Rome, February nd Riunione Annuale AISF th AISF ANNUAL MEETING

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1 Rome, February nd 2014 Riunione Annuale AISF th AISF ANNUAL MEETING Present and future treatment strategies for patients with HCV infection: chronic hepatitis and special populations IFN FREE COMBINATIONS Alessandra Mangia, San Giovanni Rotondo

2 The changing paradigm of HCV treatment IFN-free FDA Approval Timeline GT-2,3: Sofosbuvir + RBV GT-1: Sofosbuvir + Ledipasvir ABT450r+ABT26 7+ABT333 Daclatasvir Geno-1b: Faldaprevir + PEG/RBV GT-1: Daclatasvir + Asunaprevir + BMS MK MK8742 IFN free therapy: drug cocktails targeting multiple HCV enzymes become the standard tx for HCV as for HIV

3 IFN free: the changing paradigm of HCV treatment Simplified, shorter regimens with mantained or higher efficacy regardless of pts population New indications more pts to treat High safety profile

4 Different drug different strategies Coree E11 E22 NS2 NS3 NS4B1 NS5A NS5B HCV PIs NS5A Inhibitors NS5B Nucs NS5B Non Nucs NS5B NI (sofosbuvir) based strategy Non NI based: -- combining PI, NS5A and NI -- combining PI and NS5A only

5 NI based strategy: SOF as the backbone SOF + RBV wks SOF + LED wks SOF + DCV wks SOF + SIM 12 wks

6 SOF in mono or co-infected pts: EMA authorized Patient population Treatment Duration Genotype 1, 4, 5 or 6 CHC Sof 400 mg + RBV (wb)+ peg-ifn Sof 400 mg + RBV (wb) only for use in pts ineligible or intolerant to peg-ifn Genotype 2 CHC Sof 400 mg + RBV (wb) Genotype 3 CHC Sof 400 mg + RBV (wb) + peg-ifn Sof 400 mg + RBV (wb) 12 weeks 24 weeks 12 weeks 12 weeks 24 weeks Patients with CHC awaiting liver transplantation Sof 400 mg + RBV (wb) Until liver transplantation

7 SOF based regimens in GT-1 Cirrhosis Tx status Duration wks SVR (%) SOF + DCV*+ RBV NO Naive SOF + DCV*+ RBV NO PI failure SOF + SMV 1^+ RBV NO F3-4; Null Naive and Null 12/ SOF + LDV + RBV YES PI failure SOF + LDV + RBV F3-4 Experienced Q80K evaluation to be performed in 1 a, ^off label and not recommended in CTP B,C *to be approved

8 Special populations? May we treat with IFN free combinations pts with evidence of cirrhosis? When? May we treat co-infected pts?

9 Electron (Phase II study): SOF + LDV ± RBV wk 0 wk 6 wk 12 SVR 12 GT- 1 Experience d Naive F4 F3-4 F0-2 SOF/LDV FDC (n=10) SOF/LDV FDC + RBV (n=10) SOF/LDV FDC + RBV (F4=18/25) SOF/LDV FDC + GS9669 ( F4=17/26) SOF/LDV FDC + RBV (n=25) 70% 100% 100% 100% 68% Gane E et al. AASLD Abstract 73

10 Efficacy of IFN-Free DAA Combinations in Tx-Naive and Tx-Experienced Cirrhotics COSMOS: 12-wk regimens in GT1 HCV F3-4 naive or previous null responders Simeprevir + sofosbuvir + RBV Simeprevir + sofosbuvir LONESTAR: 12-wk regimens in GT1 HCV PI failures (55% cirrhotic) Sofosbuvir/ledipasvir + RBV Sofosbuvir/ledipasvir LONESTAR Cirrhotics PI failures no RBV RBV SVR4 (%) % cirrhotic n/n = 26/27 14/ /19 20/ /11 11/11 Jacobson IM, et al. AASLD Abstract LB-3. Lawitz E, et al. AASLD Abstract 215..

11 SOF + Daclatasvir + RBV Treatment naive PI failure 12 wks 24 wks AI : 12-wk regimen in GT1 treatment-naive DCV 60 mg/die cirrhotics SOF 400 mg/die Daclatasvir + asunaprevir + BMS F4 9/41 (20%) SVR4 (%) PI res 19/41 (46%) n/n = 41/41 39/40 0 n/n = 21/21 19/20 DCV/SOF DCV/SOF DVC/SOF DCV/SOF RBV RBV 0 13/15 Sulkowsky M, et al. N Engl J Med 2014;.

12 What s available now for GT1 IFN intolerant? The SPARE study: efficacy results F4 3/6 F4 2/7 N=10 N=25 N=25 Part 1 Part 2 1 pt in the high and 2 in the low RBV dose group discontinued treatment by wk 8 A total of 13 patients with advanced disease was included with SVR rate of 46% Osinusi et al. AASLD 2012; LB4

13 GT2 and 3: Phase III Studies on Sofosbuvir and RBV Study Population Total Pts %with Cirrhosis Lower Limit of Platelets SVR12 FISSION SOF/ RBV GT 2 & 3 Treatment Naïve % 75,000/mm 3 67% FUSION SOF/ RBV GT 2 & 3 Treatment-Experienced % 50,000/mm % POSITRON SOF/ RBV GT 2 & 3 IFN Unable % No Lower Limit 78% VALENCE SOF/ RBV GT 2 & 3 Treatment-Naïve & Treatment-Experienced % 50,000/mm % No upper limit to age or BMI, opiate replacement therapy permitted

14 Phase III studies: increased efficacy by longer duration in GT-2&3 with cirrhosis Cirrhosis by HCV GT SOF/RBV 12 wks SVR % (n/n) SOF/RBV wks SVR % (n/n) STUDY GT-2 Yes 91 (10/11) -- Fission (naive) GT-2 No 98 (58/59) -- Fission (naive) GT-2 Yes 60 (6/10) 78 (7/9) Fusion GT-2 No 96 (25/26) 100 (23/23) (experienced) 16 wks GT-3 Yes 34 (13/38) -- Fission (naive) GT-3 No 61 (89/145) Fission (naive) GT-3 Yes 19 (5/26) 61 (14/23) Fusion GT-3 No 37 (14/38) 63 (25/40) (experienced) 16 wks GT-3 Yes 0/2 67 (39/58) Valence (naive GT-3 No 33 (3/9) 91 (174/192) experienced) wks

15 LONESTAR-2: SOF + PegIFN/RBV for 12 Weeks in Treatment Experienced HCV-2 & 3 Patients SVR 100% Overall 83 HCV /23 20/24 10/12 10/12 HCV-2 HCV-3 F1-3 F4 Lawitz E., AASLD 2013

16 SOF + RBV in HIV/HCV coinfected pts The Photon study GT-1 (n=114) GT-2 (n=26) GT-3 (n=42) Tx duration 24 wks 12 wks 12 wks Efficacy SVR in naive 76% 88% 67% Tolerability Completed Side effects Administration Tenofovir DF/emtricitabine + Efavirenz Atazanavir/r Darunavir/r Raltegravir Rilpivirine 90% (103) 3% 88% (23) 4% Once-daily, oral, 400-mg tablet NONE NONE NONE NONE NONE NONE NONE 93% (39) 5%

17 New indications in areas of unmet clinical need Pre-liver transplant Post liver transplant

18 IFN-based treatment of pre and post transplant HCV infected pts Pre OLT antiviral Tx with P/R Viral clearance post OLT 20% TT post OLT 30-40% SVR Everson GT, et al Hepatology 2013; Forns X, et al. J Hepatol 2003; Carrion JA,et al.j Hepatol 2009 Iacobellis A et al Clin Gastr Hepatol 2011; Coilly A, et al AASLD 2013; Todd-Stravitz R et al AASLD 2013

19 SOF + RBV before OLT: duration of HCV RNA undetectable before OLT and lack of recurrence No. 61 pts with HCC meeting Milan criteria: CTP 7; MELD 8 (6-14); Transplanted n=44 (STD immunosuppression P/MMF/ tacrolimus) No recurrence (n = 28) Recurrence (n = 10) HCV RNA <LLOQ at Transplant (n=41/44) (93%) Recurrence (n=10) 1 imputed recurrence* Post OLTx Follow-up (n=27/41) Death (n=3) Median days TND (P <.001) No recurrence: 95 Recurrence: 5.5 *1 patient lost to follow-up after post-transplant Week 8 (HCV RNA <LLOQ). Curry MP, et al. AASLD Abstract 21

20 SOF + RBV for recurrent infection after OLT SOF 400 mg QB + RBV x 24 wks 40 pts with recurrent HCV MELD 17, CTP 7 Cirrhosis n=16 Genotype 1, n =33 Yrs since OLT 4.3 Relapse in 9 pts (22.5%) Discontinuation due to AEs n=2 Anemia 20% Virologic Response Rate (%) 27/35 *1 patient still on treatment; 4 patients have not reached SVR4 visit. Charlton M, et al. AASLD 2013.

21 Non nucleotide-based strategies 2 or 3 DAA - The Abbvie approach. PI NNI NS5A inhibitors ABT 450 r AB T 333 Dual DAA regimen ABT 450 r AB T 333 AB T DAA regimen but also the BMS approach

22 3 DAA regimen +/-RBV in broad range of GT1 patient populations 3DAA + RBV M SAPPHIRE-I (GT1 naїve, no cirrhosis vs placebo) 12 wks N=600 M SAPPHIRE-II (GT1 exp, no cirrhosisvs placebo) 12 wksn=400 RBV-free M PEARL-II (GT1b exp, no cirrhosis+/-rbv) up to12 wks N=210 M PEARL-III (GT1b naїve, no cirrhosis+/-rbv) 12 wks N=400 M PEARL-IV (GT1a naїve, no cirrhosis+/- RBV) 12 wksn=300 Special Population s M TURQUIOSE-II (GT1 naїve/exp, cirrhotics) 12 vs 24 wksn=300 *M TURQUIOSE-I (GT1 HIV/HCV no cirrhosis) 12 vs 24 wks N=300 *Submitted as a supplement to the NDA

23 ABT 450/r + ABT ABT RBV: data on cirrhotic patients Study Patients Treatment Regimen SVR 12 GT1 a and b treatmentnaive and treatment- weeks (n=208) AbbVie regimen + RBV, 12 experienced with TURQUOISE-II ompensated cirrhosis (12 & 24 weeks) AbbVie regimen + RBV, 24 (N=380) weeks (n=172) 92% (191/208) 96% (165/172) TURQUOISE-II multi-center, randomized, open-label study evaluating the efficacy and safety of 12 or 24 weeks of treatment with AbbVie's regimen with RBV in compensated cirrhotic. AE: fatigue, headache and nausea. Discontinuations due to SAE were reported in 4 (2%) patients receiving the regimen with RBV for 12 weeks and 4 (2%) patients in the 24-week arm. Virologic relapse or breakthrough was noted in 6% of patients in the 12-week arm and 2 %in the 24-week arm.

24 Non nucleotide-based strategies: The BMS approach 2 DAA 3 DAA DCV/ASN DCV/ASN/BMS GT1 GT1 DCV/SIM GT1 DCV/SOF GT1,2,3 DCV/VX135 GT1

25 DCV + ASN N=135 IFN intolerant Japanese pts including 8% of cirrhotics N=87 NR Japanese pts including 13% of cirrhotics BMS BID* 75 mg* x 12 wks Cirrhotics N= Non cirrhothics N= weeks 150 mg* SVR 24 SVR 12 1) Chayama K et al AASLD 2013 Everson GT et al AASLD 2013

26 IFN free regimens available in the coming months in EU Treatment Genotype % of the population % SVR Duration wks Side Effects Cost (12 wks) SOF + RBV HCV 2 naive cirrhosis 100% (D) (UK)? (I) SOF + RBV SOF + RBV SOF + RBV HCV 2 experienced cirrhosis HCV 3 naive cirrhosis HCV 3 experienced cirrhosis 100% % % ? 24 -? x ? x2 SOF + DCV 1 HCV 3 experienced 100% ? SOF + RBV HCV 4 IFN inelegible 100% ? x2 SOF + RBV HCV 1 IFN inelegible 100% ? x2 SOF + RBV 1 DCV to be approved Pre-OLT or cirrhosis CTP B or C 100% ~ x?

27 Summary 12 wks of SOF/RBV combination for GT2 & selected GT 12 wks IFN/RBV+ SOF for GT 1/4 or GT 3 cirrhotics IF elegible IFN free combinations in the near future for G1 without differences between null and naive IFN free regimens for 24 wks with SOF/RBV to address unmet clinical needs or for GT 1, 3, 4 IFN inelegible No Ribavirin with some IFN free future combinations

28 Thank you

29 Disclosures I have the following financial relationships to disclose within the past 12 months: ROCHE, Merck, Gilead, Janssen-Cilag, BMS, Abbvie

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31 Lonestar study: SOF + LDV ± RBV wk 0 wk 8 wk 12 SVR 12 Cohort 1 N=60 Treatment naive No cirrhosis SOF/LDV FDC (n=20) SOF/LDV FDC + RBV (n=20) SOF/LDV FDC (n=20) 95* Cohort 2 N=40 PI Failure (50% cirrhosis) SOF/LDV FDC(n=20) SOF/LDV FDC + RBV (n=20) * *relapse; lost to follow up

32 SOF + RBV before OLT: duration of HCV RNA undetectable before OLT and lack of recurrence Pts with HCC meeting Milan criteria: CTP 7; MELD 8 (6-14); Transplanted n=44 STD immunosuppression P/MMF/ tacrolimus) > 30 days TND No recurrence (n = 28) Recurrence (n = 10) 64% (23/36) of pts HCV RNA negative 12 wks post-lt (93% at LT) Continuous days TND pre-lt only factor predicting HCV recurrence in multivariate analysis Median days TND (P <.001) No recurrence: 95 Recurrence: Days With HCV RNA Continuously TND Prior to Liver Transplant 330 Curry MP, et al. AASLD Abstract 213. Reproduced with permission.