DAA per l'epatite C: promesse e problemi. Giovanni Battista Gaeta Cattedra di Malattie Infettive UOC Epatiti Virali Seconda Università di Napoli

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1 DAA per l'epatite C: promesse e problemi Giovanni Battista Gaeta Cattedra di Malattie Infettive UOC Epatiti Virali Seconda Università di Napoli

2 SVR rates with telaprevir-based therapy versus PR alone in naïve patients 74 79* n/n = PR48 166/361 T12/PR 683/903 *p< T12/PR vs PR48 (79% versus 46%) in ADVANCE SVR, considered virologic cure, was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used Telaprevir EU SmPC

3 SVR with Boceprevir-based therapy vs PR alone in naïve patients * * PR48 BOC RGT BOC44/PR48 n/n = 137/ / /366 For non-black patients, p< for both boceprevir arms versus PR48; for Black patients, p=0.044 and p=0.004 for BOC RGT and BOC44/PR48, respectively, versus PR48 Adapted from Poordad F, et al. Hepatology 2010;52(Suppl.):402A

4 SVR (%) Telaprevir and Boceprevir SVR by Patient Type [1,2] [3,4] [3-4] [1,2] [1,6] [5] * 0 Relapser Naive White/ Nonblack Naive Black Partial Responder Null Cirrhotic Responder Null Responder *Pooled TVR arms of REALIZE trial. 1. Zeuzem S, et al. N Engl J Med. 2011;364: Bacon BR, et al. N Engl J Med. 2011;364: Jacobson IM, et al. N Engl J Med. 2011;364: Poordad F, et al. N Engl J Med. 2011;364: Zeuzem S, et al. EASL Abstract Vierling JM, et al. AASLD Abstract 931.

5 Sustained virologic response Telaprevir (TVR) / Boceprevir (BOC) Triple treatment in experienced patients REALIZE (+/- Lead-in) TVR 12 wks + PEG2a + Riba 48 weeks 86% 57% RESPOND-2/PROVIDE* Lead-in (+/-RGT) BOC + PEG2b + Riba 36 / 48 weeks 75% 52% % 15% 31% 5% % 7% 36%* 0 TVR SOC REL TVR SOC TVR SOC P-NR NULL 0 BOC SOC REL BOC SOC P-NR NULL Relapser (REL): negative at end-of-treatment but relapse thereafter Partial Non-Responder (P-NR): 2log wk12 but pos HCV RNA wk 24 Null-Responder (NULL): <2log wk 12 Bacon et al., NEJM 2011 Zeuzem et al., NEJM 2011 *PROVIDE study, Vierling et al., AASLD 2011

6 Limitations of triple therapy with Boceprevir or Telaprevir The efficacy of Boceprevir and Telaprevir is largely dependent on IFN sensitivity Stage of fibrosis IL-28B genotype Previous response to PegIFN/RBV Increased number of adverse events Eligibility to triple therapy is poor SVR rate unsatisfactory in most patients

7 HCV RNA change from baseline (log 10 IU/mL) Synergistic reductions in HCV RNA with telaprevir plus PEG-IFN alfa-2a 1 Genotype 1, treatment-naive patients Resistant mutations emerged within 4 7 days Study time (days) Peg-IFN -2a + placebo n=4 Telaprevir (n=8) Telaprevir + Peg-IFN -2a (n=8) Kieffer T, et al. Hepatology 2007; 46: 631

8 SVR (%) Bacon AASLD 2011; Foster EASL 2011 Position paper AISF Response to Peg-IFN+RBV lead-in A sensitivity test BOCEPREVIR BASED TRIPLE Tx <I log Naive Experienced F0-F2 F3-F4 TELAPREVIR BASED TRIPLE Tx Experienced patients

9 La fibrosi al centro della decisione I pazienti con fibrosi avanzata o cirrosi (F3 F4) sono i principali candidati al trattamento Nei pazienti con fibrosi lieve-moderata (F0-F2) la indicazione alla triplice terapia va valutata individualmente Position paper AISF

10 SVR (%) ADVANCE (telaprevir): SVR rates by fibrosis stage in treatment-naïve patients 100 F0-F1 F2 F3 F PR48 T12PR PR48 T12PR PR48 T12PR PR48 T12PR n/n= 67/ /134 67/ /156 17/52 32/52 7/21 13/21 SVR, considered virologic cure, was defined as HCV RNA undetectable 24 weeks after last planned dose Marcellin P, et al. J Hepatol 2011; 54 (Suppl 1): S183

11 SVR % Impact of severe Fibrosis on SVR Bruno S, et al EASL 2011 Boceprevir data F0/1/2 F3/4 PR 48 BOC RGT BOC/PR48 Bruno S, et al EASL 2011

12 RVS (%) RVS (%) Role of IL28B CC genotype in BOC or TVR based Tx? Boceprevir Telaprevir 100 CC CT TT 100 CC 90 CT TT n/n= PR48 50/64 BOC RGT 63/77 BOC44/ PR48 44/55 PR48 BOC RGT 33/116 67/103 BOC44/ PR48 82/115 PR48 10/37 BOC RGT 23/42 BOC44/ PR48 26/44 0 PR48 n/n= 35/55 T12PR 45/50 PR48 20/80 T12PR 48/68 PR48 6/26 T12PR 16/22 Poordad F, et al. J Hepatol 2011;54(Suppl.):S6 Jacobson IM, et al. J Hepatol 2011;54(Suppl.):S542 Of the pts included into the two original cohorts of BOC and TVR phase III studies, only 62% and 42%, respectively were tested

13 SVR% SVR% SVR by Week 4 Lead-in Response According to F3 and F4 Score COMBINED STUDIES (SPRINT-2 and RESPOND-2) <1.0 log 10 decline 100 >1.0 log 10 decline PR BOC RGT BOC/PR F3/4 F3 F4 PR 0/8 0/4 0/4 BOCRGT 5/23 4/12 1/11 BOCPR48 3/23 1/9 2/14 F3/4 F3 F4 PR 11/29 5/11 6/18 BOCRGT 22/41 13/21 9/20 BOCPR48 40/49 15/18 25/31 Bruno S, et al. J Hepatol,

14 Triple therapy in cirrhosis Real practice studies US (BOC/TVR) pts; 34% F4 AE 76%; HB <10g/dl 56% Decompensation 4% Germany BOC/TVR 2 48 cirrhotics MELD >10 = 15% SAE = 35% Infections = 15% Decompensation =11% Spain BOC pts; 85% F4 SAE= 32% Infections = 5% Transfusion=9% Decompensation= 4% Italy (EAP TVR) 4 Cirrhosis 62 pts Grade 4 anemia = 2 (3.2%) Disc for anemia = 1 (1.6%) Transfusion = 12.9% EPO use = 37.1% Germany BOC/TVR pts; 23% F4 Cirrhotics: at least 1 SAE 38% transfusion France BOC/TVR 6 205/299 cirrhotics Serious AEs 40/57% Infections 4.4/6.5% Decomp 1.8/0.9% 1.Fried, EASL 2013, Abs 818; 2. Maasoumi, EASL 2013, Abs 857; 3. Calleja, EASL 2013, Abs 799; 4. Gaeta, ICAR 2013; 5.Petersen, EASL 2013, Abs 89; 6.Fontaine,EASL 2013 Abs 60

15 Algoritmo decisionale La indicazione al trattamento deve essere valutata in tutti i pazienti con epatite cronica C (con esclusione della cirrosi scompensata) Rischio individuale di progressione della malattia Stadio di fibrosi Probabilità di successo terapeutico Cirrosi Null responder Volontà individuale Position paper AISF

16 ..il trattamento con duplice terapia per 4 settimane per valutare la RVR permette di scegliere in maniera ragionata la terapia ottimale per il singolo paziente, escludendo da un trattamento con triplice i pazienti che hanno una elevata possibilità di conseguire la guarigione con la duplice terapia dalle Raccomandazioni AISF

17 Si possono individuare i pazienti con elevato tasso di risposta alla duplice terapia? Analisi di 1210 pazienti genotipo 1 Trattati con Peg-IFN + ribavirina N % SVR IL-28B CC Carica virale bassa (< ) ɣgt normale Andriulli et al. submitted

18 Combinazione dei fattori predittivi IL-28B Fattori predittivi SVR CC Alta carica virale Elevata ɣgt 47.1% CC 1 fattore favorevole 65-69% CC 2 fattori favorevoli 83.6% Solo il 6% dei pazienti presenta 3 predittori favorevoli Andriulli et al.

19 La RVR nella pratica clinica RVR Fattori predittivi SVR Sì Sì Sì Non-CC Alta viremia 1 fattore predittivo positivo 2 fattori predittivi positivi 68.2% >80% 100% Circa il 20% dei pazienti può essere trattato con duplice Andriulli et al.

20 Daily schedule for telaprevir and boceprevir day hours

21 SVR (%) SVR rates by degree of adherence to telaprevir in treatment-naïve patients (ADVANCE/ILLUMINATE) 100 >95% adherence to telaprevir 95 adherence to telaprevir N = 0 T12PR T12PR % adherence corresponds to 4.2 days missed doses Adiwijaya BS, et al. HepDART Poster 53

22 Stopping rules for telaprevir TVR phase (0-12wks) Telaprevir 750mg q8h + Peg-IFN-alfa/RBV Peg-IFN-alfa/RBV Peg-IFN-alfa/RBV Follow-up Follow-up Week HCV RNA >1000 IU/mL discontinue TVR and Peg-IFNα and RBV If HCV-RNA detectable discontinue Peg-IFNα and RBV RVR = HCV-RNA undetectable at week 4 ervr= HCV-RNA undetectable through weeks 4-12

23 Stopping rules during boceprevir dosing period Stop all drugs If 100 IU/mL at Week 12 If detectable at Week Weeks 28 >3log STOP Boceprevir EU SmPC

24 What are the key points of next generation anti-hcv drugs? Tolerability Resistance Pangenotypic coverage Efficacy in difficult to treat General applicability Reduced need for testing (HCV RNA; biomarkers) Affordable Shorter duration QD dosing (oral) Easy combinability between drugs No or few DDIs IFN-free costs

25 Characteristics of HCV DAA Classes Protease Inhibitors Nucleos(t)ide Polymerase Inhibitors Nonnucleoside Polymerase Inhibitors NS5A Inhibitors Potency High; variable among HCV genotypes Moderate-high; consistent across genotype, subtype Variable; variable among HCV genotypes High; multiple HCV genotypes Barrier to resistance Drug interaction potential Low 1a < 1b Higher for 2 nd generation High 1a = 1b Very low 1a < 1b Low 1a < 1b High Low Variable Low to moderate Toxicity Rash; anemia; bilirubin Mitochondrial; nuc interactions (ART) Variable Variable Pharmacokinetics Variable; QD to TID QD Variable; QD to TID QD

26 Pipeline of anti-hcv drugs and combination strategies

27 HCV New treatment Options (1) IFN-dependent therapies Higher genetic barrier More favorable PK Improved tolerability

28 Simeprevir (TMC 435) NS3/4A PI Once daily Oral Multigenotipic (excl 4) QUEST-2 is a multicenter, phase 3 randomized, double blind, placebo-controlled trial which assessed efficacy and safety of simeprevir plus PR vs. PR in naive G1 chronic HCV

29 % SVR 12 The QUEST-2 trial: SVR *. P< Simeprevir am Control arm * 91% met RGT criteria; SVR= 86% Manns et al; EASL 2013 abs# 1413

30 % SVR 12 The QUEST-2 trial: SVR 12 according to fibrosis stage , ,7 64, Simeprevir PR F0-F2 F3 F4 Manns et al; EASL 2013 abs# 1413

31 SOFOSBUVIR Nucleotide analog Pol inhibitor High genetic barrier One daily dose (400 mg) No food effect No drug interaction Pangentype NEUTRINO - Sofo + PR in geno , for 12 weeks FISSION SOFO + RBV in geno 2/3 FUSION SOFO + RBV in geno 2/3 experienced Combination with other DAA: SOFO + LEDISPOVIR ± RBV SOFO + SIMEPREVIR ± RBV SOFO + Danoprevir ± RBV

32 HCV-RNA <25 IU/mL Sofosbuvir + PR in HCV genotype 1/4/5/6 (NEUTRINO Study) Single arm Geotypes 1/4/5/6 SOFO +PR; 12 weeks; (RBV ) PLT 90,000; Neutr!,500; cirrhosis n = 58 N= % 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% w2 w4 w12 SVR12 SVR 12 (%) G1 =89 G4 = 96 G 5/6 = 100 No Cirrhosis=92 Cirrhosis= 80 Lawitz, EASL 2013, Abs #1411

33 HCV Treatment Options (2) Combinations of DAA which can avoid interferon High genetic barrier Shorter duration of tx Active in up to 100% Excellent tolerability Active against different HCV genotypes

34 HCV-RNA <25 IU/mL Sofosbuvir + RBV in HCV genotype 2/3 naive patients FISSION Study Randomized, phase 3 w12 w24 100% 80% 60% 40% 20% 0% w2 w4 w12 SVR12 SVR 12 (%) SR PR Geno Cirrhosis Geno Cirrhosis Gane, EASL 2013, Abs #5

35 HCV-RNA <25 IU/mL Sofosbuvir + RBV for 12 or 16 weeks in experienced HCV G2/3 FUSION Study Randomized, phase 3 100% 80% 60% 40% SVR 12 (%) 12w 16w Geno Cirrhosis % 0% w2 w4 w12 EOT SVR12 Geno Cirrhosis Nelson, EASL 2013, Abs #6

36 AVIATOR: IFN-Free Regimens With ABT-450/RTV (PI), ABT-267 (NS5 in), ABT-333 (NNPI), and RBV Naive cohort G1 - SVR12 and SVR 24 Kowdley, EASL 2013, Abs#3

37 AVIATOR: Null responder cohort - SVR12 and SVR 24 Kowdley, EASL 2013, Abs#3

38 To treat or wait? Prospect of new drugs Personal planning Probability of SVR Individualized decision Severity of liver disease Extra-hepatic manifestations Anticipated tolerability Comorbidities

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40 DAA and Host Targeting Agents (HTA) Profile DAA HTA NS3 1 NS3 2 NS5A nuc NS5B non-nuc NS5B Cyp Resistance profile Pan-genotypic efficacy Efficacy Adverse events Good profile Average profile Least favorable profile 1: 1 st generation 2: 2 nd generation

41 Sustained virologic response Telaprevir (TVR) / Boceprevir (BOC) Triple treatment-experienced patients REALIZE (+/- Lead-in) TVR 12 wks + PEG2a + Riba 48 weeks 86% 57% RESPOND-2/PROVIDE* Lead-in (+/-RGT) BOC + PEG2b + Riba 36 / 48 weeks 75% 52% % 15% 31% 5% % 7% 36%* 0 TVR REL SOC TVR SOC TVR SOC P-NR NULL 0 BOC REL SOC BOC SOC P-NR NULL Relapser (REL): negative at end-of-treatment but relapse thereafter Partial Non-Responder (P-NR): 2log wk12 but pos HCV RNA wk 24 Null-Responder (NULL): <2log wk 12 Bacon et al., NEJM 2011 Zeuzem et al., NEJM 2011 *PROVIDE study, Vierling et al., AASLD 2011

42 On-treatment virologic failure Probability of resistance during therapy Patients with virologic treatment failure (viral break-through or stopping rule) 60 Telaprevir 57% 60 Boceprevir % (13% for 8 wks. TVR) 1% 18% naiv REL P-NR NULL BT or stopping rule TVR wk 4,6,8 >100 /1000 IU/ml entire tx. <2log wk 12/HCV RNA pos. wk 24 Jacobson et al., NEJM 2011; Zeuzem et al., NEJM % 20% 42%* naiv REL P-NR NULL BT or stopping rule tx wk 24 or. wk 12 Bacon et al., NEJM 2011; Poordad et al., NEJM 2011 * PROVIDE Study, Vierling AASLD 2011

43 SVR rate (%) Evolution of HCV genotype 1 treatment 63 79% % IFN % IFN + RBV % Peg-IFN + RBV 2 4 DAA + Peg-IFN + RBV 5, Future? 1. McHutchison JG, et al. N Engl J Med 1998;339: ; 2. Fried M, et al. N Engl J Med 2002;347: Manns MP, et al. Lancet 2001;358:958 65; 4. Hadziyannis SJ, et al. Ann Intern Med 2004;140: Telaprevir EU SmPC; 6. Boceprevir EU SmPC