Strategies towards cure of HCV infection: a personalized approach. Heiner Wedemeyer Hannover Medical School Hannover, Germany

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1 Strategies towards cure of HCV infection: a personalized approach Heiner Wedemeyer Hannover Medical School Hannover, Germany 1

2 Disclosures Honoraria for consulting or speaking (last 5 years): Abbott, Biolex, BMS, Boehringer Ingelheim, Gilead, ITS, JJ/Janssen Cilag, Merck/Schering Plough, Novartis, Roche, Roche Diagnostics, Siemens, Transgene, ViiV Research grants: Abbott, BMS, Gilead, Merck, Novartis, Roche, Roche Diagnostics, Siemens

3 Antiviral Targets Against Hepatitis C Entry Inhibitors TLR Agonists Therapeutic Vaccine Other IFNs PEG-IFN lambda Ribavirin NS5A Inhibitors Protease Inhibitors Cyclophillin Inhibitors Polymeraseinhibitors NI NNI

4 Peg-IFN-lambda-induced antiviral activity via a similar signaling pathway, but distinct receptor Type I Interferons Type III Interferons Broad receptor distribution throughout various body tissues Receptors distributed primarily in epithelial cells and hepatocytes Antiviral effects Antiviral effects Adverse events of treatment Flu-like symptoms Haematologic disorders Psychiatric symptoms Type I IFNs Peg-Intron PegIFN-2a IFN omega IFN-alfa-2b XL Belerofon Albuferon Locteron Type III IFNs Peg-IFNlambda (Peg-rIL-29) Potentially fewer adverse events than with type I interferons 4 Adapted from 1. Marcello T et al. Gastroenterology 2006;131: ; 2. Muir AJ et al AASLD. Abstract 1591; 3. O'Brien TR. Nat Genet. 2009;41:

5 5 EMERGE Phase 2b study: Lambda/RBV, compared with alfa-2a/rbv Blinded and randomised study of 526 non-cirrhotic treatment-naïve adults 118 chronically infected with HCV GT 2 or GT 3. HCV RNA 100,000 IU/mL Lambda + RBV (N=393) Alfa-2a + RBV (N=133) 120 μg 180 μg 240 μg 180 μg Weeks GT 1+4 GT 2+3 GT 1+4 GT 2+3 GT 1+4 GT 2+3 GT 1+4 GT 2+3 Follow up Follow up Follow up Follow up cevr=complete early virological response; EOT=end-of-treatment; GT=genotype RVR=rapid virological response; RBV=ribavirin; SVR=sustained virological response Adapted from 1. Zeuzem S, et al. EASL Oral Presentation LB-1360; 2. Zeuzem S, et al. EASL Oral Presentation Follow up Follow up Follow up Follow up RVR cevr 12-week data EOT GT 2+3 Data presented in later slides EOT GT 1+4 SVR 24 GT 2+3 SVR 24 GT 1+4 Data to be presented in the future Presented data: GT 1+4, 12-week on-treatment; 1 GT 2+3, 48-week (SVR 24 ) 2

6 GT 1/4: Virological responses through Week 12 HCV RNA, mean (SE) log 10 IU/mL Study week Lambda 120 μg Lambda 180 μg Lambda 240 μg Alfa-2a 180 μg Percent response (± 95% CI) *p <0.05 vs alfa-2a * * * * RVR cevr RVR cevr RVR cevr RVR cevr 120 μg 180 μg 240 μg Alfa-2a Lambda * Rapid HCV-RNA suppression observed with lambda vs alfa-2a 6 Roche COBAS TaqMan HPS v2.0; lower limit of detection=10 IU/mL; cevr=complete early virological response; RVR=rapid virological response; GT=genotype Adapted from Zeuzem S, et al. EASL Oral Presentation LB-1360.

7 GT 2/3: Virological responses through SVR 24 HCV RNA <10 IU/mL (percent of patients ± 95% CI) * RVR cevr SVR RVR cevr SVR RVR cevr SVR RVR cevr SVR Lambda 120 μg Lambda 180 μg Lambda 240 μg Alfa-2a 180 μg N= * *p<0.05 vs alfa Relapse rates were comparable between lambda and alfa-2a arms 7 Modified intention-to-treat (mitt) efficacy analysis: discontinuations prior to an endpoint classified as nonresponders; cevr=complete early virological response RVR=rapid virological response; SVR=sustained virological response Adapted from Zeuzem S, et al. EASL Oral Presentation 1435.

8 GT 2/3: Adverse event summary 1 % Lambda 120 µg (N=29) Lambda 180 µg (N=29) Lambda 240 µg (N=30) Alfa-2a (N=30) Discontinuations for AEs Related to treatment Reduced peg-ifn dose Held/reduced RBV dose Patients with any serious AEs Related to treatment AE categories of special interest* Musculoskeletal Constitutional Flu-like Psychiatric Neurological Adverse events and rates of discontinuations in GT 1/4 were similar through Week 12 2 *Categories of interest are based on preferred terms found in the alfa label reported in at least 5% of patients; Includes depression, irritability or insomnia 8 AE=adverse event; Peg-IFN=pegylated interferon; RBV=ribavirin Adapted from 1.Zeuzem S, et al. EASL Oral Presentation 1435; 2. Zeuzem S, et al. EASL Oral Presentation LB-1360.

9 GT 2/3: Haematological toxicities and associated dose adjustments at Week 24 1 Haematological toxicity, % Lambda 180 µg (N=29) Alfa-2a 180 µg (N=30) Haemoglobin low (<10 g/dl OR decrease of >3.4 g/dl from BL) RBV dose reduction for low haemoglobin Neutrophils low (<750/mm 3 ) Platelets low (<100,000/mm 3 ) Peg-IFN dose reduction for haematological abnormality Haematological adverse events and dose reductions in GT 1/4 were similar through Week 12 2 Lambda recipients compensate for RBV-induced haemolysis via a greater erythropoietic response than that observed with alfa-2a 3 9 BL=baseline; GT=genotype; pegifn=pegylated interferon; RBV=ribavirin Adapted from 1. Zeuzem S, et al. EASL Oral Presentation 1435; 2. Zeuzem S, et al. EASL Oral Presentation LB-1360; 3. Everson G, et al. AASLD Poster 1343.

10 GT 2/3: Liver-related abnormalities and associated dose adjustments at Week 24 1 Lab toxicity, % ALT and/or AST Total bilirubin Severity Lambda 120 µg (N=29) Lambda 180 µg (N=29) Lambda 240 µg (N=30) Alfa-2a 180 µg (N=30) > ULN >10 ULN ULN ULN >5.0 ULN Peg-IFN dose reductions for liver-related lab abnormality Peg-IFN discontinuations for liver-related lab abnormality Both due to hyperbilirubinaemia Neither met the criteria for pdili* Both resolved following discontinuation *FDA criteria for pdili: ALT >5 baseline or pre-event nadir AND >10 ULN, and bilirubin >2 ULN 10 ALT=alanine aminotransferase; AST=aspartate aminotransferase; pdili=possible drug-induced liver injury; peg-ifn=pegylated interferon; ULN=upper limit of normal Adapted from 1. Zeuzem S, et al. EASL Oral Presentation 1435.

11 Interferon lambda Summary In the Phase 2 EMERGE study, lambda, compared with alfa-2a, demonstrated Higher cevr rates in patients infected with genotypes 1/4 Similar or numerically greater SVR 24 rates in patients with GT 2/3 Rapid time to virological reduction Fewer IFN or RBV dose reductions, musculoskeletal or flu-like events and less haematological toxicity* Ongoing / planed studies ( Phase 2 PEG-IFN lambda + RBV + Daclatasvir / Asunaprevir (Gen 1) Phase 3 PEG-IFN lambda + RBV + Telaprevir (800 Gen 1 patients) Phase 3 PEG-IFN lambda + RBV +/- Daclatasvir (875 Gen 2/3 patients) Phase 2 PEG-IFN lambda in HBeAg-positive Hepatitis B 11 *Rates of AEs 2-fold difference between the lambda and alfa-2a groups; GT=genotype IFN=interferon; RBV=ribavirin; SVR=sustained virological response

12 Entry Inhibitors Advanced BMS Programs TLR Agonists Therapeutic Vaccine Other IFNs PEG IFN lambda NS5A Inhibitors Protease Inhibitors Cyclophillin Inhibitors Polymeraseinhibitors NI NNI

13 DAAs against HCV in clinical development Protease Inhibitors 2nd wave vs. 2nd generation Polymerase Inhibitors Non nucleos(t)ides Polymerase Inhibitors nucleos(t)ides NS5A Inhibitors Potency Pan genotype efficacy Resistance Barrier Potency Pan genotype efficacy Resistance Barrier Potency Pan genotype efficacy Resistance Barrier Potency Pan genotype efficacy Resistance Barrier +++ +/++ +/ ( ) + ( ) / /++ +/++ Additional Issues: Issues: Drug-Drug Interactions, Dosing, Safety Safety (e.g. (e.g. Anemia, Rash) Rash)

14 Potential roles of future DAAs IFN-sparing treatment regimens (shorter treatment durations) Increase of SVR rates in difficult-to-treat patients (triple therapies, quadruple therapies) IFN-free treatment including patients who cannot be treated with IFNa with an an easy dosing schedule, reduced pill pill burden, less toxicity, effective in in all all genotypes,

15 Entry Inhibitors Advanced BMS Programs TLR Agonists Therapeutic Vaccine Other IFNs PEG IFN lambda PEG-IFN lambda Asunaprevir Protease Inhibitors Cyclophillin Inhibitors NS5A Inhibitors Polymeraseinhibitors NI Daclatasvir NNI

16 Asunaprevir (ASV, BMS ): NS3 Inhibitor Daclatasvir (DCV, BMS ): NS5A Inhibitor

17

18 GT 1 null responder: Asunaprevir and daclatasvir + peg-alfa/rbv study design SVR 4 SVR 12 SVR 24 SVR 48 n = 20 ASV 200 mg BID + DCV 60 mg QD + peg-alfa-2a/rbv (GT 1a/1b) Follow up n = 21 ASV 200 mg QD + DCV 60 mg QD + peg-alfa-2a/rbv (GT 1a/1b) Follow up Prior null responders to peg-alfa and RBV * ASV 200 mg BID + DCV 60 mg QD (GT 1b only) Follow up * ASV 200 mg QD + DCV 60 mg QD (GT 1b only) Follow up * ASV 200 mg BID + DCV 60 mg QD + RBV (GT 1a/1b) Follow up Week 12 Interim analysis Week *SVR data not yet available; ASV= asunaprevir; DCV=daclatasvir; GT=genotype; peg-alfa=pegylated interferon alfa; RBV=ribavirin; SVR=sustained virological response Adapted from Lok A, et al. EASL Poster LB-1415.

19 IFN-sparing

20 GT 1 null responder: Asunaprevir and daclatasvir + peg-alfa/rbv virological response rates Patients achieving endpoint (%) n= 95 * 95 * ASV 200 mg BID + DCV + pegalfa/rbv ASV 200 mg QD + DCV + pegalfa/rbv Solid bars <LOD Hatched bars Detectable and <LLOQ 0 Week 4 Week 12 EOTR (Week 24) SVR 4 20 *1 patient with missing HCV-RNA measurement ASV=asunaprevir; DCV=daclatasvir; EOTR=end-of-treatment response; LOD=lower limit of detection (~10 IU/mL); LLOQ=lower limit of quantitation (25 IU/mL); peg-alfa=pegylated interferon alfa-2a; RBV=ribavirin; SVR=sustained virological response Adapted from Lok A, et al. EASL Poster LB-1415.

21 GT 1 null responder: Asunaprevir and daclatasvir + peg-alfa/rbv adverse events through Week 12 Event ASV 200 mg BID + DCV 60 mg QD + peg-alfa-2a/rbv (N=20) ASV 200 mg QD + DCV 60 mg QD + peg-alfa-2a/rbv (N=21) Total (N=41) Grade 3 4 AEs, n (%) 1 (5) 2 (10) Discontinuations due to AEs 3 (7) SAEs 3 (15) 1 (5) 4 (10) Deaths ASV and DCV in combination with peg-alfa/rbv were generally well tolerated The most common AEs were headache, asthenia, diarrhoea, alopecia, fatigue and irritability* No Grade 3 4 ALT elevations were reported 1 patient (ASV 200 mg BID) had AST >5 x ULN (Week 12) 4 patients (2 per study arm) had transient elevations of total bilirubin (peaking at Week 2) 21 *AEs occurring in 30% in either treatment arm; AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; SAE=serious adverse event; peg-alfa=pegylated interferon alfa; RBV=ribavirin; ULN=upper limit of normal Adapted from Lok A, et al. EASL Poster LB-1415.

22 IFN-free

23 600 mg Asunaprevir 2xtgl. 60 mg Daclatasiavir 1xtgl. SVR: 2/9 genotype 1a 2/2 genotype 1b

24 GT 1b null responders and ineligible/intolerant: Daclatasvir + asunaprevir study design (Japan) Null responders (n=21) DCV 60 mg QD + ASV 200 mg BID * Ineligible/intolerant (n=22) DCV 60 mg QD + ASV 200 mg BID Follow up x 24 weeks Follow up x 24 weeks Week 4 (RVR) Week 12 (cevr) Week 24 (EOTR) SVR 12 SVR 24 Non-cirrhotic Japanese adults with HCV GT 1 infection, HCV-RNA 10 5 IU/mL Null responders: <2 log 10 HCV-RNA decline after 12 weeks of peg-alfa/rbv Ineligible/intolerant: previously intolerant to peg-alfa/rbv OR peg-alfa/rbv medically unsuitable Sentinel cohort of 10 null responders reported previously (SVR 24 90%); a results combined here with data for additional null responders 24 *ASV ASV=asunaprevir; initially 600 mg cevr=complete BID in sentinel early cohort virological of 10 null response; responders, DCV=daclatasvir reduced to 200 mg BID during treatment EOTR=end-of-treatment response; GT=genotype; RBV=ribavirin; peg-alfa=pegylated interferon alfa; RVR=rapid virological response; SVR=sustained virological response Adapted from Suzuki F, et al. EASL Oral Presentation 2344; a Chayama K, et al. Hepatology 2012;55:742 8.

25 GT 1b null responders and ineligible/intolerant: Daclatasvir + asunaprevir virological endpoints Null responders (N = 21) Ineligible/intolerant (N = 22) HCV-RNA undetectable (% of patients) 11/21 19/22 19/21 20/22 19/21 19/22 19/21 14/22 19/21 14/22 Week 4 RVR Week 12 cevr EOT * SVR 12 SVR *EOT (end-of-treatment)=week 24 or last on-treatment visit for patients who discontinued early Intention to treat (missing=failure) analysis; RVR= rapid virological response; cevr=complete early virological response; SVR=sustained virological response; Lower limit of quantitation for HCV-RNA determinations=15 IU/mL Adapted from Suzuki F, et al. EASL Oral Presentation 2344.

26 GT 1b null responders and ineligible/intolerant: Daclatasvir + asunaprevir overall safety Adverse event profile generally compared favourably with the typical peg-alfa/rbv profile The most frequent AEs were headache, diarrhoea, nasopharyngitis and transaminase elevations 6 serious adverse events in 5 patients, no deaths 3 discontinuations due to adverse events before Week 24 Grade 4 hyperbilirubinaemia (Week 2) 2 transaminase elevations (Weeks 12 and 16) 1 discontinuation due to lymphopenia at Week 52 (off-study) in patient with peg-alfa/rbv added at Week 6 26 GT=genotype; peg-alfa=pegylated interferon alfa; RBV=ribavirin Suzuki F, et al. EASL Oral Presentation 2344.

27 Entry Inhibitors Asunaprevir Strategies towards cure of HCV infection: the future will be personalized medicine! Protease Inhibitors Cyclophillin Inhibitors NS5A Inhibitors Polymeraseinhibitors NI TLR Agonists Therapeutic Vaccine Other IFNs PEG IFN lambda Viral factors (e.g. genotype 1a vs. 1b vs. other) Host factors (Il28b genotype?) PEG-IFN lambda Stage of liver disease Previous therapies Comorbidities / DDI / Safety Resources,.. Daclatasvir NNI