division of infectious and tropical diseases hepatology outpatient unit university of pavia-irccs...
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Division of Infectious and Tropical Diseases Hepatology Outpatient Unit
University of Pavia-IRCCS San Matteo
Raffaele Bruno
Overview sulla nuove terapie dell'epatite HCV correlata
HCV Genome and Protein Synthesis
(Penin F, Dubuisson J, Rey FA, Moradpour D, Pawlotsky JM. Hepatology 2004;39:5-19)
Infectedhepatocytes
production de novo infection
Non-infectedhepatocytes
Infected celldeath
HCV Kinetics
Infectedhepatocytes
Peripheral blood(“viral load”)
production de novo infection
Non-infectedhepatocytes
Infected celldeath
HCV Kinetics
Infectedhepatocytes
Peripheral blood(“viral load”)
production de novo infection
Non-infectedhepatocytes
Infected celldeath
HCV Kinetics
Infectedhepatocytes
Peripheral blood(“viral load”)
production de novo infection
Non-infectedhepatocytes
Infected celldeath
Treatment Targets
Infectedhepatocytes
Peripheral blood(“viral load”)
production de novo infection
Non-infectedhepatocytes
Infected celldeath
Treatment Targets
Infectedhepatocytes
Peripheral blood(“viral load”)
production de novo infection
Non-infectedhepatocytes
Infected celldeath
Treatment Targets
Infectedhepatocytes
Peripheral blood(“viral load”)
production de novo infection
Non-infectedhepatocytes
Infected celldeath
Treatment Targets
Infectedhepatocytes
Peripheral blood(“viral load”)
production de novo infection
Non-infectedhepatocytes
Infected celldeath
Treatment Targets
Infectedhepatocytes
Peripheral blood(“viral load”)
production de novo infection
Non-infectedhepatocytes
Infected celldeath
Treatment Targets
Infectedhepatocytes
Peripheral blood(“viral load”)
production de novo infection
Non-infectedhepatocytes
Infected celldeath
Treatment Targets
Infectedhepatocytes
Peripheral blood(“viral load”)
production de novo infection
Non-infectedhepatocytes
Infected celldeath
Treatment Targets
Infectedhepatocytes
Peripheral blood(“viral load”)
production de novo infection
Non-infectedhepatocytes
Infected celldeath
Treatment Targets
Potential Targets of New Hepatitis C Antivirals
capsid
NS3 Protease domain
NS5B RNA-dependentRNA polymerase
C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B
NS3 Helicase domain
NS3 Bifunctionalprotease / helicase
© 2002 JG McHutchison, DUMC
envelope protease/helicase polymerase
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 HCV-
1 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, 2006EASL Annual Meeting April 29, 2006Vienna, AustriaVienna, Austria
O
OHVal-O
CH3
N
NH
NH2
O
HO
Valopicitabine (NM283)2’-C-methylcytidine-3’-O-L-valine ester
Valopicitabine (NM283)First Nucleoside-Type HCV Pol Inhibitor
• NS5b polymerase inhibitor– Ribonucleoside; cytidine
analogue – NM107-triphosphate inhibits viral
polymerase by viral RNA chain termination
• 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
Key Eligibility CriteriaValopicitabine (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
400→800 mgNM283 QD
peg-IFNα + 800 mg NM283 Follow-up
200 mgNM283 QD
peg-IFNα + 200 mg NM283 Follow-up
800 mgNM283 QD
peg-IFNα + 800 mg NM283 Follow-up
peg-IFNα + 800 mg NM283 Follow-up
peg-IFNα + 800 mg NM283 Follow-upNo Treatment peg-IFNα only
Baseline Week 1 Week 4 Week 48 Week 72
A
E
B
C
D
Initial Study DesignValopicitabine (NM283) Phase IIb Study in Treatment Naïve Patients
Baseline ParametersValopicitabine (NM283) Phase IIb Study in Treatment Naïve Patients
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
Mean HCV RNA (log10 IU/mL) 6.27 6.38 6.21 6.46 6.22
Mean serum ALT (U/L) 89 80 88 102 83
A Peg-IFN 180 µg QW @ D8 + NM283 400→800 mg QD @D29B NM283 200 mg QD @ D1 + Peg-IFN 180 µg QW @ D8C NM283 400→800 mg QD ramp @ D1 + Peg-IFN 180 µg QW @ D8D NM283 800 mg QD @ D1 + Peg-IFN 180 µg QW @ D8E NM283 800 mg QD @ D1 + Peg-IFN 180 µg QW @ D1
Treatment Group
HCV RNA Reduction to Week 4 Valopicitabine (NM283) plus peg-IFN vs. pegIFN alone
peg-IFNαinitiated in arms A-D
Mean log10
Reductionin HCV RNA from
Baseline(IU/mL)
A Peg-IFN 180 µg QW @ D8 + NM283 400→800 mg QD @D29 (n= 34)B NM283 200 mg QD @ D1 + Peg-IFN 180 µg QW @ D8 (n= 34)C NM283 400→800 mg QD ramp @ D1 + Peg-IFN 180 µg QW @ D8 (n= 34)D NM283 800 mg QD @ D1 + Peg-IFN 180 µg QW @ D8 (n= 36)E NM283 800 mg QD @ D1 + Peg-IFN 180 µg QW @ D1 (n= 35)
Week 4
All NM283+pegIFN arms with greater antiviralefficacy than pegIFN alone, at Week 4
-1.87
-2.92-3.12
-3.67-3.18
-5
-4
-3
-2
-1
0
1
0 2 4 6 8 10 12
Weeks
Convergence of HCV RNA Reductions by Week 12Valopicitabine (NM283) Phase IIb Study in Treatment Naïve Patients
-3.93 log10
-3.99 log10 -4.27 log10
-4.32 log10 -4.46 log10
peg-IFNαinitiated in arms A-D
No peg-IFNα alonearm after Week 4
Mean log10
Reductionin HCV RNA from
Baseline(IU/mL)
A Peg-IFN 180 µg QW @ D8 + NM283 400→800 mg QD @D29 (n= 30)B NM283 200 mg QD @ D1 + Peg-IFN 180 µg QW @ D8 (n= 31)C NM283 400→800 mg QD ramp @ D1 + Peg-IFN 180 µg QW @ D8 (n= 31)D NM283 800 mg QD @ D1 + Peg-IFN 180 µg QW @ D8 (n= 30)E NM283 800 mg QD @ D1 + Peg-IFN 180 µg QW @ D1 (n= 31)
Week 12 (partial data)
NM283 started for Group A
B: 87%E: 81%
A: 87%
C: 94% D: 90%
EVR (%)
-5
-4
-3
-2
-1
0
1
0 2 4 6 8 10 12
Weeks
Evidence for Antiviral Synergy: NM283 + pegIFNPredicted and Observed Viral Load Reductions, Week 4
peg-IFNαinitiated
200 mg valopicitabine 800 mg valopicitabine
Predicted
Observed
0 5 10 15 20 25 30
Study Day
Ch
an
ge
fro
m B
as
elin
e in
HC
V R
NA
log
10
-4
-3
-2
-1
0
NM283 Mono (001)
Peg-IFN Mono (006)283+Peg-IFN (Hyp. Add.)
283+Peg-IFN (Obs 006)
0 5 10 15 20 25 30
Study Day
Ch
an
ge
fro
m B
as
elin
e in
HC
V R
NA
log
10
-4
-3
-2
-1
0
A Peg-IFN 180 µg QW @ D8 + NM283 400→800 mg QD @D29B NM283 200 mg QD @ D1 + Peg-IFN 180 µg QW @ D8C NM283 400→800 mg QD ramp @ D1 + Peg-IFN 180 µg QW @ D8D NM283 800 mg QD @ D1 + Peg-IFN 180 µg QW @ D8E NM283 800 mg QD @ D1 + Peg-IFN 180 µg QW @ D1
Percent of Patients with HCV RNA PCR NegativeValopicitabine (NM283) Phase IIb Study in Treatment Naïve Patients
6045 48
6752
61 62 6072
50
0
10
20
30
40
50
60
70
80
90
Week 12 Week 16
PercentOf
Patients
Solid Bars: < 600 IU/mL (Amplicor detection limit)Stippled Bars: < 20 IU/mL (Taqman detection limit)
70 7165 67
77 7673
8377 80
Adverse events (>6%)Valopicitabine (NM283) Phase IIb Study in Treatment Naïve Patients
A
pegIFN + 800mg NM283
wk 4(n=32)
B
200mg NM283 + pegIFN day 8
(n=31)
C
400→800mg NM283 + pegIFN
day 8(n=32)
D
800mg NM283 + pegIFN day 8
(n=36)
E
800mg NM283 + pegIFN day 1
(n=33)Total
(n=164)
Preferred Term N (%) N (%) N (%) N (%) N (%) 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)
DIARRHEA 6 (18.8) 9 (29.0) 10 (31.3) 16 (44.4) 12 (36.4) 53 (32.3)
FLU-LIKE ILLNESS 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 (3.1) 1 (2.8) 1 (3.0) 10 (6.1)
Safety SummaryValopicitabine (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 ModificationValopicitabine (NM283) Phase IIb Study in Treatment Naïve Patients
• 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
GI tolerance issues for some patients at 800 mg/d NM283 dose level, so a dose reduction has been implemented:
Valopicitabine Development: Next StepsFirst 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
ConclusionsValopicitabine (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, 2006EASL Annual Meeting April 28, 2006Vienna, AustriaVienna, Austria
ObjectivesValopicitabine (NM283) Phase IIb Trial in Non-responders
• Compare antiviral efficacy and safety/tolerability of:• 3 different dosing regimens of valopicitabine + peg-
IFNα-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 CriteriaValopicitabine (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 DesignValopicitabine (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)
400→800 mgNM283 QD
peg-IFNα + 800 mg NM283 Follow-up
400 mgNM283 QD
peg-IFNα + 400 mg NM283 Follow-up
800 mgNM283 QD
peg-IFNα + 800 mg NM283 Follow-up
peg-IFNα + 1000-1200 mg ribavirin Follow-up
Follow-up
Baseline Week 1 Week 48 Week 72
A
E
B
C
D
Initial Study DesignValopicitabine (NM283) Phase IIb Trial in Non-responders
NoTreatment
800 mg NM283 monotherapy
Current Status and Patient DispositionValopicitabine (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 24Valopicitabine (NM283) Phase IIb Trial in Non-responders
E 2.27 logB 2.45 log
C 2.99 log
D 3.29 log
A NM283 800 mg QD (n=21) B NM283 400 mg QD + peg-IFN 180 µg QW (n=41) C NM283 400→800 mg QD ramp (1st week)→ 800 mg QD +peg-IFN 180 µg QW (n=41)D NM283 800 mg QD + peg-IFN 180 µg QW (n=41)E Ribavirin + peg-IFN 180 µg QW @ D8 (n=34)
SerumHCV RNA
(Mean Log10
ChangeFrom
Baseline)
Wks 12-24 n=7
Study Week
A 0.46 log
n = ITT Population
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
0 6 12 18 24 30
Antiviral Efficacy at Week 24Valopicitabine (NM283) Phase IIb Trial in Non-responders
Treatment Group N
Mean HCV RNA (log10 IU/mL)
>2 log Reduction Number (%)
PCR –veNumber (%)
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%)#
* 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 incontrol arm E vs. high-dose NM283 arms (C and D) at W24. Favors increasingdifference 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 400-800 mg
+ Peg-IFN(N=41)
D: NM283 800 mg+ Peg-IFN
(N=41)
E: RBV+ Peg-IFN
(N=34)Overall(N=178)
Preferred Term n (%) n (%) n (%) n (%) n (%) n (%)
>1 AE 20 (95.2) 41 (100.0) 41 (100.0) 41 (100.0) 34 (100.0) 177 (99.4)
NAUSEA 14 (66.7) 30 (73.2) 33 (80.5) 33 (80.5) 11 (32.4) 121 (68.0)
FATIGUE 3 (14.3) 21 (51.2) 20 (48.8) 25 (61.0) 22 (64.7) 91 (51.1)
VOMITING 10 (47.6) 20 (48.8) 21 (51.2) 32 (78.0) 3 (8.8) 86 (48.3)
DIARRHOEA 7 (33.3) 13 (31.7) 25 (61.0) 14 (34.1) 5 (14.7) 64 (36.0)
HEADACHE 2 (9.5) 16 (39.0) 15 (36.6) 12 (29.3) 9 (26.5) 54 (30.3)
DECREASED APPETITE
5 (23.8) 5 (12.2) 8 (19.5) 11 (26.8) 5 (14.7) 34 (19.1)
Safety Summary to Week 24Valopicitabine (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 plus PegIntron® in G1 NR to PegIntron® ± RBV – Phase I
P1 P2 P3
A7 days SCH 503034 mono *
14 days Peg-alfa 2b mono 14 days combo
B 14 days Peg-alfa 2b mono 14 days combo7 days SCH 503034 mono *
C 14 days combo7 days SCH 503034 mono *
14 days Peg-alfa 2b mono
* dose: 200 or 400 mg, q8h
Zeuzem et al, EASL 2006, oral
SCH 503034 plus Peg-alfa 2b in G1 NR to Peg-alfa 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 patientsZeuzem et al, EASL 2006, oral
Follow-up
Follow-up
Follow-up
Follow-up
Follow-up
SCH 503034 plus PegIntron® ± RBV – Ongoing Phase II Study – Study Design
Randomi-zation
Study Weeks 480 72
CH
C,
G1,
NR
to
Peg
-IF
N +
RB
V,
n=
300
PegIntron® plus SCH 503034 100 mg q8
PegIntron® plus SCH 503034 200 mg q8
Follow-up
PegIntron® plus SCH 503034 400 mg q8
24
PegIntron® plus RBV plusSCH 503034 400 mg q8
PegIntron® plus SCH 503034 400 mg q8
PegIntron® plus RBV
VX-950 Phase Ib – Study Design
Naï
ve,
G1,
n=
20
VX-950 750 mg q8h plus PEGASYS® 180 µg qw
VX-950 750 mg q8h
0 2
PEGASYS® 180 µg qw plus Placebo
Randomization Study weeks
n=8
n=8
n=4
Reesink et al, EASL 2006, oral late breaker
VX-950 – Results
5.50
44.00
11.00
00.00
1.00
2.00
3.00
4.00
5.00
6.00
Median log10 reduction of HCVRNA
Number of patients with HCV RNA<10 IU/mL
Combination therapy VX-950 PEGASYS
Reesink et al, EASL 2006, oral late breaker
VX-950 – Phase IIa – Study DesignC
HC
, G
1, n
aïve
, n
=12
VX-950§ 750 mg q8h plus PEGASYS® 180 µg plus
COPEGUS® 1000-1200 mg
Study Weeks
0 4
VX05-950-102
§ One-time loading dose 1250 mg
* Patients continue on PEGASYS®/COPEGUS®
*
VX-950 – Results
6
1112 12
23
9
12
0123456789
101112
Week 1 Week 2 Week 3 Week 4
Nu
mb
er o
f p
atie
nts
HCV RNA <30 IU/mL HCV RNA <10 IU/mL
VX05-950-102
End of
VX-950 in Naïve G1– Phase II – Study Design – Expected Start May 2006
Study Weeks 480
Placebo plus PEGASYS® plus COPEGUS®
VX-950 750 mg q8h plus PEGASYS® plus
COPEGUS®
VX-950 750 mg q8h plus PEGASYS®
VX-950 750 mg q8h plus PEGASYS® plus
COPEGUS®
CH
C,
naï
ve,
G1,
n=
320
2412
VX-05-950-104
PEGASYS® plus COPEGUS®
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
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
Albuferon in Naïve G1 – Phase IIb – Study Design
Study Weeks 480 72
CH
C,
naï
ve,
G1,
n=
458
Follow-upPEGASYS® 180 µg qw
plus COPEGUS® 1000/1200 mg/d
Zeuzem et al, EASL 2006, oral late breaker
Follow-upAlbuferon 900 µg q2w
plus RBV 1000/1200 mg/d
Follow-upAlbuferon 1200 µg q2w
plus RBV 1000/1200 mg/d
Follow-upAlbuferon 1200 µg q4w
plus RBV 1000/1200 mg/d
Albuferon in Naïve G1 – Week 12 Results
Zeuzem et al, EASL 2006, oral late breaker
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)
VISER 1 – Phase III, Pivotal Study – Study Design
Follow-upPegIntron®
plus Viramidine 1200 mg/d
Study Weeks
0 48 72
Follow-upPegIntron®
plus RBV 1000/1200 mg/d
CH
C, n
aïv
e, n
=9
70
* Treatment duration according to genotype: G2/3 24 weeks, G1/4 48 weeks
24 *
VISER 1 – Efficacy Results
Viramidine Ribavirin
SVR * (ITT analysis) 38% 52%
Anemia rate (Hb <10 g/dL) 5% 24% p<0.0001
* Percent of patients with HCV RNA <39 IU/mL
Press release, 21.03.2006
VISER 1 – Viramidine * Weight-Based Analysis
Viramidine dose 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%
* 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
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, placebo-controlled
• 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
CPG 10101 plus PegIntron® ± RBV in G1 Relapsers – Study Design
Randomization Study Weeks480 72
CH
C,
G1,
rel
apse
rs t
o
PE
G-I
FN
+ R
BV
, n
=74
Follow-upPegIntron® 1.5 µg/kg/wk plus RBV 800-1400 mg/d
Follow-upPegIntron® 1.5 µg/kg/wk plus RBV
800-1400 mg/d plus CPG 0.2 mg/kg/wk
Follow-upPegIntron® 1.5 µg/kg/wk plus CPG 0.2 mg/kg/wk
Follow-upCPG 0.2 mg/kg/wk
plus RBV 800-1400 mg/d
Follow-upCPG 0.2 mg/kg/wk
CPG 10101 plus PegIntron® ± RBV in G1 Relapsers – Week 12 Results
• 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
PEG + RBV
CPG + RBV + CPG
CPG + PEG
CPG + RBV
CPG
HCV RNA (Mean log10 decrease) a 2.19 3.26 2.15 1.41 0.1 *
EVR at week 12 b 57% 86% 57% 21% 0%* p<0.001 vs PEG + RBV, a at week 12, b no definition provided
McHutchison et al, EASL 2006, oral late breaker