HCV Pipeline: The Next 18 Months Michael W. Fried, MD

HCV Pipeline: The Next 18 Months Michael W. Fried, MD Professor of Medicine Director, UNC Liver Center University of North Carolina at Chapel Hill

Michael W. Fried, MD Commercial Disclosures Grants/Research Support Genentech, Merck, Vertex, Janssen, Bristol-Myers Squibb, Anadys, Abbott, Gilead Consultant: Genentech, Janssen, Vertex, Merck, Novartis, Abbott, Janssen, Gilead, Idenix Stock/Shareholder: None Speakers Bureau: None Other Financial Support: NIH Grants

Great Bridges of the World

Triple Therapy is a Bridge to All Oral Regimens Why is/was the Triple Therapy Bridge important? Provided highly effective first generation regimens Provided info about toxicity of DAAs against the known background of PEG/RBV AE profile Provided clinical information about viral resistance and clues about potentially effective oral combinations Provided a safety net for testing new DAAs in POC studies Taught us what to aspire for in next generation therapies

Walking, Before You Can Run QUAD Regimens Protease Inhibitor NS5A Inhibitor QUAD Regimens PEG-± + RBV QUAD Regimens Nucleotide Polymerase Inhibitor Non-Nuc Polymerase Inhibitor All-Oral Regimens PEG-lambda + RBV + NS5A Inhibitor

HCV Treatment Regimens by 2015 Estimated U.S. Approval Geno Regimen Population Studied in Phase III 4Q 2013 1 P/R + Simeprevir Naïve/Relapsers 4Q 2013 1 P/R + Sofosbuvir Naive Off Label 1 Simeprevir + Sofosbuvir Only phase II data Unknown 1 P/R + Faldeprevir Naïve and treatment experienced 4Q 2014 1 Sofosbuvir/Ledipasvir/RBV Naïve and treatment experienced 4Q 2013 2 and 3 Sofosbuvir + RBV Naïve and treatment experienced 4Q 2014-1Q 2015 1 ABT450/r + ABT333+ ABT 267 + RBV Naïve and treatment experienced 4Q 2015 1 Asunaprevir+ Daclatasvir + NNI Naive Unknown All Peg-Lambda, MK-5172 (PI), VX135 (Nuc) Multiple other potential combinations and classes Ongoing

Simeprevir (TMC435) + PEG/RBV: Phase III QUEST-1/QUEST-2: Treatment-naïve, Genotype 1 Q1: n=264 Q2: n=257 TMC435 150mg + PEG/RBV PEG/RBV RGT No? PEG + RBV RGT Yes? Post-Treatment F/U Q1: n=130 Q2: n=134 Placebo + PEG/RBV PEG/RBV 0 12 24 48 72 RGT* Week QUEST-1: 30% F3-F4 QUEST-2: 22% F3-F4 RGT duration in TMC435 arms; End treatment at Week 24, if HCV RNA <25 IU/mL detectable/undetectable at W4 and <25 IU/mL undetectable at W12 (all others continued PegIFN/RBV up to 48 W) Jacobson et al. EASL 2013; Manns et al. EASL 2013

Simeprevir (TMC435) + PEG/RBV: Phase III QUEST-1 and QUEST-2: Treatment-naïve, Genotype 1 100% 80% % SVR12 60% 40% 20% 85% Met RGT TMC435 PEG/RBV 91% 80% 81% n=394 n=391 50% 50% 0% QUEST-1 QUEST-2 85%-93% qualified for shorter duration of therapy AEs, including rash and anemia, similar to placebo and c/w phase II studies Mild and reversible increase in bilirubin with TMC435 Lower response rates in cirrhosis, genotype 1a (Q80K) Jacobson et al. EASL 2013; Manns et al. EASL 2013

Simeprevir (TMC435) + PEG/RBV: Phase III QUEST-1: Impact of Subtype and Fibrosis Stage TMC435 PEG/RBV F0-F2 F3 F4 100% 80% 60% 40% 20% 0% 90% 71% 49% 52% Geno 1a Geno 1b 100% 80% 60% 40% 20% 0% 83% 78% 58% TMC435 60% 26% 29% PEG/RBV SVR: G1b > G1a SVR: F0-2 > F4 Jacobson et al. EASL 2013;

Simeprevir (TMC435) + PEG/RBV: Phase III QUEST-1: Differences in SVR12 Between Treatment Groups

Sofosbuvir + PEG + RBV: Phase III NEUTRINO Study (Geno 1,4,5,6) Phase III registration trial Regimen: SOF 400mg/d + PEG 180mics/wk +RBV 1000-1200mg/d for 12 weeks Predefined historical control = 60% as comparator Participant characteristics (n=327): Geno 1: 89% (n=292) Cirrhosis: 17% (n=56) AE in >20%: Fatigue, Nausea, Headache, Insomnia, Dizziness 5 premature discontinuations due to AE Press release, Gilead Feb 2013

Sofosbuvir + PEG + RBV: Phase III NEUTRINO Study (Geno 1,4,5,6) 100% 80% 100% 90% Sofosbuvir + P/R x 12 wks 89% 97% 80% 60% 40% 20% 10% 0% EOT ITT SVR12 Relapse Geno 1 Geno 4,5,6 Cirrhosis n=327 n=292 35 56 Lawitz et al NEJM 2013

Unexpected Path to All-Oral Regimen (Off-Label) PEG RBV Sofosbuvir (NUC) RBV PEG RBV Simeprevir (PI)

Sofosbuvir + Simeprevir +/-RBV Interim Analysis: COSMOS Genotype 1, Prior null responders, F0-F2 0nly Simeprevir 150 mg QD + Sofosbuvir 400 mg QD + RBV x12 weeks (n = 27) SVR4 SVR8 96 (26/27) 96 (26/27) Simeprevir 150 mg QD + Sofosbuvir 400 mg QD x12 weeks (n = 14) 93 (13/14) 93 (13/14) Lawitz E, et al. CROI 2013 0 Weeks 12 No anemia in dual therapy arm (11% with RBV) No grade 3/4 AE or treatment discontinuations

Sofosbuvir + RBV: Phase III POSITRON Study (Geno 2,3) 100% 100% Sofosbuvir + RBV x 12 wks 93% 80% 78% 60% 61% 61% 40% 20% 0% EOT ITT SVR12 Geno 2 Geno 3 Cirrhosis *All treatment-naïve, IFN-ineligible G3 Cirrhosis = 21% (3/14) G3 Non-cirrhosis= 68% (57/84) SOF 400mg qd + RBV 1000-1200mg/d x 12 weeks Jacobson et al, EASL 2013

Sofosbuvir + RBV vs PEG + RBV in Genotype 2,3: Phase III (FISSION) SOF + RBV Peg-IFN + RBV 100 80 98 82 91 62 61 71 SVR12 (%) 60 40 34 30 20 0 58/59 44/54 10/11 8/13 89/145 99/139 13/38 11/37 No cirrhosis Cirrhosis No cirrhosis Cirrhosis *All treatment-naïve, GT 2 GT 3 SOF 400mg qd + RBV 1000-1200mg/d x 12 weeks vs PEG + RBV x 24 weeks

Sofosbuvir + RBV in Genotype 2,3 12 wks vs 16 weeks: FUSION SOF + RBV 12 weeks SOF + RBV 16 weeks 100 80 96 100 60 78 100 80 63 61 SVR12 (%) 60 40 60 40 37 19 20 20 0 25/26 23/23 6/10 7/9 14/38 25/40 5/26 14/23 No cirrhosis Cirrhosis 0 No cirrhosis Cirrhosis GT 2 GT 3 Nelson et al, EASL 2013

Sofosbuvir (NI) + Ledipasvir (NS5A) + RBV Genotype 1 HCV: ELECTRON Interim analysis of nonrandomized phase II ELECTRON study SVR12 outcomes with sofosbuvir + RBV previously reported No serious AEs related to study drugs AE profile consistent with RBV toxicity profile Wk 12 SVR12, % (n/n) Treatment naïve (n = 25) Null responders (n = 10) Treatment naïve (n = 25) Null responders (n = 10) Sofosbuvir + RBV Sofosbuvir + RBV Sofosbuvir + Ledipasvir + RBV Sofosbuvir + Ledipasvir + RBV 84 (21/25) 10 (1/10) 100 (25/25) 100 (9/9) 1. Gane E, et al. CROI 2013. Abstract 41LB. 2. Gane EJ, et al. AASLD 2012. Abstract 229

AVIATOR Study: ABT-450/r, ABT-267 (NS5A), ABT-333 (NNI) +/- RBV in Non-cirrhotic, Naïve and Null Responders No. Patients SVR 12 % SVR 24 * % VBT/Relapse 89 88 0 / 10 85 83 1 / 4 91 89 1 / 8 90 87 1 / 5 99 96 0 / 1 93 90 0 / 2 89 89 0 / 5 93 93 3 / 0 98 95 1 / 0 Kowdley et al.easl2013 3 patients relapsed between SVR 12 and SVR 24.

AVIATOR Study: Grade 3 or Grade 4 Laboratory Abnormalities (12- and 24-week Arms of 3 DAA + RBV) Grade 3 event, n Pooled (N =247) 3 DAAs + RBV Treatment-Naïve (N =159) Null Responders (N = 88) ALT >5x 20x ULN 1 1 0 AST >5x 20x ULN 0 0 0 Alkaline Phosphatase >3x 20x ULN 0 0 0 Total bilirubin > 3x 10xULN 6 4 2 Hemoglobin < 8.0 6.5 g/dl 0 0 0 Grade 4 event, n ALT > 20x ULN 0 0 0 AST > 20x ULN 0 0 0 Alkaline Phosphatase > 20x ULN 0 0 0 Total bilirubin > 10x ULN 0 0 0 Hemoglobin < 6.5 g/dl 0 0 0 Kowdley KV, et al. Presented at: EASL: The International Liver Congress Note: Value must also be more extreme than the baseline value

AVIATOR Study: Most Common Adverse Events with the12- and 24-week arms of 3 DAA + RBV The majority of adverse events were mild 3 DAAs + RBV Event, % Total (N =247) Treatment-Naïve (N =159) Null Responders (N = 88) Headache 31.2 31.4 30.7 Fatigue 29.6 32.7 23.9 Nausea 22.7 24.5 19.3 Insomnia 19.8 22.6 14.8 Diarrhea 15.0 13.2 18.2

Faldaprevir (PI) + PEG/RBV Treatment Naïve, GT1 100 80 79 80 SVR12 (%) 60 40 52 20 0 69/132 204/259 210/261 Placebo FDV 120 mg FDV 240 mg Enrollment in Europe and Japan FDV + PR x 12 weeks + PR x 12 weeks by RGT FDV 120mg: SVR G1b=84% vs G1a=69% Ferenci et al, EASL 2013

Phase IIb COMMAND Study: Daclatasvir (NS5A) + PegIFN/RBV in Treatmentnaive GT1 or GT4 12 Wks DCV + P/R, then those with protocol-defined response rerandomized to triple therapy through Wk 24 or placebo + P/R through Wk 24 SVR12, % 100 80 60 40 65 64 59 58 36 38 78 87 31 67 100 50 DCV 20 mg QD + P/R DCV 60 mg + P/R Placebo + P/R 20 n/n = 95/ 147 0 94/ 26/ 146 72 63/ 106 66/ 113 21/ 56 GT 1 GT 1a GT 1b GT 4 32/ 41 27/ 31 5/ 16 8/ 12 12/ 12 3/ 6 Hezode C, et al. AASLD 2012.

DCV + SOF in Telaprevir or Bocepevir / PR Failures: Virologic Response HCV RNA < LLOQ (% patients) 100 80 60 40 20 0 N = 100 95 100 100 100 100 100 95* 91 80 21 20 21 20 21 20 21 20 21 20 Week 2 Week 4 EOT SVR 4 SVR 12 DCV + SOF DCV + SOF + RBV Missing 41 adult HCV GT1-infected patients who had virologic non-response during prior treatment with TVR or BOC + PEG-IFN/RBV (PR) were treated with: Daclatasvir (DCV): 60 mg QD NS5A replication complex inhibitor Sofosbuvir (SOF): 400 mg QD NS5B nucleotide inhibitor with or without RBV for 24 weeks of therapy Demographics: 1a (83%), IL28b non-cc (98%), Non-cirrhotic (100%) Sulkowski et al, EASL 2013

PEG-Lambda + RBV + Daclatasvir or Asunaprevir* 100% 80% 60% 90% 84% 91% 91% 73% 73% 76% 75% L/R/DCV L/R/ASV 40% 20% 0% PDR RVR* ervr* SVR12* PEG-Lambda 180 mics/week + RBV weight-based + DCV 60mg/d or ASV 200mg/bid x24wks PDR (Protocol Defined Response): HCV RNA <LLOQ at Wk 4 and <LLOD at Wk 12; ~90% G1 patients treated with lambda/rbv + DCV or ASV achieved PDR and qualified for shortened duration (24 wk) Reduced efficacy in G1a vs 1b, DCV = 65% vs 93%; ASV 67% vs 91% Less hematologic toxicity than PEG-2a ALT and bilirubin elevations (6%) in ASV arm Vierling et al. AASLD 2012, Boston, #LB-9

MK-5172 (PI) + P/R x 24 Weeks for Genotype 1, Treatment Naive Patients (%) 100 80 60 40 Dose finding study, RGT criteria (n=136) MK5172 +P/R x 12 wks + P/R x 12 wks: if HCV RNA TND at week 4 High rates of RVR and SVR MK-5172 doses >200mg associated with hepatotoxicity TND 97 100 91 91 RVR TD (<LOD) 96 97 88 86 77 59 Patients (%) 100 80 60 40 96 88 87 SVR12 82 54 20 0 N= 66 68 67 65 66 MK 100 mg + PR MK 200 mg + PR MK 400 mg + PR Marcellin P, et al. AASLD 2012 MK 800 mg + PR BOC + PR RGT 20 N= 0 66 68 67 65 66 MK 100 mg + PR MK 200 mg + PR MK 400 mg + PR MK 800 mg + PR BOC + PR RGT

Everson GT, et al. Presented at: EASL: The International Liver Congress 2013; April 24-28, 2013; Amsterdam, The Netherlands. Abstract 1423. IFN- and RBV-free: Daclatasvir (DCV), Asunaprevir (ASV), and BMS-791325 Phase 2 randomized study, treatment-naïve, HCV GT1, non-cirrhotic patients (N=32) SVR > 90%: Similar with either 12 or 24 weeks of treatment and with 75 mg or 150mg dose of BMS-791325

ALS-2200 (VX-135) in Treatmentnaïve G1-4 with Cirrhosis Median Change From Baseline After 7 Days of Treatment (Log10 IU/mL) 1 0-1 -2-3 -4-5 Genotype 1, 3, 4 Genotype 1 Genotype 3, 4 0.05 0.06-4.18-4.54-4.65 Genotype 1, Cirrhotic -4.08 Placebo ALS-2200 200mg ALS-2200 200mg + RBV ALS-2200, nucleotide HCV polymerase inhibitor Phase 1, viral kinetic study, N=44 Marcellin P, et al. Presented at: EASL: The International Liver Congress

So What Will the Next 6-12 Months Look Like? Over the next 6-9 months for GT 1: PEG + RBV + Simeprevir PEG + RBV + Sofosbuvir Over the next 6-9 months for GT 2,3 Sofosbuvir + RBV Genotype 2- highly effective Genotype 3/ G3 cirrhosis suboptimal response (?add PEG) Off label combination of available DAA classes Simeprevir + Sofosbuvir + RBV for GT1

HCV Pipeline: The Next 18 Months Highly effective regimens will shorten treatment duration Cirrhosis and genotypes 1a and 3 are more difficult to treat and represent the stress test for new agents Ribavirin may still be important in all-oral regimens DAAs effective in P/R combination have a high chance of success when combined with other DAA classes in all-oral regimens Complete transition to all-oral regimens by Q4 2015 PEG/RBV backbone may still be needed in QUAD regimens for difficult to cure populations