Costo ed efficacia delle nuove strategie terapeutiche nell epatite cronica C

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1 Costo ed efficacia delle nuove strategie terapeutiche nell epatite cronica C Rome, June 25, 2015 Mario Angelico Liver Unit, Università Tor Vergata, Roma

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3 Where do we come from? A priori probability of response to dual (Peg-IFN + ribavirin) therapy SVR Virological Profile 24 to 72 weeks 80-95% HCV-2 Easy-to-Treat 75-80% HCV-3 Low viremia 60-70% HCV-3 High viremia 50-60% HCV-4 50% HCV-1 Low viremia 30-35% HCV-1 High viremia Difficult-to-Treat

4 DAA (Directly Acting Agents)

5 The HCV replication complex A polyprotein of approx 3100 aminoacids 6 nonstructural HCV proteins (incl. enzymes essential for HCV life cycle)

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7 Birth and premature death of 1st wave DAAs (protease NS3/4 inhibitors) Boceprevir Telaprevir

8 Birth and premature death of 1st wave DAAs (protease NS3/4 inhibitors) Potent, but. Boceprevir Telaprevir Severe side effects Too many pills Potentially harmful drug-drug interactions Need of peg-ifn and ribavirin coadministration Still long-treatment schedules

9 Virological targets 2nd wave DAAs Approved NS5B NS5A NS3/4A

10 DAAs as components of new treatment paradigm for hepatitis C Peg-IFN + RBV (SOC) IFN-based 1 x DAA + SOC 2 x DAAs + SOC Prospect of shorter treatment duration for a greater proportion of patients IFN-free IFN-free Time DAA=direct-acting antiviral; SOC=standard of care

11 Sofosbuvir (SOF, GS-7977) HCV-specific uridine nucleotide NS5B polymerase inhibitor (chain terminator) Potent antiviral activity against HCV genotypes 1 6 High barrier to resistance Once-daily, oral, 400-mg tablet Favorable clinical pharmacology profile No food effect Renally cleared - limited potential for drug interactions No CYP3A/4 metabolism H 3 C H 3 C CH 3 O Well-tolerated with an excellent safety profile in clinical studies O O HN P O O HO O O NH N O CH 3 F

12 Kinetics of HCV-RNA decay following administration of SOF +/- RBV in 18 patients Unpublished, Tor Vergata Liver and Virology Units, 2014 Patients with severe HCVrecurrence post-olt (n=11) Patients awaiting for OLT (n=7) 7.0 No RBV + RBV No RBV + RBV Log HCV-RNA (IU/ml) HCV-genotypes: GT-1a = 2 GT-1b = 3 GT-2 =1 GT-3 = 3 GT-4 = 2 HCV-genotypes: GT-1a = 1 GT-1b = 3 GT-3 = LLoQ LLoD Baseline 1w 2w 3w 4w 5w 6w Baseline 1w 2w 3w 4w 5w 6w OLT, orthotopic liver transplantation; RBV, ribavirin; IU, international units; GT, genotype; LLOQ, lower limit of quantification (12 IU/ml); LLOD, lower limit of detection.

13 SOF Phase 3 Study Designs GT 1/4/5/6 Week No response-guided therapy NEUTRINO Treatment-Naïve SOF + PegIFN + RBV, n=327 SVR12 SVR24 FISSION Treatment-Naïve SOF + RBV, n=256 PegIFN + RBV, n=243 FUSION Treatment-Experienced SVR12 SOF + RBV, n=103 PBO SVR12 SVR12 GT 1/2/3 All Oral Therapy SOF + RBV, n=98 POSITRON PegIFN-Unable SOF + RBV, n=207 PBO, n=71 VALENCE Treatment-Naïve and Treatment-Experienced GT2: SOF + RBV, n=73 GT3: SOF + RBV, n=250 PHOTON-1 Treatment-Naïve SOF + RBV, n=68 SOF + RBV, n=114 SVR12 SVR12 SVR12 SVR12 SVR12 SVR12 SOF 400 mg/d; PegIFN 180 μg/wk; RBV mg/d for SOF+RBV arms and 800 mg/d for PegIFN+RBV arm

14 Rates of Sustained Virologic Response in the NEUTRINO and FISSION Studies, According to Subgroup and Baseline Factors. Lawitz E et al. N Engl J Med 2013;368:

15 SOF Phase 3 Fibrosis Analysis SVR12 Rates in GT 1, 4, 5, 6 (NEUTRINO) SVR12 Rates by Biopsy Fibrosis Stage (n=232) SVR12 Rates by FibroTest Stage (n=323) SVR12 (%) ( ) n = 16/16 124/137 34/38 32/41 n = 76/78 101/105 46/54 68/86 16/16 124/137 34/38 32/41 076/78 26/29 75/76 46/54 68/86 63/65 23/26 66/67 41/49 64/81 Treating at earlier stages of fibrosis is associated with higher response! Patel K, et al. AASLD Washington, DC. #1093

16 Simeprevir plus sofosbuvir w/wo ribavirin, to treat HCV-G1-infected previous non-responders and naïve patients: The COSMOS randomized study Lawitz et al, Lancet 2014; 384: Cohort 1 Patients with null response to previous treatments (METAVIR F0-F2) Coorte 2 Patients with null response to previous treatment and naive patients with severe fibrosis (METAVIR F3 o F4) 12 weeks treatment SMV+SOF+RBV (n=27) SMV/SOF (n=14) SMV/SOF+RBV (n=27) SMV/SOF (n=14) SVR 4 26 (96%) 13 (93%) 26 (96%) 14 (100) SVR (96%) 13 (93%) 25 (92%) 12 (93%)

17 TURQUOISE II STUDY - published on April 12, 2014, at NEJ

18 Ledipasvir/Sofosbuvir: A Single Tablet Ledipasvir Regimen (STR) ( Harvoni ) Once-daily, oral, 90-mg NS5A inhibitor LDV NS5A inhibitor O H O N O N N N H F F H N H N N O N O H O Sofosbuvir Once-daily, oral, 400-mg NS5B inhibitor H 3 C H 3 C O O CH 3 O HN P O O O O N NH O CH 3 HO F SOF nucleotide NS5B polymerase inhibitor Ledipasvir/Sofosbuvir FDC Once-daily, oral, fixed-dose LDV NS5A LDV inhibitor NS5A inhibitor FDA Approval 10 Oct 2014 European Approval 18 Nov 2014 SOF SOF SOF NS5B SOF nucleotide nucleotide polymerase polymerase polymerase nucleotide inhibitor inhibitor inhibitor polymerase inhibitor

19 ION-1 & ION-2 published on April 12, 2014, at NEJM.org

20 LDV/SOF ± RBV: Compensated Cirrhosis Results: SVR12 by Treatment Regimen Overall SVR wk wk Duration 24 wk Treatment Naïve 98% 97% 99% Treatment Experienced 95% 94% 98% Regimen LDV/SOF LDV/SOF + RBV 96% 99% 95% 96% LDV/SOF 12 wk 96% 90% Duration/ ± RBV LDV/SOF + RBV 12 wk LDV/SOF 24 wk 98% 97% 96% 98% LDV/SOF + RBV 24 wk 100% 100% Bourliere, AASLD, 2014, Oral #82 Among TE cirrhotic patients, 12 weeks of LDV/SOF + RBV resulted in similar SVR rates to 24 weeks of LDV/SOF alone

21 LDV/SOF ± RBV: Compensated Cirrhosis Results: SVR12 by Baseline Characteristics AA Treatment Treatment Naïve Treatment Experienced Treatment Experienced Overall SVR12 98% 95% Genotype GT 1a GT 1b 98% 97% 95% 96% Age <65 years 65 years 98% 94% 95% 98% PI Failure Yes No 96% 95% Bourliere, AASLD, 2014, Oral #82

22 2013 AASLD Meeting, Washington, oral presentation Gastroenterology 2015; 148: Pretransplant Sofosbuvir and Ribavirin to Prevent Recurrence of HCV Infection After Liver Transplantation Michael P. Curry, Xavier Forns, Raymond Chung, Norah Terrault, Robert Brown Jr, Jonathan M. Fenkel, Fredric Gordon, Jacqueline O Leary, Alexander Kuo, Thomas Schiano, Gregory Everson, Eugene Schiff, Alex Befeler, John G. McHutchison, William T. Symonds, Jill Denning, Lindsay McNair, Sarah Arterburn, Dilip Moonka, Edward Gane, Nezam Afdhal

23 Pre-Transplant SOF + RBV to Prevent HCV Recurrence Post-Transplant No Recurrence vs. Recurrence in GT 1 4 Days Continuously TND Prior to Transplant: PTVR vs. Recurrence in GT 1 4 * No Recurrence (n=28) Recurrence (n=10) 1/25 patients had recurrence after > 4 weeks continuous TND Median days TND No recurrence: 95 Recurrence: 5.5 p < Days with HCV RNA Continuously TND Prior to Liver Transplant *3 patients with recurrent HCV had 0 consecutive days TND before transplant. Curry MP, et al.

24 Hepatology, 2015 EASL, 2014 Sofosbuvir Compassionate Use Program for Patients with Severe Recurrent Hepatitis C Including Fibrosing Cholestatic Hepatitis Following Liver Transplantation Xavier Forns 1, Martín Prieto 2, Michael Charlton 3, John G. McHutchison 4, William T. Symonds 4, Diana Brainard 4, Jill Denning 4, Theo Brandt-Sarif 4, Paul Chang 4, Valerie Kivett 4, Robert J. Fontana 5, Thomas F. Baumert 6, Audrey Coilly 7, Lluís Castells 8, François Habersetzer 6 1 Liver Unit, IDIBAPS, CIBEREHD, Hospital Clinic, Barcelona, Spain; 2 Hepatology Unit, CIBEREHD, Hospital Universitari i Politècnic La Fe, Valencia, Spain; 3 Mayo Clinic, Rochester, MN, USA; 4 Gilead Sciences, Foster City, CA, USA; 5 University of Michigan, Ann Arbor, MI, USA; 6 Hôpitaux Universitaires de Strasbourg, Inserm U 1110, Strasbourg, France; 7 Centre Hépato-Bilaire, Hôpital Paul Brousse, Inserm UMR-S785, Villejuif, France; 8 Liver Unit Internal Medicine Department, CIBEREHD, Hospital Universitari Vall Hebron, Barcelona International Liver Congress 2014, London, UK

25 Results: Patient Disposition Severe acute hepatitis/early recurrence (<12 months from liver transplant with typical biochemical and histological findings) n=48 Post transplant compensated and decompensated cirrhosis (liver biopsy (F4) or clinical decompensation) n=56 Early term due to AE n=7 Liver transplant n=12 SOF Compassionate Use Program SOF + RBV ± PEG n=104 Death n=13 Completed weeks treatment n=72 25

26 Results: Overall Virologic Response 8/93 4/93 4/85 13/85 15/85 Patients (%) 26

27 Results: Clinical Outcomes Patients (%) All patients who received 1 dose of SOF are included *Significant decrease in hepatic encephalopathy, improvement or disappearance of ascites, or improvement in liver-related laboratory values. 27

28 Laboratory Results: MELD Score Change From Baseline to Follow-Up Week 4 CPT B CPT C 12 wk (n=30)* 24 wk (n=29)* 12 wk (n=23)* 24 wk (n=26)* (+10) n=5 n=5 n=2 n=3 *Missing FU-4: n=2 CPT B 12 wk; n=4 CPT B 24 wk; n=2 CPT C 12 wk; n=7 CPT C 24 wk. (-8) 28

29 SVR for different IFN-free regimens in F3/F4 (compensated) Genotype 2 patients SOF + RBV Naive SOF + SMV ± RBV SOF + DCV ± RBV SOF/LDV ± RBV ABT450/r/ombitasvir + dasabuvir + RBV SVR (%) Size of the red circle corresponds to the number of patients enrolled into the study. Adapted from Lens S, et al. Sem Liver Disease 2014; 34:58 71.

30 SVR for different IFN-free regimens in F3/F4 (compensated) Genotype 1 and 4 patients SOF + RBV Naive SOF + SMV ± RBV SOF + DCV ± RBV SOF/LDV ± RBV Naive and experienced ABT450/r/ombitasvir + dasabuvir + RBV SVR (%) Size of the red circle corresponds to the number of patients enrolled into the study. Adapted from Lens S, et al. Sem Liver Disease 2014; 34:58 71.

31 SVR for different IFN-free regimens in non cirrhotic Genotype 3 patients SOF + RBV SOF + SMV ± RBV SOF + DCV ± RBV SOF/LDV ± RBV Naive and experienced ABT450/r/ombitasvir + dasabuvir + RBV SVR (%) Size of the red circle corresponds to the number of patients enrolled into the study. Adapted from Lens S, et al. Sem Liver Disease 2014; 34:58 71.

32 SVR for different IFN-free regimens in cirrhotic Genotype 3 patients SOF + RBV SOF + SMV ± RBV SOF + DCV ± RBV SOF/LDV ± RBV Naive and experienced ABT450/r/ombitasvir + dasabuvir + RBV SVR (%) Size of the red circle corresponds to the number of patients enrolled into the study. Adapted from Lens S, et al. Sem Liver Disease 2014; 34:58 71.

33 HCV Regimens in US, Canada and Germany, 2014 SOF/SMV/RBV 14.9% SOF/PEG/R BV 23.1% SOF/RBV 8.8% SOF SMV 1.37% SOF/PEG/RBV 0.9% Genotype 1 SOF/PEG/RBV 8.5% SOF/RBV 99.1% Genotype 2 Genotype 3 SOF/RBV 91.5% N=1994 SOF Containing Regime

34 From December, 2014 to April, 2015 in US

35 SOF PEG RBV Demographics SOF RBV SOF SMV SOF SMV RBV Total* n(%) N=384 N=667 N=784 N=228 N=2063 MALE 253(66.2) 422 (63.6) 478 (62.0) 147 (65.3) 1300 (63.7) MEAN Age, y (range) 53.9 (23-79) 56.9 (21-82) 59.5 (20-83) 58.8 (29-80) 57.6 (20-83) Age (8.1) 131 (19.7) 190 (24.6) 40 (17.8) 392 (19.2) CAUCASIAN 270 (70.3) 539 (80.8) 584 (74.5) 177 (77.6) 1570 (76.1) BLACK 68 (17.8) 37 (5.6) 96 (12.5) 33 (14.7) 234 (11.5) TREATMENT STATUS NAIVE 211 (54.9) 371 (55.6) 318 (40.6) 82 (36.0) 982 (47.6) EXPERIENCED 172 (44.8) 296 (44.4) 465 (59.3) 144 (63.2) 1077 (52.2) PI FAILURE 47 (27.3) 25 (8.4) 76 (24.8) 45 (31.3) 193 (17.9) CIRRHOSIS 120 (31.3) 302 (45.3) 440 (56.1) 137 (60.1) 999 (48.4) Hx Decompensation 12 (11.4) 136 (49.5) 167 (44.8) 60 (50.8) 375 (43.1) MELD >10 18 (17.1) 120 (43.6) 122 (32.7) 34 (28.8) 294 (33.8) LIVER CANCER 25 (6.5) 66 (9.9) 88 (11.2) 32 (14.0) 211 (10.2) LIVER TRANSPLANT 27 (7.0) 57 (8.5) 111 (14.2) 32 (14.0) 227 (11.0) HIV 14 (3.6) 18 (2.7) 8 (1.0) 7 (3.1) 47 (2.3) 78% (253/323) of G1, non-cirrhotic, naïve had a baseline HCV RNA <6 million IU/mL *Total, patients who started therapy SOF Containing Regimen

36 HCV RNA Outcomes for SOF/SMV±RBV: Genotype 1 SOF + SMV ± RBV N=378 Latest Available HCV RNA BLOQ 91% (335/369) Latest Available HCV RNA Quantified 9% (34/369) SVR4 + evaluable 303/369 SVR4 + 89% 269/303 Prior PI Failures excluded from this analysis VBT 0.33% (1/303) Relapse 8.9% (27/303) SVR4 + No cirrhosis: 92% (113/123) Cirrhosis: 87% (156/180) Prior decomp: 75% (61/81) Non-Response 2% (6/303) Lost to f/u 0% (0/303) SVR4 + G1a: 86% (154/180) G1b: 95% (88/93) Cohort of patients with treatment start on or before 4/15/14 ; BLOQ=Below Level of Quantitation; SOF Containing Regimen

37 HCV RNA Outcomes for SOF/SMV±RBV: Genotype 1 PRIOR PI FAILURES SOF + SMV ± RBV N=72 Latest Available HCV RNA BLOQ 86% (59/69) Latest Available HCV RNA Quantified 14% (10/69) SVR4 + evaluable 54/69 SVR4 + 81% 44/54 VBT 0% (0/54) Relapse 19% (10/54) Non-Response 0% (0/54) Lost to f/u 0% (0/303) SVR4 + No cirrhosis: 85% (17/20) Cirrhosis: 79% (27/34) Cohort of patients with treatment start on or before 4/15/14 ; BLOQ=Below Level of Quantitation; SOF Containing Regimen

38 HCV RNA Outcomes for SOF + RBV: Genotype 2 SOF + RBV GT2 N=235 Latest Available HCV RNA BLOQ 91% (204/223) Latest Available HCV RNA Quantified 9% (19/223) SVR4 + evaluable 187/223 SVR4+ 90% (168/187) VBT 0.5% (1/187) Relapse 8% (14/187) Non-Response 1.1% (2/187) SVR4 Non-cirrhotic: 91% (116/128) Cirrhotic: 88% (52/59) Lost to f/u 1.1% (2/187) SOF Containing Regimens Cohort of patients with treatment start on or before 4/15/14 ; BLOQ=Below Level of Quantitation

39 Summary of efficacy of DAAs in cirrhotic patients SVR rates with DAA therapy in cirrhosis are lower than in non cirrhotic patients, especially in those with previous treatment failure or decompensation Treatment must be initiated ASAP! Strategies successful in improving SVR rates include: Longer duration of therapy Addition of ribavirin Addition of another DAA (treatment personalization?) Presence of significant portal hypertension (platelet count <80-100) may be an important predictor of reduced SVR

40 Patients and doctors expectations for HCV treatment with DAAs SVR rates >90% IFN-free treatment schedules Short treatment duration (12-24 weeks or less) All oral treatment Few pills, better once daily Lack of SAE and good tolerability High genetic barrier Possibly pan-genotypic (?)

41 Patients and doctors expectations for HCV treatment with DAAs SVR rates >90% IFN-free treatment schedules Short treatment duration (12-24 weeks or less) All oral treatment Few pills, better once daily Lack of SAE and good tolerability High genetic barrier Possibly pan-genotypic (?) Equitable access to treatment Reasonable and sustainable costs Need to identify urgency-based treatment priorities

42 2 nd wave DAA approval timeline Sofosbuvir (Sovaldi) and Simeprevir (Olysio) approved in December 2013 in Japan and US and by EMA in January 2014 Sofosbuvir (Sovaldi) approved in Italy from December 2014 Simeprevir (Olysio) approved in Italy since March 2015 Daclatasvir (Daklinza) approved in Italy in early May 2015 ABT-450, -257, 333 (Viekierax and Exviera) approved in Italy in late May 2015 (or 3D) Sofosbuvir + Ledipasvir (Harvoni) approved in Italy in late May 2015

43 HCV-infected patients admitted to reimbursement of DAA therapy according to AIFA rules, CPT Class A or B cirrhosis, with or without HCC with complete response to surgical or ablative treatments, whose prognosis is dependent on the underlying liver disease 2. Liver transplant recipients with recurrent HCV infection (with METAVIR score >2, or with fibrosing cholestatic hepatitis) 3. Chronic HCV-infection with severe extrahepatic manifestations (cryoglobulinemia, B-cell lymphoma) 4. Chronic hepatitis with fibrosis METAVIR score F3 5. MELD <25 cirrhosis and/or HCC within Milan criteria listed for liver transplant, with an expected waiting time >2 months 6. Transplant recipients of solid organs (except liver) with fibrosis METAVIR score >2 7. (Chronic hepatitis with fibrosis METAVIR score F0-F2)

44 Open issues and grey areas with DAA in 2015 Real effectiveness in decompensated cirrhosis Treatment of HCV infected patients with renal dysfunction What to do in failures to sofosbuvir and other DAAs? What residual role for ribavirin (and pegifn), if any? How to optimize treatment of G3 infected patients Predictors of SVR: what to do in slow responders? Does IL28B matter in non responders? DAA-induced delisting for liver transplant: does it improve prognosis? When should we be able to treat all infected patients (not only those deserving prioritization)? How to choose between Harvoni, Viekirax/Exviera, and SOF+SIM or SOF+DAC in the real world? Only on money constraints?

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