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Paris, 30 & 31 January 2012 Robert Flisiak Department of Infectious Diseases and Hepatology Medical University of Białystok, Poland Overview of clinical.

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Presentation on theme: "Paris, 30 & 31 January 2012 Robert Flisiak Department of Infectious Diseases and Hepatology Medical University of Białystok, Poland Overview of clinical."— Presentation transcript:

1 Paris, 30 & 31 January 2012 Robert Flisiak Department of Infectious Diseases and Hepatology Medical University of Białystok, Poland Overview of clinical trials data

2 What attributes make an ideal HCV therapy? Efficacy High (>70%) efficacy High barrier to viral resistance Pan-genotypic activity Safety Very good safety profile Low treatment discontinuation rate Well defined drug-drug interactions Dosing Oral dosing Once-/twice-daily dosing

3 New HCV therapies fall into two categories based on their mechanism of actionDAAHTA Target: HCV viral proteinsTarget: host proteins needed for HCV replication Act on viral proteins – resistance may still be an issue, and efficacy may differ across genotypes Act on specific host proteins – high barrier to resistance and efficacy across genotypes NS3-iNS5B-iNS5A-iCyp-iImmuno- modulators Boceprevir Telaprevir Simeprevir (TMC435) BI 201335 GS-9256 GS-9451 PSI-7977 RG7128 BI 207127 VX-222 Daclatasvir (BMS-790052) ACH-2928 GS-5885 Alisporivir SCY635 PegIFNλ IMO-2125 (TLR agonist) Note: List is not exhaustive DAA=direct-acting antiviral; HTA=host-targeting antiviral; TLR=toll-like receptor; MoA=mechanism of action Kronenberger B and Zeuzem S. Ann Hepat 2009;8:103–112

4 Simeprevir (TMC435) combined with PegIFN  2a + RBV phase 2b (PILLAR study) virologic response cEVR, complete early virologic response; ITT, intent-to-treat; Pbo, placebo; P/R, peginterferon  -2a + ribavirin; RVR, rapid virologic response; W, weeks Fried MW et al. AASLD 2011 Virologic response (%) EOT HCV RNA <25 IU/mL undetectable: week 4 (RVR)week 12 (cEVR) TMC435 75 mg 12W P/R (n=78) TMC435 75 mg 24W P/R (n=75) TMC435 150 mg 12W P/R (n=77) TMC435 150 mg 24W P/R (n=79) Pbo/P/R (n=77) SVR TVR  (Advance & Illuminate) = 28-31% BOC  (Sprint-2) = 27-28% TVR  (Advance & Illuminate) = 28-31% BOC  (Sprint-2) = 27-28% NS3-i

5 IL28B, polymorphism on chromosome 19 s12979860 Pbo, placebo; P/R, peginterferon  -2a + ribavirin; SVR, sustained virologic response Proportion of patients (%) Among consenting patients (67.9%), distribution of IL28B genotype was: 30% CC, 58% CT, and 12% TT N=313512787234 CC CC CT/TT CT/TT Fried MW et al. AASLD 2011 Pbo P/R Pbo P/R TMC435 75mg P/R TMC435 75mg P/R TMC435 150mg P/R TMC435 150mg P/R Simeprevir (TMC435) combined with PegIFN  2a + RBV phase 2b (PILLAR study) SVR by IL28B genotype  = 23-28% NS3-i

6 Simeprevir (TMC435) combined with PegIFN  2a + RBV phase 2b (PILLAR study) safety Number of subjects with AE: n (%) All TMC435 N=309(%) Pbo/P/R 48W N=77(%) AE leading to permanent stop of TMC435/Pbo & P/R 11 (3.6) 4 (5.2) Grade 3 or 4 AE 99 (32.0) 27 (35.1) Serious AE 20 (6.5) 10 (13.0) Five most common AEs Fatigue 131 (42.4) 37 (48.1) Influenza-like illness 98 (31.7) 29 (37.7) Pruritus 96 (31.1) 35 (45.5) Headache 142 (46.0) 40 (51.9) Nausea 86 (27.8) 21 (27.3) Other AEs of interest Rash 65 (21.0) 18 (23.4) Anemia 63 (20.4) 16 (20.8) Neutropenia 75 (24.3) 16 (20.8) AE, adverse event; Pbo, placebo; P/R, peginterferon  -2a + ribavirin; W, week Fried MW et al... AASLD 2011 No effect of TMC435 on incidence of AEs was observed NS3-i

7 12 weeks of PSI-7977 + RBV treatment +/- PegIFN  2a in G2/G3 infected (Electron) Gane EJ et al. AASLD 2011 Need to be confirmed in larger population nuc-NS5B-i

8 Electron: Response to PSI-7977 + RBV No need of PegIFN  in G2/G3 Electron/Nuclear: Response to PSI-7977 G1 = G2/3 Proton: Response to PSI-7977 +PegIFN  /RBV 200mg = 400mg nuc-NS5B-i Gane EJ et al. AASLD 2011 Lawitz E et al. EASL 2011.

9 Lawitz E et al. AASLD 2011 Virologic response rate 12 weeks of triple therapy with PSI-7977 in G1 naive patients (Proton study) Peg/RBVPeg/RBV Peg/RBVPeg/RBV Peg/RBVPeg/RBV Peg/RBVPeg/RBV eRVR non-eRVR eRVR non-eRVR 041224 48 week Peg/RBVPeg/RBV PSI-7977, 400mg Peg/RBV PSI-7977, 200mg Peg/RBV nuc-NS5B-i N=48 N=47 N=26

10 PSI-7977RBV Peg 12wks n=11PSI-7977RBV Peg 8wks n=10PSI-7977RBV Peg 4wks n=9PSI-7977RBV NO Peg n=10 Neutropenia <750/mm3 8 (73%) 5 (50%) 4 (44%) 0 Leucopenia <1500/mm3 4 (36%) 3 (30%) 2 (22%) 0 Gane EJ et al. AASLD 2011 PSI-7977 safety (Electron) haematology HemoglobinNeutrophils nuc-NS5B-i

11 Pol S et al. ICAAC, Chicago 2011; H1-376 Daclatasvir (BMS-790052) + PegIFNa2a + RBV Efficacy and safety, phase 2a study in G1 patients The most advanced NS5A inhibitor. HCV genotype 1 mono-infected treatment naïve patients. Randomized to PegIFN  2a + RBV with either placebo or 3, 10 or 60 mg BMS-790052 given once daily (N=48; n=12 per study arm). Therapy was given for 48 weeks plus 24 weeks of follow-up. Efficacy Safety NS5A-i

12 Hezode C et al. AASLD 2011; 227. Daclatasvir (BMS-790052) + PegIFN  2a + RBV week 12 efficacy in G1 & G4 patients HCV genotype 1 (N=365) or 4 (N=30) mono-infected treatment naïve patients. Randomized to PegIFN  2a + RBV with either placebo, 20 or 60 mg BMS-790052 once daily. Treatment period 24 or 48 weeks. Week 4 HCV RNA<25 IU/mL + week 10 HCV RNA<10IU/mL  24wks triple or  12wks triple + 12wks dual therapy. No week 4/10 response  48 wks triple % 24wks eligibleNA71%72% NS5A-i

13 Flisiak R et al. Hepatology 2009; 49: 1460-8. PegIFN  2a +/- RBV +/- ALV (naive G1) PegIFN  2a + RBV +/- ALVPR+ALV 24 wks. PR+ALV PegIFN  2a +/- ALV PegIFNa2a + ALV ALV PegIFNa2a Peg Peg+ALV PR 48 wks. PR ALV triple therapy shorten treatment time by 50% Flisiak R et al. EASL, Berlin 2011, #190 PegIFN  2a antiviral effect is doubled by ALV even without RBV. 48 weeks of ALV triple therapy improve efficacy significantly PR+ALV 48 wks. PR+ALV PR+ALVRGTPR+ALVRGT Cyp-i

14 Dual ALV+RBV therapy (without PegIFN  in G2/G3 patients (Vital-1) Pawlotsky JM et al. AASLD 2011 RVR achieved dual treatment (without PegIFN  2a) continued n=89 (36%) RVR not achieved triple therapy (with PegIFN  2a) from week 6 n=155 (64%) Cyp-i + PegIFN  2a

15 ALV safety hyperbilirubinemia Total Bilirubin Transient and reversible hyperbilirubinemia during ALV loading dosage (1st week of therapy) In 4.2% patients bilirubin above 5xULN  resolved by wk 4 Hyperbilirubinemia always normalize after treatment termination No association with ALT or GGT (much faster decrease of ALT with ALV) PR48 PR/ALV48 PR/ALV24 PR/ALV-RGT ALT Cyp-i Flisiak R et al. HepDart 2011

16 n =100102103103 0 10 20 30 40 50 60 70 80 90 100 PegIFN-λ 120 μg PegIFN-λ 180 μg PegIFN-λ 240 μg PegIFN-α-2a 180 μg 6.0 14.7 16.5 5.8 RVRRVRRVRRVR 55.0 55.9 56.3 37.9 RVRcEVRRVRcEVRRVRcEVRRVRcEVR Zeuzem S et al., EASL 2011, #422 Undetectable HCV RNA at Week 4 (RVR) and Week 12 (cEVR): HCV Genotypes 1, 4 HCV RNA Undetectable ( percentage of patients ± 95% CI) Data indicate HCV RNA not detected by Roche COBAS TaqMan HPS v2.0 * P < 0.05 Immunomodulator

17 n =30293029 43.3 75.9 66.7 31.0 0 10 20 30 40 50 60 70 80 90 100 PegIFN-λ 120 μg PegIFN-λ 180 μg PegIFN-λ 240 μg PegIFN-α-2a 180 μg 90.0 96.6 83.3 86.2 RVRcEVRRVRcEVRRVRcEVRRVRcEVR RVRRVRRVRRVR Zeuzem S et al., EASL 2011, #422 Undetectable HCV RNA at Week 4 (RVR) and Week 12 (cEVR): HCV Genotypes 2, 3 HCV RNA Undetectable ( percentage of patients ± 95% CI) Data indicate HCV RNA not detected by Roche COBAS TaqMan HPS v2.0 NS Immunomodulator

18 PegIFNλ vs. PegIFNα2a safety AEs & haematology changes during Total PegIFN-λ 180  g PegIFNα2a AE(N = 393)(N = 133) Any AE, %86.895.5 Fatigue36.442.9 Headache23.933.1 Myalgia8.730.1 Pyrexia6.629.3 Nausea27.527.1 Arthralgia7.421.8 Chills2.020.3 Insomnia19.820.3 Rash7.415.0 Pruritus13.713.5 Diarrhea9.211.3 Cough7.111.3 Decreased appetite9.910.5 Depression 7.19.8 Irritability14.89.8 Listed by descending frequency on pegIFN-α-2a. Shading indicates events with >2-fold difference in frequency, total pegIFN-λ vs pegIFN-α-2a. Immunomodulator Zeuzem S et al., EASL 2011, #422

19 Viral breakthrough [%] TVR (T8/T12) 3 n=7278-13 BOC (48w/RGT) 5 n=6279-10 TMC435 (150 mg arms) 2 n=1565.2 ALV (48w/RGT) 1 n=1442.8 PSI-7977 4 n=953.2 Viral Breakthrough rates triple therapies naive, GT1 1.Flisiak R et al. EASL 2011 2.Fried MW et al. AASLD 2011 3.Jacobson I et al. N Engl J Med. 2011; 364: 2405-16 4.Lawitz E et al. AASLD 2011 5.Poordad F et al. N Engl J Med. 2011; 364: 1195-1206

20 Can triple retreatment with DAA be effective if resistant variants were selected during previous DAA therapy? an example of TVR triple retreatment in cases of TVRr variants Sarrazin C et al. AASLD 2011, 35 9 non-SVR patients exposed to TVR during previous therapy followed by selection of resistant variants. HCV RNA <25 IU/mL [%]

21 How durable is response to DAA containing triple therapy? an example of follow-up of phase 2&3 TVR clinical trials n=383 SVR n=221 no SVR n=162 4-45m. durable SVR n=220 (99,5%) relapse n=1 (0,5%) 44 wks after early treatment termination 7-49m. TVR resistant variants n=28 (17%) wild type n=134 (83%) G1a: 78% G1b: 98%* G1a: 78% G1b: 98%* *faster disappearance of variants related to G1b (V36A, T54A, A156S/T) than G1a (V36M, R155K) *faster disappearance of variants related to G1b (V36A, T54A, A156S/T) than G1a (V36M, R155K) Sherman KE et al. AASLD 2011, 248

22 DAA and HTA profile DAAHTA NS3-i 1 NS3-i 2 NS5A-i nuc NS5B-i non-nuc NS5B-i Cyp-i Resistance profile Pan-genotypic efficacy Efficacy Adverse events Good profileAverage profileLeast favourable profile

23 Conclusions for the future 1.Efficacy: SVR can be improved up to 90% in G1 and 100% in G2/G3 (NS3-i 2, NS5A-i, nuc-NS5B-i) Breaktrough <5% (nuc-NS5B-i, Cyp-i) High genetic barrier (nuc-NS5B-i, Cyp-i) Pangenotypic at least for G1-4 (nuc-NS5B-i, Cyp-i, NS5A-i) 2.Safety: No (NS3-i 2, nuc-NS5B-i) or transient (NS5A-i, Cyp-i) side effects Low rate of discontinuation due to AE Drug to drug interactions - unclear 3.Dosing: Once a day administration (NS5A-i, Cyp-i) Duration of G1 treatment 12-24 weeks (NS3-i 2, nuc-NS5B-i). 4. Interferon sparing therapy? In G2/3 at least in RVR (nuc-NS5B-i, Cyp-i) In G1 selection of eligible subpopulation need further studies (nuc-NS5B-i)

24 DAAHTA NS3-iNS5B-iNS5A-iCyp-i VertexTelaprevirVX-222 BMSBMS-650032BMS-790052 BMS/TibotecTMC435BMS-790052 GileadGS-9256GS-9190 GileadGS-9451GS-5885 PharmassetPSI-938PSI-7977 Gilead/Pharmasset ?GS-9256PSI-7977 Boehringer Ingelh.BI-201335BI-207127 IdenixIDX-320IDX-184 RocheDanoprevirMericitabine NovartisALV + RBV Possible interferon sparing combinations

25 Are we close to ideal HCV therapy? Efficacy High (>70%) efficacy High barrier to viral resistance Pan-genotypic activity Safety Very good safety profile Low treatment discontinuation rate Well defined drug-drug interactions Dosing Oral dosing Once-/twice-daily dosing

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