Transcript New protease inhibitors and direct acting antivirals for hepatitis C

Treatment of Hepatitis C in patients
with thalassaemia. Where are we now?
• Telaprevir and boceprevir harbingers of important
treatment advance
• Improved response rates observed :
– naive and experienced patients
• SVR > 70% have been reported
– in genotype 1 infection
• Efficacy in the treatment of genotype 2-6 has not
been fully tested.
The natural history of fibrosis in chronic
viral hepatitis
F0
Courtesy Pierre Bedossa
F2
F3
F4
Telaprevir ADVANCE: SVR in naïve patients
Percent of patients with HCV RNA Undetectable
T12PR
T8PR
PR
P<0.0001
100
90
P<0.0001
75
80
69
70
60
44
50
40
30
20
10
0
n/N =
271/363
250/364
158/361
SVR
Jacobson IM, et al. N Engl J Med 2011;364:2405-16; 2.
Evidence for efficacy: boceprevir in
treatment-naïve, genotype 1 patients (SPRINT-2)
100
SVR (%)
80
63*
66 *
PR48
BOC RGT
BOC44/PR48
137/363
233/368
242/366
60
38
40
20
0
n/N =
*p<0.001 for both boceprevir arms versus PR48
SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow-up Week 24.
If there was no such value, the follow-up Week 12 value was carried forward
Boceprevir EU SmPC
The first generation protease inhibitors.
Where are we now?
• Response rates in patients with cirrhosis
improved but suboptimal
• Naïve patients without severe fibrosis
– respond better
• Prior null response and cirrhosis less likely to
respond to retreatment
• Inherited IL28b haplotypes continue to influence
response rates
• Response rates lower in subtype 1a vs 1b.
• Side effects testing for patients
REALIZE (telaprevir): SVR by baseline fibrosis
stage and prior response to Peg-IFN/RBV
Prior
relapsers
Prior partial
responders
Prior null
responders
100
Pbo/PR48
87
85
84
80
SVR (%)
Pooled T12/PR48
77
56
60
40
34
32
20
13
Stage
20
18
7
6
0
0
n/N=
42
41
12/38 145/167
2/15 53/62
No, minimal Bridging
or portal
fibrosis
fibrosis
1/15 48/57
3/17 36/47
0/5
10/18
Cirrhosis No, minimal Bridging
or portal
fibrosis
fibrosis
1/5
11/32
1/18 24/59
10
0
0/9
16/38
Cirrhosis No, minimal Bridging
or portal
fibrosis
fibrosis
SVR 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
14
1/10
7/50
Cirrhosis
Pol S, et al. Hepatology 2011;54(Suppl. S1):374A
The paradox of progress
• Advances have brought higher rates of cure
– but more complexity to treatment of hepatitis C- a
paradox of progress
– Do not make treatment more straightforward
– Complex process of decision making is required to
assess
• Side effects?
• Resistance in patients who fail treatment
Managing adverse events:
– Rashes
• varying grades of severity and duration have been
reported in 55% telaprevir
• Most drug related dermatitis moderate severity
• Unpredictably progress
• 5 % of patients experienced severe rash
• Drug Rash with Eosinophilia and Systemic Symptoms
(DRESS) occurred in 0.4% and Stevens-Johnson
syndrome in 0.1% in clinical trials.
– Anaemia
• Particular relevance in patients with thalassaemia
Still stuck with IFN
• The requisite backbone of PEG IFN:
– other problems associated with PEG IFN and RBV
use
• Including depression, psychiatric symptoms worsening
of liver function and severe infections
– render a large group intolerant of PEG IFN
ineligible for treatment.
ATOMIC study: GS7977 + IFN + RBV 12 weeks
Interferon sparing: a new threshold
100
94
98
94
98
90
99
92
97
99
92
Patients (%)
75
Wk 4
EOT
SVR4
SVR12
50
25
0
GS-7977 + PR
12 wk
GS-7977 + PR
24 wk
 SVR12 not yet reported for the 24 week groups
Kowdley KV, et al. EASL 2012, Barcelona, #1
GS-7977 + PR
12 + 12 wk
BMS-790052 + BMS-650032: AI447011
Quad versus DAA combination
 In null-responders, BMS-790052 + BMS-650032 appear to require
PegIFN/RBV to prevent breakthrough and the occurrence of resistance
BMS-790052 + BMS-650032
BMS-790052 + BMS-650032 + PR
7
6
6
Log10 HCV RNA
Log10 HCV RNA
Quadruple regimen
7
5
4
3
2
1
5
4
LOQ 25 IU/mL
LOD <10 IU/mL
3
2
LOQ
LOQ
LOD
LOD
0
1
1
2
3
4
6
Week
8
10
12
0
*
1
2
3
4
6
Week
8
10
12
initiation of PegIFN/RBV
(NS5a inhibitor and Protease inhibitor)
Lok A, et al NEJM
ASPIRE (TMC435):
SVR24 by prior response and Metavir score
Partial responders
Null responders
Patients with SVR24 (%)
Relapsers
n=
PR48
TMC435 TMC435
100mg* 150mg*
PR48
PR48
PR48
TMC435
100mg*
PR48
TMC435
150mg*
PR48
PR48
16 10 6
48 29 10
12 10 2
38 29 13
48 21 11
13 3 2
*All TMC435 duration pooled
52 26 15
TMC435 TMC435
100mg* 150mg*
PR48
PR48
30 20 11
29 21 13
Zeuzem S, et al. J Hepatol 2012;56 (Suppl 2):S1
Will we have better, more
tolerable interferons?
Lambda interferon
No haematological toxicity
Daclatasvir and GS-7977 across HCV genotypes 1–3
mITT*
Patients achieving endpoint (%)
100
100 100 100
G1a/b
87 86 93
G2/3
100 100 100
100
75
75
50
50
25
25
0
87 93 73
87 86 93
100 100 100
Wk 4
Wk 24 (EOT)
f/u
(SVR4)
Group A
Group C
Group E
Sulkowski M, et al. EASL 2012, Barcelona, #1422
0
100 100 100
%
<LLOQ
94 100 86
88 100 86
88 79 64
93 93 86
%
88 100 79 <LOD
Wk 4
Wk 24 (EOT)
Group B
Group D
f/u
(SVR4)
Group F
*Bars <100% after 4 weeks reflect missing values
All oral regimens: a realistic dream?
• Therapeutic landscape is undoubtedly forever changed
for the better
• High barrier to resistance and pan-genotypic effects.
• Do not yet know whether RBV remains important, or
the appropriate dose of RBV in these regimens
• Null responders to PEG IFN and RBV are null
responders to both agents?
• Multiple DAAs without RBV?
• Costs will escalate
DAA + IFN (IFN freer) or IFN free?
Treatm en t: n ext w ave
12 weeks
D A A + P E G IFN RBV
T M C 435 + P E G IFN RBV
7977 + P E G IFN RBV
D aclatisvir + P E G IFN RBV
A sunaprevir + P E G IFN RBV
BI 1201335 + P E G IFN RBV
M K 5172 + P E G IFN RBV
DAA + DAA +
(D A A , R )
Q u ad ru p le th erap y