Hepatite crônica C. Novos tratamentos. Prof. Henrique Sergio Moraes Coelho. III Workshop Internacional de Atualização em Hepatologia

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1 Hepatite crônica C Novos tratamentos Prof. Henrique Sergio Moraes Coelho III Workshop Internacional de Atualização em Hepatologia Abril de 2008 Curitiba-Paran Paraná

2 Hepatology

3 Real-World SVR Results Canadian Expanded-Access Program N=863, treated with PEG IFN alfa-2b QW + RBV 800 mg/d SVR (%) Naive, No Cirrhosis Naive, Cirrhosis PEG IFN, pegylated interferon; RBV, ribavirin; SVR, sustained virologic response Relapsers All Genotypes Genotype 1 Genotype Nonresponders Yoshida E, et al., DDW; May 14-19, Abstract S1572.

4 Necessidade de novas drogas para hepatite C Problemas com a terapia antiviral Peg/RBVl Requer injeções repetidas; Tempo de tratamento prolongado Efeitos colaterais são freqüentes e difíceis de aceitar em pacientes assintomáticos; Contra-indicações são freqüentes (20 30% dos candidatos); Metade dos pacientes não responde;

5 Quem serão os candidatos às novas terapias antivirais? a) Pacientes com cirrose hepática ; b) Pacientes co-infectados (C + HIV); c) No pós-transplante hepático; d) Nos recidivantes, após tratamento com PegINF/RBV; e) Não respondedores a PegInf/RBV(avaliar fatores preditivos) f) Pacientes com genótipo 1 com fatores preditivos de má resposta

6 Potenciais alvos das novas moléculas Inibidores de Protease Inibidores da Polimerase Kwong A, et al. Beyond interferon and ribavirin: Antiviral therapies for hepatitis C virus. Drug Discovery Today: Therapeutic Strategies. 2006;3:

7 Protease Inhibitor Telaprevir for Treatment of Hepatitis C

8 Telaprevir(VX 950) Selective, specific peptidomimetic inhibitor 14 days Most sustained viral suppression with 750 mg q8h ; highest trough levels Mean log drop 4.4 with 750 mg dosing Leveling off or rebound associated with identifiable mutations Even more profound viral suppression reported with PEG IFN (median 5.5 log) - Vertex press release Jan 8, 2006 Reesink HW, et al. Hepatology. 2005;42:234A.

9 Telaprevir Median HCV RNA Over Time 7 Median HCV RNA (Log 10 IU/mL) Resistance profiles established Study Time (Days) Placebo VX mg q8h VX mg q8h VX mg q12h Reesink HW, et al. DDW; May 14-19, Abstract 527.

10 Update on Investigational Agents in HCV: 2007 PROVE 1: Telaprevir + PegIFN/RBV in Treatment-Naive HCV GT 1 Patients Patients (%) SVR Rates in 12 and 24-Week Arms 12 wks TVR/pegIFN/RBV; 12 wks pegifn/rbv 12 wks TVR/pegIFN/RBV 61 Intent-to-treat Interim Analysis End-of-Treatment Response in 48-Week Arms 48 wks pegifn/rbv 12 wks TVR/pegIFN/RBV; 36 wks pegifn/rbv (n = 79) (n = 17) (n = 75) (n = 79) Jacobson I, et al. AASLD Abstract 177. clinicaloptions.com/hep

11 Update on Investigational Agents in HCV: 2007 PROVE 2: Telaprevir + PegIFN/RBV in Treatment-Naive HCV GT 1 Patients Wk 12 Interim Analysis Wk 24 Wk 36 Wk 48 Treatmentnaive patients infected with HCV genotype 1* (n = 323) Placebo + PegIFN alfa-2a 180 µg/wk + RBV mg QD (n = 82) Telaprevir 750 mg every 8 hrs + PegIFN alfa-2a + RBV (n = 81) Telaprevir 750 mg every 8 hrs + PegIFN alfa-2a + RBV (n = 82) Telaprevir 750 mg every 8 hrs + PegIFN alfa-2a (n = 78) PegIFN alfa-2a + RBV (n = 81) Follow-up Follow-up Follow-up *Patients received telaprevir 1250-mg loading dose or placebo based on the arm to which they were randomized. Patients received 12 or 24 weeks regardless of whether RVR occurred. Hezode C, et al. AASLD Abstract 80. clinicaloptions.com/hep

12 Update on Investigational Agents in HCV: 2007 PROVE 2: Telaprevir + PegIFN/RBV in Treatment-Naive HCV GT 1 Patients Outcome, % Undetectable HCV RNA Wk 4 Wk 12 Placebo + PegIFN + RBV (n = 82) TVR + PegIFN + RBV for 24 Wks (n = 81) SVR Ongoing Viral breakthrough * 73* TVR + PegIFN + RBV for 12 Wks (n = 82) 80* 79* TVR + PegIFN for 12 Wks (n = 78) *P <.001 vs pegifn/rbv/placebo arm. SVR at 12 wks posttreatment for 24-week arm; SVR at 24 wks posttreatment for 12-week and no-rbv arms. HCV RNA increase of > 1 log above the nadir, or increase to > 100 IU/mL in patients with previously undetectable HCV RNA. 51* 62* Hezode C, et al. AASLD Abstract 80. clinicaloptions.com/hep

13 Update on Investigational Agents in HCV: 2007 PROVE 2: Telaprevir + PegIFN/RBV in Treatment-Naive HCV GT 1 Patients Total adverse events leading to discontinuation during Weeks 1-12 Control: 5% 24-week arm: 15% 12-week arm: 13% No RBV arm: 10% Adverse Event, % Pruritus Grade 3 Nausea Grade 3 Rash, all types Grade 3 Insomnia Dyspnea Grade 3 Anemia Grade 3 Placebo + PegIFN + RBV (n = 81) Hezode C, et al. AASLD Abstract 80. TVR + PegIFN + RBV for 12/24 Wks (n = 163) < TVR + PegIFN for 12 Wks (n = 78) clinicaloptions.com/hep

14 Boceprevir (SCH ) Me Me Me Me Me H N O H N N Me Me Me O O O H N NH 2 O Dados In vitro K i * =14 nm elastase/hcv = 2000 Replicon IC 50 = 200 nm Replicon IC 90 = 400 nm (200 ng/ml) No inhibition of CYP Dados Farmacocinéticos Biodisponibilidade oral Distribuição Fígado/Plasma: ~30 Nenhum problema na estabilidade plasmática

15 Farmacodinâmica Boceprevir Estudo Monoterapia em Não Respondedores Médias de Redução em Log 10 HCV RNA 0,5 0-0,5-1 -1,5-2 Tratamento Follow-up Placebo 100 mg BID 200 mg BID 400 mg BID 400 mg TID Dias Após Início Tratamento Zeuzem et al. AASLD 2005

16 SCH Plus PEG IFN Antiviral Activity in Genotype 1 Nonresponders Mean HCV RNA Change (Log 10 ) Treatment Day PEG IFN alfa-2b Alone (n = 22) PEG IFN alfa-2b +SCH mg TID (n = 12) PEG IFN alfa-2b +SCH mg TID (n = 12) Zeuzem S, et al. Hepatology. 2005;42:233A.

17 SPRINT -1 Study N= 595 pacientes - Naive e Genótipo 1 Estados Unidos, Canadá e Europa 77% americanos 16% Afro-americanos 7% cirróticos

18 HCV SPRINT-1 Study - Fase II Pacientes Naïve G1 Arm 1 Boceprevir 800mg TID + PegIntron (1,5mcg/kg/sem) + Rebetol ( mg/dia) Boceprevir 800mg TID + PegIntron + Rebetol 28 Weeks 48 Weeks Follow-up 24 Weeks Follow-up 24 Weeks Screening Arm 2 PegIntron + Ribavirin 4 Semanas Boceprevir 800mg TID +PegIntron + Rebetol Boceprevir 800mg TID + PegIntron + Rebetol 44 Weeks Follow-up 24 Weeks Follow-up 24 Weeks 24 Weeks Arm 3 Arm 4 Boceprevir 800 mg TID + PegIntron (1,5mcg/kg/sem) + low dose Rebetol ( mg/dia) 48 Semanas PegIntron (1,5mcg/kg/sem) + Rebetol ( mg/dia) 48 Semanas Follow-up 24 Weeks Follow-up 24 Weeks

19 Resultados RVPc Semana % 80% 70% 79% 60% 40% 54% 34% RVPc - PCR negativo na semana 12 (<15UI/ml) 20% 0% Grupo 1 Grupo 2 Grupo 3 Grupo 4

20 Polymerase Inhibitors for Hepatitis C

21 Update on Investigational Agents in HCV: 2007 Polymerase Inhibitor R1626 in Treatment-Naive Genotype 1 Patients Interim results of multicenter, randomized, active-controlled, double-blind, phase IIa trial Wk 4 interim analysis Wk 48 Treatmentnaive patients with HCV genotype 1 infection (N = 104) PegIFN alfa-2a 180 µg/wk + RBV mg QD (n = 20) R mg BID + PegIFN PegIFN + RBV (n = 21) R mg BID + PegIFN PegIFN + RBV (n = 32) R mg BID + PegIFN + RBV PegIFN + RBV (n = 31) Pockros PJ, et al. AASLD Abstract week follow-up clinicaloptions.com/hep

22 Update on Investigational Agents in HCV: 2007 Polymerase Inhibitor R1626 for Treatment-Naive Genotype 1 Patients Mean HCV RNA Reduction at Wk 4 Undetectable HCV RNA at Wk 4 PegIFN/RBV R /pegIFN R /pegIFN R /pegIFN/RBV Log 10 IU/mL HCV RNA Patients (%) Pockros PJ, et al. AASLD Abstract 167. clinicaloptions.com/hep

23 Update on Investigational Agents in HCV: 2007 Polymerase Inhibitor R1626 for Treatment-Naive Genotype 1 Patients No emergence of R1626 resistance detected Gastrointestinal adverse effects common with R1626, particularly in 3000 mg dosing arm Cytopenias, especially neutropenia, commonly associated with R1626 Neutropenia not associated with increased incidence of infection Week 4 Cumulative Laboratory Abnormalities, n (%) Neutropenia Grade 3 Grade 4 Thrombocytopenia Grade 3/4 Anemia Grade 1/2 Grade 3/4 R mg + PegIFN (n = 21) 8 (38) 10 (48) 2 (10) 0 (0) 0 (0) Pockros PJ, et al. AASLD Abstract 167. R mg + PegIFN (n = 32) 5 (16) 25 (78) 15 (47) 3 (9) 0 (0) R mg + PegIFN/RBV (n = 31) 16 (52) 12 (39) 4 (13) 10 (32) 3 (10) PegIFN/RBV (n = 20) 6 (30) 2 (10) 0 (0) 1 (5) 0 (0) clinicaloptions.com/hep

24 Treatment With Nitazoxanide for Hepatitis C

25 Update on Investigational Agents in HCV: 2007 Nitazoxanide-Based Therapy for HCV Genotype 4-Infected Patients STEALTH C-1: phase II, randomized, controlled trial of nitazoxanide in HCV Nitazoxanide: a thiazolide with in vitro activity against HBV and HCV Approved for treatment of diarrhea caused by Giardia and Cryptosporidium SVR12 Wk 12 Wk 48 Wk 60 HCV GT 4 patients from 2 sites in Egypt Nitazoxanide 500 mg BID (n = 40)* PegIFN alfa-2a 180 μg/wk + RBV mg QD (n = 40 [all interferon naive]) Nitazoxanide 500 mg BID + PegIFN alfa-2a 180 μg/wk Follow-up Follow-up (N = 120) Nitazoxanide 500 mg BID (n = 40)* Nitazoxanide 500 mg BID + PegIFN alfa-2a 180 μg/wk + RBV mg QD *n = 28 interferon-based regimen naive; 12 interferon-based regimen experienced. Rossignol JF, et al. AASLD Abstract 178. Follow-up clinicaloptions.com/hep

26 Update on Investigational Agents in HCV: 2007 Nitazoxanide-Based Therapy for HCV Genotype 4-Infected Patients (cont d) ITT Analysis in Interferon-Naive Patients: SVR12 in treatment-experienced HCV RNA Negative* During Combination Therapy patients PegIFN/RBV Nitazoxanide/ Nitazoxanide/ Nitazoxanide + pegifn + RBV: 25% pegifn pegifn/rbv Nitazoxanide + pegifn: 8% 100 P = Discontinuations during therapy in treatment-naive patients Nitazoxanide + pegifn: 18% 43 Nitazoxanide + pegifn + RBV: 14% PegIFN + RBV: 18% Patients (%) 20 0 Wk 4 Wk 12 ETR SVR 12 *HCV RNA < 10 IU/mL. Nitazoxanide generally well tolerated Grade 3 neutropenia more common in nitazoxanide-containing arms Rossignol JF, et al. AASLD Abstract 178. clinicaloptions.com/hep

27 HCV Treatment Update Phase II Study: Eltrombopag Increased Platelet Counts at All Doses Evaluated Significantly more patients with HCV-associated thrombocytopenia achieved 100,000 cells/μl at Week 4 in all eltrombopag dose groups compared with placebo (P.0003) Treatment Week Baseline Week 4 Placebo 55 (27-75) 53 (34-74) Median Platelet Count, x 10 3 /µl (Range) Eltrombopag 30 mg/day 59 (34-94) 137 (40-528) Eltrombopag 50 mg/day 52 (26-66) 214 (47-499) Eltrombopag 75 mg/day 54 (28-75) 209 (78-527) Best responses with eltrombopag 75 mg/day 91% of this group able to initiate HCV therapy 65% of this group able to complete 12 weeks of therapy McHutchinson JG, et al. AASLD Abstract LB3. clinicaloptions.com/hep

28 New Interferon Formulations for Hepatitis C

29 Update on Investigational Agents in HCV: 2007 Albinterferon alfa-2b in Treatment- Naive Genotype 1 Patients (cont d) HCV RNA Negative, % Wk 4 Wk 12 Wk 48 SVR PegIFN + RBV (n = 114) AlbIFN 900 µg Every 2 Wks + RBV (n = 118) Among adherent patients weighing 75 kg, albifn 900 μg every 2 wks + RBV achieved a higher rate of SVR vs pegifn + RBV: 74.2% vs 53.3% Significant predictors of SVR (pooled all groups) % adherence to therapy vs < 80% adherence: 67% vs 39% (P <.001) Baseline ALT > 3 x ULN vs < 3 x ULN: 66% vs 54% (P <.001) HCV RNA < 400,000 IU/mL vs > 400,000 IU/mL: 76% vs 48% (P <.001) Gamma glutamyltransferase < ULN vs ULN: 62% vs 42% (P <.001) Zeuzem S, et al. AASLD Abstract 180. AlbIFN 1200 µg Every 2 Wks + RBV (n = 110) AlbIFN 1200 µg Every 4 Wks + RBV (n = 116) clinicaloptions.com/hep

30 STAT-C Likely Picture - Near Future Viral enzyme inhibitors RBV or ± ± related drugs Immune modulation Interferon as a platform for future combinations Duration of treatment?dosis?other combinations?