Transcript Treatment of Hepatitis C

The next generation of
Treatment for Hepatitis C
Treatment of CHC: Outcomes
Goal
of therapy is to render the patient PCR
negative for HCV RNA
Need to remain PCR negative 6 months
after end of therapy
Response rates for combination therapy
Genotype
1 up to 40%
Genotypes 2 or 3 up to 80%
Evolution of HCV genotype 1 treatment
SVR rate (%)
100
80
60
42–54%
40
16–28%
20
2–7%
IFN
+
RBV1
Peg-IFN
+
RBV2–4
IFN1
1990
IFN: interferon; RBV: ribavirin
Peg-IFN: peginterferon
DAA: direct-acting antiviral
SVR: sustained virologic response
2000
2010
2020
1. McHutchison JG, et al. N Engl J Med 1998;339:1485–92; 2. Fried M, et al. N Engl J Med 2002;347:975–82
3. Manns MP, et al. Lancet 2001;358:958–65; 4. Hadziyannis SJ, et al. Ann Intern Med 2004;140:346–55
5. Jacobson IM, et al. Hepatology 2010;52(Suppl):427A; 6. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A
7. Poordad F, et al. Hepatology 2010;52(Suppl.):402A; 8. Foster GR, et al. Hepatol Int 2011;5(Suppl.1):14
Treatment Issues
• Genotypes 2/3 – nothing new on horizon
• Genotype 1 – failure rate 50-60%
• No good options for treatment failures
New treatment for
Genotype 1 HCV
(Rx naïve patients)
Direct Acting Anivirals (DAAs)
• DAA-based triple combination therapy led to improved SVR
rates over current therapy in Phase II trials
– 61–85% SVR with telaprevir-based therapy4–6
– 54–75% SVR with boceprevir-based therapy7
• Telaprevir and boceprevir have recently completed
Phase III trials in treatment-naïve patients
– Telaprevir: ADVANCE8 and ILLUMINATE9
– Boceprevir: SPRINT-210
ADVANCE (telaprevir): study design (N=1088)
PR48
(control)
(N=361)
SVR
Pbo + PR
Follow-up
PR
eRVR+
Follow-up
T12PR
(N=363)
TVR + PR
SVR
Follow-up
eRVR–
PR
SVR
Follow-up
PR
T8PR
(N=364)
TVR
+
PR
Pbo
+
PR
eRVR+
Follow-up
PR
SVR
Follow-up
SVR
eRVR–
Follow-up
PR
0
8
12
24
Peg-IFN alfa-2a dose: 180 µg/week; RBV dose: 1000 or 1200 mg/day
eRVR: extended rapid virologic response (undetectable HCV RNA at
Weeks 4 and 12); Pbo: placebo; PR: peginterferon/ribavirin; TVR: telaprevir
36
Weeks
48
72
Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A
SPRINT-2 (boceprevir): study design (N=1097)
PR48
Control
PR
N=363 lead-in
SVR
Follow-up
PR + Placebo
Weeks 8–24 HCV RNA undetectable
SVR
Follow-up
BOC
RGT
N=368
PR
lead-in
PR + Boceprevir
Weeks 8–24 HCV RNA detectable*
SVR
Follow-up
PR + Placebo
BOC44/
PR48
PR
N=366 lead-in
0
SVR
PR + Boceprevir
4
8
*But with undetectable HCV RNA at Week 24
Peg-IFN alfa-2b dose: 1.5 µg/kg/week
RBV dose: 600–1400 mg/day in a divided daily dose
RGT: response-guided therapy
24
28
Weeks
Follow-up
48
72
Poordad F, et al. Hepatology 2010;52(Suppl.):402A
ILLUMINATE (telaprevir): study design (N=540)
SVR
Follow-up
72 weeks
Follow-up
PR
eRVR+
T12PR
eRVR+
T12PR24
N=162
Non-inferiority (NI)
Randomized Treatments
PR
SVR
eRVR+
T12PR48
N=160
SVR
eRVR–
T12PR48
N=118
Follow-up
PR
Assigned Treatment
eRVR–
Follow-up
PR
0
20
12
20
24
36
48
60
72
Weeks
Patients discontinued for any reason before Week 20 randomization were
categorized as ‘Other’ (N=100)
Stopping rules were similar to ADVANCE
Sherman KE, et al. Hepatology 2010;52(Suppl.):401A
ADVANCE and ILLUMINATE: SVR rates with telaprevirbased therapy versus PR alone
72–75*
PR48
T12PR
158/361
659/903
*p<0.0001 vs PR48 in ADVANCE (75% versus 44%)
Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A; Sherman KE, et al. CROI 2011. Abstract 957
SPRINT-2: SVR rates with boceprevir-based therapy
versus PR alone
PR48
BOC RGT
BOC44/PR48
137/363
233/368
242/366
For non-Black patients, p<0.0001 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
Tripple therapy works in advanced fibrosis
ADVANCE (telaprevir): SVR rates by fibrosis stage
ADVANCE1
Bridging fibrosis
or cirrhosis
SVR (%)
No, minimal
or portal fibrosis
n/N=
PR48
T12PR
PR48
T12PR
134/288
226/290
24/73
45/73
1. Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A;
Tripple therapy works in all IL28B genotypes
ADVANCE (telaprevir): SVR rates by IL28B genotype
CT
TT
SVR (%)
CC
n/N=
PR48
T12PR
PR48
T12PR
PR48
T12PR
35/55
45/50
20/80
48/68
6/26
16/22
Samples were available for 454/1088 (42%) patients enrolled in ADVANCE
Jacobson IM, et al. J Hepatol 2011;54(Suppl.):S542
Safety and tolerability with DAAs
• Common AEs with PR include:1–3
– Fatigue, headache, nausea, pyrexia and myalgia
– Anemia and neutropenia
– Depression, irritability and insomnia
– Rash
• Additional management considerations with DAAs
– Telaprevir:4–6 rash, anemia
– Boceprevir:7,8 anemia and dysgeusia
AE: adverse event
1. Pegintron EMA Summary of Product Characteristics; 2. Pegasys EMA Summary of Product Characteristics
3. Rebetol EMA Summary of Product Characteristics; 4. Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A
5. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A; 6. Foster GR, et al. Hepatol Int 2011;5(Suppl. 1):14
7. Poordad F, et al. Hepatology 2010;52(Suppl.):402A; 8. Bacon BR, et al. Hepatology 2010;52(Suppl.):430A
Evolution of HCV genotype 1 treatment
SVR rate (%)
100
59–75%
80
60
42–54%
40
16–28%
20
2–7%
IFN
+
RBV1
Peg-IFN
+
RBV2–4
DAA
+
Peg-IFN
+
RBV5–8
IFN1
1990
IFN: interferon; RBV: ribavirin
Peg-IFN: peginterferon
DAA: direct-acting antiviral
SVR: sustained virologic response
2000
2010
2020
1. McHutchison JG, et al. N Engl J Med 1998;339:1485–92; 2. Fried M, et al. N Engl J Med 2002;347:975–82
3. Manns MP, et al. Lancet 2001;358:958–65; 4. Hadziyannis SJ, et al. Ann Intern Med 2004;140:346–55
5. Jacobson IM, et al. Hepatology 2010;52(Suppl):427A; 6. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A
7. Poordad F, et al. Hepatology 2010;52(Suppl.):402A; 8. Foster GR, et al. Hepatol Int 2011;5(Suppl.1):14
What about Genotype 1
patients with previous
treatment failure?
Definitions of failure on prior Peg-IFN/RBV therapy
HCV RNA level
Non-response
Null response
Relapse
2 log10 drop
Partial response
Detection limit
Treatment
Adapted from Shiffman M. Curr Gastroenterol Rep 2006;8:46–52
Neumann A, et al. Science 1998;282:103–7; De Bruijne J, et al. Neth J Med 2008;66:311–22
REALIZE (telaprevir): SVR in prior relapsers,
partial responders and null responders
Prior relapsers
Prior partial
responders
Prior null
responders
*
*
SVR (%)
*
*
*
PR48
n/N=
LI T12/
PR48
T12/
PR48
124/141
121/145
16/68
*p<0.001 vs PR48; post-hoc analysis
PR48
4/27
*
LI T12/
PR48
T12/
PR48
PR48
LI T12/
PR48
T12/
PR48
26/48
29/49
2/37
25/75
21/72
Foster GR, et al. Hepatol Int 2011;5(Suppl. 1):14
RESPOND-2 (boceprevir): SVR in prior relapsers
and partial responders
Prior relapsers
Prior partial
responders
SVR (%)
Prior null
responders were
excluded from
RESPOND-2
PR48
n/N=
15/51
BOC
RGT
BOC44/
PR48
72/105
77/103
PR48
2/29
BOC
RGT
BOC44/
PR48
23/57
30/58
Bacon BR, et al. Hepatology 2010;52(Suppl.):430A
Summary of Tripple therapy with
DAAs
• Only for Genotype 1 Hepatitis C
• Uses Peg Inf + Ribavirin + DDA
• Improved response in naïve patients (65-75%)
• Improved response in prior non-responders
• Improved response in difficult to treat groups
COST
Cost
of treatment
genotype
1
genotype 2 or 3
Supportive
£12,782 for 48 weeks treatment
£5,233 for 24 weeks
therapy with:
Epoetin
- 8000 units twice weekly = £3,216 for 6 months
G-CSF - Neupogen 30million units/wk = £1752 for 6 months
Cost
of addition of DAA £14,000 - £24,000
To be confirmed Sept 2011
Who will get the new
drugs?