Rome, February 20-21 nd 2014 Riunione Annuale AISF 2014 14 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
The changing paradigm of HCV treatment IFN-free FDA Approval Timeline 2013 2014 2015 GT-2,3: Sofosbuvir + RBV GT-1: Sofosbuvir + Ledipasvir ABT450r+ABT26 7+ABT333 Daclatasvir Geno-1b: Faldaprevir + PEG/RBV GT-1: Daclatasvir + Asunaprevir + BMS791325 MK5172 + MK8742 IFN free therapy: drug cocktails targeting multiple HCV enzymes become the standard tx for HCV as for HIV
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
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
NI based strategy: SOF as the backbone SOF + RBV 12-24 wks SOF + LED 8-12 -24 wks SOF + DCV 12-24 wks SOF + SIM 12 wks
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
SOF based regimens in GT-1 Cirrhosis Tx status Duration wks SVR (%) SOF + DCV*+ RBV NO Naive 12 95 SOF + DCV*+ RBV NO PI failure 24 95 SOF + SMV 1^+ RBV NO F3-4; Null Naive and Null 12/24 12 80-90 95 SOF + LDV + RBV YES PI failure 12 95 SOF + LDV + RBV + 9669 F3-4 Experienced 12 100 1 Q80K evaluation to be performed in 1 a, ^off label and not recommended in CTP B,C *to be approved
Special populations? May we treat with IFN free combinations pts with evidence of cirrhosis? When? May we treat co-infected pts?
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 2013. Abstract 73
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 100 100 96 80 LONESTAR: 12-wk regimens in GT1 HCV PI failures (55% cirrhotic) 100 80 Sofosbuvir/ledipasvir + RBV Sofosbuvir/ledipasvir 95 95 100 80 LONESTAR Cirrhotics PI failures no RBV RBV 91 100 SVR4 (%) 60 40 47% cirrhotic 60 40 60 40 20 20 20 0 n/n = 26/27 14/14 0 18/19 20/21 0 10/11 11/11 Jacobson IM, et al. AASLD 2013. Abstract LB-3. Lawitz E, et al. AASLD 2013. Abstract 215..
SOF + Daclatasvir + RBV 100 80 Treatment naive PI failure 12 wks 24 wks 100 95 100 80 100 95 AI443-014: 12-wk regimen in GT1 treatment-naive DCV 60 mg/die cirrhotics SOF 400 mg/die Daclatasvir + asunaprevir + BMS-791325 100 80 87 F4 9/41 (20%) SVR4 (%) 60 40 60 40 60 PI res 19/41 (46%) 40 20 20 20 0 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;.
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
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 499 20% 75,000/mm 3 67% FUSION SOF/ RBV GT 2 & 3 Treatment-Experienced 201 34% 50,000/mm 3 50-73% POSITRON SOF/ RBV GT 2 & 3 IFN Unable 278 16% No Lower Limit 78% VALENCE SOF/ RBV GT 2 & 3 Treatment-Naïve & Treatment-Experienced 323 21% 50,000/mm 3 84-93% No upper limit to age or BMI, opiate replacement therapy permitted
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 16-24 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) 12-24 wks
LONESTAR-2: SOF + PegIFN/RBV for 12 Weeks in Treatment Experienced HCV-2 & 3 Patients SVR 100% 90 80 70 60 50 40 30 20 10 0 96 Overall 83 HCV-3 83 83 22/23 20/24 10/12 10/12 HCV-2 HCV-3 F1-3 F4 Lawitz E., AASLD 2013
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%
New indications in areas of unmet clinical need Pre-liver transplant Post liver transplant
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
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 2013. Abstract 21
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.
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 267 3- DAA regimen but also the BMS approach
3 DAA regimen +/-RBV in broad range of GT1 patient populations 3DAA + RBV M11-646 SAPPHIRE-I (GT1 naїve, no cirrhosis vs placebo) 12 wks N=600 M13-098 SAPPHIRE-II (GT1 exp, no cirrhosisvs placebo) 12 wksn=400 RBV-free M13-389 PEARL-II (GT1b exp, no cirrhosis+/-rbv) up to12 wks N=210 M13-961 PEARL-III (GT1b naїve, no cirrhosis+/-rbv) 12 wks N=400 M14-002 PEARL-IV (GT1a naїve, no cirrhosis+/- RBV) 12 wksn=300 Special Population s M13-099 TURQUIOSE-II (GT1 naїve/exp, cirrhotics) 12 vs 24 wksn=300 *M14-004 TURQUIOSE-I (GT1 HIV/HCV no cirrhosis) 12 vs 24 wks N=300 *Submitted as a supplement to the NDA
ABT 450/r + ABT 267 + ABT 333 + 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.
Non nucleotide-based strategies: The BMS approach 2 DAA 3 DAA DCV/ASN DCV/ASN/BMS 791325 GT1 GT1 DCV/SIM GT1 DCV/SOF GT1,2,3 DCV/VX135 GT1
DCV + ASN N=135 IFN intolerant Japanese pts including 8% of cirrhotics N=87 NR Japanese pts including 13% of cirrhotics 87 80 + BMS-791325 BID* 75 mg* x 12 wks Cirrhotics N=15 100 71 Non cirrhothics N=151 91 94 24 weeks 150 mg* SVR 24 SVR 12 1) Chayama K et al AASLD 2013 Everson GT et al AASLD 2013
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% 94 91 12 12-49.000 (D) 42.000(UK)? (I) SOF + RBV SOF + RBV SOF + RBV HCV 2 experienced cirrhosis HCV 3 naive cirrhosis HCV 3 experienced cirrhosis 100% 88 78 100% 93 92 100% 87 60 12 16 -? 24 -? x2 24 24 -? x2 SOF + DCV 1 HCV 3 experienced 100% 100 24 -? SOF + RBV HCV 4 IFN inelegible 100% 100 24 -? x2 SOF + RBV HCV 1 IFN inelegible 100% 68 24 -? x2 SOF + RBV 1 DCV to be approved Pre-OLT or cirrhosis CTP B or C 100% 62 4-48 ~ 4.000 x?
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
Thank you
Disclosures I have the following financial relationships to disclose within the past 12 months: ROCHE, Merck, Gilead, Janssen-Cilag, BMS, Abbvie
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* 100 95 Cohort 2 N=40 PI Failure (50% cirrhosis) SOF/LDV FDC(n=20) SOF/LDV FDC + RBV (n=20) 95 100* *relapse; lost to follow up
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: 5.5 0 30 60 90 120 150 180 210 240 270 300 Days With HCV RNA Continuously TND Prior to Liver Transplant 330 Curry MP, et al. AASLD 2013. Abstract 213. Reproduced with permission.