR % 6 5 4 3 51 28 38 2 1 4 PR 48 BOC RGT BOC PR 48 766/197 (69%) 275/197 (25%) 69/197 (7%) Poordad F, et al. NEJM 211

2. SVR rates according to fibrosis/cirrhosis 1% 9% N=78 8% 7% 68 SVR % 6% 5% 4% 3% 2% 1% % 44 13 32 31 15 B+PR 36/48 RGT B+PR 48 PR 48 Bruno S, et al. EASL 211

SVR rates according to poorly response or response Poorly Responsive at wk 4 Responsive at wk 4 1 1 9 8 7 9 8 7 73 79 SVR % 6 5 4 3 33 34 6 5 4 3 25 2 2 1 12 15 46 15 44 PR 48 BOC RGT BOC PR 48 1 17 67 8 11 9 114 PR 48 BOC RGT BOC PR 48 Bacon et al, NEJM, 211

RESPOND-2: SVR according to historical and TW4 response SVR (%) SVR (%) 1 8 6 4 2 1 8 6 4 2 7 2 29 PR48 Partial responders 4 23 57 BOC RGT 52 3 58 BOC/PR48 <1 log 1 HCV RNA reduction at Week 4 33 34 _ 15 _ 15 _ 12 PR48 46 BOC RGT 44 BOC/PR48 SVR (%) 1 SVR (%) 8 6 4 2 1 8 6 4 2 29 15 51 PR48 25 Relapsers 69 75 72 15 BOC RGT 73 77 13 BOC/PR48 79 17 _ 8 _ 9 _ 67 11 114 PR48 BOC RGT BOC/PR48 1 log 1 HCV RNA reduction at Week 4 Bacon BR., et al. N Engl J Med 211; 364:127-1217.

SVR rates according to Viral load SVR % 1 9 8 7 6 5 4 3 2 1 8, IU/mL >8, IU/mL 85 76 63 61 45/53 197/313 41/54 192/314 BOC PR 48 BOC RGT

RESPOND-2: SVR according to historical and TW4 response Historical response Historical response 1 1 9 9 8 8 7 7 SVR % 6 5 4 3 6 5 4 3 61 81 2 1 37 31 36,5 72 Partial Relapse 2 1 36,5 72 Partial Relapse < 1 log decline at wk 4 > 1 log decline at wk 4

Real-Time Interferon Response (TW 4): RESPOND-2 STUDY SVR Rates According to Virologic Response by Wk 4 1 IFN responsiveness at TW 4 8 82 Poor <1 log 1 HCV-RNA decline Patients (%) 6 4 4 6 Good 1 log 1 HCV-RNA decline 2 18 Historical Partial responders Relapsers Overall, 26% of previous partial responders and relapsers are poorly IFN responsiveness Esteban R et al., EASL 211

SVR rates by week 4 response 1 9 8 7 >1 log decline/undetectable <1 log decline undetectable 97 89 81 79 9 SVR % 6 5 4 3 51 28 38 2 1 4 PR 48 BOC RGT BOC PR 48 766/197 (69%) 275/197 (25%) 69/197 (7%) Poordad F, et al. NEJM 211

DRUG-DRUG Interactions Drug Class Alfha 1-adrenoreceptor antagonist Anticonvulsants Ergot derivatives GI motility agents Herbal products HMG CoA reductase inhibitors Oral contraceptives Neuroleptic PDE5 inhibitor Sedative/hypnotics Controindicated with BOC Alfuzosin Carbamazepine, phenobarbital, phenytoin Dihydroergotamine, ergonovine, ergotamine, methylergo novine Cisapride Hypericum perforatum Lovastatin, simvastatin Drospirenone Pimozide Sildenafil or tadalafil when used for treatment of pulmonary arterial hypertension Triazolam, midazolam Poordad F, et al., AASLD 211