New Treatments for Chronic Hepatitis C. Rafael Esteban Hospital Valle Hebron. Barcelona Spain

Transcription

1 New Treatments for Chronic Hepatitis C Rafael Esteban Hospital Valle Hebron. Barcelona Spain

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3 The present: a complex treatment with a better SVR Genotype 1 Genotypes 2 and 3 Triple therapy Boceprevir (BOC) or telaprevir (TVR) plus PegIFN and RBV Duration of 24, 36 and 48 weeks Stopping rule differences: PegIFN and RBV Duration 24 weeks Stopping rule at Week 12 Adverse events easy to handle BOC at Weeks 8 and 12 TVR at Weeks 4 and 12 Lead-in phase/non lead-in phase

4 The present: a more complex evaluation for patients with HCV G1 HCV subtype IL28B Drug drug interactions Baseline Fibrosis Treatment experience Response to previous therapy HCV=hepatitis C virus; G=genotype

5 The present: new and more side effects that require additional controls Rash HCV Drug Resistance Anaemia Drug drug interactions Transfusions/ Erythropoietin Anorectal symptoms Food interactions Disgeusia

6 What are the key attributes of a new treatment or regimen? Simple treatment algorithm Improved SVR rates in all patients Improved tolerability Reduced treatment duration Optimised HCV regimen Manageable adverse events Pangenotypic High resistance barrier Once-daily dosing SVR=sustained virological response

7 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 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:

8 EMERGE: Efficacy and Safety of IFN lambda in Genotype 2&3 SVR rates comparable in pegifn lambda-1a arms vs pegifn alfa- 2a SVR24 (%) N = Lambda 120 µg Lambda 180 µg Lambda 240 µg 53.3 Alfa 180 µg PegIFN lambda-1a 180 μg dosage chosen for phase III trials Adverse Event, % Lambda 180 µg (N = 29) Alfa 180 µg (N = 30) Hemoglobin low <10g/dL or > 3.4 g/dl RBV dose reduction (Hemoglobin associated) Neutrophils low < 750/mm Platelets low <,000/mm PegIFN dose reduction (hematologic abnormality) Zeuzem S, et al. EASL Abstract 10.

9 Better understanding of the life cycle of HCV has revealed several potential innovative drug targets Viral targets C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Host targets NS3 NS5A NS5B Cyclophilin A The NS3/4A serine protease is essential for post-translational processing of HCV polyproteins 1 Boceprevir Telaprevir ABT-450/r,ACH-1625 Asunaprevir, TMC-435 (Simeprevir),BI Danoprevir/r,GS-9451 MK-5172 Multifunctional membraneassociated phosphoprotein essential component of the HCV-RNA replication complex 2,3 Daclatasvir GS-5885 ABT-267 PPI-668 * *On clinical hold, Idenix press release; **On clinical hold, Novartis press release NS5B is an HCV-specific, RNAdependent RNA polymerase 1 Nucleos(t)ide analogue GS-7977,Mericitabine, IDX-184* Non-nucleoside analogue BI ,ABT-333 ABT-072,BMS Tegobuvir,Setrobuvir VX-222,Filibuvir Adapted from 1. PawlotskyJM, et al. Gastroenterology2007;132: ; 2. TellinghuisenTL, et al. Nature2005;435:374 9; 3. Gish R &Meanwell NA. Clin Liver Dis.2011;15:627 39; 4. Coelmont L, et al. PLoSOne2010;5:e Host protein involved in HCV replication through interaction with NS5A and the HCV polymerase 4 Alisporivir** SCY-635

10 Each class appears to have some characteristic features NS3/4A Protease Inhibitors NS5A Replication Complex Inhibitor NS5B Nucleos(t)ide Inhibitors NS5B Non-nucleos(t)ide Inhibitors Cyclophilin Inhibitors (HTA) Poor/no activity against GT3 1 Low-to-medium barrier to resistance 1 Extensive crossresistance 1 QD, BID or TID dosing Potential for CYP-mediated DDIs 2,3 Picomolar activity against multiple GTs in vitro 4 Low-to-medium barrier to resistance 1 QD dosing 5,6 Potential for CYP-mediated DDIs 7 Broad GT coverage 1 High barrier to resistance 1 QD or BID dosing 8 Limited potential for CYPmediated DDIs Most are GT/subtype specific 1 Low barrier to resistance 1 QD or BID dosing 8 Limited potential for CYP-mediated DDIs 9 Broad GT coverage in vitro 1 Limited resistance data available BID/QD dosing 10 Potential for CYP-mediated DDIs 9,11 DDI=drug-drug interactions; HTA=host-targeted antiviral; GT=genotype Created from 1.Sarrazin C, et al. J Hepatol. 2012;56:S88 S; 2. Eley T, et al. AASLD Poster 381; 3. Sekar V, et al. EASL 2010, Poster 1076; 4. Gao M, et al. Nature 2010;465:96 ; 5. Pol S, et al. ICAAC Oral Presentation HI-376; 6. Lawitz EJ, et al. J Hepatol. 2012;Feb 4 [epub]; 7. Bifano M, et al. CROI Poster 618; 8. Poordad F, et al. Am J Manag Care 2011;17:S123 S130; 9. Seden K, et al. J Antimicrob Chemother. 2010;65: ; 10. Flisiak R, et al. EASL Oral 4; 11. Park S, et al. AASLD Abstract 364.

11 ASPIRE: TMC 435 (PI) + PEG-IFN/RBV in Treatment Experienced Patients Treatment experienced, G1, includes cirrhotics n=66 n=65 n=68 n=66 TMC435 +PEG-IFN + RBV TMC PEG-IFN/RBV TMC PEG/R PEG-IFN + RBV PEG-IFN + RBV weeks * Represents pooled TMC duration at 150mg do Zeuzem S, et al. EASL Abstract 2 PEG-IFN + RBV SVR 24 (%) * Relapsers 9 75* Partial Responders 19 51* Null Responders

12 Each class appears to have some characteristic features NS3/4A Protease Inhibitors NS5A Replication Complex Inhibitor NS5B Nucleos(t)ide Inhibitors NS5B Non-nucleos(t)ide Inhibitors Cyclophilin Inhibitors (HTA) Poor/no activity against GT3 1 Low-to-medium barrier to resistance 1 Extensive crossresistance 1 QD, BID or TID dosing Potential for CYP-mediated DDIs 2,3 Picomolar activity against multiple GTs in vitro 4 Low-to-medium barrier to resistance 1 QD dosing 5,6 Potential for CYP-mediated DDIs 7 Broad GT coverage 1 High barrier to resistance 1 QD or BID dosing 8 Limited potential for CYPmediated DDIs Most are GT/subtype specific 1 Low barrier to resistance 1 QD or BID dosing 8 Limited potential for CYP-mediated DDIs 9 Broad GT coverage in vitro 1 Limited resistance data available BID/QD dosing 10 Potential for CYP-mediated DDIs 9,11 DDI=drug-drug interactions; HTA=host-targeted antiviral; GT=genotype Created from 1.Sarrazin C, et al. J Hepatol. 2012;56:S88 S; 2. Eley T, et al. AASLD Poster 381; 3. Sekar V, et al. EASL 2010, Poster 1076; 4. Gao M, et al. Nature 2010;465:96 ; 5. Pol S, et al. ICAAC Oral Presentation HI-376; 6. Lawitz EJ, et al. J Hepatol. 2012;Feb 4 [epub]; 7. Bifano M, et al. CROI Poster 618; 8. Poordad F, et al. Am J Manag Care 2011;17:S123 S130; 9. Seden K, et al. J Antimicrob Chemother. 2010;65: ; 10. Flisiak R, et al. EASL Oral 4; 11. Park S, et al. AASLD Abstract 364.

13 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 24 *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.

14 GT 1 null responder: Asunaprevir and daclatasvir + peg-alfa/rbv virological response rates Patients achieving endpoint (%) n= 0 95 * 95 * Week 4 Week 12 EOTR (Week 24) SVR 4 95 ASV 200 mg BID + DCV + pegalfa/rbv ASV 200 mg QD + DCV + pegalfa/rbv Solid bars <LOD Hatched bars Detectable and <LLOQ *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.

15 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 24 *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.

16 ASV and DCV trough plasma concentrations in patients with SVR or virologic failure Asunaprevir C trough (ng/ml) Median 201 Virologic failures * * Median 57 SVR Relapse Breakthrough Note: Multiple determinations are shown for some patients *Pharmacokinetic values from a single patient with documented non-compliance after sampling Daclatasvir C trough (ng/ml) Almost all trough concentrations for both DCV and ASV were below the median in patients with virologic failure SVR=sustained virological response Adapted from Suzuki F, et al. EASL Oral Presentation 2344.

17 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) 3 (7) Discontinuations due to AEs 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) *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.

18 GT 1 treatment-naïve: BI and BI SVR 12 according to IL28B GT and HCV subtype 1a non-cc 1a CC 1b non-cc 1b CC SVR 12 (%) n/n= 7/22 6/8 31/37 9/11 BI mg Duration (weeks) RBV All groups received BI mg QD for the same duration as BI (16, 28 or 40 weeks) Common moderate/severe AEs included rash, photosensitivity, jaundice, vomiting and diarrhoea BID 28 + Intent-to-treat analysis AE=adverse event; GT=genotype; RBV=ribavirin; SVR=sustained virological response Adapted from Zeuzem S, et al. EASL Oral Presentation 101.

19 Each class appears to have some characteristic features NS3/4A Protease Inhibitors NS5A Replication Complex Inhibitor NS5B Nucleos(t)ide Inhibitors NS5B Non-nucleos(t)ide Inhibitors Cyclophilin Inhibitors (HTA) Poor/no activity against GT3 1 Low-to-medium barrier to resistance 1 Extensive crossresistance 1 QD, BID or TID dosing Potential for CYP-mediated DDIs 2,3 Picomolar activity against multiple GTs in vitro 4 Low-to-medium barrier to resistance 1 QD dosing 5,6 Potential for CYP-mediated DDIs 7 Broad GT coverage 1 High barrier to resistance 1 QD or BID dosing 8 Limited potential for CYPmediated DDIs Most are GT/subtype specific 1 Low barrier to resistance 1 QD or BID dosing 8 Limited potential for CYP-mediated DDIs 9 Broad GT coverage in vitro 1 Limited resistance data available BID/QD dosing 10 Potential for CYP-mediated DDIs 9,11 DDI=drug-drug interactions; HTA=host-targeted antiviral; GT=genotype Created from 1.Sarrazin C, et al. J Hepatol. 2012;56:S88 S; 2. Eley T, et al. AASLD Poster 381; 3. Sekar V, et al. EASL 2010, Poster 1076; 4. Gao M, et al. Nature 2010;465:96 ; 5. Pol S, et al. ICAAC Oral Presentation HI-376; 6. Lawitz EJ, et al. J Hepatol. 2012;Feb 4 [epub]; 7. Bifano M, et al. CROI Poster 618; 8. Poordad F, et al. Am J Manag Care 2011;17:S123 S130; 9. Seden K, et al. J Antimicrob Chemother. 2010;65: ; 10. Flisiak R, et al. EASL Oral 4; 11. Park S, et al. AASLD Abstract 364.

20 ELECTRON GS-7977 ± RBV (GT-2/3) GS + R 12 weeks n=10 GS + PR 4 weeks n=10 GS mg + PegIFN/RBV GS mg + RBV GS mg + RBV GS + PR 8 weeks n=10 GS mg + PegIFN/RBV GS mg + RBV GS + PR 12 weeks n=10 GS 12 weeks n=10 GS mg + PegIFN/RBV GS mg Week Gane EJ, et al. AASLD Abstract 34

21 GS 7977 ± RBV (GT 2/3) 60 GS + R GS + PR 4 wks GS + PR 8 wks GS + PR 12 wks GS Gane EJ, et al. AASLD Abstract 34

22 GT 1 treatment-naïve and null responders: GS RBV SVR 4 rates ELECTRON study 1 QUANTUM study 2 GT 1 treatment-naïve GT 1 null responders GT 1 treatment-naïve Patients (%) Patients (%) n/n= 0 25/25 22/25 EOT SVR 4 9/9 1/9 EOT SVR 4 n/n= 0 10/17 SVR 4 One serious AE occurred in the null responder arm No Grade 3 4 AEs or treatment discontinuations in either study group No patients experienced viral rebound while on treatment and no patients discontinued therapy due to an adverse event AE=adverse event; EOT=end-of-treatment; GT=genotype; RBV=ribavirin; SVR=sustained virological response Created from 1. Gane E, et al. EASL Poster 1113; 2. Gilead press release.

23 What are the potential advantages of combination regimens containing multiple DAAs? Maximise potency, barrier to resistance, and genotypic coverage Improved tolerability Fewer or easily manageable adverse events Increased eligibility e.g. patients with advanced disease, or IFN-intolerant patients Shortened treatment duration Easier dosing regimens Reduced pill burden, once-daily drugs Fixed-dose combinations DAA=direct-acting antiviral; IFN=interferon Gane E. Liver Int. 2012;32:62 7; Lee LY, et al. Int J ClinPract. 2012;66:

24 GT 1 treatment-naïve and non-responders: ABT- 450/ritonavir + ABT RBV Virologic results by treatment arm based on assay limit of detection (LLOD) Patients (%) 4 12 Arm 1 (n=19) Arm 2 (n=4) Arm 3 (n=17) ABT-450/r 150/ mg QD ABT mg BID + RBV Treatment-naïve ABT-450/r 250/ mg QD ABT mg BID + RBV Treatment-naïve ABT-450/r 150/ mg QD ABT mg BID + RBV Non-responders No deaths or serious adverse events; One adverse event leading to premature discontinuation Four subjects with adverse events assessed as severe, none requiring study drug interruption or discontinuation (hyperbilirubinaemia 6.2 mg/dl(106 mmol/l), fatigue, pain, vomiting) Adapted from Poordad, et al. EASL 2012 Oral Presentation 41.

25 GT 1 and 2/3 treatment-naïve: Daclatasvir and GS /- RBV study design Week 1 Week 4 Week 12 Week 24 SVR 4 SVR 12 SVR 48 N=15 GT 1a/1b: GS mg QD x 7d, then add DCV 60 mg QD Follow up N=16 GT 2/3: GS mg QD x 7d, then add DCV 60 mg QD Follow up Chronic HCV GT 1a/1b or GT 2/3 infection, treatment-naïve N=14 N=14 GT 1a/1b:DCV 60 mg QD + GS mg QD GT 2/3: DCV 60 mg QD + GS mg QD Follow up Follow up N=15 GT 1a/1b: DCV 60 mg QD + GS mg QD + RBV Follow up N=14 GT 2/3: DCV 60 mg QD + GS mg QD + RBV Follow up RBV: 1,000 1,200 mg daily according to body weight for GT 1 patients; 800 mg daily for GT 2/3 patients RBV=ribavirin; SVR=sustained virological response Adapted from SulkowskiM, et al. EASL Poster LB-1422.

26 GT 1 treatment-naïve: Daclatasvir and GS /- RBV virological response Patients achieving endpoint (%) N= SVR Week 2 Week 4 Week 12 EOTR PT Week 4 (Week 24) % <LLOQ % <LOD GS-7977 LI + DCV DCV + GS-7977 DCV + GS RBV Solid bars <LOD Hatched bars Detectable and <LLOQ The majority of patients were GT 1a (73% GT 1a vs 27% GT 1b) mitt analysis, bars not reaching % after Week 4 reflect missing values; DCV=daclatasvir; EOTR=end-of-treatment response; LI=lead in; LLOQ=lower limit of quantification (25 IU/mL); LOD=lower limit of detection (<15 IU/mL); PT=post treatment; SVR=sustained virological response Adapted from Sulkowski M, et al. EASL Poster LB-1422.

27 GT 2/3 treatment-naïve: Daclatasvir and GS /- RBV virological response Patients achieving endpoint (%) N= Week 2 Week 4 Week 12 EOTR (Week 24) PT Week 4 mitt analysis, bars not reaching % after Week 4 reflect missing values *1 patient required treatment intensification, 1 patient with relapse at post-treatment Week 4 2 patients lost to follow up (Weeks 12 and 24) * SVR 4 86 % <LLOQ % <LOD GS-7977 LI + DCV DCV + GS-7977 DCV + GS RBV Solid bars <LOD Hatched bars Detectable and <LLOQ DCV=daclatasvir, EOTR=end-of-treatment response; LI=lead in; LLOQ=lower limit of quantification (25 IU/mL); LOD=lower limit of detection (<15 IU/mL); PT=post treatment; SVR=sustained virological response Adapted from Sulkowski M, et al. EASL Poster LB-1422.

28 Daclatasvir and GS /- RBV: Pooled safety in GT 1, 2, 3 through Week 12 on-treatment Patients with event, n (%) GS-7977 LI + DCV (N=31) DCV + GS-7977 (N=28) DCV + GS RBV (N=29) Grade 3 4 AEs 0 4 (14) 1 (4) Discontinuations due to AEs 0 1 (4) 1 (4) SAEs 2 (6) 5 (18) 3 (10) The most frequently observed AEs were fatigue, headache and nausea* Two patients discontinued due to AEs: Cerebrovascular accident and fibromyalgia, both considered unrelated to study therapy No Grade 3 4 elevations of ALT, AST, or total or direct bilirubin were reported The most common Grade 3 4 laboratory abnormality was anaemia, which occurred only in patients receiving RBV *AE occurring in 20% in any group; AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; DCV=daclatasvir; LI=lead in; RBV=ribavirin SAE=serious adverse event Adapted from Sulkowski M, et al. EASL Poster LB-1422.

29 Each class appears to have some characteristic features NS3/4A Protease Inhibitors NS5A Replication Complex Inhibitor NS5B Nucleos(t)ide Inhibitors NS5B Non-nucleos(t)ide Inhibitors Cyclophilin Inhibitors (HTA) Poor/no activity against GT3 1 Low-to-medium barrier to resistance 1 Extensive crossresistance 1 QD, BID or TID dosing Potential for CYP-mediated DDIs 2,3 Picomolar activity against multiple GTs in vitro 4 Low-to-medium barrier to resistance 1 QD dosing 5,6 Potential for CYP-mediated DDIs 7 Broad GT coverage 1 High barrier to resistance 1 QD or BID dosing 8 Limited potential for CYPmediated DDIs Most are GT/subtype specific 1 Low barrier to resistance 1 QD or BID dosing 8 Limited potential for CYP-mediated DDIs 9 Broad GT coverage in vitro 1 Limited resistance data available BID/QD dosing 10 Potential for CYP-mediated DDIs 9,11 DDI=drug-drug interactions; HTA=host-targeted antiviral; GT=genotype Created from 1.Sarrazin C, et al. J Hepatol. 2012;56:S88 S; 2. Eley T, et al. AASLD Poster 381; 3. Sekar V, et al. EASL 2010, Poster 1076; 4. Gao M, et al. Nature 2010;465:96 ; 5. Pol S, et al. ICAAC Oral Presentation HI-376; 6. Lawitz EJ, et al. J Hepatol. 2012;Feb 4 [epub]; 7. Bifano M, et al. CROI Poster 618; 8. Poordad F, et al. Am J Manag Care 2011;17:S123 S130; 9. Seden K, et al. J Antimicrob Chemother. 2010;65: ; 10. Flisiak R, et al. EASL Oral 4; 11. Park S, et al. AASLD Abstract 364.

30 VITAL 1: SVR12 by Per Protocol Analysis High SVR rates with alisporivir based therapy, including IFN free regimens However, development of alisporivir currently on hold due to 3 cases of pancreatitis (with 1 death) in > 1800 patients treated to date 80 Overall SVR SVR12 in Pts Receiving IFN-free Therapy SVR12 (%) n = n = ALV0 ALV600 ALV800 ALV600 P/R ALV0 ALV600 ALV800 RBV RBV Peg RBV RBV Pawlotsky JM, et al. EASL Abstract

31 DAA Summary A large number of regimens containing combinations of DAAs (with or without RBV) are currently being investigated Regimens containing one or more DAAs ± pegalfa/rbv appear likely to address many of the current unmet needs in the future Future research efforts should focus on the evolving unmet medical needs of HCV patients, especially those who remain difficult to treat

32 HCV treatment: future perspectives 2014/2015? 2016/2017? PI + PR NS5B Polymerase inhibitor + PR QUAD therapy Interferon free/sparing regimens TMC435 + PR GS PR Telaprevir + VX PR VX telaprevir + RBV GS RBV +/- DCV BI BI RBV PI: protease inhibitor; PR: peginterferon + ribavirin; DAA: direct-acting antiviral; DCV: daclatasvir