Transcript No Slide Title

Overview sulla nuove terapie
dell'epatite HCV correlata
Raffaele Bruno
Division of Infectious and Tropical Diseases
Hepatology Outpatient Unit
University of Pavia-IRCCS San Matteo
HCV Genome and Protein Synthesis
(Penin F, Dubuisson J, Rey FA, Moradpour D, Pawlotsky JM. Hepatology 2004;39:5-19)
HCV Life Cycle
HCV Life Cycle
HCV Life Cycle
HCV Life Cycle
HCV Life Cycle
HCV Life Cycle
HCV Life Cycle
HCV Life Cycle
HCV Life Cycle
HCV Life Cycle
HCV Life Cycle
HCV Kinetics
Infected
hepatocytes
Non-infected
hepatocytes
HCV Kinetics
Infected
hepatocytes
production
Non-infected
hepatocytes
HCV Kinetics
Infected
hepatocytes
production
Non-infected
hepatocytes
de novo infection
HCV Kinetics
Infected
hepatocytes
production
Non-infected
hepatocytes
de novo infection
HCV Kinetics
Infected
hepatocytes
Infected cell
death
production
Non-infected
hepatocytes
de novo infection
HCV Kinetics
Infected
hepatocytes
Infected cell
death
production
Non-infected
hepatocytes
de novo infection
Peripheral blood
(“viral load”)
HCV Kinetics
Infected
hepatocytes
Infected cell
death
production
Non-infected
hepatocytes
de novo infection
Peripheral blood
(“viral load”)
Treatment Targets
Infected
hepatocytes
Infected cell
death
production
Non-infected
hepatocytes
de novo infection
Peripheral blood
(“viral load”)
Treatment Targets
Infected
hepatocytes
Infected cell
death
production
Non-infected
hepatocytes
de novo infection
Peripheral blood
(“viral load”)
Treatment Targets
Infected
hepatocytes
Infected cell
death
production
Non-infected
hepatocytes
de novo infection
Peripheral blood
(“viral load”)
Treatment Targets
Infected
hepatocytes
Infected cell
death
production
Non-infected
hepatocytes
de novo infection
Peripheral blood
(“viral load”)
Treatment Targets
Infected
hepatocytes
Infected cell
death
production
Non-infected
hepatocytes
de novo infection
Peripheral blood
(“viral load”)
Treatment Targets
Infected
hepatocytes
Infected cell
death
production
Non-infected
hepatocytes
de novo infection
Peripheral blood
(“viral load”)
Treatment Targets
Infected
hepatocytes
Infected cell
death
production
Non-infected
hepatocytes
de novo infection
Peripheral blood
(“viral load”)
Treatment Targets
Infected
hepatocytes
Infected cell
death
production
Non-infected
hepatocytes
de novo infection
Peripheral blood
(“viral load”)
Treatment Targets
Infected
hepatocytes
Infected cell
death
production
Non-infected
hepatocytes
de novo infection
Peripheral blood
(“viral load”)
Potential Targets of New Hepatitis C Antivirals
capsid
C
envelope
E1
NS3 Protease
domain
E2
protease/helicase
p7
NS2
NS3 Helicase
domain
NS3
NS4A
polymerase
NS4B
NS3 Bifunctional
protease / helicase
NS5A
NS5B
NS5B RNA-dependent
RNA polymerase
© 2002 JG McHutchison, DUMC
New Compounds - Agenda
•
•
•
•
•
•
NM283 Valopicitabine (Idenix)
SCH 503034 (Schering Plough)
VX-950 (Vertex)
Albuferon (HGS)
Viramidine (Valeant)
CPG10101
Early Clearance of HCV RNA with Valopicitabine (NM283)
plus Peg-Interferon in Treatment-Naïve Patients with HCV1 infection: First Results from a Phase IIb Trial
D Dieterich, E Lawitz, T Nguyen, Z Younes, J Santoro,
N Gitlin, D McEniry, R Chasen, J Goff, S Knox,
K Kleber, B Belanger K, N Brown and
the Valopicitabine 006 Study Group
EASL Annual Meeting April 29, 2006
Vienna, Austria
Valopicitabine (NM283)
First Nucleoside-Type HCV Pol Inhibitor
• NS5b polymerase inhibitor
– Ribonucleoside; cytidine
analogue
– NM107-triphosphate inhibits viral
polymerase by viral RNA chain
termination
NH2
NH
O
N
HO
O
• Oral agent
– Valyl ester pro-drug provides high
oral bioavailability
– Plasma half life (4-6 hrs) &
intracellular half life (15 hrs)
support once daily dosing
CH3
Val-O
OH
Valopicitabine (NM283)
2’-C-methylcytidine-3’-O-L-valine ester
Key Eligibility Criteria
Valopicitabine (NM283) Phase IIb Study in Treatment Naïve Patients
• 18-65 years of age, male or female
• HCV genotype 1
• Treatment Naïve
– no previous antiviral therapy for HCV
• Baseline
– HCV RNA ≥5 log10 IU/mL
– ALT >1.0 x ULN and <5 x ULN
• Compensated liver disease
• Candidate for interferon therapy
Initial Study Design
Valopicitabine (NM283) Phase IIb Study in Treatment Naïve Patients
Baseline
Week 1
Week 4
Week 48
Week 72
A
No Treatment
B
200 mg
NM283 QD
peg-IFNα + 200 mg NM283
Follow-up
C
400→800 mg
NM283 QD
peg-IFNα + 800 mg NM283
Follow-up
D
800 mg
NM283 QD
peg-IFNα + 800 mg NM283
Follow-up
peg-IFNα + 800 mg NM283
Follow-up
E
peg-IFNα only
peg-IFNα + 800 mg NM283
Follow-up
Baseline Parameters
Valopicitabine (NM283) Phase IIb Study in Treatment Naïve Patients
Treatment Group
A
B
C
D
E
Number (n=173)
34
34
34
36
35
Gender (% Male)
53
53
50
64
51
Age (mean years)
45
48
48
50
47
6.27
6.38
6.21
6.46
6.22
89
80
88
102
83
Mean HCV RNA (log10 IU/mL)
Mean serum ALT (U/L)
A
B
C
D
E
Peg-IFN 180 µg QW @ D8 + NM283 400→800 mg QD @D29
NM283 200 mg QD @ D1 + Peg-IFN 180 µg QW @ D8
NM283 400→800 mg QD ramp @ D1 + Peg-IFN 180 µg QW @ D8
NM283 800 mg QD @ D1 + Peg-IFN 180 µg QW @ D8
NM283 800 mg QD @ D1 + Peg-IFN 180 µg QW @ D1
HCV RNA Reduction to Week 4
Valopicitabine (NM283) plus peg-IFN vs. pegIFN alone
peg-IFNα
initiated
in arms
A-D
1
0
Mean log10
Reduction
in HCV
RNA
from
Baseline
(IU/mL)
-1
All NM283+pegIFN arms with greater antiviral
efficacy than pegIFN alone, at Week 4
-1.87
-2
-2.92
-3.12
-3.18
-3.67
-3
-4
-5
0
2
4
6
8
10
12
Weeks
A
B
C
D
E
Peg-IFN 180 µg QW @ D8 + NM283 400→800 mg QD @D29
NM283 200 mg QD @ D1 + Peg-IFN 180 µg QW @ D8
NM283 400→800 mg QD ramp @ D1 + Peg-IFN 180 µg QW @ D8
NM283 800 mg QD @ D1 + Peg-IFN 180 µg QW @ D8
NM283 800 mg QD @ D1 + Peg-IFN 180 µg QW @ D1
Week 4
(n= 34)
(n= 34)
(n= 34)
(n= 36)
(n= 35)
Convergence of HCV RNA Reductions by Week 12
Valopicitabine (NM283) Phase IIb Study in Treatment Naïve Patients
peg-IFNα
initiated
in arms
A-D
1
0
Mean log10
Reduction
in HCV
RNA
from
Baseline
(IU/mL)
-1
NM283 started for Group A
-2
No peg-IFNα alone
arm after Week 4
-3
-4
-5
0
2
4
6
8
10
-3.93 log10
-3.99 log10
-4.27 log10
-4.32 log10
-4.46 log10
12
EVR (%)
B: 87%
E: 81%
A: 87%
C: 94%
D: 90%
Weeks
A
B
C
D
E
Peg-IFN 180 µg QW @ D8 + NM283 400→800 mg QD @D29
NM283 200 mg QD @ D1 + Peg-IFN 180 µg QW @ D8
NM283 400→800 mg QD ramp @ D1 + Peg-IFN 180 µg QW @ D8
NM283 800 mg QD @ D1 + Peg-IFN 180 µg QW @ D8
NM283 800 mg QD @ D1 + Peg-IFN 180 µg QW @ D1
Week 12 (partial data)
(n= 30)
(n= 31)
(n= 31)
(n= 30)
(n= 31)
Evidence for Antiviral Synergy: NM283 + pegIFN
Predicted and Observed Viral Load Reductions, Week 4
800 mg valopicitabine
200 mg valopicitabine
peg-IFNα
initiated
0
Change from Baseline in HCV RNA log10
Change from Baseline in HCV RNA log10
0
-1
-2
-3
NM283 Mono (001)
Peg-IFN Mono (006)
283+Peg-IFN (Hyp. Add.)
283+Peg-IFN (Obs 006)
-4
0
5
10
15
Study Day
20
25
30
-1
-2
-3
Predicted
-4
Observed
0
5
10
15
Study Day
20
25
30
Percent of Patients with HCV RNA PCR Negative
Valopicitabine (NM283) Phase IIb Study in Treatment Naïve Patients
Solid Bars: < 600 IU/mL (Amplicor detection limit)
Stippled Bars: < 20 IU/mL (Taqman detection limit)
90
83
77
80
70
70
77
73
71
76
80
67
65
60
Percent
Of
Patients
50
40
30
67
60
45
20
48
52
61
62
72
60
10
0
Week 12
A
B
C
D
E
Week 16
Peg-IFN 180 µg QW @ D8 + NM283 400→800 mg QD @D29
NM283 200 mg QD @ D1 + Peg-IFN 180 µg QW @ D8
NM283 400→800 mg QD ramp @ D1 + Peg-IFN 180 µg QW @ D8
NM283 800 mg QD @ D1 + Peg-IFN 180 µg QW @ D8
NM283 800 mg QD @ D1 + Peg-IFN 180 µg QW @ D1
50
Adverse events (>6%)
Valopicitabine (NM283) Phase IIb Study in Treatment Naïve Patients
A
pegIFN + 800mg
NM283
wk 4(n=32)
Preferred Term
N
(%)
B
200mg NM283 +
pegIFN day 8
(n=31)
N
(%)
C
400→800mg
NM283 + pegIFN
day 8
(n=32)
N
(%)
D
800mg NM283 +
pegIFN day 8
(n=36)
N
(%)
E
800mg NM283 +
pegIFN day 1
(n=33)
N
(%)
Total
(n=164)
N
(%)
>1 AE
30
(93.8)
31
(100.0)
32
(100.0)
36
(100.0)
33
(100.0)
162
(98.8)
NAUSEA
17
(53.1)
19
(61.3)
25
(78.1)
30
(83.3)
27
(81.8)
118
(72.0)
VOMITING
9
(28.1)
9
(29.0)
15
(46.9)
20
(55.6)
25
(75.8)
78
(47.6)
FATIGUE
11
(34.4)
11
(35.5)
11
(34.4)
9
(25.0)
13
(39.4)
55
(33.5)
6
(18.8)
9
(29.0)
10
(31.3)
16
(44.4)
12
(36.4)
53
(32.3)
13
(40.6)
6
(19.4)
6
(18.8)
7
(19.4)
7
(21.2)
39
(23.8)
HEADACHE
8
(25.0)
4
(12.9)
10
(31.3)
7
(19.4)
9
(27.3)
38
(23.2)
DEPRESSION
6
(18.8)
3
(9.7)
2
(6.3)
3
(8.3)
4
(12.1)
18
(11.0)
INJECTION SITE
ERYTHEMA
4
(12.5)
5
(16.1)
1
(3.1)
4
(11.1)
4
(12.1)
18
(11.0)
INSOMNIA
8
(25.0)
3
(9.7)
1
(3.1)
1
(2.8)
5
(15.2)
18
(11.0)
RIGORS
3
(9.4)
5
(16.1)
0
5
(13.9)
2
(6.1)
15
(9.1)
ABDO PAIN
2
(6.3)
0
1
(3.1)
7
(19.4)
2
(6.1)
12
(7.3)
ANOREXIA
2
(6.3)
0
3
(9.4)
5
(13.9)
1
(3.0)
11
(6.7)
NEUTROPENIA
2
(6.3)
2
(6.5)
2
(6.3)
4
(11.1)
1
(3.0)
11
(6.7)
DIZZINESS
3
(9.4)
1
(3.2)
1
(3.1)
2
(5.6)
3
(9.1)
10
(6.1)
DYSGEUSIA
2
(6.3)
2
(6.5)
0
4
(11.1)
2
(6.1)
10
(6.1)
MYALGIA
4
(12.5)
3
(9.7)
1
1
(2.8)
1
(3.0)
10
(6.1)
DIARRHEA
FLU-LIKE ILLNESS
(3.1)
Safety Summary
Valopicitabine (NM283) Phase IIb Study in Treatment Naïve Patients
•
•
•
GI side effects common with initial dosing, usually mild-moderate; lessen within
1-2 weeks in 70-80% of affected patients, typically manageable with continued
treatment
32 of 173 (18%) patients discontinued by Week 12
– 24 (14%) for adverse events, mostly for GI side effects
– only 2 patients in 200 mg cohort discontinued
8 SAEs reported by Week 12 (all in 800 mg dose groups)
2 attributed to NM283 or NM283+pegIFN: dehydration with renal
insufficiency and pancreatitis; hyponatremia/hypokalemia
• 6 non-attributable: eye infection, flu with dehydration, CHF/diabetes,
chest pain, numbness in arm/confusion, burn
– All patients recovered
•
•
Grade 3/4 lab abnormalities
– Most were attributable to peg-IFNα (WBC, ANC, platelets)
– 9 patients with Grade 3/4 AST and 2 patients with Grade 3/4 lipase
elevation, all in 800 mg treatment groups
Protocol Amendment: Dose Modification
Valopicitabine (NM283) Phase IIb Study in Treatment Naïve Patients
GI tolerance issues for some patients at 800 mg/d NM283 dose level, so a dose
reduction has been implemented:
• Patients receiving 800 mg NM283/pegIFN will continue treatment at
reduced dose, randomly assigned (1:1) to:
• 200 mg valopicitabine/peg-IFNα or
• 400 mg valopicitabine/peg-IFNα
• 12 patients with HCV RNA ≥ 600 IU/mL at time of protocol
amendment; all discontinued treatment
• Patients in Group B (200mg NM283/pegIFN) continue study
treatment unchanged
Valopicitabine Development: Next Steps
First nucleoside-type HCV polymerase inhibitor
•
200-400 mg valopicitabine doses chosen for further study in treatment-naïve
patients
– Good antiviral efficacy with good safety/tolerance
– Antiviral efficacy at Week 12 comparable to higher (800 mg/d) dosing
regimens
•
Ribavirin / NM283 interaction study – starts 2Q2006
•
Potential investigation of double and triple regimens (NM283 + pegIFN +
ribavirin) in phase III clinical trials
•
Global Phase III program as collaboration between Idenix and Novartis
Conclusions
Valopicitabine (NM283) Phase IIb Study in Treatment Naïve Patients
• Dose-related antiviral efficacy for NM283 + pegIFN at Week 4, shows
antiviral synergy
• Convergence of HCV RNA reductions during Weeks 4-16 due to good
efficacy in all arms
– EVR in 87-94% of patients on NM283+pegIFN (arms B, C, D)
– 67-79% HCV RNA undetectable by Amplicor (< 600 IU/mL) by Week 12
•
Vs. 38-57% <600 IU with pegIFN-2a + RBV *
– 47-66% <20 IU/mL by Taqman
• Good tolerance and antiviral effect with NM283 200 mg/d + pegIFN
* Reddy, 2004; Murphy 2006
Randomized Trial of Valopicitabine (NM283)
Alone and in Combination with Peg-Interferon
vs. Retreatment with Peg-Interferon plus Ribavirin (PegIFN/RBV) in
Hepatitis C Patients with Previous Non-Response to PegIFN/RBV:
Second Interim Results
N. Afdhal, C. O’Brien, E. Godofsky, M. Rodriguez-Torres,
S. Pappas, P. Pockros, E. Lawitz, N. Bzowej, V. Rustgi, M. Sulkowski, K. Sherman,I.
Jacobson, G. Chao, S. Knox,
K. Pietropaolo, and N. Brown
EASL Annual Meeting April 28, 2006
Vienna, Austria
Objectives
Valopicitabine (NM283) Phase IIb Trial in Non-responders
•
Compare antiviral efficacy and
safety/tolerability of:
•
•
•
3 different dosing regimens of valopicitabine + pegIFNα-2a vs. re-treatment with peg-IFNα-2a +
ribavirin
also included: valopicitabine monoRx arm
Patient population: patients with genotype 1
chronic hepatitis C who were non-responders
to pegIFNα/RBV
•
relapsers to pegIFN+RBV excluded
Key Eligibility Criteria
Valopicitabine (NM283) Phase IIb Trial in Non-responders
•
•
•
•
•
18-65 years of age, male or female
HCV genotype 1
Non-responders to previous adequate treatment course
• At least 12 weeks of pegIFN + RBV
• At least 75% of the prescribed doses pegIFN/RBV
• Failed to clear HCV RNA to non-detectable levels
• Patients must have previously failed for efficacy, not safety
Screen/Baseline
• HCV RNA ≥ 105 IU/mL
• ALT < 5 x ULN
Compensated liver disease
Study Design
Valopicitabine (NM283) Phase IIb Trial in Non-responders
•
•
Multicenter (22), randomized, active control design
HCV RNA response criteria for failure and
discontinuation – reductions from baseline
• Week 4  0.5 log
• Week 12  1.0 log
• Week 24 > 2.0 log
• Primary efficacy endpoint: SVR by HCV RNA:
COBAS TaqMan™ PCR assay (20 IU/mL)
Initial Study Design
Valopicitabine (NM283) Phase IIb Trial in Non-responders
Baseline
Week 1
A
Week 48
Week 72
800 mg NM283 monotherapy
Follow-up
B
400 mg
NM283 QD
peg-IFNα + 400 mg NM283
Follow-up
C
400→800 mg
NM283 QD
peg-IFNα + 800 mg NM283
Follow-up
D
800 mg
NM283 QD
peg-IFNα + 800 mg NM283
Follow-up
E
No
Treatment
peg-IFNα + 1000-1200 mg ribavirin
Follow-up
Current Status and Patient Disposition
Valopicitabine (NM283) Phase IIb Trial in Non-responders
• 190 patients randomized (fully enrolled in 2005)
• 12 patients withdrew prior to receiving study medications
• 178 patients received study medications (ITT population)
• 60 patients discontinued by Week 24
•
•
•
34 (19 %) failed viral response criteria at 4 or 12 weeks
14 (8 %) discontinued for adverse events; only 1 on 400mg
12 (7 %) withdrew consent or discontinued for other
reasons
• 118 patients past week 24
• Trial ongoing, today’s presentation: final 24 week interval analysis
Mean Reduction HCV RNA to Week 24
Valopicitabine (NM283) Phase IIb Trial in Non-responders
0
Wks 12-24
n=7
-0.5
Serum
HCV RNA
(Mean Log10
Change
From
Baseline)
A 0.46 log
-1
-1.5
-2
-2.5
E 2.27 log
B 2.45 log
-3
C 2.99 log
D 3.29 log
-3.5
0
6
12
18
24
30
Study Week
A
B
C
D
E
NM283 800 mg QD
NM283 400 mg QD + peg-IFN 180 µg QW
NM283 400→800 mg QD ramp (1st week)→ 800 mg QD +peg-IFN 180 µg QW
NM283 800 mg QD + peg-IFN 180 µg QW
Ribavirin + peg-IFN 180 µg QW @ D8
(n=21)
(n=41)
(n=41)
(n=41)
(n=34)
n = ITT Population
Antiviral Efficacy at Week 24
Valopicitabine (NM283) Phase IIb Trial in Non-responders
>2 log Reduction
PCR –ve
N
Mean  HCV
RNA (log10 IU/mL)
Number (%)
Number (%)
A NM283 monoRx
21
0.46
0
0 (0%)
B NM283 400 + pegIFN
41
2.45
23 (56%)
7 (17%)
C NM283 400-800 + PegIFN
41
2.99 *
30 (73%) *
5 (12%)
D NM283 800 + pegIFN
41
3.29 *
29 (71%) *
10 (24%)
E pegIFN + RBV retreatment
34
2.27
16 (47%)
6 (18%)#
Treatment Group
* p < 0.02 vs pegIFN + RBV (comparisons of C and D to E)
#Residual viral load (median HCV RNA level) is ca. 1.8 log10 higher in
control arm E vs. high-dose NM283 arms (C and D) at W24. Favors increasing
difference in HCV RNA clearance to non-detectable over time.
Adverse events (>10%):
Valopicitabine (NM283) Phase IIb Trial in Non-responders
A: NM283 800mg
(N=21)
B: NM283 400 mg
+ Peg-IFN
(N=41)
C: NM283 400800 mg
+ Peg-IFN
(N=41)
Preferred Term
n
(%)
n
(%)
n
>1 AE
20
(95.2)
41
(100.0)
41
(100.0)
NAUSEA
14
(66.7)
30
(73.2)
33
FATIGUE
3
(14.3)
21
(51.2)
VOMITING
10
(47.6)
20
DIARRHOEA
7
(33.3)
HEADACHE
2
DECREASED
APPETITE
5
(%)
D: NM283 800 mg
+ Peg-IFN
(N=41)
n
E: RBV
+ Peg-IFN
(N=34)
Overall
(N=178)
(%)
n
(%)
n
(%)
41
(100.0)
34
(100.0)
177
(99.4)
(80.5)
33
(80.5)
11
(32.4)
121
(68.0)
20
(48.8)
25
(61.0)
22
(64.7)
91
(51.1)
(48.8)
21
(51.2)
32
(78.0)
3
(8.8)
86
(48.3)
13
(31.7)
25
(61.0)
14
(34.1)
5
(14.7)
64
(36.0)
(9.5)
16
(39.0)
15
(36.6)
12
(29.3)
9
(26.5)
54
(30.3)
(23.8)
5
(12.2)
8
(19.5)
11
(26.8)
5
(14.7)
34
(19.1)
Safety Summary to Week 24
Valopicitabine (NM283) Phase IIb Trial in Non-responders
• Nausea (with/without vomiting) common with initiation of NM283 +
pegIFN treatment; diarrhea is less common; usually transient or
intermittent
- 4 patients (3%) discontinued for GI side effects
• 24 serious adverse events (SAEs) through Week 24
• 6 reported possibly attributed to NM283 (anemia, colitis,
dehydration, fatigue, pancreatitis, gram-negative bacteremia
2° to UTI)
• Sporadic elevations of amylase, lipase, AST, ALT
• rarely treatment-limiting
SCH 503034
A HCV Protease Inhibitor
SCH 503034 plus PegIntron® in G1 NR to PegIntron® ± RBV – Phase I
P1
P2
P3
A
7 days SCH 503034 mono
*
14 days Peg-alfa 2b mono
14 days combo
B
14 days Peg-alfa 2b mono
14 days combo
7 days SCH 503034 mono
*
C
14 days combo
7 days SCH 503034 mono
*
14 days Peg-alfa 2b mono
* dose: 200 or 400 mg, q8h
Zeuzem et al, EASL 2006, oral
Mean HCV RNA Change
(Log 10)
PK Profile of Pegalfa 2b ± PI
SCH 503034 plus Peg-alfa 2b in G1 NR to Pegalfa 2b ± RBV – Phase I
• Results:
– Mean max log10 viral load drop 2.4 and 2.9 log
for 200 and 400 mg combined with Peg-IFN alfa
2b
• 4/10 became HCV RNA negative on combination
therapy with 400 mg SCH 503034
• HCV RNA reduction disappointing for a PI (mean
1.5 log highest monotherapy dose)
• No resistance reported
• q8h dosing is a challenge for patients
Zeuzem et al, EASL 2006, oral
CHC, G1, NR to PegIFN + RBV, n=300
SCH 503034 plus PegIntron® ± RBV –
Ongoing Phase II Study – Study Design
PegIntron® plus RBV
Follow-up
PegIntron® plus SCH 503034 100 mg q8
Follow-up
PegIntron® plus SCH 503034 200 mg q8
Follow-up
PegIntron® plus SCH 503034 400 mg q8
Follow-up
PegIntron® plus RBV plus
SCH 503034 400 mg q8
Follow-up
PegIntron® plus
SCH 503034 400 mg q8
Follow-up
Randomization
0
24 Study Weeks 48
72
VX-950
A HCV Protease Inhibitor
VX-950 Phase Ib –
Study Design
Naïve, G1, n=20
n=8
VX-950 750 mg q8h plus
PEGASYS® 180 µg qw
n=8
VX-950 750 mg q8h
n=4
PEGASYS® 180 µg qw plus Placebo
0
Randomization
Reesink et al, EASL 2006, oral late breaker
Study weeks
2
VX-950 – Results
Combination therapy
6.00
VX-950
PEGASYS
5.50
5.00
4.00
4
4.00
3.00
2.00
1.00
1
1.00
0
0.00
Median log10 reduction of HCV
RNA
Reesink et al, EASL 2006, oral late breaker
Number of patients with HCV RNA
<10 IU/mL
CHC, G1, naïve,
n=12
VX-950 – Phase IIa – Study Design
VX-950§ 750 mg q8h plus
PEGASYS® 180 µg plus
COPEGUS® 1000-1200 mg
0
4
Study Weeks
§
One-time loading dose 1250 mg
* Patients continue on PEGASYS®/COPEGUS®
VX05-950-102
*
VX-950 – Results
HCV RNA <30 IU/mL
Number of patients
12
11
10
9
8
7
6
5
4
3
2
1
0
End of
VX05-950-102
HCV RNA <10 IU/mL
12
12
12
11
9
6
3
2
Week 1
Week 2
Week 3
Week 4
VX-950 in Naïve G1– Phase II –
Study Design – Expected Start May 2006
Placebo plus PEGASYS® plus COPEGUS®
CHC, naïve,
G1, n=320
VX-950 750 mg q8h
plus PEGASYS® plus
COPEGUS®
PEGASYS® plus
COPEGUS®
VX-950 750 mg q8h
plus PEGASYS® plus
COPEGUS®
VX-950 750 mg q8h
plus PEGASYS®
0
VX-05-950-104
12
Study Weeks
24
48
VX-950 – Summary
• Highest antiviral activity (4log drop) of an
antiviral in monotherapy
• In triple combo all patients HCV RNA
negative (<10 IU/mL) by week 4
• VX-950 has potential to significantly shorten
treatment duration in combination therapy
• Q8h dosing is an issue
• High resistance in monotherapy
– Not seen in phase 2a combo
New Long Acting IFNs
Albuferon
Albuferon Characteristics
• IFN alfa-2 fused with human serum albumin
• higher efficacy not expected
• better convenience because of less frequent
dosing
• currently in phase II
• possible launch 2010
CHC, naïve, G1, n=458
Albuferon in Naïve G1 – Phase IIb –
Study Design
0
PEGASYS® 180 µg qw
plus COPEGUS® 1000/1200 mg/d
Follow-up
Albuferon 900 µg q2w
plus RBV 1000/1200 mg/d
Follow-up
Albuferon 1200 µg q2w
plus RBV 1000/1200 mg/d
Follow-up
Albuferon 1200 µg q4w
plus RBV 1000/1200 mg/d
Follow-up
Study Weeks
Zeuzem et al, EASL 2006, oral late breaker
48
72
Albuferon in Naïve G1 –
Week 12 Results
Albuferon
PEGASYS®
+ RBV
(n=114)
900 µg
q2w +
RBV
(n=110)
1200 µg
q2w +
RBV
(n=118)
1200 µg
q4w +
RBV
(n=116)
EVR (≥2 log
drop)
85.7%
(96/112)
80.4%
(90/112)
87.5%
(91/104)
73.4%
(80/109)
HCV RNA
negative at
week 12
62.5%
(70/112)
66.1%
(74/112)
74.0%
(77/104)
52.3%
(57/109)
Zeuzem et al, EASL 2006, oral late breaker
Viramidine
A Ribavirin Prodrug
CHC, naïve, n=970
VISER 1 – Phase III, Pivotal Study –
Study Design
0
PegIntron®
plus RBV 1000/1200 mg/d
Follow-up
PegIntron®
plus Viramidine 1200 mg/d
Follow-up
24 *
48
Study Weeks
* Treatment duration according to genotype: G2/3 24 weeks, G1/4 48 weeks
72
VISER 1 – Efficacy Results
Viramidine
Ribavirin
SVR * (ITT analysis)
38%
52%
Anemia rate (Hb <10 g/dL)
5%
24%
* Percent of patients with HCV RNA <39 IU/mL
Press release, 21.03.2006
p<0.0001
VISER 1 – Viramidine *
Weight-Based Analysis
n
SVR §
Anemia ‡
≤18 mg/kg
323
47%
4.3%
19-22 mg/kg
82
66%
2.4%
≥23 mg/kg
16
81%
12.5%
Viramidine dose
* Fixed dose of Viramidine averaged ~15 mg/kg, based on mean weight
for the study population
§ HCV RNA <39 IU/mL, per protocol analysis
‡ Hb <10 g/dL
Press release, 21.03.2006
VISER 2
• Identical study design to VISER 1 but
PEGASYS® instead of PegIntron®
• Results available in Q3/2006
CPG 10101
Phase Ib Trial with CPG 10101
• CPG 10101 is a synthetic oligonucleotide
and selective TollLikeReceptor9 agonist
which enhances the ability of dendritic
cells to activate killer T cells against
invaders. Actilon appears to stimulate
TLR9 in a different way resulting in
significantly stronger activation of
interferon-α production by the
plasmacytoid dendritic cells.
Phase Ib Trial with CPG 10101
• Dose escalation study (doses 0.25 to 20 mg once or
twice weekly for 4 weeks), randomized, placebocontrolled
• Patient population: 60 CHC patients (predominantly
G1 who failed previous therapy)
• Results:
– CPG 10101 was well tolerated
– ≥1 log 10 reduction was seen in all patients
receiving ≥ 1 mg
– Patients showed a dose-dependent increase in
markers of immune activation and associated
decreases in HCV RNA levels
McHutchison et al, EASL 2006, oral
CHC, G1, relapsers to
PEG-IFN + RBV, n=74
CPG 10101 plus PegIntron® ± RBV
in G1 Relapsers – Study Design
PegIntron® 1.5 µg/kg/wk
plus RBV 800-1400 mg/d
Follow-up
PegIntron® 1.5 µg/kg/wk plus RBV
800-1400 mg/d plus CPG 0.2 mg/kg/wk
Follow-up
PegIntron® 1.5 µg/kg/wk
plus CPG 0.2 mg/kg/wk
Follow-up
CPG 0.2 mg/kg/wk
plus RBV 800-1400 mg/d
Follow-up
CPG 0.2 mg/kg/wk
Follow-up
0
Randomization
Study Weeks
48
72
CPG 10101 plus PegIntron® ± RBV
in G1 Relapsers – Week 12 Results
HCV RNA (Mean
log10 decrease) a
EVR at week 12 b
PEG +
RBV
CPG +
RBV +
CPG
CPG +
PEG
2.19
3.26
2.15
1.41
0.1 *
57%
86%
57%
21%
0%
* p<0.001 vs PEG + RBV,
a
at week 12,
b
CPG + CPG
RBV
no definition provided
• Conclusion:
Preliminary data indicate a greater proportion of patients
achieving EVR received CPG + PEG + RBV than
PEG + RBV and suggest that CPG + PEG may represent a
therapeutic alternative to PEG + RBV
McHutchison et al, EASL 2006, oral late breaker
Summary
• Antiviral compounds are expected to change
HCV treatment significantly by
– increasing SVR rates
– shortening treatment duration
– Until now Peg seems to be the backbone of
HCV therapy in the future.