HCV: Beyond the current generation of protease inhibitors

Transcription

1 HCV: Beyond the current generation of protease inhibitors Antonio Craxì GI & Liver Unit, Di.Bi.M.I.S. University of Palermo, Italy

2 Antonio Craxì GI & Liver Unit, Di.Bi.M.I.S. University of Palermo, Italy Il sottoscritto ha avuto negli ultimi 12 mesi rapporti in potenziale conflitto d interesse (advisory board, speakers bureau, research grants) in relazione a questa presentazione con: Abbott, Achillion, Anadys, Boehringer-Ingelheim, Bristol Myers Squibb, Genentech, Gilead, Glaxo Smith Kline, Inhibitex, Janssen- Cilag, Merck Sharp& Dohme, Novartis, Pharmasset, Roche, Tibotec, Vertex. La presentazione contiene discussione di farmaci in studio o ad uso off-label

3 SVR to triple therapy with first-generation PIs (BOC or TPV) [1,2] [3,4] SVR (%) [3-4] [1,2] [1,6] [5] * 0 Relapser Naive White/ Nonblack Naive Black Partial Responder Null Responder Cirrhotic Null Responder *Pooled TVR arms of REALIZE trial. 1. ZeuzemS, et al. N EnglJ Med. 2011;364: Bacon BR, et al. N Engl J Med. 2011;364: Jacobson IM, et al. N EnglJ Med. 2011;364: PoordadF, et al. N EnglJ Med. 2011;364: Zeuzem S, et al. EASL Abstract Vierling JM, et al. AASLD Abstract 931.

4 Patients in whom triple therapy with firstgeneration PIs (BOC or TPV) cannot be used Contraindications or poor tolerance to pegifn or RBV: related to liver disease (advanced and decompensated cirrhosis) unrelated to liver disease Safety and efficacy of boceprevirand telaprevirnot yet established in special populations: Subjects at risk of low adherence Organ transplant recipients Patients with HIV and/or HBV coinfection Pediatric patients Risk/benefit and cost benefit still to be assessed in patients with mild chronic hepatitis (F0/F1) and in older subjects

5 Current triple therapy is complex Mean Adherence (%) Adherence to pegifn/rbv therapy decreases over time PegIFN Ribavirin (N = 5706) Treatment Wk Triple therapy has greatly increased treatment complexity, involves multiple daily pills plus injection drug BOC TID: 12 pills/day TVR TID: 6 pills/day RBV BID: 4-6 pills/day PegIFN: QW injection Increased risks with nonadherenceto triple therapy include potential for resistance Frequent testing and management of ADR add to burden Lo Re V, et al. Ann Intern Med. 2011;155:

6 What will be the key points of the next generation of anti-hcv drugs? Tolerability Resistance Pangenotypic coverage Efficacy in difficult to treat General applicability Reduced need for testing (HCV RNA; biomarkers) Shorter duration QD dosing (oral) Easy combinability between drugs No or few DDIs IFN-free Affordable costs

7 Features of anti-hcv drug classes NS3/4A Protease Inhibitors NS5B Polymerase Inhibitors NS5A Inhibitors CyclophilinA Nucleos(t)ide Analogue Non-nucleos(t)ide Inhibitors High efficacy Low genetic barrier to resistance Macrocyclicor linear Phase III: BI , TMC435 Mimic natural substrates of the polymerase Incorporated into RNA chain causing chain termination Broad genotypic coverage High genetic barrier to resistance PhaseIII: PSI-7977 Bind to several different allostericenzyme sites; results in conformational change Resistance more frequent than nucs Several agents in phase II NS5A has rolein assembly of replication complex Mechanism of inhibition under study Phase III: Daclatasvir (BMS ) Supports HCVspecific RNA replication, protein expression Interacts with NS2, NS5A, NS5B May regulate polypeptide processing, viral assembly Phase III: Alisporivir

8 Basic characteristics of direct antiviral agents (DAA) currently Efficacy Genotype dependency Barrier to resistance NS3/4A (protease inhibitors) NS5A NS5B (nucleosides) NS5B (non-nucleosides)

9 Basic characteristics of direct antiviral agents (DAA) in the future Efficacy Genotype dependency Barrier to resistance NS3/4A (protease inhibitors) NS5A NS5B (nucleosides) NS5B (non-nucleosides) e.g. PSI-7977, PSI-938; 2 e.g. MK-5172, ACH-1625; 3 e.g. PPI-461

10 Comparative efficacy of new DAAs (various classes) in GT1 treatment-naive Phase II Studies, Drug + PegIFN/RBV 100 Not head-to-head comparisons SVR (%) BOC or TVR [1,2] 1. Poordad F, et al. N Engl J Med. 2011;364: Jacobson IM, et al. N Engl J Med. 2011;364: Sulkowski M, et al. EASL Abstract Terrault N, et al. AASLD Abstract Vierling JM, et al. AASLD Abstract LB Fried M, et al. AASLD Abstract LB Manns MP, et al. AASLD Abstract Jacobson I, et al. EASL Abstract Lawitz E, et al. EASL Abstract Pol S. ICAAC Abstract HI Flisiak R, et al. EASL Abstract 4.

11 ZENITH: telaprevir + VX-222 ±Peg- IFN/RBV SVR12 data Arm C 100 mg VX-222 Arm D 400 mg VX SVR12, % Overall Patients eligible for 12 weeks treatment Patients eligible for 24 weeks treatment No patient in either QUAD arm experienced viral breakthrough. However, 2 patients relapsed in Arm C (7%) and 2 patients (including 1 patient who received only 1 week of treatment) in Arm D (7%) Nelson D, et al. AASLD Abstract LB-14.

12 PROTON: PSI-7977 & Peg-IFN/RBV in naive G1 patients: SVR Phase IIb study N=48 N=47 PSI mgqd Peg-IFNα-2a + RBV PSI mgqd Peg-IFNα-2a + RBV Peg-IFN α-2a + RBV Peg-IFNα-2a + RBV STOP Non-RVR Peg-IFN α-2a/rbv STOP Non-RVR Peg-IFN α-2a/rbv SVR follow-up N=26 Peg-IFNα-2a+ RBV Double blind, randomized, placebo controlled 121 treatment-naive HCV G1 patients * Intent-to-treat population, 3 discontinued treatment due to unrelated AEs and 1 was lost to follow-up Lawitz, et al. AASLD Abstract 225

13 PROTON: PSI-7977 & Peg-IFN/RBV in naive G1 patients: SVR HCV nucleotide analogpsi-7977 plus Peg-IFN α-2a/rbv, phase IIb study ITT responders (%) mg + PEG/RBV mg + PEG/RBV PEG/RBV % RVR ervr EOTR SVR 12 n LOD ITT % ITT <50 ITT = all patients dosed ervr= protocol-defined response (HCV RNA < LLOD (<15 IU/mL) at week 4 through to week 12) Lawitz, et al. AASLD Abstract 225

14 PROTON: PSI-7977 & Peg-IFN/RBV in naive G1 patients: SVR HCV nucleotide analogpsi-7977 plus Peg-IFN α-2a/rbv, phase IIb study Study discontinuations PSI mg + Peg-IFN/RBV Total number of subjects PSI mg + Peg-IFN/RBV PSI-7977 related safety Peg-IFN/RBV related safety Breakthrough on PSI-7977 Breakthrough on Peg-IFN/RBV Relapse Lost to follow-up Safety/tolerability Viral breakthrough & relapse Lawitz, et al. AASLD Abstract 225

15 Efficacy in null responders Agent Trial,Phase Pts MeetingEfficacy Measure, % Telaprevirand Boceprevir [1,2] BOC or TVR + PR REALIZE/PROVIDE III Investigational Protease inhibitors SVR: BI PR [3] SILEN-C2,IIb SVR: TMC435 + PR* ASPIRE, IIb SVR: Vaniprevir+ PR [4] IIb SVR: Zeuzem S, et al. N Engl J Med. 2011;364: Vierling JM, et al. AASLD Abstract Sulkowski M, et al. EASL Abstract Lawitz E, et al. AASLD Abstract LB-13.

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17 Future regimens are mostly aimed to shorten duration and increase adherence (OD/BID, less ADR) Boceprevir/telaprevir New options under investigation 24/28 wks min, 48 wks max Duration varies: dependent on treatment experience, treatment response, fibrosis level Additional assessments for futility Protease Inhibitor BID in IL28B CC Novel Therapies Currently in Trials Boceprevir Telaprevir

18 Future regimens are mostly aimed to shorten duration and increase adherence (OD/BID, less ADR) QD ABT-072 ABT-267 ABT 450* ACH-1625 BI Daclatasvir GS 5885 GS9451 IDX 184 INX-189 MK-5172 Narlaprevir* PSI-7977 PSI-938 TMC435 BID ABT-333 Asunaprevir BI BI BMS Danoprevir* Filibuvir GS9256 Mericitabine Setrobuvir Tegobuvir Vaniprevir VX-222 TID BI Danoprevir *With RTV boosting.

19 Future regimens are mostly aimed to shorten duration and increase adherence (OD/BID, less ADR) Agent Boceprevir/Telaprevir [1,2] AEs More Frequent in Experimental Arm vs PegIFN/RBV Anemia, dysgeusia,neutropenia, rash, anorectal symptoms Discontinuations due to AEs, % (Wk) (48) ABT-072 [3] (N = 27) Headache 0 (12) ABT-333 [3] (N = 18) None 0 (12) ABT-450/r [4] (N = 30) None 0 (12) Alisporivir [5] (N = 215) Transient hyperbilirubinemia 5 (48) Asunaprevir [7] (N = 36) Fatigue 11 (12) BI [6] (N = 355) GI events, jaundice, and rash 8 (48) Daclatasvir [8] (N = 36) None 8 (12) Danoprevir [9] (N = 194) ALTelevation, neutropenia, nausea, diarrhea 4 (12) Mericitabine [10] (N = 81) None 6 (36) PSI-7977 [11] (N = 95) None 3 (12) Setrobuvir [12] (N = 63) Rash 2 (12) TMC435 [13] (N = 309) Mild bilirubinincreases 7 (24) Vaniprevir [14] (N = 169) GI events 6 (48) Studies displayed include those with data through at least 12 wks and with discontinuation rates lower than BOC/TVR. 1. Boceprevir [package insert]. May Telaprevir [package insert]. May Gaultier, et al. APASL LawitzE, et al. EASL Abstract FlisiakR, et al. EASL Abstract BronowickiJP, et al. EASL Abstract SulkowskiM, et al. EASL Abstract PolS, et al. EASL Abstract TerraultN, et al. AASLD Abstract PockrosP, et al. EASL Abstract Nelson D, et al. EASL Abstract LawitzE, et al. AASLD Abstract Fried M, et al. AASLD Abstract LB LawitzE, et al. AASLD Abstract LB-13.

20 PegIFNLambda 2 0 Is there still a role for IFNs? In IL28B CC patients, IFN is a potent antiviral agent No viral resistance: in DAA combinations, IFN limits resistance development and breakthrough = improved SVR In the Phase 2 EMERGE study, pegifn lambda demonstrated Superior RVR and cevrrates (at 180μg and 240 μg doses) than pegifnalfa-2a in patients with genotype 1 and 4 HCV Fewer haematological toxicities, flu-like and musculoskeletal symptoms Fewer dose reductions Conclusion: IFNs still likely to play an important role in future HCV therapy Zeuzem S, et al. 46th EASL 2011; abstract LB1360.

21 EMERGE AI Phase 2b: Viral Response With PegIFN Lambda vs PegIFN Alfa-2a(HCV G1 and 4) HCV RNA undetectable (percentage of patients ± 95% CI) * * * * RVR cevr RVR cevr RVR cevr RVR cevr PegIFN lambda PegIFN lambda PegIFN lambda PegIFN alfa-2a 120 μg 180 μg 240 μg 180 μg n = * *P<0.05 vspegifnalfa-2a. HCV RNA not detected by Roche COBAS TaqManHPS v2.0 (LLOD 10 IU/mL). RVR = HCV RNA undetectable at Week 4, cevr= HCV RNA undetectable at Week 12 on treatment Zeuzem S, et al. 46th EASL 2011; abstract LB1360.

22 What must be considered for DAA combination therapy? At least additive antiviral activity No cross-resistance No drug-drug interaction No overlapping safety issues No combination of TID with BID drugs (= QID)

23 All-oral combination regimens in GT1 treatment-naive patients Patients (%) Strategy: protease inhibitor (telaprevir) + nonnucleosidepolymerase inhibitor (VX-222) [1] ±pegifn/rbv for 12 wks, then RGT VX mg BID + TVR + PR VX mg BID + TVR + PR Strategy: protease inhibitor (ABT- 450/r) + nonnucleosidepolymerase inhibitor (ABT-333 or ABT-072)* + RBV for 12 wks All 44 patients achieved cevr Of 10 patients tested thus far, 9 achieved SVR24 PRESS RELEASE 0 SVR24; 12 total wks of therapy SVR12; 24 total wks of therapy 1. Nelson DR, et al. AASLD Abstract LB-14.

24 Two DAAs Alone or Combined With PegIFN Alfa/RBV in Null Responders 2 4 Group A BMS BMS (n=11) Follow-up x 48 weeks Group B BMS BMS pegifnalfa/rbv (n=10) 24-week treatment Follow-up x 48 weeks Post-treatment Week 12: SVR12 BMS (NS5A RCI) 60 mg PO QD BMS (NS3 PI) 600 mg PO BID PegIFN alfa-2a 180 µg SC once weekly RBV mg daily according to body weight 19 of 21 patients had unfavourable IL28B genotypes (rs CT/TT) Null responders = patients who achieved <2 log 10 IU/mL decline in HCV RNA following 12 weeks of treatment with pegifn alfa/rbv. BID = twice daily, PO = orally, SC = subcutaneously, QD = once daily. Lok A, et al.aasld 2010; abstract LB-8, Lok A, et al.easl 2011; abstract LB1356.

25 Two DAAs Alone or Combined With PegIFN Alfa/RBV in Null Responders 100% BMS BMS Undetectable HCV RNA* 80% 60% 40% 20% * *2/9 genotype 1a, 2/2 genotype 1b 0% 7/11 RVR 6/10 5/11 EOT 10/10 *HCV RNA not detected by Roche COBAS TaqMan HPS v2.0 (LLOD 10IU/mL) cevr, undetectable HCV RNA at week 12, SVR12, undetectable HCV RNA at week 12 post-treatment. 4/11 10/10 SVR12 No SAEs or discontinuation due to adverse events Six subjects experienced ALT >3x ULN (all had bilirubin < 2x ULN) Six subjects (all receiving pegifn alfa/rbv) experienced Grade 3/4 neutropenia Lok A, et al.aasld 2010; abstract LB-8, Lok A, et al.easl 2011; abstract LB1356.

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27 Dual therapy PI (BMS ; asunaprevir) + NS5AI (BMS ; daclatasvir) in Japanese G1b null responders Week N=10 BMS mg qd BMS /200* mg bid Follow-up *Reduced the PI dose midway through treatment due to ALT flares at 600 mg in a concurrent dose-ranging study Non-cirrhotic Japanese adults with HCV G1 infection, HCV RNA >10 5 IU/mL, and prior-null response to Peg-IFN/RBV IL28B: 80% CT; 20% CC 40% male; mean age 62 years Primary endpoint: undetectable HCV RNA 12 weeks post-treatment (SVR12) ChayamaK, et al. Hepatology2011; DOI: /hep

28 Dual therapy with the NS5A inhibitor BMS and the NS3 protease inhibitor BMS in HCV genotype 1b-infected null responders open-label, phase 2a study of 10 Japanese patients with HCV 1b chronic hepatitis and prior null response to PEG IFN and ribavirin (<2 log10 HCV RNA reduction after 12 weeks) Daclatasvir + Asunaprevir = 9 = 1 ChayamaK, et al. Hepatology2011; DOI: /hep

29 All-oral combination regimens in GT1 null responders Additional announced IFN-free study designs in treatmentexperienced patients Protease inhibitor Nucleos(t)ide analogue polymerase inhibitor Nonnucleoside polymerase inhibitor Gilead Announces Data for Genotype 1 Null Responder Hepatitis C Patients Enrolled in ELECTRON Study Drug 1 Drug 2 Overall Regimen Viral Relapse Seen Post Treatment with GS-7977 Plus Ribavirin Awaiting Data for Treatment-Naïve Genotype 1 Patients FOSTER CITY, Calif.--(BUSINESS WIRE)--Feb. 17, Gilead Sciences, Inc. (NASDAQ:GILD) announced today that the majority TMC435 of hepatitis QD C genotype PSI patients QD with a prior null ± RBV response to an interferon (IFN)- containing regimen enrolled in the ongoing ELECTRON study experienced viral relapse within four weeks of 12 or 24 wks completing 12 weeks of treatment with GS-7977 plus ribavirin (RBV). Ten patients were randomized to this arm of the ELECTRON study and data are available for eight of the 10 patients at this time. Among these eight ABT-450/RTV ABT-333 BID + RBV patients, six have experienced viral relapse. Two patients have not relapsed; however, they have only reached the two week post-treatment QD time point. These data answer an important question about the use of GS-7977 and ribavirin for the treatment of genotype 1 null Danoprevir/ responder patients, RTVsuggesting Mericitabine that additional BID direct acting + RBV antivirals may be necessary to effectively treat this patient population, saidnorbert Bischofberger, PhD, Executive Vice President of BID 24 wks Research and Development and Chief Scientific Officer. We will continue to explore a number of therapeutic approaches to address this significant unmet medical need, including combinations with other oral antivirals.

30 PSI-7977 ELECTRON: PSI RBV study design for treatment-naive G2/3 Treatment-naive, non-cirrhotic, age 18 years HCV RNA >50,000 IU/mL Allowed concurrent methadone use Stratified by HCV genotype and IL28B genotype Randomized 1:1:1:1 into IFN sparing or IFN-free N=10 PSI RBV + Peg-IFN N=10 PSI RBV + Peg-IFN PSI RBV N=10 PSI RBV + Peg-IFN PSI RBV SVR12 N=10 PSI RBV Weeks GaneEJ, et al. AASLD2011. Abstract 34

31 PSI-7977 ELECTRON: IFN-free PSI RBV achieves 100% SVR12 PSI-7977 RBV 12 weeks PEG PSI-7977 RBV 8 weeks PEG PSI-7977 RBV 4 weeks PEG PSI-7977 RBV NO PEG Time, week N %<LOD N %<LOD N %<LOD N %<LOD 2 9/ /8 88 8/9 89 8/ / / / / / / / / / / / / SVR4 11/ / / / SVR8 11/ / / / SVR12 11/ / / / SVR24 6/ / / /4 100 No resistance: no viral breakthrough observed GaneEJ, et al. AASLD2011. Abstract 34

32 PSI-7977 ELECTRON: safety and tolerability with IFN-free PSI-7977/RBV PSI-7977 RBV 12 weeks PEG N=11 PSI-7977 RBV 8 weeks PEG N=10 PSI-7977 RBV 4 weeks PEG N=9 PSI-7977 RBV NO PEG N=10 SAE >1 AE, n (%) 8 (72) 5 (50) 6 (67) 4 (40) Headache 2 (18) 2 (20) 1 (11) 1 (10) Fatigue 1 (10) 1 (11) 1 (10) Depression 3 (27) Insomnia 1 (9) 2 (22) Anxiety 1 (9) 1 (11) Irritability 2 (18) Myalgia 1 (9) 1 (10) Upper RTI 1 (9) 1 (11) RTI = respiratory tract infection GaneEJ, et al. AASLD2011. Abstract 34

33 PSI-7977 ELECTRON: no Grade 3/4 hematologic abnormalities in IFN-free PSI-7977/RBV PSI-7977 RBV 12 weeks PEG N=11 PSI-7977 RBV 8 weeks PEG N=10 PSI-7977 RBV 4 weeks PEG N=9 PSI-7977 RBV NO PEG N=10 G3 Hemoglobin g/dl (11%) 0 G3 Lymphopenia /mm (20%) 1 (11%) 0 G3 Neutropenia /mm 3 7 (64%) 4 (40%) 2 (22%) 0 G3 Leucopenia /mm 3 4 (36%) 3 (30%) 2 (22%) 0 G4 Neutropenia <500/mm 3 1 (9%) 1 (10%_ 2 (22%) 0 GaneEJ, et al. AASLD2011. Abstract 34

34 All-oral regimens in phase II studies Protease inhibitor NS5A inhibitor Nucleos(t)ide analogue polymerase inhibitor Nonnucleoside polymerase inhibitor Drug 1 Drug 2 Drug 3 RBV BI BI N/A ± PSI-7977 PSI-938 N/A ± ABT-450/ RTV ABT-333 or ABT-072 N/A PSI-7977 Daclatasvir N/A ± GS-9256 Tegobuvir N/A ± GS-9451 GS-5885 ± Tegobuvir ± Asunaprevir Daclatasvir BMS N/A + All-oral regimens of single drug + RBV also under investigation.

35 IFN-free therapy: common themes SVR approaching 100% in G1b Genotype 2/3 may be uniquely susceptible In IFN-free regimens, relevance of IL28BSNPs as predictor of response is unclear. RBV needed No data in advanced fibrosis Little data in Black patients Very short course, weeks and no IFN should improve tolerability

36 Will the interplay between patient and virus factors pre-determine treatment choice? Favorable response profile Course 1: Combination DAAs Fails? Course 2: PegIFN/RBV + combination DAAs Unfavorable response profile Course 1: PegIFN/RBV + combination DAAs

37 The Evolution of HCV Therapy Current Standard of Care (SOC): PEG + RBV IFN Sparing Strategy Combination Oral Antivirals + Shorter Course IFN Ultimate Goal Broad Genotypic Oral Antiviral Regimen The First Antivirals + SOC to Improve Response Rates and Reduce Duration All Oral Antiviral Regimen IFN Free Strategy

38 The Speed of Development Has Significantly Accelerated the Timeline Ultimate Goal IFN Sparing Strategy Current Standard of Care (SOC): PEG + RBV Combination Oral Antivirals Broad + Genotypic Shorter Oral Course Antiviral IFN Regimen The First Antivirals + SOC to Improve Response Rates and Reduce Duration All Oral Antiviral Regimen IFN Free Strategy

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40 A Future of Affordable Care for HCV Role of biomarkers of response(responsiveness to IFN, but not only!) Potential for short-term, all oral, pan-genotypic monotherapy(± RBV) Issues of costs(and ensuing priorities) and of general applicability Management of ADRs and potential for DDIs Once effective, cheap, applicabletreatmentsavailable, mass screening is needed!