Interferon-based and interferon-free new treatment options White Nights of Hepatology St. Petersburg, 7. June 2013 Christoph Sarrazin Klinikum der J. W. Goethe-Universität Medizinische Klinik I Frankfurt am Main Mode of action of Interferons natural immunomodulatory effects IFN-stimulated gene activation Antiviral Apoptotic Immunomodulatory activity activity activity B-cell proliferation Reduced transcription Elevates apoptosis by CTL proliferation Reduced translation multiple mechanisms MHC upregulation Reduced RNA stability Augments NK activity Host-mediated effects are important for DAA combination therapy • Potency and additive effects • Prevention of resistance and viral breakthrough Different types of Interferons Type I Interferons Type III Interferons Broad receptor Receptors distribution distributed throughout various primarily in body tissues epithelial cells and hepatocytes Antiviral effects Antiviral effects Adverse events of Type I IFNs treatment Peg‐Intron • Flu-like symptoms PegIFN‐2a Type III IFNs Potentially fewer • Haematologic IFN omega Peg‐IFN‐ adverse events disorders IFN‐alfa‐2b XL lambda than with type I • Psychiatric Belerofon (Peg‐rIL‐29) interferons symptoms Albuferon Locteron Adapted from 1. Marcello T et al. Gastroenterology 2006;131:1887–98; 2. Muir AJ et al. 2009 AASLD. Abstract 1591; 3. O'Brien TR. Nat Genet. 2009;41:1048–50. PEG-Interferon alfa / Ribavirin Approval studies: efficacy Approval study (n=1530) Approval study (n=1121) Therapy: IFN vs. PEG-IFN alfa 2b Therapy: IFN vs. PEG-IFN alfa 2a 1,0/1,5µg/kgKG per week 180µg per week Ribavirin 1,0-1,2g/die Ribavirin 1,0-1,2g/die 100 100 80 80 54% 56% 60 47% 47% 60 44% 40 40 20 20 0 sustained virologic response (SVR) 0 sustained virologic response (SVR) IFN PEG1,0 PEG1,5 IFN PEG180 Riba Riba Riba Riba Riba Manns et al., Lancet 2001 Fried et al., N Engl J Med 2002 PEG-Interferon alfa / Ribavirin Approval studies: safety Manns et al., Lancet 2001 Fried et al., N Engl J Med 2002 IFN-lambda versus IFN-alfa Distribution of receptors IFN-λ1 IFN-α • IFNs activate antiviral Liver genes required for HCV receptor* receptor* clearance Hepatocytes High High − HCV induces a stronger Endothelial cells Not detected High IFN-lambda response vs Smooth muscle Not detected High IFN-alfa in vitro1 Fibroblasts Not detected High • Receptors for IFN-lambda and -alfa have different Haematopoietic 2 Bone marrow distributions Not detected High progenitors (CD34+) • Reduction in off-target . effects may improve T and NK cells Not detected High tolerability and increase Monocytes Not detected High eligibility and adherence3 B cells High High Central nervous system4 *Based on levels of RNA expression Brain Low High DAA=direct-acting antiviral; IFN=interferon; NK=natural killer Created from 1. Marukian S, et al. Hepatology 2011;54:1913–23; 2. Doyle SE, et al. Hepatology 2006;44:896–906; 3. Muir AJ, et al. Hepatology 2010;52:822–32. 4. Sommereyns C, et al. PLoS Pathog. 2008;4(3):e1000017 PEG-lambda/Riba versus PEG-alfa2a/Riba Clinical Phase 2b study Muir AJ, et al. AASLD 2012. Oral 214. PEG-lambda/Riba versus PEG-alfa2a/Riba Baseline characteristics genotype 1/4 Muir AJ, et al. AASLD 2012. Oral 214. PEG-lambda/Riba versus PEG-alfa2a/Riba Baseline characteristics genotype 1/4 Muir AJ, et al. AASLD 2012. Oral 214. PEG-lambda/Riba versus PEG-alfa2a/Riba Viral kinetics genotype 1/4 Muir AJ, et al. AASLD 2012. Oral 214. PEG-lambda/Riba versus PEG-alfa2a/Riba Virologic response rates genotype 1/4 Muir AJ, et al. AASLD 2012. Oral 214. PEG-lambda/Riba versus PEG-alfa2a/Riba Virologic response rates genotype 2/3 Zeuzem S, et al. EASL 2012. Oral 1435 PEG-lambda/Riba versus PEG-alfa2a/Riba Safety: SAEs, AEs Muir AJ, et al. AASLD 2012. Oral 214. PEG-lambda/Riba versus PEG-alfa2a/Riba Safety: spesific AEs Muir AJ, et al. AASLD 2012. Oral 214. PEG-lambda/Riba versus PEG-alfa2a/Riba Safety: liver-related abnormalities Muir AJ, et al. AASLD 2012. Oral 214. PEG-lambda/Riba versus PEG-alfa2a/Riba Safety: blood cell counts Muir AJ, et al. AASLD 2012. Oral 214. Era of direct antiviral agents Overview on targets within the HCV polyprotein and the host Viral targets Host targets C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B NS3 NS5A NS5B Cyclophilin A The NS3/4A serine protease Multifunctional membrane- NS5B is an HCV-specific, Host protein involved in HCV associated phosphoprotein is essential for post- RNA-dependent RNA replication through interaction essential component of the 1 translational processing of HCV-RNA replication polymerase with NS5A and the HCV 1 4 HCV polyproteins complex2,3 polymerase Nucleos(t)ide analogue Boceprevir Sofosbuvir, Mericitabine, Telaprevir Daclatasvir VX-135 ABT-450/r, ACH-1625 Ledipasvir Non-nucleoside analogue Alisporivir (currently on hold) Asunaprevir, Simeprevir, ABT-267 BI-207127, ABT-333 SCY-635 Faldaprevir PPI-668 ABT-072, BMS-791325 Danoprevir/r, GS-9451 Tegobuvir, Setrobuvir MK-5172 VX-222, Filibuvir Triple-Therapy based on IFN-lambda PEG-lambda / Ribavirin + Daclatasvir or Asunaprevir HCV Genotype 1a/b, treatment naive patients with chronic hepatitis C Vierling, et al. 63rd AASLD. Poster LB-9 Triple-Therapy based on IFN-lambda PEG-lambda / Ribavirin / Daclatasvir (Asunaprevir) Vierling, et al. 63rd AASLD. Poster LB-9 A first proof-of-principle study Viral eradication with two direct antiviral agents Group A Prior null All oral NS3 PI + NS5A Inh responders with GT-1 HCV 7 (Group A) 6 5 Daclatasvir 60 mg QD + HCV RNA 4 Asunaprevir 600 mg BID 10 3 (n=11) Log 2 LOQ Week 24 1 LOD 01234 6 8 1012 Week Indicates initiation of PegIFN/RBV Frequent viral break-through in subtype 1a pts. No viral break-through / SVR in 2/2 subtype 1b pts. Lok et al., NEJM 2012 IFN-free treatment options Many options with 2, 3, 4, 5 drugs: small studies, high SVR Durati Therapy cirrhosi SVR 4- Regimen n GT on status s 12 (%) (wks.) ABT450r + ABT333 + 79 Naive 1 12 No 98 ABT267 + RBV ABT450r + ABT333 + 95 Null-Resp. 1 12 No 93 ABT267 + RBV BI7127 + Faldaprevir + 362 Naive 1b 28 Yes 83 RBV Daclatasvir + Asunaprevir 32 Naive 1 12 No 94 + BMS791325 Daclatasvir + Asunaprevir 21 Null-Resp. 1b 12 No 90 Daclatasvir + Sofosbuvir 170 Naive 1,2,3 12 - 24 No 88 - 100 Sofosbuvir + RBV 50 Naive 2 / 3 12 Yes 100 Kowdley et al. AASLD 2012, Zeuzem et al. AASLD 2012, Everson et al. AASLD 2012, Lok et al. NEJM 2012, Sulkowsi et al. AASLD 2012, Gane et al. NEJM 2013; Highlights from EASL 2013 Genotype 2/3: less than expected Study design (GT2/3 naïve, Fission study) Week 0 12 24 36 SOF + RBV*, n=256 SVR12 Peg-IFN + RBV* (SOC), n=243 SVR12 *RBV dose 1000-1200 mg/day for SOF + RBV and 800 mg/day for Peg-IFN + RBV. Genotype 2 (28%) or 3 (72%) Expanded inclusion criteria – Targeted 20% enrollment of patients with cirrhosis (>75.000 PLT) IL28B CC (43-44%), cirrhosis (20-21%) Gane et al., EASL 2013; #5 and NEJM 2013 Highlights from EASL 2013 Genotype 2/3: less than expected SVR SOF + RBV Peg-IFN + RBV 98 91 100 82 62 71 80 61 60 34 30 40 SVR12 (%) 20 0 No cirrhosisCirrhosis No cirrhosis Cirrhosis GT 2 GT 3 . 100% on tx response, no viral break-through, failure = relapse . No resistance (deep and phenotypic) Gane et al., EASL 2013; #5 and NEJM 2013 Highlights from EASL 2013 Genotype 1: hope for BOC/TVR failures Study design n = 21 DCV 60 mg QD + SOF 400 mg QD Follow‐up Prior TVR/BOC failures, GT 1a/1b (N = 41) n = 20 DCV 60 mg QD + SOF 400 mg QD + RBV Follow‐up Week SVR12 24 SVR4 Genotype 1a (76-85%) or 1b, non-cirrhotic pts. Failure previous TVR (71-90%) or BOC (10-33%) triple therapy Exclusion of patients with TVR/BOC discont. due to AE Prior break-through or non-response: 57-85% Baseline NS3 resistance mutations: 45-48% Baseline NS5A resistance mutations: 5-10% Sulkowski et al., EASL 2013; #1417 Highlights from EASL 2013 Genotype 1: hope for BOC/TVR failures Virologic response 100 95 100 100 100 100 100 95* 100 91 DCV + SOF 80 80 DCV + SOF patients) 60 + RBV (% Missing 40 LLOQ < 21/41 patients 20 RNA have reached PT HCV Week 24; 0 N = 21 20 21 20 21 20 21 20 21 20 all have achieved SVR Week 2SVRWeek 4 EOT 4 SVR12 24 *1 patient missing at post‐treatment (PT) Week 12: HCV RNA was undetectable at PT Week 4 and at PT Week 24 (preliminary) ■ No serious AE (n=1 hypokalemia), no discont. due to AE, most common AE fatigue & headache Sulkowski et al., EASL 2013; #1417 Summary . Interferon based treatment options have a unique and broad immunemodulatury mode of action without development of resistance . Interferon lambda is at least equaly effective than Interferon alfa with the advantage of less sides effects . Triple-therapies with IFN-lambda, Ribavirin and DAAs (Daclatasvir, Asunaprevir) are well tolerated and highly effective . Interferon free treatment options are currently in phase 2/3 development - high efficacy in easy to treat patients - restricted experience in difficult to treat pts..