New DAAs - PIs, NS5a Inhibitors, Pol.-Inhibitors (Nucs and Non-Nucs): Promises and Problems

Transcription

1 New DAAs - PIs, NS5a Inhibitors, Pol.-Inhibitors (Nucs and Non-Nucs): Promises and Problems Heiner Wedemeyer Hannover Medical School Germany 1

2 Disclosures Honoraria for consulting or speaking (last 5 years): Abbott, Abvie, Biolex, BMS, Boehringer Ingelheim, Gilead, ITS, JJ/Janssen-Cilag, Medgenics, Merck/Schering-Plough, Novartis, Roche, Roche Diagnostics, Siemens, Transgene, ViiV Research grants: Abbott, BMS, Gilead, Merck, Novartis, Roche, Roche Diagnostics, Siemens and many other presenters involved in viral hepatitis will have similar disclosures. So, there is quite some interest in the field supporting the promises

3 Drug Development against HCV Entry-Inhibitors TLR-Agonists Therapeutic Vaccine Other IFNs PEG-IFN lambda NS5A-Inhibitors Protease- Inhibitors Cyclophillin Inhibitors Polymeraseinhibitors NI NNI

4 Promises

5 Some facts about DAAs in HCV infection HCV is curable! % spontaneous clearance in acute hepatitis C - (almost) no late relapse (beyond FU-w24) in SVR-patients - Cure improves the clinical long-term outcome! LR-Mortality (%) SVR non-svr p< Time - in years Van der Meer et al., JAMA 2013 in press

6 Some facts about DAAs in HCV infection HCV is curable! DAAs: Increase cure rates and IFN-sparing

7 Some facts about DAAs in HCV infection HCV is curable! DAAs: increase cure rates + IFN-sparing - even in previous IFN-nonresponder patients! e.g.: Quadruple therapy with Daclatasvir (NS5A) + Asunaprevir (PI), PEG-IFNa + Ribavirin leads to cure in up to 100% of nonresponder patients (Lok et al., NEJM 2012)

8 Some facts about DAAs in HCV infection HCV is curable! DAAs: Increase cure rates + IFN-sparing HCV is curable without interferon alpha - in vitro - in animal models - in patients

9 Some facts about DAAs in HCV infection HCV is curable! DAAs: increase cure rates + IFN-sparing HCV is curable without interferon alpha DAA combinations - can overcome resistance development - can provide pan-genotype activity - lead to SVR close to 100%

10 in clinical development Protease-Inhibitors 2nd wave vs. 2nd generation Polymerase Inhibitors Non-nucleos(t)ides Polymerase Inhibitors nucleos(t)ides NS5A Inhibitors Potency Pan-genotype efficacy Resistance Barrier Potency Pan-genotype efficacy Resistance Barrier Potency Pan-genotype efficacy Resistance Barrier Potency Pan-genotype efficacy Resistance Barrier /++ +/ (-) + (-) / /++ +/++

11 Interferon-free Combination Treatment Wedemeyer, Nat Reviews Gastroenterol 2013

12 some data The list of compounds can never not complete, I apologize for not mentioning all promising drugs in development

13 Protease Inhibitors

14 Protease inhibitors ( previrs ) Approved Phase 3 Phase 2 (phase 3 in IFN-free combin.) Boceprevir Telaprevir Simeprevir (TMC435) Faldaprevir (BI201335) Asunaprevir ABT-450/r Danoprevir/r MK-5172 GS-9256 GS-9451 IDX-320 Sovaprevir (ACH-1625)

15 New Protease inhibitors ( previrs ) High potency Resistance will remain an issue for some compounds Response-guided therapy in most phase 2 studies Ritonavir boosting required for some PIs Most PIs do not show sufficient efficacy against HCV genotype 3 Side effect profile and dosing better than telaprevir and boceprevir

16 Proportion of patients (%) Simeprevir + PEG-IFNa/RBV (Pillar-Study Phase 2 Treatment naive) 76 P< 0.05 P< 0.05 P< Week 4 (RVR) Week 12 End of treatment SVR24 TMC W TMC435 24W TMC435 12W TMC W Pbo/P/R 48 W P/R RGT 75 mg P/R RGT 75 mg P/R RGT 150 mg P/R RGT 150 mg Based on RGT, 79-86% of patients were eligible to complete treatment at Week 24 Fried et al, AASLD 2011

17 Simeprevir + PEG-IFNa/RBV (Aspire-Study Phase 2 Treatment experiences) Relapsers Partial responders Null responders SVR24, % Pbo TMC mg* TMC mg* Pbo TMC mg* TMC mg* Pbo TMC mg* TMC mg* Null F4= 33% (7/21) Zeuzem et al, EASL 2012

18 Simeprevir + PEG-IFNa/RBV High potency in Phase 2 studies ~ 80% qualified for shortened therapy ~ 50% SVR in previous null-responder > 60% SVR in F3/F4 patients (Poordad, AASLD 2012) Lower Response rates in genotype 1a (specific resistant variant: Q80R/K) Mild and transient bilirubin increase overall favorable safety profile (Fried et al., AASLD 2012)

19 Faldaprevir + PEG-IFNa/RBV Silen-C1: Phase 2 Treatment naive P/R 120mg LI 240mg LI 240mg No-LI Sulkowski et al, EASL 2011

20 Faldaprevir + PEG-IFNa/RBV Silen-C2: Phase 2 Treatment experienced Sulkowski et al, EASL 2011

21 Faldaprevir + PEG-IFNa/RBV High potency in Phase 2 studies ~ 80% qualified for shortened therapy No resistance against Q80R/K and A156S

22 MK PEG-IFNa/RBV High potency in Phase 2 studies SVR > 90%, most patients qualified for shortened therapy No resistant variants identified in phase 2 Activity against PI-resistant variants Barnard et al., AASLD 2012 Ogert et al., AASLD 2012 ALT increases at higher doses (further developed mg) Marcellin et al, AASLD 2012

23 NS5A Inhibitors

24 NS5A Inhibitors High potency at picomolar doses Pan-genotypic activity differs between compounds Viral breakthrough is associated with selection of distinct resistant variants (may differ between gen 1a and 1b)

25 NS5A Inhibitors Daclatasvir GS-5885 ABT-267 PPI-668 MK-8742

26 NS5A Inhibitors Daclatasvir GS-5885 ABT-267 PPI-668 MK-8742 Promising data presented at EASL and AASLD for IFN-free regimens

27 NS5A Inhibitors Daclatasvir GS-5885 ABT-267 PPI-668 MK-8742 Developed also in triple therapy with PEG-IFN/RBV

28 Daclatasvir + PEG-IFNa/RBV Mean HCV RNA (log 10 IU/mL) BMS mg QD BMS mg QD BMS mg QD Placebo Weeks Pol et al, Lancet Infect Diseases 2012

29 Daclatasvir + PEG-IFNa/RBV Phase 2 study: Command 1; n=395 Weeks 1-12 Weeks Follow-up from Weeks 24 or 48 SVR 20 mg daclatasvir + peg-alfa/rbv (n = 159) 60 mg daclatasvir + peg-alfa/rbv (n = 158) R V R YES NO YES NO 20 mg daclatasvir + peg-alfa/rbv Placebo + peg-alfa/rbv Placebo + peg-alfa/rbv 60 mg daclatasvir + peg-alfa/rbv Placebo + peg-alfa/rbv Placebo + peg-alfa/rbv Follow-up Follow-up Peg-alfa/RBV Follow-up Follow-up Peg-alfa/RBV Follow- Up 65% 64% Placebo + peg-alfa/rbv (n = 78) Placebo + peg-alfa/rbv Peg-alfa/RBV 36% Week 4 RNA Week 10 RNA Hezode et al., AASLD 2012

30 Daclatasvir + PEG-IFNa/RBV Phase 2 study: Command 1; n=395 Weeks 1-12 Weeks mg daclatasvir + peg-alfa/rbv (n = 159) 60 mg daclatasvir + peg-alfa/rbv (n = 158) R V R YES NO YES NO 20 mg daclatasvir + peg-alfa/rbv Placebo + peg-alfa/rbv Placebo + peg-alfa/rbv 60 mg daclatasvir + peg-alfa/rbv Placebo + peg-alfa/rbv Placebo + peg-alfa/rbv Follow-up from Weeks 24 or 48 Follow-up Follow-up Peg-alfa/RBV Follow-up Follow-up Peg-alfa/RBV Follow- Up SVR 80% 85% 81% 83% Placebo + peg-alfa/rbv (n = 78) Placebo + peg-alfa/rbv Peg-alfa/RBV Week 4 RNA Week 10 RNA Hezode et al., AASLD 2012

31 Non-Nucleoside Polymerase Inhibitors Polymerase Inhibitors:.buvir.

32 Non-Nucleoside Polymerase Inhibitors Thumb domain 1 Thumb domain 2 Palm domain 1 Palm domain 2 BI Filibuvir VX-222 Setrobuvir(ANA-598) ABT-333/ABT-072 Tegobuvir Moderate potency No cross-resistance between different targets Low barrier to resistance, usually not pangenotypic, 1b>1a Antiviral potency differs

33 Non-Nucleoside Polymerase Inhibitors Developed in the context of IFN-free therapies Limited (no) role in triple therapy with PEG- IFNa/RBV

34 Nucleos(t)ide Polymerase Inhibitors

35 Nucleos(t)ide Polymerase Inhibitors Cause chain-termination (not an inhibitor of the polymerase) Triphosphorylated form recquired for activity Pangenotypic activity (highly conserved binding site) Resistant variants show very low fitness - high genetic barrier

36 Nucleos(t)ide Polymerase Inhibitors - Sofosbuvir (GS-7977, Gilead): Phase 3 - Mericitabine (RG-7128, Roche): Phase 2 - ALS-2200 (Alios/Vertex): Phase 2

37 Mericitabine + Danoprevir Treatment duration: 14 Days Gane et al., Lancet 2010

38 Mericitabine + PEG-IFNa/RBV Propel-Study: Mericitabine 12 weeks Jump-C-Study: Mericitabine 24 weeks PEG-IFNa/RBV RGT until week 48 Propel: SVR rates similar to control Wedemeyer et al., Hepatology in press

39 Mericitabine + PEG-IFNa/RBV Propel-Study: Mericitabine 12 weeks Jump-C-Study: Mericitabine 24 weeks PEG-IFNa/RBV RGT until week 48 Propel: SVR rates similar Jump-C: SVR rates 20% higher Pockros et al., Hepatology in press

40 Sofosbuvir Sofosbuvir + PEG-IFNa/RBV Sofosbuvir IFN-free

41 Sofosbuvir Sofosbuvir + PEG-IFNa/RBV Proton: Phase pts. Genotype 1 (Lawitz AASLD 2011) Atomic: Phase pts. Genotype 1 (4/6), non-cirrhotic (Kowdley EASL & AASLD 2012)

42 Sofosbuvir: Proton Study Phase 2 HCV GT1 Wk 0 N=48 PSI mg QD PEG/RBV PEG/RBV stop NON-eRVR PEG/RBV SVR24 SVR 88% N=47 PSI mg QD PEG/RBV PEG/RBV sto p NON-eRVR PEG/RBV SVR24 91% N=26 PEG/RBV Lawitz et al. AASLD 2011

43 Sofosbuvir: Atomic Study Phase 2 SVR-24 85% 89% 88% Modified Analysis excluding Lost-to-FU: SVR % No resistance selected Kowdley et al., EASL 2012 & AASLD 2012

44 Promises Next step: Cure rates >100%!!

45 Problems

46 Triple Therapy for Hepatitis C: Experiences from the Hannover Medical School Hepatitis clinic First 208 patients evaluated for triple therapy Therapyassociated Safety Concerns Poor Chance for SVR No Triple Therapy n=103 Multiple reasons influenced the final decision Low Treatment Urgency: Wait for better Options Nonmedical Patient related Reasons Maasoumy et al., AASLD 2012

47 Triple Therapy for Hepatitis C: Experiences from the Hannover Medical School Hepatitis clinic Patients Treated N=86 N=25 Treatment Failure N=5 Discontinued -2 death -3 virological failure N=4 Stopping rule Treatment failure At least n=36 (40%) Continued after week 12 N=61 (71%) Half-Time Week 24/28 N=56 (65%) Chance for SVR N=52 (60%) Maasoumy et al, AASLD 2012

48 and any problems with the new DAAs?

49 Any problems with the new DAAs? Pill-Burden? times per day; 1-3 pills

50 Any problems with the new DAAs? Pill-Burden? Response depending on host genetics? IL28b may play a role (in weaker combinations) Probably not a major issue

51 Any problems with the new DAAs? Pill-Burden? Probably not a major issue Response depending on host genetics? May be in some combinations Side effects? so far not a major issue some GI symptoms, photosensitivity, bilirubin increase, ALT increases but let s wait for the phase III study results!!!

52 Any problems with the new DAAs? Pill-Burden? Probably not a major issue Response depending on host genetics? May be in some combinations Side effects? Let s wait for phase III data Duration of therapy? most regimens 12 weeks, but 24 weeks may not be the solution for all 12 weeks-failures.

53 Any problems with the new DAAs? Pill-Burden? Probably not a major issue Response depending on host genetics? May be in some combinations Side effects? Let s wait for phase III data Duration of therapy? 12 weeks in most cases Drug-Drug interactions? Different for each single drug Studies needed not only in healthy subjects but in patients with HCV infection and advanced liver disease!

54 Any problems with the new DAAs? Pill-Burden? Probably not a major issue Response depending on host genetics? May be in some combinations Side effects? Let s wait for phase III data Duration of therapy? 12 weeks in most cases Drug-Drug interactions? For some DAAs Resistance? In the short-term maybe in the long-term probably not

55 Any problems with the new DAAs? Pill-Burden? Probably not a major issue Response depending on host genetics? May be in some combinations Side effects? Let s wait for phase III data Duration of therapy? 12 weeks in most cases Drug-Drug interactions? Resistance? David will tell us Most likely not an issue Costs??????

56 To treat now or to wait?????

57 The probably most important point All oral therapy will lead to a change in treatment paradigm The number of treatable patients will increase dramatically! HCV infected patients Diagnosed patients Can be treated with IFNa Cured with IFNa

58 The probably most important point All oral therapy will lead to a change in treatment paradigm The number of treatable patients will increase dramatically! HCV infected patients Diagnosed patients Can be treated IFN-free Cured IFN-free

59 The probably most important point All oral therapy will lead to a change in treatment paradigm The number of treatable patients will increase dramatically! HCV infected patients Diagnosed patients Cured IFN-free