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Hepatite crônica CHepatite crônica C
Novos tratamentosNovos tratamentos
Prof. Henrique Sergio Moraes CoelhoProf. Henrique Sergio Moraes Coelho
III Workshop Internacional de AtualizaIII Workshop Internacional de Atualizaçção em Hepatologiaão em Hepatologia
Abril de 2008 CuritibaAbril de 2008 Curitiba--ParanParanáá
HepatologyHepatology 20042004
56-61
“Real-World” SVR ResultsCanadian Expanded-Access Program
Yoshida E, et al., DDW; May 14-19, 2005. Abstract S1572.
N=863, treated with PEG IFN alfa-2b QW + RBV 800 mg/d
Naive, No Cirrhosis
Naive, Cirrhosis
0102030405060708090
100
Relapsers Nonresponders
SVR
(%) 56
41
77
4134
58
4035
51
23 20
35
All GenotypesGenotype 1Genotype 2-3
PEG IFN, pegylated interferon; RBV, ribavirin; SVR, sustained virologic response
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;
Necessidade de novas drogas para hepatite C
Problemas com a terapia antiviral Peg/RBVl
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
Quem serão os candidatos às novas terapias antivirais?
6
Potenciais alvos das novas moléculas
InibidoresInibidores de de ProteaseProtease
InibidoresInibidores dada PolimerasePolimerase
Kwong A, et al. Beyond interferon and ribavirin: Antiviral therapies for hepatitis C virus. Drug Discovery Today: Therapeutic Strategies. 2006;3:211-220.
Protease Inhibitor Telaprevir for Treatment of Hepatitis C
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 releaseJan 8, 2006
Reesink HW, et al. Hepatology. 2005;42:234A.
Placebo VX-950 450 mg q8h VX-950 750 mg q8h VX-950 1250 mg q12h
11
22
33
44
55
66
77
00 11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414
Study Time (Days)Study Time (Days)
Med
ian
HC
V R
NA
(Log
10IU
/mL)
TelaprevirMedian HCV RNA Over Time
Reesink HW, et al. DDW; May 14-19, 2005. Abstract 527.
Resistance profiles established
clinicaloptions.com/hep
Update on Investigational Agents in HCV: 2007
PROVE 1: Telaprevir + PegIFN/RBV in Treatment-Naive HCV GT 1 Patients
Jacobson I, et al. AASLD 2007. Abstract 177.
45
6561
35
0
20
40
60
80
10012 wks TVR/pegIFN/RBV;12 wks pegIFN/RBV 12 wks TVR/pegIFN/RBV
SVR Rates in12 and 24-Week Arms
Patie
nts
(%)
48 wks pegIFN/RBV12 wks TVR/pegIFN/RBV; 36 wks pegIFN/RBV
End-of-Treatment Response in 48-Week Arms
0
20
40
60
80
100
Intent-to-treat Interim Analysis
(n = 79) (n = 17) (n = 75) (n = 79)
clinicaloptions.com/hep
Update on Investigational Agents in HCV: 2007
Treatment-naive patients
infected with HCV
genotype 1*
(n = 323)
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)
Hezode C, et al. AASLD 2007. Abstract 80.
Wk 12
*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.
Wk 24 Wk 48
PROVE 2: Telaprevir + PegIFN/RBV in Treatment-Naive HCV GT 1 Patients
Placebo + PegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg QD(n = 82)
PegIFN alfa-2a + RBV(n = 81)
Interim AnalysisWk 36
Follow-up
Follow-up
Follow-up
clinicaloptions.com/hep
Update on Investigational Agents in HCV: 2007
PROVE 2: Telaprevir + PegIFN/RBV in Treatment-Naive HCV GT 1 Patients
Hezode C, et al. AASLD 2007. Abstract 80.
2421Viral breakthrough‡
295965OngoingSVR†
51*62*
80*79*
69*73*
1341
Undetectable HCV RNA
Wk 4Wk 12
TVR + PegIFN for
12 Wks(n = 78)
TVR + PegIFN + RBV for
12 Wks(n = 82)
TVR + PegIFN + RBV for
24 Wks(n = 81)
Placebo +PegIFN + RBV
(n = 82)
Outcome, %
*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.
clinicaloptions.com/hep
Update on Investigational Agents in HCV: 2007
PROVE 2: Telaprevir + PegIFN/RBV in Treatment-Naive HCV GT 1 Patients
51
202
122
AnemiaGrade 3
90
231
110
DyspneaGrade 3
152615Insomnia
404
476
260
Rash, all typesGrade 3
280
48< 1
320
NauseaGrade 3
581
561
240
PruritusGrade 3
•TVR + PegIFN•for 12 Wks
•(n = 78)
TVR + PegIFN + RBVfor 12/24 Wks
(n = 163)
Placebo + PegIFN + RBV
(n = 81)
Adverse Event, %
Hezode C, et al. AASLD 2007. Abstract 80.
Total adverse events leading to discontinuation during Weeks 1-12– Control: 5% – 24-week arm: 15% – 12-week arm: 13% – No RBV arm: 10%
Boceprevir (SCH 503034)
N
HN NH2
OO
HN
HN
O
O
MeMeO
Me
Me
Me
Me Me
Me
Dados In vitro• Ki* =14 nM • elastase/HCV = 2000• Replicon IC50 = 200 nM• Replicon IC90 = 400 nM
(200 ng/mL)• No inhibition of CYP
Dados Farmacocinéticos• Biodisponibilidade oral• Distribuição Fígado/Plasma: ~30• Nenhum problema naestabilidade plasmática
Zeuzem et al. AASLD 2005
Farmacodinâmica Boceprevir – EstudoMonoterapia em Não Respondedores
-2
-1,5
-1
-0,5
0
0,5
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Dias Após Início Tratamento
Méd
ias
de R
eduç
ão e
mLo
g 10 H
CV
RN
A
Placebo100 mg BID200 mg BID400 mg BID400 mg TID
Tratamento Follow-up
SCH 503034 Plus PEG IFNAntiviral Activity in Genotype 1
NonrespondersPEG IFN alfa-2bAlone (n = 22)PEG IFN alfa-2b+SCH503034200 mg TID(n = 12)PEG IFN alfa-2b+SCH503034400 mg TID(n = 12)
-3
-2.5
-2
-1.5
-1
-0.5
0
Mean
HCV
RNA
Cha
nge (
Log
Mean
HCV
RNA
Cha
nge (
Log 1010
))
Treatment DayTreatment Day0 5 10 15
Zeuzem S, et al. Hepatology. 2005;42:233A.
SPRINT -1 Study
•• N= 595 pacientes N= 595 pacientes -- Naive e GenNaive e Genóótipo 1tipo 1
•• Estados Unidos, CanadEstados Unidos, Canadáá e Europae Europa
•• 77% americanos77% americanos
•• 16% Afro16% Afro--americanosamericanos
•• 7% cirr7% cirróóticosticos
Scre
enin
g
HCV SPRINT-1 Study - Fase II – Pacientes Naïve G1
Arm 2
Arm 1
Arm 3
Boceprevir 800 mg TID + PegIntron (1,5mcg/kg/sem) +
low dose Rebetol (400+1000mg/dia)
48 Semanas
Follow-up
24 Weeks
PegIntron (1,5mcg/kg/sem) + Rebetol (800-1400mg/dia)
48 SemanasArm 4
Follow-up
24 Weeks
Boceprevir 800mg TID + PegIntron + Rebetol
28 Weeks
Follow-up
24 Weeks
Follow-up
24 Weeks
Boceprevir 800mg TID + PegIntron (1,5mcg/kg/sem) + Rebetol (800 + 1400mg/dia)
48 Weeks
Boceprevir 800mg TID + PegIntron +
Rebetol
24 Weeks
Follow-up
24 Weeks
Follow-up
24 WeeksBoceprevir 800mg TID +PegIntron +
Rebetol
44 WeeksPegIntron + Ribavirin
4 Semanas
Resultados – RVPc Semana 12
70%79%
54%
34%
0%
20%
40%
60%
80%
100%
Grupo 1 Grupo 2 Grupo 3 Grupo 4
RVPc - PCRnegativo nasemana 12(<15UI/ml)
Polymerase Inhibitors for Hepatitis C
clinicaloptions.com/hep
Update on Investigational Agents in HCV: 2007
Treatment-naive patients
with HCV genotype 1
infection
(N = 104)
R1626 1500 mg BID+ PegIFN(n = 21)
R1626 3000 mg BID + PegIFN(n = 32)
R1626 1500 mg BID + PegIFN + RBV
(n = 31)
Wk 48Wk 4
interim analysis
PegIFN alfa-2a 180 µg/wk +RBV 1000-1200 mg QD
(n = 20)
PegIFN + RBV
PegIFN + RBV
PegIFN + RBV
24-week follow-up
Polymerase Inhibitor R1626 in Treatment-Naive Genotype 1 Patients
Pockros PJ, et al. AASLD 2007. Abstract 167.
Interim results of multicenter, randomized, active-controlled, double-blind, phase IIa trial
clinicaloptions.com/hep
Update on Investigational Agents in HCV: 2007
Polymerase Inhibitor R1626 for Treatment-Naive Genotype 1 Patients
Pockros PJ, et al. AASLD 2007. Abstract 167.
-2.4
-3.6-4.5
-5.2-6
-5
-4
-3
-2
-1
0
PegIFN/RBV R1626 1500/pegIFN R1626 3000/pegIFN R1626 1500/pegIFN/RBV
Mean HCV RNA Reduction at Wk 4
Log 1
0IU
/mL
HC
V R
NA
0
20
40
60
80
100
5
33
6981
Patie
nts
(%)
Undetectable HCV RNA at Wk 4
clinicaloptions.com/hep
Update on Investigational Agents in HCV: 2007
Polymerase Inhibitor R1626 for Treatment-Naive Genotype 1 Patients
No emergence of R1626 resistance detectedGastrointestinal adverse effects common with R1626, particularly in 3000 mg dosing armCytopenias, especially neutropenia, commonly associated with R1626
– Neutropenia not associated with increased incidence of infection
Pockros PJ, et al. AASLD 2007. Abstract 167.
1 (5)0 (0)
10 (32)3 (10)
3 (9)0 (0)
0 (0)0 (0)
AnemiaGrade 1/2Grade 3/4
0 (0)4 (13)15 (47)2 (10)ThrombocytopeniaGrade 3/4
6 (30)2 (10)
16 (52)12 (39)
5 (16)25 (78)
8 (38)10 (48)
NeutropeniaGrade 3Grade 4
PegIFN/RBV(n = 20)
R1626 1500 mg
+ PegIFN/RBV(n = 31)
R1626 3000 mg
+ PegIFN(n = 32)
R1626 1500 mg
+ PegIFN(n = 21)
Week 4 Cumulative LaboratoryAbnormalities, n (%)
Treatment With Nitazoxanide for Hepatitis C
clinicaloptions.com/hep
Update on Investigational Agents in HCV: 2007
HCV GT 4 patients from
2 sites in Egypt
(N = 120)
Nitazoxanide 500 mg BID
(n = 40)*
Nitazoxanide500 mg BID
(n = 40)*
Wk 48
*n = 28 interferon-based regimen naive; 12 interferon-based regimen experienced.
PegIFN alfa-2a 180 μg/wk+ RBV 1000-1200 mg QD
(n = 40 [all interferon naive])
Nitazoxanide 500 mg BID+ PegIFN alfa-2a 180 μg/wk
Nitazoxanide 500 mg BID+ PegIFN alfa-2a 180 μg/wk
+ RBV 1000-1200 mg QD
Wk 12SVR12Wk 60
Follow-up
Follow-up
Follow-up
Nitazoxanide-Based Therapy for HCV Genotype 4-Infected Patients
Rossignol JF, et al. AASLD 2007. Abstract 178.
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
clinicaloptions.com/hep
Update on Investigational Agents in HCV: 2007
Nitazoxanide-Based Therapy for HCV Genotype 4-Infected Patients (cont’d)
SVR12 in treatment-experienced patients
– Nitazoxanide + pegIFN + RBV: 25%
– Nitazoxanide + pegIFN: 8%
Discontinuations during therapy in treatment-naive patients
– Nitazoxanide + pegIFN: 18%
– Nitazoxanide + pegIFN + RBV: 14%
– PegIFN + RBV: 18%
Nitazoxanide generally welltolerated
– Grade 3 neutropenia more common in nitazoxanide-containing arms
Rossignol JF, et al. AASLD 2007. Abstract 178.
54
71 71 6864
8679 79
38
73
58
43
0
20
40
60
80
100
Wk 4 Wk 12 ETR SVR 12
Nitazoxanide/pegIFN
Nitazoxanide/pegIFN/RBV
PegIFN/RBV
ITT Analysis in Interferon-Naive Patients: HCV RNA Negative* During Combination Therapy
*HCV RNA < 10 IU/mL.
P = .006
Patie
nts
(%)
clinicaloptions.com/hep
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)
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
209 (78-527)214 (47-499)137 (40-528)53 (34-74)Week 454 (28-75)52 (26-66)59 (34-94)55 (27-75)Baseline
Eltrombopag75 mg/day
Eltrombopag50 mg/day
Eltrombopag30 mg/dayPlacebo
Median Platelet Count, x 103/µL (Range)Treatment Week
McHutchinson JG, et al. AASLD 2006. Abstract LB3.
New Interferon Formulationsfor Hepatitis C
clinicaloptions.com/hep
Update on Investigational Agents in HCV: 2007
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)– ≥ 80% 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)
Albinterferon alfa-2b in Treatment-Naive Genotype 1 Patients (cont’d)
Zeuzem S, et al. AASLD 2007. Abstract 180.
51555858SVR70807379Wk 4853756966Wk 1218342526Wk 4
AlbIFN 1200 µg Every 4 Wks + RBV
(n = 116)
AlbIFN 1200 µg Every 2 Wks + RBV
(n = 110)
AlbIFN 900 µg Every 2 Wks + RBV
(n = 118)
PegIFN+ RBV
(n = 114)
HCV RNA Negative, %
STAT-CLikely Picture - Near Future
Viral enzymeinhibitors
Immunemodulation
RBV orrelated drugs± ±
Interferon as a platform for future combinations
Duration of treatment?Dosis?Other combinations?