Interferon-based and interferon-free new treatment options

Transcription

1 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

2 Mode of action of Interferons natural immunomodulatory effects IFN-stimulated gene activation Antiviral activity Apoptotic activity Immunomodulatory activity Reduced transcription Reduced translation Reduced RNA stability Elevates apoptosis by multiple mechanisms B-cell proliferation CTL proliferation MHC upregulation Augments NK activity Host-mediated effects are important for DAA combination therapy Potency and additive effects Prevention of resistance and viral breakthrough

3 Different types of Interferons Type I Interferons Type III Interferons Broad receptor distribution throughout various body tissues Receptors distributed primarily in epithelial cells and hepatocytes Antiviral effects Antiviral effects Adverse events of treatment Flu-like symptoms Haematologic disorders Psychiatric symptoms Type I IFNs Peg Intron PegIFN 2a IFN omega IFN alfa 2b XL Belerofon Albuferon Locteron Type III IFNs Peg IFNlambda (Peg ril 29) Potentially fewer adverse events than with type I interferons Adapted from 1. Marcello T et al. Gastroenterology 2006;131: ; 2. Muir AJ et al AASLD. Abstract 1591; 3. O'Brien TR. Nat Genet. 2009;41:

4 PEG-Interferon alfa / Ribavirin Approval studies: efficacy Approval study (n=1530) Therapy: IFN vs. PEG-IFN alfa 2b 1,0/1,5µg/kgKG per week Ribavirin 1,0-1,2g/die Approval study (n=1121) Therapy: IFN vs. PEG-IFN alfa 2a 180µg per week Ribavirin 1,0-1,2g/die sustained virologic response (SVR) % 47% 54% IFN PEG1,0 PEG1,5 Riba Riba Riba sustained virologic response (SVR) % IFN Riba 56% PEG180 Riba Manns et al., Lancet 2001 Fried et al., N Engl J Med 2002

5 PEG-Interferon alfa / Ribavirin Approval studies: safety Manns et al., Lancet 2001 Fried et al., N Engl J Med 2002

6 IFN-lambda versus IFN-alfa Distribution of receptors IFNs activate antiviral genes required for HCV clearance HCV induces a stronger IFN-lambda response vs IFN-alfa in vitro 1 Receptors for IFN-lambda and -alfa have different distributions 2 Reduction in off-target effects may improve tolerability and increase eligibility and adherence 3 *Based on levels of RNA expression Liver IFN-λ1 receptor* IFN-α receptor* Hepatocytes High High Endothelial cells Not detected High Smooth muscle Not detected High Fibroblasts Not detected High Haematopoietic Bone marrow progenitors (CD34+) Not detected High T and NK cells Not detected High Monocytes Not detected High B cells High High Central nervous system 4 Brain Low High DAA=direct-acting antiviral; IFN=interferon; NK=natural killer Created from 1. Marukian S, et al. Hepatology 2011;54: ; 2. Doyle SE, et al. Hepatology 2006;44: ; 3. Muir AJ, et al. Hepatology 2010;52: Sommereyns C, et al. PLoS Pathog. 2008;4(3):e

7 PEG-lambda/Riba versus PEG-alfa2a/Riba Clinical Phase 2b study Muir AJ, et al. AASLD Oral 214.

8 PEG-lambda/Riba versus PEG-alfa2a/Riba Baseline characteristics genotype 1/4 Muir AJ, et al. AASLD Oral 214.

9 PEG-lambda/Riba versus PEG-alfa2a/Riba Baseline characteristics genotype 1/4 Muir AJ, et al. AASLD Oral 214.

10 PEG-lambda/Riba versus PEG-alfa2a/Riba Viral kinetics genotype 1/4 Muir AJ, et al. AASLD Oral 214.

11 PEG-lambda/Riba versus PEG-alfa2a/Riba Virologic response rates genotype 1/4 Muir AJ, et al. AASLD Oral 214.

12 PEG-lambda/Riba versus PEG-alfa2a/Riba Virologic response rates genotype 2/3 Zeuzem S, et al. EASL Oral 1435

13 PEG-lambda/Riba versus PEG-alfa2a/Riba Safety: SAEs, AEs Muir AJ, et al. AASLD Oral 214.

14 PEG-lambda/Riba versus PEG-alfa2a/Riba Safety: spesific AEs Muir AJ, et al. AASLD Oral 214.

15 PEG-lambda/Riba versus PEG-alfa2a/Riba Safety: liver-related abnormalities Muir AJ, et al. AASLD Oral 214.

16 PEG-lambda/Riba versus PEG-alfa2a/Riba Safety: blood cell counts Muir AJ, et al. AASLD Oral 214.

17 Era of direct antiviral agents Overview on targets within the HCV polyprotein and the host Viral targets C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Host targets NS3 NS5A NS5B Cyclophilin A The NS3/4A serine protease is essential for posttranslational processing of HCV polyproteins 1 Boceprevir Telaprevir ABT-450/r, ACH-1625 Asunaprevir, Simeprevir, Faldaprevir Danoprevir/r, GS-9451 MK-5172 Multifunctional membraneassociated phosphoprotein essential component of the HCV-RNA replication complex 2,3 Daclatasvir Ledipasvir ABT-267 PPI-668 NS5B is an HCV-specific, RNA-dependent RNA polymerase 1 Nucleos(t)ide analogue Sofosbuvir, Mericitabine, VX-135 Non-nucleoside analogue BI , ABT-333 ABT-072, BMS Tegobuvir, Setrobuvir VX-222, Filibuvir Host protein involved in HCV replication through interaction with NS5A and the HCV polymerase 4 Alisporivir (currently on hold) SCY-635

18 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. 63 rd AASLD. Poster LB-9

19 Triple-Therapy based on IFN-lambda PEG-lambda / Ribavirin / Daclatasvir (Asunaprevir) Vierling, et al. 63 rd AASLD. Poster LB-9

20 A first proof-of-principle study Viral eradication with two direct antiviral agents Prior null responders with GT-1 HCV (Group A) 7 6 Group A All oral NS3 PI + NS5A Inh Daclatasvir 60 mg QD + Asunaprevir 600 mg BID (n=11) Log 10 HCV RNA Week LOQ LOD 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

21 IFN-free treatment options Many options with 2, 3, 4, 5 drugs: small studies, high SVR Regimen ABT450r + ABT333 + ABT267 + RBV ABT450r + ABT333 + ABT267 + RBV BI Faldaprevir + RBV Daclatasvir + Asunaprevir + BMS n Therapy status GT Durati on (wks.) cirrhosi s SVR 4-12 (%) 79 Naive 1 12 No Null-Resp No Naive 1b 28 Yes Naive 1 12 No 94 Daclatasvir + Asunaprevir 21 Null-Resp. 1b 12 No 90 Daclatasvir + Sofosbuvir 170 Naive 1,2, No 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;

22 Highlights from EASL 2013 Genotype 2/3: less than expected Study design (GT2/3 naïve, Fission study) Week SOF + RBV*, n=256 SVR12 Peg-IFN + RBV* (SOC), n=243 SVR12 *RBV dose 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 (> PLT) IL28B CC (43-44%), cirrhosis (20-21%) Gane et al., EASL 2013; #5 and NEJM 2013

23 Highlights from EASL 2013 Genotype 2/3: less than expected SVR SOF + RBV Peg-IFN + RBV SVR12 (%) No cirrhosis Cirrhosis No cirrhosis GT 2 GT 3 100% on tx response, no viral break-through, failure = relapse No resistance (deep and phenotypic) Cirrhosis Gane et al., EASL 2013; #5 and NEJM 2013

24 Study design Highlights from EASL 2013 Genotype 1: hope for BOC/TVR failures Prior TVR/BOC failures, GT 1a/1b (N = 41) n = 21 n = 20 DCV 60 mg QD + SOF 400 mg QD DCV 60 mg QD + SOF 400 mg QD + RBV Follow up Follow up 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% Week 24 SVR 4 SVR 12 Sulkowski et al., EASL 2013; #1417

25 Highlights from EASL 2013 Genotype 1: hope for BOC/TVR failures Virologic response HCV RNA < LLOQ (% patients) N = * Week 2 Week 4 EOT SVR 4 SVR 12 DCV + SOF DCV + SOF + RBV Missing 21/41 patients have reached PT Week 24; all have achieved SVR 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

26 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.