Transcript Document

Future Directions in HCV Therapy
Eric Lawitz, MD, AGAF,CPI
Medical Director, The Texas Liver Institute
Clinical Professor of Medicine
University of Texas Health Science Center
San Antonio, Texas
Milestones in Therapy of CHC:
Average SVR Rates from Clinical Trials
100
Peginterferon
SVR (%)
80
60
2001
+ Ribavirin
1998
Standard
Interferon
1991
+ DAAs
2011
70+%
55%
42%
40
39%
34%
16%
20
6%
0
IFN 6m
IFN 12m
IFN/RBV 6m
IFN/RBV 12 m
Peg-IFN 12m
Adapted from US Food and Drug Administration,
Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring MD.
Peg-IFN/RBV 12m Peg-IFN/RBV/DAA
DAAs with an Indication for the
Treatment of G1 Chronic Hepatitis C
Generic Name
Trade Name
Manufacturer
Boceprevir
Telaprevir
Victrelis™
Incivek™
Merck Pharmaceuticals, Inc
Vertex Pharmaceuticals, Inc
• Both compounds act by inhibiting HCV
nonstructural NS3/4A protease and are referred
to as direct acting antivirals (DAAs)
US Food and Drug Administration. Available at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/
Limitations of Current Therapy
• Telaprevir and boceprevir only approved for Genotype 1
• Interferon backbone required
• TID dosing for telaprevir/boceprevir
• Response guided therapy (both) and lead-in (boceprevir)
complicated
• 24-48 week treatment
• Limited efficacy in difficult to cure patients (e.g., patients
with cirrhosis, prior null responders, African-Americans)
• Hematologic (both) and rash/dermatological (telaprevir)
adverse events
• Drug-drug interactions
Sofosbuvir (SOF) (GS-7977)
• NS5B nucleotide polymerase inhibitor
• Favorable administration profile
– Once daily, no food effect
– No drug-drug interactions
Completed Phase 3 Trials
• NEUTRINO
– GT 1, 4, 5, 6; treatment naïve
– No comparator
• FISSION
– GT 2 and 3; treatment naïve
– Compared to 24 weeks of peginterferon + ribavirin
• POSITRON
– GT 2 and 3; patients ineligible for or intolerant of interferon therapy
– Compared to placebo
• FUSION
– GT 2 and 3; patients unresponsive to prior treatment
– Compared to 16 weeks of sofosbuvir + ribavirin
NEUTRINO
• Patients
– GT 1, 4, 5, 6 treatment naive
– 17% compensated cirrhosis
– 17% black
– 29% IL28B genotype CC
• Regimen for all patients
– Sofosbuvir 400 mg qd
– Ribavirin 1000/1200 mg qd
– Peginterferon alfa-2a 180 mcg weekly
E. Lawitz et al, Abstract 1411. EASL, April 2013; Lawitz et al., N Engl J Med 2013, 368: 1878-1887.
NEUTRINO: Study Design
Week 0
12
Sofosbuvir/PEG/RBV, n=327
24
SVR12
• Open label
– SOF+PEG+RBV for 12 weeks (no response-guided therapy)
• Expanded inclusion criteria
– No upper limit to age or BMI
– Opiate replacement therapy permitted
– Platelets ≥90,000/mm3, neutrophils ≥1,500/mm3 or
1,000/mm3 (blacks)
E. Lawitz et al, Abstract 1411. EASL, April 2013; Lawitz et al., N Engl J Med 2013, 368: 1878-1887.
>90% Of Patients Have Undetectable
Virus After 2 Weeks and Achieve SVR
100
99
99
299/327
321/325
326/327
295/327
Week 2
Week 4
Week 12
Week 12
91
90
80
60
40
20
0
On treatment
Post-treatment
E. Lawitz et al, Abstract 1411. EASL, April 2013; Lawitz et al., N Engl J Med 2013, 368: 1878-1887.
NEUTRINO: SVR by Genotype
100
96
90
100
89
SVR12 (%)
80
60
40
20
n = 292
295/327
261/292
n = 28
n=7
27/28
7/7
0
All Patients
1
4
Genotype
E. Lawitz et al, Abstract 1411. EASL, April 2013; Lawitz et al., N Engl J Med 2013, 368: 1878-1887.
5, 6
NEUTRINO: SVR by Subgroup
100
98
92
87
80
80
SVR12 (%)
87
60
40
20
0
n = 273
n = 54
n = 273
n = 54
No cirrhosis Cirrhosis
n = 95
n = 95
CC
n = 54
n = 232
n = 232
CT/TT
n = 54
Black
IL28B genotype
E. Lawitz et al, Abstract 1411. EASL, April 2013; Lawitz et al., N Engl J Med 2013, 368: 1878-1887.
Conclusions
• 12 weeks of SOF+PEG+RBV achieved 90%
SVR in treatment naïve patients with GT 1, 4, 5,
or 6
• 99% of patients had HCV RNA < LLOQ by
treatment week 4 and all virologic failures were
due to relapse
• This regimen was well tolerated
E. Lawitz et al, Abstract 1411. EASL, April 2013; Lawitz et al., N Engl J Med 2013, 368: 1878-1887.
GT2 and GT 3: Study Designs
FISSION (TN)
Week
0
12
24
SOF + RBV, n=256
36
SVR12
Peg-IFN + RBV (SOC), n=243
SVR12
RBV does 1000-1200 mg/day for SOF + RBV and 800 mg/day for Peg-IFN + RBV.
Week
0
12
SOF + RBV, n=103
16
Placebo
24
28
SVR12
SOF + RBV, n=98
SVR12
SOF dose 400 mg once daily; RBV dose 1000-1200 mg/day.
Week
0
12
24
SOF + RBV, n=207
SVR12
Placebo, n=71
SVR12
SOF dose 400 mg once daily; RBV dose 1000-1200 mg/day.
Jacobson et al. N Engl J Med 2013, 368: 1867-1877, Lawitz et al., N Engl J Med 2013, 368: 1878-1887,
GT2 and GT 3: SVR by Genotype
SVR12 (%)
FISSION (TN)
100
80
60
40
20
0
97
67
78
67
SOF + RBV 12 Weeks
170/
253
162/
243
68/
70
SVR12 (%)
Overall
100
80
60
40
20
0
63
56
P
<0.001
73
50
52/
67
GT 2
110/
176
Peg-IFN + RBV 24 Weeks
GT 3
94
86
102/
183
P
<0.001
62
30
69/
95
50/
100
Overall
31/
36
30/
32
GT 2
SOF + RBV 12 weeks
39/
63
19/64
SOF + RBV 16 weeks
GT 3
SVR12 (%)
93
100
80
60
40
20
0
78
61
SOF + RBV 12 weeks
161/207
101/109
60/98
Overall
GT 2
GT 3
Jacobson et al. N Engl J Med 2013, 368: 1867-1877, Lawitz et al., N Engl J Med 2013, 368: 1878-1887,
SVR: Patients with Cirrhosis
vs No Cirrhosis
FISSION (TN)
98
SVR12 (%)
100
91
82
71
61
62
80
34
60
40
20
58/
59
10/
11
44/
54
0
No cirrhosis
89/
145
8/1
3
Cirrhosis
99/
139
SVR12 (%)
96
100
78
60
20
0
80
40
25/
26
23/
23
6/10 7/9
No Cirrhosis
Cirrhosis
20
0
61
37
63
25/
14/38 40
SVR12 (%)
5/26
No Cirrhosis
14/
23
SOF + RBV 16 weeks
Cirrhosis
GT 3
94
100
68
80
60
21
40
20
SOF + RBV 12 weeks
19
GT 2
92
Peg-IFN + RBV 24 Weeks
Cirrhosis
100
60
60
40
SOF + RBV 12 Weeks
GT 3
100
80
13/38 11/37
No cirrhosis
GT 2
30
No cirrhosis
Cirrhosis
85/92
16/17
67/84
3/14
0
GT 2
GT 3
Jacobson et al. N Engl J Med 2013, 368: 1867-1877, Lawitz et al., N Engl J Med 2013, 368: 1878-1887,
Conclusions
• 12 weeks of SOF+RBV results in SVR>90% in GT 2 treatment naive
patients with and without cirrhosis
• SVR rates were lower in GT 2 treatment experienced patients with
cirrhosis compared to non-cirrhosis
• SOF+RBV led to similar results as PEG+RBV for GT 3 treatment
naïve patients
– Lowest rates observed in patients with cirrhosis
• SOF+RBV for 12 weeks is suboptimal for GT 3 treatment
experienced patients
– 16 weeks total duration significantly increased SVR rates
• SOF+RBV well tolerated with fewer adverse events than PEG+RBV
• Genotype 3 ≠ genotype 2 HCV
– Strategies to improve GT 3 results are needed
Simeprevir (TMC 435) (PI)
Simeprevir (TMC 435)
• NS3/4A protease inhibitor
• Antiviral activity against GT 1, 2, 4, 5 and 6
• One capsule, once per day
Completed Phase 3 Studies
• QUEST-1 and QUEST-2
– Same study design but studies conducted
independent of one another
– Treatment naïve GT 1 patients
• PROMISE
– Same study design as QUEST-1 and QUEST-2
– GT 1 prior relapsers
QUEST-1, QUEST-2 and
PROMISE Study Designs
Response Guided Treatment
0
PEG/RBV
SMV 150
mg/PEG/RBV
PEG/RBV
Placebo/
PEG/RBV
PEG/RBV
Post-Therapy Follow-Up
Post-Therapy Follow-Up
12
PEG/RBV
24
Weeks
Post-Therapy Follow-Up
48
72
• Response Guided Therapy: if HCV RNA <25 IU/mL at Week 4
and undetectable at Week 12, complete treatment at Week 24
– 85-93% of patients met the criteria and qualified for total treatment
duration of 24 weeks.
Simeprevir + PEG/RBV Achieved SVR in
~80% of Treatment Naïve and Prior Relapsers
Simeprevir/PEG/RBV
100
SVR12 (%)
80
81%
80%
60
50%
PEG/RBV
79%
50%
37%
40
20
0
210/
264
65/
130
QUEST-1
209/
257
67/
134
QUEST-2
206/
260
49/
133
PROMISE
QUEST-1: SVR by Subgroup
SIM + PR
PR
Patients Achieving SVR12 (%)
120
100
94
90
83
80
78
71
70
76
65
60
60
52
49
40
42
28
24
20
0
152/
183
54/
90
F0-F2
54/
77
11/
40
F3-F4
Fibrosis
I. Jacobson et al, Abstract 1425. EASL, April 2013
105/
147
36/
74
1a
105/
117
29/
56
1b/other
Genotype
72/
77
29/
37
CC
114/
150
32/
76
CT
IL28B genotype
24/
37
4/
17
TT
SVR Higher When Simeprevir
Added to PEG/RBV For Patients With All Stages
of Fibrosis/Cirrhosis (QUEST-2)
Simeprevir/PEG/RBV
Patients Achieving SVR12 (%)
100
PEG/RBV
84.6
80
66.7
60
64.7
52.9
51
40
40
20
0
165/
195
52/
102
F0-F2
24/
36
9/
17
F3
11/
17
6/
15
F4 (Cirrhosis)
Similar results seen in QUEST-1 and PROMISE studies
Conclusions
• Simeprevir 150 mg + PEG/RBV was highly
effective against GT 1 treatment naïve patients
with SVR (80%)
• Most patients (85%) receiving simeprevir were
able to shorten therapy to 24 weeks
• Simeprevir 150 mg + PEG/RBV was generally
well tolerated
– Rates of anemia and rash were similar in the
simeprevir and placebo groups
I. Jacobson et al, Abstract 1425. EASL, April 2013
Simeprevir (TMC 435) (PI) +
Sofosbuvir (GS-7977) (nuc)
COSMOS: Study Design
Arm 1
SMV + SOF + RBV
Arm 2
SMV + SOF
n = 24
Post-treatment follow-up
n = 15
Post-treatment follow-up
Arm 3
SMV +
SOF + RBV
Post-treatment follow-up
n = 27
Arm 4
SMV+
SOF
Post-treatment follow-up
n = 14
Weeks
0
12
Interim analysis SVR4
24
36
48
Primary endpoint SVR12
• Cohort 1: n=80 patients randomized 2:1:2:1
• Cohort 2: n=87 patients randomized 2:1:2:1
• SMV 150 mg QD + SOF 400 mg QD with/without RBV (Copegus®) 1000 or 1200 mg/day (BID)
• Interim analysis of Cohort 1 conducted when all patients in 12 week treatment arms (arms 3
and 4) reached SVR4 time point or discontinued early
Lawitz et al., CROI, March 2013
COSMOS: Key Eligibility Criteria –
Cohort 1
• Chronic HCV GT 1 infection
• 78% GT 1a
• Prior null response to PEG/RBV
‒ Failure to achieve >2 log10 decline in HCV RNA by Week 12
• Fibrosis
• F0-F1: 41%
• F2: 59%
• IL28B
• CT: 70%
• TT: 24%
• 29% African-American
Lawitz et al., CROI, March 2013
COSMOS: Virologic Response (12 Week
Arms)
SMV+SOF+RBV
100
100
100
96.3
92.9
SMV+SOF
96.3
92.9
85.2
SVR8 (%)
80
57.1
60
40
20
0
23/
27
8/
14
RVR, n/N (%)
Lawitz et al., CROI, March 2013
27/
27
14/
14
Undetectable end of
treatment, n/N (%)
26/
27
13/
14
SVR4, n/N (%)
26/
27
13/
14
SVR8, n/N (%)
COSMOS: Safety & Tolerability
24 weeks
Patients
SMV + SOF
+ RBV
(n=24)
12 weeks
SMV + SOF SMV + SOF + SMV + SOF
RBV
Total
(n=15)
(n=27)
(n=14)
(n=80)
AEs during treatment, %
87.5
1
Grade 3/4 AEs , %
4.2
Serious AEs, %
0
Most common AEs (≥10% of total patients)
25.0
Fatigue, %
93.3
13.3
0
88.9
18.5
0
78.6
0
0
87.5
10.0
0
26.7
18.5
21.4
22.5
Headache, %
16.7
26.7
14.8
28.6
20.0
Insomnia, %
16.7
13.3
18.5
21.4
17.5
Nausea, %
4.2
6.7
18.5
28.6
13.8
Anemia, %
25.0
0
11.1
0
11.3
Cough, %
20.8
6.7
3.7
7.1
10.0
12.5
13.3
11.1
0
10.0
1
2
16.7
1
1
NA
0
0
3.7
0
0
NA
2
3
9.8
Rash, %
Treatment discontinuation
Due to AEs, n
Non-safety reason, n
RBV dose reduction, %
1WHO
Toxicity Grading Scale, 2003
Lawitz et al., CROI, March 2013
COSMOS: Cohort 2
• SMV+SOF+RBV for 12 weeks
• GT 1 treatment naive and prior null
responders with advanced disease (F3/F4)
• SVR4 results
– SMV+SOF+RBV: 96% (26/27)
– SMV+SOF: 100% (14/14)
Medivir/Janssen Press Release, August 29, 2013
COSMOS: Summary
• 12 weeks of SMV+SOF led to an SVR8 rate
of 96% with RBV and 93% without RBV in
prior null responders with F0-F2 disease
• 12 weeks of SMV+SOF led to an SVR4 rate
of 96% with RBV and 100% without RBV in
treatment naïve and prior null responders
with F3-F4 disease
• SMV+SOF+RBV was generally well tolerated
Daclatasvir (NS5A inhibitor) +
Sofosbuvir (GS-7977) (nuc)
Background
• Patients who experience virologic failure on telaprevir or
boceprevir-based regimens currently have no treatment
options
• DCV plus SOF with or without RBV achieved SVR4 in
98% of 126 HCV GT 1-infected treatment-naive patients
(Sulkowski et al. AASLD 2012)
• Study Aim
– To evaluate the efficacy and safety of DCV+SOF with
or without RBV for 24 weeks in GT 1-infected patients
who failed prior treatment with TVR or BOC +
PEG/RBV
M.S. Sulkowski et al, Abstract 1417. EASL, April 2013
Study Design
Prior TVR/BOC
Failures,
GT 1a/1b
(N = 41)
n = 21
DCV 60 mg QD + SOF 400 mg QD
Follow-up
n = 20
DCV 60 mg QD + SOF 400 mg QD + RBV
Follow-up
• Patients
SVR12
Week 24
SVR4
– GT 1, non-cirrhotic
– Prior nonresponse, relapse, or breakthrough
during treatment with PEG/RBV+TVR or BOC
– Patients who discontinued TVR or BOC due
to an AE were excluded
M.S. Sulkowski et al, Abstract 1417. EASL, April 2013
HCV RNA < LLOQ (% patients)
Virologic Response
100
DCV + SOF
80
DCV + SOF
+ RBV
60
Missing
40
20
0
N=
21
20
Week 2
21
20
Week 4
21
20
EOT
21
20
SVR4
21
20
SVR12
• 1 patient missing at post-treatment (PT) Week 12: HCV RNA was
undetectable at PT Week 4 and at PT Week 24
• 21/41 patients have reached PT Week 24; all have achieved SVR24
M.S. Sulkowski et al, Abstract 1417. EASL, April 2013
Conclusions
• The all-oral, once-daily combination of
DCV+SOF with or without RBV achieved SVR in
all GT 1 infected patients (n=41) who failed prior
treatment with TVR or BOC+PEG/RBV
• DCV+SOF with or without RBV was
well tolerated
• No Grade 3 or 4 hepatic or hematologic
abnormalities
M.S. Sulkowski et al, Abstract 1417. EASL, April 2013
Daclatasvir (BMS-790062) (NS5A inhibitor)
+
Asunaprevir (BMS-650032) (PI)
Study AI447-011 Expansion Cohort:
Prior Null Responders to PEG/RBV
Week 24
SVR12 primary endpoint
N = 18
A1 (DUAL): DCV 60 mg QD +
ASV 200 mg BID (GT 1b only)
Follow-up
N = 20
A2 (DUAL): DCV 60 mg QD +
ASV 200 mg QD (GT 1b only)
Follow-up
N = 20
B1 (QUAD): DCV 60 mg QD + ASV 200 mg
BID + PEG/RBV (GT 1a/1b)
Follow-up
N = 21
B2 (QUAD): DCV 60 mg QD + ASV 200
mg QD + PEG/RBV (GT 1a/1b)
Follow-up
N = 22
B3 (TRIPLE): DCV 60 mg QD +
ASV 200 mg BID + RBV (GT 1a/1b)
Follow-up
Week 12
A. Lok, et al; APASL 2013.
SVR4
SVR24
SVR48
TRIPLE Therapy (Arm B3): GT 1a vs GT 1b
Individual HCV RNA Levels
DCV + ASV 200 mg BID + RBV
Graphs truncated at viral breakthrough
GT 1b patients, n=4
8
7
6
5
4
3
2
1
0
LLOQ
LOD
0
4
8
12
Weeks
16
20
24
PT4
HCV RNA, log10 IU/mL
HCV RNA, log10 IU/mL
GT 1a patients, n=18
8
7
6
5
4
3
2
1
0
LLOQ
LOD
0
4
8
12
16
20
24
Weeks
• 1/18 GT 1a patient completed triple therapy and achieved SVR4
PT4
Conclusions
• In non-cirrhotic prior null responders,
24 weeks of daclatasvir + asunaprevir
appears to be an efficacious combination
for GT 1b but not GT 1a
Daclatasvir (BMS-790062) (NS5A
inhibitor) +
Asunaprevir (BMS-650032) (PI) +
BMS-791325 (non-nuc)
AI443-014: Study Design
Primary endpoint: SVR 12
Group 1 DCV+ASV+BMS -791325 75 mg
Group 2
DCV+ASV+
BMS -791325 75 mg
12-week follow-up
12-week follow-up
Additional
follow-up
to SVR48
Group 3 DCV+ASV+BMS -791325 150 mg
Group 4
0
DCV+ASV+
BMS-791325 150 mg
12-week follow-up
12-week follow-up
12
24
Study week
•
•
Treatment naïve non-cirrhotic patients
GT 1a: 74% and CT/TT: 70%
G. Everson et al, Abstract 1423. EASL, April 2013
36
Summary
The all oral, IFN-free, RBV-free, ritonavirfree combination of DCV, ASV, and BMS791325
• Achieved >90% (61/66) SVR4 and SVR12
(30/32)
• Had infrequent virologic failure (4.5%, 3/66)
• Most common AEs (≥10% total) were headache,
asthenia, and gastrointestinal
G. Everson et al, Abstract 1423. EASL, April 2013
Faldaprevir (BI 201335) (PI)
Faldaprevir: Phase 3 Studies (IFN-Containing)
• STARTVerso 1
– Treatment naïve GT 1 patients
– All patients from Europe and Japan
– Only Phase 3 study with results reported as of October 2013
• STARTVerso 2
– Treatment naïve GT 1 patients
– Studying shorter durations (12 vs 24 weeks)
• STARTVerso 3
– Treatment experienced GT 1 patients
• STARTVerso 4
– Treatment naïve/prior relapsers who are coinfected with HCV
and HIV
STARTVerso1
• Phase III, randomized, double-blind, placebo-controlled trial
• Patients
– Treatment naïve GT 1 infection
– 78% Caucasian, 20% Asian
– 39% IL28B CC
– 66% GT 1b
• Regimen
– PEG+RBV for 24 weeks plus faldaprevir/placebo
• Patients with early treatment success stopped all treatment at
Week 24
• Patients without Early Treatment Success and those in control
arm received PEG/RBV for 48 weeks
P. Ferenci et al, Abstract 1416. EASL, April 2013
STARTVerso1: Study Design
PEG/RBV
PBO/PEG/RBV
ETS
FDV 120 mg/
PEG/RBV
No ETS
FDV 240
mg/PEG/RBV
Day 1
•
PBO/
PEG/RBV
Observation Period
FDV 120 mg/
PEG/RBV
PEG/RBV
ETS
PBO/
PEG/RBV
No ETS
Week 12
Observation Period
Observation Period
Observation Period
PEG/RBV
Week 24
Observation Period
Week 48
Week 72
Criteria for response guided therapy
– Early Treatment Success (ETS): HCV RNA <25 IU/mL at Week 4 and
undetectable at Week 12, complete treatment at Week 24
– 88% met the criteria and qualified for total treatment duration of 24 weeks.
P. Ferenci et al, Abstract 1416. EASL, April 2013
STARTVerso1 SVR12 rates
100
79
80
69
132
204
259
210
261
PEG/RBV
FDV 120 + PR
FDV 240 + PR
SVR12 (%)
80
60
52
40
20
0
P. Ferenci et al, Abstract 1416. EASL, April 2013
SVR in Patients With Cirrhosis
100
SVR (%)
80
83%
80%
56%
60
40%
40
20
0
195/243
204/246
9/16
6/15
FDV 120 mg/
PEG/RBV
FDV 240 mg/
PEG/RBV
FDV 120 mg/
PEG/RBV
FDV 240 mg/
PEG/RBV
No Cirrhosis
P. Ferenci et al, Abstract 1416. EASL, April 2013
Cirrhosis
SVR By GT 1 Subtype
100
84%
80
83%
76%
SVR12 (%)
69%
60%
60
40
36%
20
0
16/45
PEG/RBV
60/87
68/90
FDV 120 mg/ FDV 240 mg/
PEG/RBV
PEG/RBV
GT1a
P. Ferenci et al, Abstract 1416. EASL, April 2013
52/86
PEG/RBV
143/171 142/171
FDV 120 mg/ FDV 240 mg/
PEG/RBV
PEG/RBV
GT1b
STARTVerso1 Conclusions
•
FDV+PEG/RBV significantly increased SVR12 rates in
GT 1 patients compared with PEG/RBV
•
In total, 88% of patients treated with FDV were eligible
to stop all treatment at Week 24
•
Patients without cirrhosis had higher SVR than patients
with cirrhosis
•
GT 1b infected patients had higher SVR than GT 1a
infected patients
•
FDV+PEG/RBV was well tolerated
P. Ferenci et al, Abstract 1416. EASL, April 2013
Faldaprevir (BI 201335) (PI) +
Deleobuvir (non nuc)
SOUND-C2: IFN-Free
– Faldaprevir + deleobuvir + RBV
– SVR rates between 59-69% in GT 1 treatment
naïve patients with 16, 28 or 40 weeks of
treatment
• Higher SVR in GT 1b (56-85%) vs GT 1a (38-47%)
• High rate of relapse (41%) in GT 1a treated for 16
weeks
– Arm with no RBV had low SVR (39%)
Zeuzem et al., N Engl J Med 2013, 369; 630-639.
Faldaprevir: IFN-Free
(Results Are Anticipated in 2014)
• HCVerso 1 (NCT01732796) and HCVerso 2
(NCT01728324)
– Faldaprevir + deleobuvir + RBV
– GT 1b only
– Includes IFN-ineligible patients as well as patients with cirrhosis
– Duration of therapy: 16 vs 24 weeks
– Anticipated primary results: 1H 2014
• Study with PPI-668 (NS5A inhibitor)(NCT01859962)
–
–
–
–
Faldaprevir + deleobuvir + PPI-668 + RBV
GT 1a
Treatment naïve
Anticipated primary results: 1H 2014
ABT-450/r (PI with ritonavir), ABT267 (NS5A inhibitor) and ABT-333
(non nuc)
AVIATOR
• Phase 2b, randomized, open-label, multicenter
study
• Patients
– GT 1 (66% GT 1a)
– Treatment-naive and prior null response
– Non-cirrhotic
• Duration
– 8, 12 and 24 weeks
K.V. Kowdley et al, Abstract 3. EASL, April 2013
Treatment naive
AVIATOR: Study Design
N
Regimen/duration
80
ABT450
41
ABT450
79
ABT450
ABT267
79
ABT450
ABT267
ABT333
79
ABT450
ABT267
ABT333
80
ABT450
ABT267
ABT333
ABT267
SVR24**
SVR24
(%)
VBT/
Relapse
ABT333
RBV
89
88
0/10
ABT333
RBV
85
83
1/4
RBV
91
89
1/8
90
87
1/5
RBV
99
96
0/1
RBV
93
90
0/2
SVR12
(%)
SVR24
(%)
VBT/
Relapse
RBV
89
89
0/5
Week
Null response
SVR12
(%)
8
12
24
N
Regimen/duration
45
ABT450
ABT267
45
ABT450
ABT267
ABT333
RBV
93
93
3/0
43
ABT450
ABT267
ABT333
RBV
98
95
1/0
** 8 patients who achieved SVR12 did not return >24 weeks and were counted as virological failures for SVR24
3 patients relapsed between SVR12 and SVR24
K.V. Kowdley et al, Abstract 3. EASL, April 2013
SVR24 by Baseline Subgroups –
Treatment-Naïve Patients*
100
92
94
98
91
89
94
94
91
95
89
% with SVR24
80
60
40
1b
≥7 log
<7 log
F0-F1
81
108 50
35
124
113 42
*Includes patients randomized to the quad therapy arms (12 or 24 weeks duration).
K.V. Kowdley et al, Abstract 3. EASL, April 2013
CC
1a
78
F2-F3
Female
N=
Male
0
Non-CC
20
115 44
SVR24 by Baseline Subgroups –
Null Responders*
100
93
97
93
97
91
96
95
95
100
94
% with SVR24
80
60
40
20
Female
1a
1b
≥7 log
<7 log
F0-F1
F2-F3
Non-CC
CC
N=
Male
0
55
33
55
33
22
66
41
45
85
3
*Includes patients randomized to the quad therapy arms (12 or 24 weeks duration).
K.V. Kowdley et al, Abstract 3. EASL, April 2013
Most Common Adverse Events*
Event, %
Total
(N=247)
Treatment-Naïve
(N=159)
Null Responders
(N=88)
Headache
31.2
31.4
30.7
Fatigue
29.6
32.7
23.9
Nausea
22.7
24.5
19.3
Insomnia
19.8
22.6
14.8
Diarrhea
15.0
13.2
18.2
*Includes patients randomized to the quad therapy arms (12 or 24 weeks duration)
K.V. Kowdley et al, Abstract 3. EASL, April 2013
Safety
• 6 patients (2.4%) discontinued due to study drug-related
AEs; 4 of 6 considered related to treatment.
• 4 patients (1.6%) experienced SAEs
– 1 (arthralgia) was possibly study drug-related
• Moderate-to-severe study drug-related AEs with >10%
incidence in any arm were asthenia and fatigue.
• 6 patients (2.8%) and 1 patient (0.6%) experienced
Grade 3-4 laboratory abnormalities in total bilirubin and
ALT, respectively; all resolved with continued dosing.
K.V. Kowdley et al, Abstract 3. EASL, April 2013
AVIATOR Conclusions
• Comparable SVR12 and 24 seen with 12 and 24
weeks of treatment
• SVR rates >90% were achieved in naive
and prior null responders with a
3-DAA+RBV regimen
– No clinically meaningful differences were observed
by gender, HCV subtype, IL28B genotype, baseline
HCV-RNA or severity of fibrosis.
K.V. Kowdley et al, Abstract 3. EASL, April 2013
Overall Summary
• All oral therapy expected to be available for GT2
and GT3 by early 2014.
• All oral therapy for GT 1 will be available no
sooner than 2H2014.
• Even with PEG/RBV backbone, soon to be
available DAAs for GT 1 offer advantages over
currently approved DAAs.