Future Directions in HCV Therapy Eric Lawitz, MD, AGAF,CPI Medical Director, The Texas Liver Institute Clinical Professor of Medicine University of Texas Health Science Center San Antonio, Texas

Standard Interferon + Ribavirin Peginterferon DAAs Milestones in Therapy of CHC: Average SVR Rates from Clinical Trials Adapted from US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring MD. 6% 16% 34% 42% 39% 55% 70+%

Generic NameTrade NameManufacturer Boceprevir Telaprevir Victrelis™ Incivek™ Merck Pharmaceuticals, Inc Vertex Pharmaceuticals, Inc DAAs with an Indication for the Treatment of G1 Chronic Hepatitis C Both compounds act by inhibiting HCV nonstructural NS3/4A protease and are referred to as direct acting antivirals (DAAs) US Food and Drug Administration. Available at

Limitations of Current Therapy Telaprevir and boceprevir only approved for Genotype 1 Interferon backbone required TID dosing for telaprevir/boceprevir Response guided therapy (both) and lead-in (boceprevir) complicated week treatment Limited efficacy in difficult to cure patients (e.g., patients with cirrhosis, prior null responders, African-Americans) Hematologic (both) and rash/dermatological (telaprevir) adverse events Drug-drug interactions

Sofosbuvir (SOF) (GS-7977) NS5B nucleotide polymerase inhibitor Favorable administration profile –Once daily, no food effect –No drug-drug interactions

Completed Phase 3 Trials NEUTRINO –GT 1, 4, 5, 6; treatment naïve –No comparator FISSION –GT 2 and 3; treatment naïve –Compared to 24 weeks of peginterferon + ribavirin POSITRON –GT 2 and 3; patients ineligible for or intolerant of interferon therapy –Compared to placebo FUSION –GT 2 and 3; patients unresponsive to prior treatment –Compared to 16 weeks of sofosbuvir + ribavirin

E. Lawitz et al, Abstract EASL, April 2013; Lawitz et al., N Engl J Med 2013, 368: NEUTRINO Patients –GT 1, 4, 5, 6 treatment naive –17% compensated cirrhosis –17% black –29% IL28B genotype CC Regimen for all patients –Sofosbuvir 400 mg qd –Ribavirin 1000/1200 mg qd –Peginterferon alfa-2a 180 mcg weekly

SVR12Sofosbuvir/PEG/RBV, n=327 Week NEUTRINO: Study Design Open label –SOF+PEG+RBV for 12 weeks (no response-guided therapy) Expanded inclusion criteria –No upper limit to age or BMI –Opiate replacement therapy permitted –Platelets ≥90,000/mm 3, neutrophils ≥1,500/mm 3 or 1,000/mm 3 (blacks) E. Lawitz et al, Abstract EASL, April 2013; Lawitz et al., N Engl J Med 2013, 368:

Post-treatment On treatment 299/ / /327 Week 2Week 4Week /327 >90% Of Patients Have Undetectable Virus After 2 Weeks and Achieve SVR E. Lawitz et al, Abstract EASL, April 2013; Lawitz et al., N Engl J Med 2013, 368:

n = 292 n = 28 n = 7 NEUTRINO: SVR by Genotype 295/327261/29227/287/7 E. Lawitz et al, Abstract EASL, April 2013; Lawitz et al., N Engl J Med 2013, 368:

n = 273 n = 54 n = 95 NEUTRINO: SVR by Subgroup n = 273n = 54 No cirrhosis Cirrhosis CC CT/TT IL28B genotype Black n = 95n = 232 E. Lawitz et al, Abstract EASL, April 2013; Lawitz et al., N Engl J Med 2013, 368:

Conclusions 12 weeks of SOF+PEG+RBV achieved 90% SVR in treatment naïve patients with GT 1, 4, 5, or 6 99% of patients had HCV RNA < LLOQ by treatment week 4 and all virologic failures were due to relapse This regimen was well tolerated E. Lawitz et al, Abstract EASL, April 2013; Lawitz et al., N Engl J Med 2013, 368:

Week SOF + RBV, n=256 SVR12 Peg-IFN + RBV (SOC), n=243 SVR12 SOF + RBV, n=207 SVR12 Placebo, n=71 SVR12 Week01224 SOF + RBV, n=103 Placebo SVR12 SOF + RBV, n=98 SVR12 Week RBV does mg/day for SOF + RBV and 800 mg/day for Peg-IFN + RBV. SOF dose 400 mg once daily; RBV dose mg/day. Jacobson et al. N Engl J Med 2013, 368: , Lawitz et al., N Engl J Med 2013, 368: , GT2 and GT 3: Study Designs FISSION (TN)

P <0.001 SVR12 (%) / / / 70 52/ / / / / 95 31/ 36 30/ 32 19/64 39/ / /10960/ SOF + RBV 12 weeks Jacobson et al. N Engl J Med 2013, 368: , Lawitz et al., N Engl J Med 2013, 368: , GT2 and GT 3: SVR by Genotype FISSION (TN)

SVR12 (%) / 59 44/ 54 25/ /9267/ / / 11 8/1 3 89/ / /38 11/37 GT 2GT 3 23/ 23 6/10 7/9 GT 2 14/ / 40 5/26 14/ 23 GT 3 3/14 SVR: Patients with Cirrhosis vs No Cirrhosis Jacobson et al. N Engl J Med 2013, 368: , Lawitz et al., N Engl J Med 2013, 368: , FISSION (TN)

12 weeks of SOF+RBV results in SVR>90% in GT 2 treatment naive patients with and without cirrhosis SVR rates were lower in GT 2 treatment experienced patients with cirrhosis compared to non-cirrhosis SOF+RBV led to similar results as PEG+RBV for GT 3 treatment naïve patients –Lowest rates observed in patients with cirrhosis SOF+RBV for 12 weeks is suboptimal for GT 3 treatment experienced patients –16 weeks total duration significantly increased SVR rates SOF+RBV well tolerated with fewer adverse events than PEG+RBV Genotype 3 ≠ genotype 2 HCV –Strategies to improve GT 3 results are needed Conclusions

Simeprevir (TMC 435) (PI)

NS3/4A protease inhibitor Antiviral activity against GT 1, 2, 4, 5 and 6 One capsule, once per day Simeprevir (TMC 435)

Completed Phase 3 Studies QUEST-1 and QUEST-2 –Same study design but studies conducted independent of one another –Treatment naïve GT 1 patients PROMISE –Same study design as QUEST-1 and QUEST-2 –GT 1 prior relapsers

SMV 150 mg/PEG/RBV PEG/RBV Post-Therapy Follow-Up Response Guided Treatment Placebo/ PEG/RBV Post-Therapy Follow-Up Weeks Response Guided Therapy: if HCV RNA <25 IU/mL at Week 4 and undetectable at Week 12, complete treatment at Week 24 –85-93% of patients met the criteria and qualified for total treatment duration of 24 weeks. QUEST-1, QUEST-2 and PROMISE Study Designs

80% Simeprevir + PEG/RBV Achieved SVR in ~80% of Treatment Naïve and Prior Relapsers 50% 81% 50% 79% 37%

QUEST-1: SVR by Subgroup Fibrosis 152/ 183 I. Jacobson et al, Abstract EASL, April 2013 GenotypeIL28B genotype 54/ 90 54/ 77 11/ / / / / 56 72/ 77 29/ / / 76 24/ 37 4/ 17

F0-F2F3 F4 (Cirrhosis) Similar results seen in QUEST-1 and PROMISE studies SVR Higher When Simeprevir Added to PEG/RBV For Patients With All Stages of Fibrosis/Cirrhosis (QUEST-2) 165/ / / 36 9/ 17 11/ 17 6/ 15

Conclusions Simeprevir 150 mg + PEG/RBV was highly effective against GT 1 treatment naïve patients with SVR (80%) Most patients (85%) receiving simeprevir were able to shorten therapy to 24 weeks Simeprevir 150 mg + PEG/RBV was generally well tolerated –Rates of anemia and rash were similar in the simeprevir and placebo groups I. Jacobson et al, Abstract EASL, April 2013

Simeprevir (TMC 435) (PI) + Sofosbuvir (GS-7977) (nuc)

Arm 1 Arm 2 Arm 3 Arm 4 Weeks SMV + SOF + RBV SMV + SOF + RBV SMV + SOF SMV+ SOF Post-treatment follow-up n = 24 n = 15 n = 27 n = 14 Interim analysis SVR4 Primary endpoint SVR12 Post-treatment follow-up Cohort 1: n=80 patients randomized 2:1:2:1 Cohort 2: n=87 patients randomized 2:1:2:1 SMV 150 mg QD + SOF 400 mg QD with/without RBV (Copegus ® ) 1000 or 1200 mg/day (BID) Interim analysis of Cohort 1 conducted when all patients in 12 week treatment arms (arms 3 and 4) reached SVR4 time point or discontinued early COSMOS: Study Design Lawitz et al., CROI, March 2013

Chronic HCV GT 1 infection 78% GT 1a Prior null response to PEG/RBV ‒ Failure to achieve >2 log 10 decline in HCV RNA by Week 12 Fibrosis F0-F1: 41% F2: 59% IL28B CT: 70% TT: 24% 29% African-American COSMOS: Key Eligibility Criteria – Cohort 1 Lawitz et al., CROI, March 2013

COSMOS: Virologic Response (12 Week Arms) RVR, n/N (%)Undetectable end of treatment, n/N (%) SVR4, n/N (%)SVR8, n/N (%) 23/ 27 8/ 14 27/ 27 14/ 14 26/ 27 13/ 14 26/ 27 13/ 14 Lawitz et al., CROI, March 2013 SVR8 (%)

Patients 24 weeks12 weeks SMV + SOF + RBV SMV + SOFSMV + SOF + RBV SMV + SOFTotal (n=24)(n=15)(n=27)(n=14)(n=80) AEs during treatment, % Grade 3/4 AEs 1, % Serious AEs, % Most common AEs (≥10% of total patients) Fatigue, % Headache, % Insomnia, % Nausea, % Anemia, % Cough, % Rash, % Treatment discontinuation Due to AEs, n11002 Non-safety reason, n21003 RBV dose reduction, %16.7NA3.7NA9.8 COSMOS: Safety & Tolerability 1 WHO Toxicity Grading Scale, 2003 Lawitz et al., CROI, March 2013

COSMOS: Cohort 2 SMV+SOF+RBV for 12 weeks GT 1 treatment naive and prior null responders with advanced disease (F3/F4) SVR4 results –SMV+SOF+RBV: 96% (26/27) –SMV+SOF: 100% (14/14) Medivir/Janssen Press Release, August 29, 2013

COSMOS: Summary 12 weeks of SMV+SOF led to an SVR8 rate of 96% with RBV and 93% without RBV in prior null responders with F0-F2 disease 12 weeks of SMV+SOF led to an SVR4 rate of 96% with RBV and 100% without RBV in treatment naïve and prior null responders with F3-F4 disease SMV+SOF+RBV was generally well tolerated

Daclatasvir (NS5A inhibitor) + Sofosbuvir (GS-7977) (nuc)

Background Patients who experience virologic failure on telaprevir or boceprevir-based regimens currently have no treatment options DCV plus SOF with or without RBV achieved SVR4 in 98% of 126 HCV GT 1-infected treatment-naive patients (Sulkowski et al. AASLD 2012) Study Aim –To evaluate the efficacy and safety of DCV+SOF with or without RBV for 24 weeks in GT 1-infected patients who failed prior treatment with TVR or BOC + PEG/RBV M.S. Sulkowski et al, Abstract EASL, April 2013

Study Design Patients –GT 1, non-cirrhotic –Prior nonresponse, relapse, or breakthrough during treatment with PEG/RBV+TVR or BOC –Patients who discontinued TVR or BOC due to an AE were excluded Week 24 Prior TVR/BOC Failures, GT 1a/1b (N = 41) n = 21 Follow-up n = 20 DCV 60 mg QD + SOF 400 mg QD DCV 60 mg QD + SOF 400 mg QD + RBV Follow-up SVR 4 SVR 12 M.S. Sulkowski et al, Abstract EASL, April 2013

Virologic Response 1 patient missing at post-treatment (PT) Week 12: HCV RNA was undetectable at PT Week 4 and at PT Week 24 21/41 patients have reached PT Week 24; all have achieved SVR 24 EOT HCV RNA < LLOQ (% patients) Week 2SVR 4 N = Week SVR DCV + SOF DCV + SOF + RBV Missing M.S. Sulkowski et al, Abstract EASL, April 2013

Conclusions M.S. Sulkowski et al, Abstract EASL, April 2013 The all-oral, once-daily combination of DCV+SOF with or without RBV achieved SVR in all GT 1 infected patients (n=41) who failed prior treatment with TVR or BOC+PEG/RBV DCV+SOF with or without RBV was well tolerated No Grade 3 or 4 hepatic or hematologic abnormalities

Daclatasvir (BMS ) (NS5A inhibitor) + Asunaprevir (BMS ) (PI)

Study AI Expansion Cohort: Prior Null Responders to PEG/RBV A. Lok, et al; APASL A1 (DUAL): DCV 60 mg QD + ASV 200 mg BID (GT 1b only) A2 (DUAL): DCV 60 mg QD + ASV 200 mg QD (GT 1b only) B1 (QUAD): DCV 60 mg QD + ASV 200 mg BID + PEG/RBV (GT 1a/1b) B2 (QUAD): DCV 60 mg QD + ASV 200 mg QD + PEG/RBV (GT 1a/1b) B3 (TRIPLE): DCV 60 mg QD + ASV 200 mg BID + RBV (GT 1a/1b) Follow-up N = 21 N = 22 N = 20 N = 18 Week 12 SVR 4 SVR 24 Week 24SVR 12 primary endpointSVR 48

TRIPLE Therapy (Arm B3): GT 1a vs GT 1b Individual HCV RNA Levels 1/18 GT 1a patient completed triple therapy and achieved SVR 4 DCV + ASV 200 mg BID + RBV Graphs truncated at viral breakthrough LLOQ LOD LLOQ LOD

Conclusions In non-cirrhotic prior null responders, 24 weeks of daclatasvir + asunaprevir appears to be an efficacious combination for GT 1b but not GT 1a

Daclatasvir (BMS ) (NS5A inhibitor) + Asunaprevir (BMS ) (PI) + BMS (non-nuc)

AI : Study Design Treatment naïve non-cirrhotic patients GT 1a: 74% and CT/TT: 70% G. Everson et al, Abstract EASL, April 2013

Summary The all oral, IFN-free, RBV-free, ritonavir- free combination of DCV, ASV, and BMS Achieved >90% (61/66) SVR4 and SVR12 (30/32) Had infrequent virologic failure (4.5%, 3/66) Most common AEs (≥10% total) were headache, asthenia, and gastrointestinal G. Everson et al, Abstract EASL, April 2013

Faldaprevir (BI ) (PI)

Faldaprevir: Phase 3 Studies (IFN-Containing) STARTVerso 1 –Treatment naïve GT 1 patients –All patients from Europe and Japan –Only Phase 3 study with results reported as of October 2013 STARTVerso 2 –Treatment naïve GT 1 patients –Studying shorter durations (12 vs 24 weeks) STARTVerso 3 –Treatment experienced GT 1 patients STARTVerso 4 –Treatment naïve/prior relapsers who are coinfected with HCV and HIV

STARTVerso1 Phase III, randomized, double-blind, placebo-controlled trial Patients –Treatment naïve GT 1 infection –78% Caucasian, 20% Asian –39% IL28B CC –66% GT 1b Regimen –PEG+RBV for 24 weeks plus faldaprevir/placebo Patients with early treatment success stopped all treatment at Week 24 Patients without Early Treatment Success and those in control arm received PEG/RBV for 48 weeks P. Ferenci et al, Abstract EASL, April 2013

PEG/RBV PBO/PEG/RBV Observation Period Day 1Week 12Week 24Week 48Week 72 FDV 240 mg/PEG/RBV Observation Period PBO/ PEG/RBV PEG/RBVObservation Period ETS No ETS Observation Period FDV 120 mg/ PEG/RBV PEG/RBV Observation Period ETS No ETS FDV 120 mg/ PEG/RBV PBO/ PEG/RBV STARTVerso1: Study Design Criteria for response guided therapy –Early Treatment Success (ETS): HCV RNA <25 IU/mL at Week 4 and undetectable at Week 12, complete treatment at Week 24 –88% met the criteria and qualified for total treatment duration of 24 weeks. P. Ferenci et al, Abstract EASL, April 2013

STARTVerso1 SVR12 rates P. Ferenci et al, Abstract EASL, April 2013

195/243204/246 9/166/15 No CirrhosisCirrhosis FDV 120 mg/ PEG/RBV FDV 120 mg/ PEG/RBV FDV 240 mg/ PEG/RBV FDV 240 mg/ PEG/RBV SVR in Patients With Cirrhosis P. Ferenci et al, Abstract EASL, April 2013

60/87143/17168/90142/17116/4552/86 FDV 240 mg/ PEG/RBV FDV 120 mg/ PEG/RBV FDV 240 mg/ PEG/RBV FDV 120 mg/ PEG/RBV SVR By GT 1 Subtype P. Ferenci et al, Abstract EASL, April 2013 GT1aGT1b

STARTVerso1 Conclusions FDV+PEG/RBV significantly increased SVR12 rates in GT 1 patients compared with PEG/RBV In total, 88% of patients treated with FDV were eligible to stop all treatment at Week 24 Patients without cirrhosis had higher SVR than patients with cirrhosis GT 1b infected patients had higher SVR than GT 1a infected patients FDV+PEG/RBV was well tolerated P. Ferenci et al, Abstract EASL, April 2013

Faldaprevir (BI ) (PI) + Deleobuvir (non nuc)

SOUND-C2: IFN-Free –Faldaprevir + deleobuvir + RBV –SVR rates between 59-69% in GT 1 treatment naïve patients with 16, 28 or 40 weeks of treatment Higher SVR in GT 1b (56-85%) vs GT 1a (38-47%) High rate of relapse (41%) in GT 1a treated for 16 weeks –Arm with no RBV had low SVR (39%) Zeuzem et al., N Engl J Med 2013, 369;

Faldaprevir: IFN-Free (Results Are Anticipated in 2014) HCVerso 1 (NCT ) and HCVerso 2 (NCT ) –Faldaprevir + deleobuvir + RBV –GT 1b only –Includes IFN-ineligible patients as well as patients with cirrhosis –Duration of therapy: 16 vs 24 weeks –Anticipated primary results: 1H 2014 Study with PPI-668 (NS5A inhibitor)(NCT ) –Faldaprevir + deleobuvir + PPI RBV –GT 1a –Treatment naïve –Anticipated primary results: 1H 2014

ABT-450/r (PI with ritonavir), ABT- 267 (NS5A inhibitor) and ABT-333 (non nuc)

AVIATOR Phase 2b, randomized, open-label, multicenter study Patients –GT 1 (66% GT 1a) –Treatment-naive and prior null response –Non-cirrhotic Duration –8, 12 and 24 weeks K.V. Kowdley et al, Abstract 3. EASL, April 2013

SVR12 (%) SVR24 (%) VBT/ Relapse 89880/ / / / / /2 SVR12 (%) SVR24 (%) VBT/ Relapse 89 0/5 93 3/ /0 N Regimen/duration SVR12 (%) SVR24** (%) VBT/ Relapse 80 ABT450ABT267ABT333RBV89880/10 41 ABT450ABT333RBV85831/4 79 ABT450ABT267RBV91891/8 79 ABT450ABT267ABT /5 79 ABT450ABT267ABT333RBV99960/1 80 ABT450ABT267ABT333RBV93900/2 N Regimen/duration SVR12 (%) SVR24 (%) VBT/ Relapse 45 ABT450ABT267RBV89 0/5 45 ABT450ABT267ABT333RBV93 3/0 43 ABT450ABT267ABT333RBV98951/0 Week Treatment naive Null response ** 8 patients who achieved SVR12 did not return >24 weeks and were counted as virological failures for SVR24 3 patients relapsed between SVR12 and SVR24 AVIATOR: Study Design K.V. Kowdley et al, Abstract 3. EASL, April 2013

SVR 24 by Baseline Subgroups – Treatment-Naïve Patients* *Includes patients randomized to the quad therapy arms (12 or 24 weeks duration). Male Female 1a1b ≥7 log <7 log F0-F1F2-F3 Non-CC CC N= K.V. Kowdley et al, Abstract 3. EASL, April 2013

SVR 24 by Baseline Subgroups – Null Responders* *Includes patients randomized to the quad therapy arms (12 or 24 weeks duration). Male Female 1a1b ≥7 log <7 log F0-F1F2-F3 Non-CC CC N= K.V. Kowdley et al, Abstract 3. EASL, April 2013

Event, % Total (N=247) Treatment-Naïve (N=159) Null Responders (N=88) Headache Fatigue Nausea Insomnia Diarrhea *Includes patients randomized to the quad therapy arms (12 or 24 weeks duration) K.V. Kowdley et al, Abstract 3. EASL, April 2013 Most Common Adverse Events*

Safety 6 patients (2.4%) discontinued due to study drug-related AEs; 4 of 6 considered related to treatment. 4 patients (1.6%) experienced SAEs –1 (arthralgia) was possibly study drug-related Moderate-to-severe study drug-related AEs with >10% incidence in any arm were asthenia and fatigue. 6 patients (2.8%) and 1 patient (0.6%) experienced Grade 3-4 laboratory abnormalities in total bilirubin and ALT, respectively; all resolved with continued dosing. K.V. Kowdley et al, Abstract 3. EASL, April 2013

AVIATOR Conclusions Comparable SVR12 and 24 seen with 12 and 24 weeks of treatment SVR rates >90% were achieved in naive and prior null responders with a 3-DAA+RBV regimen –No clinically meaningful differences were observed by gender, HCV subtype, IL28B genotype, baseline HCV-RNA or severity of fibrosis. K.V. Kowdley et al, Abstract 3. EASL, April 2013

Overall Summary All oral therapy expected to be available for GT2 and GT3 by early All oral therapy for GT 1 will be available no sooner than 2H2014. Even with PEG/RBV backbone, soon to be available DAAs for GT 1 offer advantages over currently approved DAAs.