Massimo Puoti Dept. of Infectious Diseases AO Ospedale Niguarda Cà Granda Milan, Italy ELPA Symposium: COMPASSIONATE USE IN HEPATITIS C What patients populations have the highest unmet needs ?

Patients population with the highest unmet need Cirrhosis Patients without response to previous therapy (triple & double) Patients intolerant to Interferon

Patients population with the highest unmet need Cirrhosis Patients without response to previous therapy (triple & double) Patients intolerant to Interferon

No SVR SVR 100 Patients With Liver Complications (%) Mos Cumulative Incidence of Liver-Related Complications Following SVR in Cirrhosis Bruno S, et al. Hepatology. 2007;45: Pts at Risk, n

Cirrhosis: Efficacy of triple therapy in HCV G1 StudyNaïveRelapsersPartial Responders Null Responders Telaprevir Phase III Studies % (F4) 59% (F3-F4) 84% (F4) 34% (F4) 14% (F4) Boceprevir Phase III Studies %83% (F3-F4) 46% (F3-F4) 1/2 CUPIC Real Life Telaprevir 6 _71% (SVR 12) 29% (SVR12) _ CUPIC Real Life Boceprevir 6 _52% (SVR 12) 31% (SVR 12) _ 1.Marcellin P, et al. J Hepatol 2011; 54 (Suppl 1): S Pol S, et al. Hepatology 2011;54(Suppl. S1):374A 3. Buti M. AASLD Poordad F, et al. N Engl J Med 2011;364:1195– Bacon BR, et al. N Engl J Med 2011;364:1207–17 5. Vierling J et al AASLD Hezode C et al EASL 2013 Submitted

Safety in cirrhotics: Clinical Trials vs Real World n=530n=323 n=734n=727 n=159n=296 Clinical trials (including cirrhotics) Real world (cirrhotics only) Treatment-naïveTreatment-experienced Telaprevir Boceprevir n=132n=80 n=363n=361 PegIFN/RBV (courtesy F. Poordad)

CUPIC: Risk of occurrence of death or severe complications FactorsPlatelet count > Platelet Count < Albumin > 3.5 g/dL 3.3%4.8% Albumin < 3.5 g/dL 7.1%40.6% Hezode C et al EASL 2013 Submitted

Standard of Care (PEG IFN + RBV) in Decompensated Cirrhosis Martinez-Camacho A, Fortune BE, Everson GT. Treating HCV Prior to Liver Transplantation. In Chronic Hepatitis C: Advances in Treatment, Promise for the Future. ML Shiffman (ed) Springer Science-Business. NY. HCV-RNA Neg AuthorNRxEOTSVR Iacobellis66Peg/RBV49%20% Forns51Peg/RBV29%20% Tekin20Peg/RBV45%30% Annichiarico15Peg/RBV47%20% Everson124IFN/RBV46%24% Forns30IFN/RBV30%20% Thomas20IFN60%20% Amarapukar18IFN/RBV61%38% Crippin15IFN/RBV33%0% TOTALS35944%24%

Deaths and AEs in the first 6 month of follow-up according to treatment or not OR 0.7 OR 0.6 OR 0.6 OR 0.9 OR (1.02 – 5.77) OR 2.9 OR 1.2 OR 1.9 Iacobellis A, et al. J Hepatol 2007 Safety and tolerability

G1 Cirrhosis awaiting LT DAA in PNC-HCV Triple therapy (PR + TPV or BOC)

G1 Cirrhosis awaiting LT DAA in PNC-HCV Triple therapy (PR + TPV or BOC)

Patients populations with the highest unmet needs Cirrhosis: – Most urgent need  response = short term survival – Lower rate of response to treatment – Highest rate of side effects: Reasonable in compensated patients w/o advanced disease Chance of death or hospitalization > treatment response in advanced disease Treatment not indicated in decompensated patients

SOUND-C2: Faldaprevir + BI ± R in treatment-naїve patients SVR12: cirrhosis vs. no cirrhosis /21 124/217 6/ /69 1/3 17/43 CirrhosisNo cirrhosisCirrhosis No cirrhosis BI dosingTIDBIDTID Duration (weeks)16, 28 & 4028 RBV++- The presence of cirrhosis did not significantly influence the achievement of SVR12 in univariate regression analysis (odds ratio 0.84; p=0.66) Soriano V et al. AASLD 2012:

Ribavirin + Sofosbuvir + PEGIFN Data in 153 cirrhosis Summary of Fusion (68 HCVG2&3 experienced), Fission (100 HCV G2&3 naives), Positron (31 HCV G2/3 IFN intolerant) and Neutrino (54 G1&4-6 naives) Studies Lawitz E NEJM 2013; Jacobson IM NEJM 2013

Patients population with the highest unmet need Cirrhosis Patients without response after previous therapy (double & triple) Patients intolerant to Interferon

PROPORTION OF NAÏVE HCV GENOTYPE 1 PATIENTS WITHOUT RESPONSE TREATMENT SVR (%) PegIFN/RBVBOC or TVR + PegIFN/RBV % Poordad F, et al. N Engl J Med. 2011;364: Jacobson IM, et al. N Engl J Med. 2011;364: Setting% without Response HCV G1 naive25-37

PROPORTION OF EXPERIENCED HCV GENOTYPE 1 PATIENTS WITHOUT RESPONSE AFTER TREATMENT SVR (%) RelapsersPartial Responders PegIFN + RBV Bacon BR, et al. N Engl J Med. 2011;364: Zeuzem S, et al. N Engl J Med. 2011;364: Vierling JM, et al. AASLD Abstract 931. Null Responders BOC or TVR + PegIFN + RBV Setting% without Response HCV G1 naive25-37 HCV G1 relapsers17-31 HCV G1 partial responders HCV G1 null responders63-71

18 HCV Genotype 2 and 3: good results with PEGIFN + RBV but 30-40% without response n= Virological response (%) Genotype 2 (n=1025)Genotype 3 (n=1259) The error bars correspond to the 95% confidence intervals Virological response defined as: HCV RNA <50 IU/mL by week 2, 4 (RVR) or 12, or ≥24 weeks after end of treatment (SVR) Week 2Week 4 (RVR) Week 12SVR24Week 2Week 4 (RVR) Week 12SVR24 Primary analysis population Marcellin PM, et al. Hepatology 2012 [Epub ahead of print] Setting% without Response HCV G1 naive25-37 HCV G1 relapsers17-31 HCV G1 partial responders HCV G1 null responders63-71 HCV G229 HCV G328

19 Virological response : G1 and G4 two genotypes same pitfall of the Standard of Care Genotype 4 (n=317) Genotype 1 (n=4520) Virological response (%) n= 1891 Week 2Week 4 (RVR) Week 12SVR Week 2Week 4 (RVR) Week 12SVR24 The error bars correspond to the 95% confidence intervals Virological response defined as: HCV RNA <50 IU/mL by week 2, 4 (RVR) or 12, or ≥24 weeks after end of treatment (SVR) Marcellin PM, et al. Hepatology 2012 [Epub ahead of print] Setting% without Response HCV G1 naive25-37 HCV G1 relapsers17-31 HCV G1 partial responders HCV G1 null responders63-71 HCV G229 HCV G328 HCV G459

Patients populations with the highest unmet needs Cirrhosis: – Most urgent need  response = short term survival – Lower rate of response to treatment – Highest rate of side effects: Reasonable in compensated patients w/o advanced disease Chance of death or hospitalization > treatment response in advanced disease Treatment not indicated in decompensated patients With actual treatment options > 40% of patients without response (60% HCV genotype 4 – 30% HCV genotype 2)

84 62/74 93* [2] 38/41 Previous Null Responders: Quad Therapy SVR12 or 24 (%) 90 [1] 9/10  Quad therapy may be a good option for null responders  Well tolerated BUT cirrhotics excluded *Asunaprevir QD and BID combined. 88% GT1a n/N = SVR12 (%) 61% GT1a n/N = Daclatasvir (NS5A) + Asunaprevir (PI) + PegIFN/RBV x 24 wks (Quad) Danoprevir/r (PI) + Mericitabine (Nuc) + PegIFN/RBV x 24 wks (Quad) [3] 1. Lok AS, et al. N Engl J Med. 2012;366: Lok AS, et al. AASLD Abstract Feld JJ, et al. AASLD Abstract 81.

SAFETY AND EFFICACY OF INTERFERON-FREE REGIMENS OF ABT-450/r, ABT- 267, ABT-333 +/- RIBAVIRIN IN PATIENTS WITH CHRONIC HCV GT1 INFECTION: RESULTS FROM THE AVIATOR STUDY Kowdley KV EASL 2013

Simeprevir + Sofosbuvir + RBV Genotype 1 F0-F2 non responders Simeprevir Sofosbuvir RBV Simeprevir Sofosbuvir RBV Simeprevir Sofosbuvir 24 weeks 12 weeks Number RVR % UND EOTR SVR84/6 66%5/5 100%26/27 96%13/14 (92%) Anemia % Bilirubin increase 2020 CAVEAT SVR w8 mild fibrosis Lawitz CROI 2013

SVR Daclatasvir + Sofosbuvir + RBV G1 Telaprevir /Boceprevir failure DCV +SOFDCV + SOF + RBV N2120 EOT UNDETECTABLE 21/21 (100%)19/20 (95%) SVR 421/21 (100%)20 (100%) SVR 12 Non cirhosis, breakthrough, relapsers and non responders 1a 80% IL28b; nonCC 98%; > F2 83% Sulkowski EASL 2013

Sofosbuvir + Ribavirin in HCV G2 &3 Non responders: Fusion Study HCV genotype 2 or 3 patients who failed prior interferon-based therapy were randomized (1:1) to receive either a 12-week (n=103) or 16-week (n=98) course of sofosbuvir 400 mg once daily plus RBV (1,000 or 1,200 mg/day). 63% HCV genotype 3. 34% Cirrhosis Historical control group: 25% SVR Jacobson IM NEJM 2013 % SVR

Patients population with the highest unmet need Cirrhosis Patients without response after triple therapy Patients intolerant to Interferon

Gaps in Care Resulting in Low Overall Effectiveness of HCV Treatment in Veterans with Chronic HCV Kramer JR et al, J Hepatol 2011 % of HCV infected Veterans (n = 99,166)

Patients populations with the highest unmet needs Cirrhosis: – Most urgent need  response = short term survival – Lower rate of response to treatment – Highest rate of side effects: Reasonable in compensated patients w/o advanced disease Chance of death or hospitalization > treatment response in advanced disease Treatment not indicated in decompensated patients Patients w/o response to the most advanced treatment options & patients with genotype 4 with poor response to PEGIFN + RBV HIV+ response  reduced all cause mortality but uncommon with PEGIFN + RIBA, few data with triple therapy Intolerant to interferon  the missed target that could change the landscape

Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options Suzuki J Hepatol 2013

Asunaprevir and Daclatasvir in 22 Japanese HCV G1b ineligible/intolerant to Interferon Daclatasvir and asunaprevir trough plasma concentrations HCV RNA levels, individual patients Suzuki J Hepatol 2013

POSITRON Efficacy of a 12-Week of Sofosbuvir Plus Ribavirin for Chronic Hepatitis C Patients HCV G2 or 3 who are Unable or Unwilling to Take Interferon Study population: HCV G2 or G3 were interferon intolerant, interferon ineligible or unwilling to take interferon randomized (3:1) to receive 12 weeks of either sofosbuvir 400 mg once daily plus weight-based RBV twice daily (n=207) or matching placebo (n=71). 207 patients randomized to the sofosbuvir/RBV arm, – 15 percent had compensated cirrhosis (more advanced liver disease) – 53 percent were infected with genotype 2. 0/71 59/97 102/110 Jacobson IM NEJM

Patients populations with the highest unmet needs Cirrhosis: – Most urgent need  response = short term survival – Lower rate of response to treatment – Highest rate of side effects: Reasonable in compensated patients w/o advanced disease Chance of death or hospitalization > treatment response in advanced disease Treatment not indicated in decompensated patients Patients w/o response to the most advanced treatment options & patients with genotype 4 with poor response to PEGIFN + RBV HIV+ response  reduced all cause mortality but uncommon with PEGIFN + RIBA, few data with triple therapy Intolerant to interferon  the missed target that could change the landscape

The paradox of new anti HCV drugs development Studies mainly in easy to treat populations with the lower urgent need: –HCV G1b –Naives –Non cirrhotics –HIV- Few studies in difficult to treat populations with the most urgent need: –Transplanted patients –Decompensated and compensated cirrhosis –Null responders –HCV G1a –HIV+ Marketing of new anti HCV drugs with high prices  cost effectiveness only in sickest patients without enough data from phase III studies