Treatment of Hepatitis C in patients with thalassaemia Treatment of Hepatitis C in patients with thalassaemia. Where are we now? Telaprevir and boceprevir harbingers of important treatment advance Improved response rates observed : naive and experienced patients SVR > 70% have been reported in genotype 1 infection Efficacy in the treatment of genotype 2-6 has not been fully tested.

The natural history of fibrosis in chronic viral hepatitis Courtesy Pierre Bedossa

Telaprevir ADVANCE: SVR in naïve patients T12PR T8PR PR P<0.0001 P<0.0001 75 69 Percent of patients with HCV RNA Undetectable 44 Results n/N = 271/363 250/364 158/361 SVR Jacobson IM, et al. N Engl J Med 2011;364:2405-16; 2.

Evidence for efficacy: boceprevir in treatment-naïve, genotype 1 patients (SPRINT-2) * * PR48 137/363 BOC RGT 233/368 BOC44/PR48 242/366 n/N = *p<0.001 for both boceprevir arms versus PR48 SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow-up Week 24. If there was no such value, the follow-up Week 12 value was carried forward Boceprevir EU SmPC

The first generation protease inhibitors. Where are we now? Response rates in patients with cirrhosis improved but suboptimal Naïve patients without severe fibrosis respond better Prior null response and cirrhosis less likely to respond to retreatment Inherited IL28b haplotypes continue to influence response rates Response rates lower in subtype 1a vs 1b. Side effects testing for patients

REALIZE (telaprevir): SVR by baseline fibrosis stage and prior response to Peg-IFN/RBV Prior relapsers Prior partial responders Prior null responders Pbo/PR48 Pooled T12/PR48 SVR (%) Key Point Regardless of fibrosis stage and across all prior response categories, telaprevir plus PR was associated with increased SVR rates versus PR alone. Notes Fibrosis stage is a predictor of SVR with telaprevir-based therapy. In general and apart from prior relapsers, telaprevir-treated patients with bridging fibrosis/cirrhosis had lower SVR rates than those without. In prior relapsers treated with telaprevir, SVR rates were similar between patients with no, minimal or portal fibrosis and those with bridging fibrosis/cirrhosis. SVR rates were lowest in null responders with cirrhosis. Given the small numbers of patients in some of the subgroups on this slide, these data should be interpreted with a degree of caution. References Pol S, et al. Hepatology 2011;54(Suppl. S1):374A. n/N= 12/38 145/167 2/15 53/62 1/15 48/57 3/17 36/47 0/5 10/18 1/5 11/32 1/18 24/59 0/9 16/38 1/10 7/50 No, minimal or portal fibrosis Bridging fibrosis Cirrhosis No, minimal or portal fibrosis Bridging fibrosis Cirrhosis No, minimal or portal fibrosis Bridging fibrosis Cirrhosis Stage SVR was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used Pol S, et al. Hepatology 2011;54(Suppl. S1):374A

Boceprevir (SPRINT-2): SVR rates by IL28B genotype CC CT TT SVR (%) n/N= 50/64 63/77 44/55 33/116 67/103 82/115 10/37 23/42 26/44 PR48 BOC RGT BOC44/ PR48 PR48 BOC RGT BOC44/ PR48 PR48 BOC RGT BOC44/ PR48 Samples were available for 653/1048 (62%) patients enrolled in SPRINT-2 SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow-up Week 24. If there was no such value, the follow-up Week 12 value was carried forward Boceprevir EU SmPC

Telaprevir (ADVANCE): SVR rates by IL28B genotype CC CT TT SVR (%) n/N= 35/55 38/45 45/50 20/80 43/76 48/68 6/26 19/32 16/22 PR T8/PR T12/PR PR T8/PR T12/PR PR T8/PR T12/PR Samples were available for 454/1088 (42%) patients (Caucasian) enrolled in ADVANCE SVR: sustained virologic response, defined as undetectable HCV RNA 24 weeks after last planned dose Jacobson IM, et al. J Hepatol 2011;54(Suppl.):S542

Interim results: Royal Free Cohort Undetectable VL at TW4 n (%) Met stopping rule at TW4 Met stopping rule week TRW12 1a 21 (70) 4 (13) 9 (30)* 1b 16 (84) rs860 Non CC 31 (76) 4 (10) 8 (20) rs860 CC 8 (89 ) rs916 Non TT 19 (70) 4 (15) 6 (23) rs917 TT 20 (87) 2 (9) VL> 800,000 29 (73) 8 (21) VL <800,000 12 (92) 1 (8) triple therapy week 4, n (%) At triple therapy week 4 and 12

The paradox of progress Advances have brought higher rates of cure but more complexity to treatment of hepatitis C- a paradox of progress Do not make treatment more straightforward Complex process of decision making is required to assess Side effects? Resistance in patients who fail treatment the indications for treatment for naive and previously treated patients, and for patients with mild disease versus patients with cirrhosis or advanced cirrhosis

Managing adverse events: Rashes varying grades of severity and duration have been reported in 55% telaprevir Most drug related dermatitis moderate severity Unpredictably progress 5 % of patients experienced severe rash Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) occurred in 0.4% and Stevens-Johnson syndrome in 0.1% in clinical trials. Anaemia Particular relevance in patients with thalassaemia

Boceprevir: similar SVR when RBV dose modification and EPO are used to manage anemia 178 249 178 251 Treatment-naive G1 patients (n=687) received BOC-based therapy. Overall, 500 patients developed anemia (Hb ≤10g/dL or were expected to reach that nadir before next visit) and were randomized to have anemia managed with either EPO (40,000 units/wk subcutaneously), or RBV dose reduction (by 200–400mg/day). Transfusion in patients with Hb ≤8.5 g/dL was allowed to prevent study discontinuation. Poordad F, et al. EASL 2012. Abstract 1419. Poster presented on Thursday 19th April

Still stuck with IFN The requisite backbone of PEG IFN: other problems associated with PEG IFN and RBV use Including depression, psychiatric symptoms worsening of liver function and severe infections render a large group intolerant of PEG IFN ineligible for treatment.

What threat does resistance pose? HCV does not replicate via DNA intermediate HCV genome does not integrate into the human genome there is no stable genetic reservoir Drug selection pressure discontinued advantage is lost: RAV’s outgrown by more fit, wild-type virus Theoretical possibility of restoration of drug susceptibility Drug selection pressure discontinued advantage is lost and resistant variants are again outgrown by more fit, wild-type virus discontinuation of telaprevir or boceprevir: wild-type variants increase relatively rapidly and may completely replace resistant variants in the quasispecies The result is the theoretical possibility of restoration of drug susceptibility

EXTEND (telaprevir): resistant variants no longer detected in 85% of patients by last visit 100 100 95 91 85 84 82 80 60 Percent of patients with no detectable variants 40 Population Sequencing 20 Key Point Among patients who did not achieve SVR with telaprevir-based treatment, resistant variants were replaced by wild-type virus in 85% of patients after a median of 29 months (range 7–49) after the end of therapy. Furthermore, clonal sequencing in representative samples indicated that HCV populations returned to the pre-treatment state during long-term follow-up. Notes One objective of the EXTEND follow-up study is to determine how HCV variants change over time in patients who did not achieve SVR with telaprevir-based treatment. This will help to answer the question of whether resistant variants persist. In the EXTEND study, after a median follow-up time of 29 months from the end of telaprevir-based treatment, 85% of patients no longer had detectable resistant variants by population sequencing. Specific single variants associated with decreased susceptibility to telaprevir (V36M, T54A, R155K and A156T) were no longer detectable in 84–100% of patients after 25 months’ follow-up. Similarly, the double variant V36M+R155K was no longer detectable in 49 out of 60 patients (82%) after 29 months’ median follow-up. References Sherman KE, et al. Hepatology 2011;54 (Suppl. S1):485A. n/N = 107/126 74/81 20/21 69/82 11/11 0/1 49/60 patients Overall 36 54 155 156 168 36+155 variants Variants at HCV NS3 position Median follow-up time from treatment-failure: 29 months (range 7–49) Clonal sequencing performed in representative Phase 2 samples (n=20 patients) indicated that HCV populations returned to pre-treatment state* Variant categories are not mutually exclusive *Zeuzem S, et al. Hepatology 2010;52(Suppl):227A Sherman KE, et al. Hepatology 2011;54 (Suppl. S1):485A

Patients with RAVs no longer detected by population sequencing (%) Boceprevir resistance analysis: detectability of most common RAVs* declines during follow-up Patients with RAVs no longer detected by population sequencing (%) *In non-SVR patients with detectable RAVs at treatment failure in SPRINT-2 and RESPOND-2. As of latest follow-up time point (range 6–14 months) Barnard RJO, et al. Hepatology 2011;54 (Suppl. S1): Abstract 164

Treatment-naïve patients Treatment-experienced patients Viral kinetics in patients who met the >1000 IU/mL HCV RNA Week 4 stopping rule with telaprevir Treatment-naïve patients Treatment-experienced patients 108 107 106 105 104 103 102 10 108 107 106 105 104 103 102 10 HCV RNA (IU/mL) HCV RNA (IU/mL) 2 4 6 8 10 12 2 4 6 8 10 12 Weeks Weeks Adda N, et al. HepDART 2011. Abstract 45

ATOMIC study: GS7977 + IFN + RBV 12 weeks Interferon sparing: a new threshold Background and aims: PSI-7977, a potent uridine nucleotide analog, has demonstrated >90% SVR in HCV GT1, GT2, or GT3, independent of predictors of poor responsiveness to interferon. ATOMIC was designed to assess a 12-week regimen of once-daily PSI-7977 400 mg + PEG/RBV. Methods: Treatment-naïve, non-cirrhotic patients with HCV GT1 and HCV RNA ≥50,000 IU/mL were randomized (1:2:3) into one of three treatment arms: A) PSI-7977+PEG/RBVx12wk, B) PSI-7977+ PEG/RBVx24wk, or C) PSI-7977+PEG/RBVx12wk, with re-randomization at Week 12 to PSI-7977 or PSI-7977/RBV. 25 patients with HCV GT4/5/6 could be enrolled into Arm B. Results: 316 subjects with HCV GT1, 11 with GT4, and 5 with GT6 were enrolled: mean age 50 years, mean BMI 28, 65% male, 10% Black, 20% Hispanic. Mean baseline HCV RNA 6.4 log10 IU/mL and 18% subjects have IL28B genotype TT. At abstract submission, all subjects have received >8 weeks of PSI-7977. Rapid and consistent antiviral suppression was demonstrated, with 259/332 (78%) achieving HCV RNA < LOD (15 IU/mL) by Week 2 and 323/332 (97%) achieving RVR. The two non-RVR subjects had ~5 log10 IU/mL change from baseline. To date, there has been no viral breakthrough during 12-24 weeks of PSI-7977 and no relapse following completion of treatment in 32 subjects who have reached follow-up. PSI-7977+PEG/RBV was well-tolerated, with 20 overall discontinuations [14/332 (4%) due to AEs]. Frequency and severity of AEs were consistent with the historical safety profile of PEG/RBV and included fatigue (54%), nausea (29%), headache (29%), chills (19%) and insomnia (19%). Six unrelated SAEs have been reported. Grade 3/4 lab abnormalities included 6% Gr3 Hgb (7-8.9g/dL) and 17% Gr3/Gr4 neutropenia (< 750/mm3). Arm C subjects who received PSI-7977/PEG/RBV x 12 wks and were then re-randomized to PSI-7977+/-RBV demonstrated almost immediate return to baseline values in Hgb and ANC, confirming the predominant effect of PEG in hematologic abnormalities. Conclusion: PSI-7977 400mg QD with PEG/RBV resulted in 97% RVR in HCV GT1, GT4, or GT6. To date no viral breakthrough or relapse has been observed in subjects completing at least 10 weeks of PSI-7977. SVR for 12 and 24-week regimens of PSI-7977/PEG/RBV will be presented. SVR12 not yet reported for the 24 week groups Kowdley KV, et al. EASL 2012, Barcelona, #1

BMS-790052 + BMS-650032: AI447011 Quad versus DAA combination In null-responders, BMS-790052 + BMS-650032 appear to require PegIFN/RBV to prevent breakthrough and the occurrence of resistance BMS-790052 + BMS-650032 BMS-790052 + BMS-650032 + PR Quadruple regimen 7 6 5 4 3 2 1 7 6 5 4 3 2 1 Log10 HCV RNA Log10 HCV RNA LOQ 25 IU/mL LOD <10 IU/mL 6/11 patients in group A experienced viral breakthrough; no patient experienced viral breakthrough in group B Group A: drug-resistant variants in both the NS3 protease and NS5A * LOQ LOQ LOD LOD 0 1 2 3 4 6 8 10 12 0 1 2 3 4 6 8 10 12 Week Week initiation of PegIFN/RBV (NS5a inhibitor and Protease inhibitor) Lok A, et al NEJM 19

ASPIRE (TMC435): SVR24 by prior response and Metavir score Relapsers Partial responders Null responders Patients with SVR24 (%) PR48 16 10 6 TMC435 100mg* PR48 48 29 10 TMC435 150mg* PR48 52 26 15 PR48 12 10 2 TMC435 100mg* PR48 38 29 13 TMC435 150mg* PR48 48 21 11 PR48 13 3 2 TMC435 100mg* PR48 30 20 11 TMC435 150mg* PR48 29 21 13 n= *All TMC435 duration pooled Zeuzem S, et al. J Hepatol 2012;56 (Suppl 2):S1

Will we have better, more tolerable interferons? Lambda interferon No haematological toxicity

Daclatasvir and GS-7977 across HCV genotypes 1–3 mITT* G1a/b G2/3 % <LLOQ 100 100 100 87 86 93 100 100 100 100 100 100 94 100 86 88 100 86 Background: Oral combinations of direct-acting antivirals, without peginterferon-alfa, are much needed therapeutic options for patients with chronic HCV infection. Ongoing study AI-444040 evaluates daclatasvir 60mg QD (DCV; BMS-790052), a first-in-class NS5A replication complex inhibitor, in combination with GS-7977 (PSI-7977) 400mg QD, a nucleotide analog NS5B inhibitor, with or without ribavirin, in treatment-naïve patients. Both DCV and GS-7977 have potent antiviral activity, broad genotypic coverage in vitro, and once-daily administration. Methods: In this parallel, open-label study, 44 noncirrhotic patients with HCV GT1 and 44 noncirrhotics with HCV GT2/3 were randomized (1:1:1) to: (i) GS-7977 for 7 days then DCV + GS-7977 for 23 weeks; or (ii) DCV + GS-7977 for 24 weeks; or (iii) DCV +GS-7977 + ribavirin for 24 weeks. The primary endpoint is undetectable HCV RNA at 12 weeks post-treatment. Interim 12-week on-treatment results are reported. Results: GT1 patients were 73% GT1a and 27% GT1b; GT2/3 patients were 59% GT2 and 41% GT3. HCV RNA was < LLOQ at week 4 in 100% of patients (see table). Virologic breakthrough occurred in one GT3 patient who had Peg-IFN/RBV added for confirmed detectable HCV RNA < LLOQ after week 8. Inclusion of ribavirin did not increase on-treatment virologic response. The most frequent AEs (≥25% overall) were fatigue, headache, and nausea. Two patients discontinued therapy for non-drug related AEs (fibromyalgia, CVA). Grade 3-4 laboratory abnormalities included elevated cholesterol (n=1), elevated glucose (2), low hemoglobin (6), lymphopenia (1), and low phosphorus (2). Conclusions: Interim results of this phase 2 study show that the once-daily combination of DCV and GS-7977 was generally well tolerated and achieved high rates of early virologic suppression in treatment-naïve patients infected with HCV genotypes 1a, 1b, 2, or 3 % <LOD *Bars <100% after 4 weeks reflect missing values Sulkowski M, et al. EASL 2012, Barcelona, #1422

All oral regimens: a realistic dream? Therapeutic landscape is undoubtedly forever changed for the better High barrier to resistance and pan-genotypic effects. Do not yet know whether RBV remains important, or the appropriate dose of RBV in these regimens Null responders to PEG IFN and RBV are null responders to both agents? Multiple DAAs without RBV? Costs will escalate

DAA + IFN (IFN freer) or IFN free? 12 weeks

Next priorities for all oral More data in patients with Cirrhosis Decompensated cirrhosis Post transplant recurrent hepatitis C HIV and HCV coinfected patients Patients with haemoglobinopathies Patients with renal impairment or post renal transplant patients Children Surely the next group of patients requiring attention will be those resistance to first generation PI’s?

Overcoming null response May be nullified in patients treated with potent regimens given for sufficient time to effect clearance of HCV from the liver and perhaps extrahepatic sites. An inverse correlation between the influence of the innate response and potency of DAA agents. Difficult to develop an experimental model

Who should be treated now and who should wait? Whoever wants treatment Whoever is fit for treatment Fit for the regimen No contraindications Motivated to have treatment Understands : likelihood of response Risks and benefits of treatment Understands what is coming down the line Agrees it is an opportune time Reimbursed Indicated Introduce thinking and evidence