Transcript sample slide 1 - View the full AIDS 2016 programme

Innovations in HCV treatment:
what the future holds
21st International AIDS Conference,
Session: Synergistic Epidemics: New
drugs, New challenges, Tuesday 20th July
2016, Durban, South Africa
Jürgen Kurt Rockstroh
Department of Medicine I,
University Hospital Bonn,
Bonn, Germany
#AIDS2016 | @AIDS_conference
Conflict of Interest
Jürgen Rockstroh has received:
•
Honoraria for lectures and/or consultancies from
Abbott, AbbVie, Bionor, BMS, Cipla, Gilead,
Janssen, Merck and ViiV.
•
Research grants from Dt. Leberstiftung, DZIF,
NEAT ID.
#AIDS2016 | @AIDS_conference
HCV a global epidemic
Genotype Map
#AIDS2016 | @AIDS_conference
New Era of HCV Therapy
Discovery
of HCV
1989
FDA approves IFN
as the first therapy
FDA approves RBV
to combine with IFN
1991
100%
?
#AIDS2016 | @AIDS_conference
Treatment Options 2015/2016
IFN-free regimens
GT
Sofosbuvir + RBV
2, 3
Sofosbuvir/Ledipasvir (± RBV)
1, 4, 5, 6
Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir (± RBV)
1
Sofosbuvir + Simeprevir (± RBV)
1, 4
Sofosbuvir + Daclatasvir (± RBV)
All
Ombitasvir/Paritaprevir/Ritonavir (± RBV)
4
IFN-containing regimens
PegIFNa + RBV + sofosbuvir
All
PegIFNa + RBV + simeprevir
1, 4
(J-M Pawlotsky, ILC2015, Vienna, Austria, April 24, 2015. EASL Recommendations on Treatment of Hepatitis C 2015)
#AIDS2016 | @AIDS_conference
Summary of EASL 2014
100%
100
90
SVR24 rate (%)
80
70
60
Perfectovir
50
40
30
20
10
0
#AIDS2016 | @AIDS_conference
J-M Pawlotsky
Any difficult-to-treat populations left?
•
•
•
•
•
•
Patients with inherited blood disorders
Patients after kidney +/- liver transplantion
Patients with chronic renal insufficiency
Patients with ongoing substance abuse
Patients with HIV coinfection
Patients with……………………..
#AIDS2016 | @AIDS_conference
What are the remaining challenges?
•
•
•
•
Cost, cost and cost
Access and implementation of HCV therapy
To minimize pre-diagnostic requirements
Virological failure in patient with 2K/1B Chimeras
after receiving SOF + RBV
• Broad pangenotypic activity in particular also for
genotype 3
• Lack of data in genotype 5 and 6 for some DAA
combinations
• To develop DAAs which can be used in advanced
cirrhosis and have low risk for drug-drug interactions
#AIDS2016 | @AIDS_conference
ALLY-3+: Results
100
90
80
70
60
50
40
30
20
10
0
Treatment History
Treatment-Experienced
All Patients
Cirrhotic Patients
92
89
12
13
33
37
Naive
Experienced
HCV RNA < LLOQTD/TND (%)
HCV RNA < LLOQTD/TND (%)
SVR12 (ITT) by Prior Treatment
100
90
80
70
60
50
40
30
20
10
0
87
88
86
26
30
14
16
12
14
Overall
12 Weeks
#AIDS2016 | @AIDS_conference
Leroy V, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-3.
16 Weeks
Requirements for HCV Therapy
SVR > 95%
No Toxicity
Must haves
Excellent Tolerability
Short duration
High barrier to resistance
Helpful
One size fits all: pangenotypic
No drug–drug interactions
Low pill burden
#AIDS2016 | @AIDS_conference
Nice
bonus
Present and Future Major DAAs
Manufacturer
Protease
inhibitors
NS5A replication
complex
inhibitors
Nucleotide
NS5B inhibitors
Non-nucleoside
NS5B inhibitors
Gilead
GS-9857
Ledipasvir
Velpatasvir
Sofosbuvir
GS-9669
Merck (MSD)
Boceprevir
Grazoprevir
Elbasvir
MK-8408
Samatasvir
MK-3682
MK-8876
AbbVie
Paritaprevir
ABT-493
Ombitasvir
ABT-530
-
Dasabuvir
BMS
Asunaprevir
Daclatasvir
-
Beclabuvir
#AIDS2016 | @AIDS_conference
ASTRAL-1: Study Design
Week 0
Week 12
Week 24
n=500
SOF/VEL
SVR12
n=100
Placebo
SVR12
• Double blind, placebo controlled
• Broad inclusion criteria
• 5:1 randomization to SOF/VEL or placebo
– Stratified by HCV genotype and cirrhosis (presence/absence)
– GT 5 patients not randomized
• Conducted at 81 sites in US, Canada, UK, Germany,
France, Italy, Belgium, and Hong Kong
#AIDS2016 | @AIDS_conference
Feld J, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-2
ASTRAL-1: SVR12 by HCV Genotype
100
99
98
99
100
100
97
100
SVR12 (%)
80
60
40
1 relapse
2 lost to follow-up
1 withdrew consent
1 relapse
1 death
20
0
618
624
206
210
117
118
104
104
116
116
34
35
41
41
Total
1a
1b
2
4
5
6
Genotype
#AIDS2016 | @AIDS_conference
Feld J, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-2.
ASTRAL-2: Study Design
Week 0
Week 12
Week 24
n=120
SOF/VEL
SVR12
n=120
SOF + RBV
SVR12
• Open-label, active-comparator trial in GT2 patients
• Broad Inclusion criteria
• 1:1 randomization to SOF/VEL or SOF + RBV
– Stratified by prior treatment (TN/TE) and cirrhosis
(presence/absence)
• Conducted at 51 sites in US
#AIDS2016 | @AIDS_conference
Sulkowski M, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. 205.
ASTRAL-2: SVR12 by Treatment
p=0.018
99
94
100
SVR12 (%)
80
60
1 LTFU
6 Relapse
2 LTFU
133/134
124/132
SOF/VEL
SOF + RBV
40
20
0
#AIDS2016 | @AIDS_conference
Sulkowski M, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. 205.
ASTRAL-3: SOF/VEL FDC Daily for 12 Weeks
Versus SOF/RBV for 24 Weeks in Patients
with HCV Genotype 3 Infection
SOF/VEL
97
100
87
97
91
90
86
66
80
SVR12 (%)
SOF+RBV
63
60
22 relapses
6 other
7 relapses
40
4 relapses
2 other
20
16 relapses
8 other
191
197
163
187
7 relapses
15 relapses
13 other
4 relapses
2 other
73
80
55
83
1 non-response
23 relapses
2 other
200
206
176
204
64
71
45
71
0
No
Yes
Cirrhosis Status
#AIDS2016 | @AIDS_conference
Naïve
Experienced
Treatment History
Mangia A, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. 249.
Wk 0
Study Design
ASTRAL-4
Wk 12
Wk 24
n=75
SOF/VEL
SVR12
n=75
SOF/VEL + RBV
SVR12
n=75
SOF/VEL
•
•
•
•
Wk 36
SVR12
Open-label, randomized (1:1:1) US study
GT 1-6 treatment-naïve or -experienced patients with CPT B cirrhosis
Eligibility criteria: CrCL >50 mL/min, platelets >30,000 x 103/μL; no HCC or liver
transplant
Weight-based RBV dosing (1000 or 1200 mg/day)
#AIDS2016 | @AIDS_conference
Charlton M, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-13.
Results: Overall SVR12
ASTRAL-4
100
94
86
83
SVR12 (%)
80
60
40
20
75
——
90
82
——
87
77
——
90
0
SOF/VEL
12 week
SOF/VEL+ RBV
12 week
SOF/VEL
24 week
• P-value < 0.001 for comparison of SVR12 rate to 1%
for each treatment group
#AIDS2016 | @AIDS_conference
Charlton M, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-13.
ABT-493 + ABT-530 in G1 and G2
SURVERYOR-1 and –II Study Design
8-week Treatment Arms Only
SVR12
SURVERYOR-I
G1 without cirrhosis
• Open-label study
• Treatment-naïve or
P/R experienced
ABT-493 (300 mg)
+ ABT-530 (120 mg)
SURVERYOR-II
G2 without cirrhosis
• Open-label study
• Treatment-naïve or
P/R experienced
ABT-493 (300 mg)
+ ABT-530 (120 mg)
Week
0
N=34
N=54
8
24
• SURVEYOR-I: 71% G1a, 85% TN, 71% F0-F1
• SURVEYOR-II: 70% G2b, 87% TN, 82% F0-F1
P/R. pegIFN/RBv; pegIFN, pegylated interferon; RBV, ribavirin.
#AIDS2016 | @AIDS_conference
Poordad F, et al. 51st EASL; Barcelona, Spain; April 13-17, 2016. Abst. SAT-157.
Results SVR Rates after 8 weeks of
Treatment mITT
ITT
100
98
97
SVR 12 mITT (%)
SVR 12 ITT (%)
100
33
33
53
53
80
80
60
40
20
100
100
53
54
33
34
60
40
20
0
0
GT1
GT2
ABT-493 (300mg) + ABT-530 (120mg)
8weeks
GT1
GT2
ABT-493 (300mg) + ABT-530 (120mg)
8weeks
Error bars represent 2-sided 95% confidence intervals (Cis) calculated using the Wilson score method. ITT rates are presented ont eh
left for all treated subjects. mITT rates are presented on the right for all treated subjects excluding non-virologic failures.
Poordad F, et al. 51st EASL; Barcelona, Spain; April 13-17, 2016. Abst. SAT-157.
#AIDS2016 | @AIDS_conference
ABT-493 and ABT-530 Co-Administered for 8 Weeks
Results SVR Rate – G3 Non-cirrhotics
• No virologic failures
• 1 patient withdrew consent after treatment week 6 due to intolerance of
blood draws and had an undetectable HCV RNA at the time of
discontinuation
100
97
100
• Safe and well tolerated
SVR12, % Patients
80
60
40
20
mITT SVR12 rate excludes non-virologic failures
Muir AJ, et al.
51st
EASL; Barcelona, Spain; April 13-17, 2016. Abst. PS098.
#AIDS2016 | @AIDS_conference
0
28 /
29
SVR12
28 /
28
.
mITT
SVR12
ABT-493 and ABT-530 +/- RBV in GT3
with Cirrhosis
Results: SVR12 by ITT Analysis
100
100
24 /
24
24 /
24
100
SVR12, % Patients
80
60
40
20
0
ABT-493
+ ABT-530
.
ABT-493
+ ABT-530 + RBV
Kwo P,#AIDS2016
et al. 51st EASL;
Barcelona, Spain; April 13-17, 2016. Abst.
| @AIDS_conference
LB01.
#AIDS2016 | @AIDS_conference
PYRAMID-1 study-Egypt: Phase 3 registrational trial in Egyptian HCV gt-4 patients,
#AIDS2016 | @AIDS_conference
Esmat AASLD 2015 and CROI 2016
DNDi/Pharco: Sofosbuvir + ravidasvir
• Goal: short, pangenotypic, easy to use, high
efficacy, safe, all oral.
• Phase II/III Malaysia Thailand started, n=750.
– Possible partnership with South Africa, Vietnam.
• Price <300 $ per course of 12 weeks
• License territories: include Asia, Latin
America, Eastern Europe.
• Possibility to negotiate a license that covers
Europe from 2018.
#AIDS2016 | @AIDS_conference
Slide courtesy from Isabelle Andrieux-Meyer
Hot topic: Generics
HCV RNA <LLOQ (25 IU/ml)
Redemption-1 HCV RNA <LLOQ at EOT and SVR4
100
99.6%
(220/221)
99.2%
(122/123)
100%
(95/95)
94.2%
(129/137)
93.2%
(55/59)
97.4%
(37/38)
80
60
GLOBAL ACCESS TO DAA THERAPY
40
20
0
EOT
overall
EOT
SOF+LDV
EOT
SOF+DCV
SVR4 GT1-6
overall
SVR4 GT1
SOF+LDV
SVR GT1
SOF+DCV
•
At the end of treatment 99.6% of patients were <LLOQ
– One virological breakthrough reduced the result of LDV
•
The overall SVR4 rate was 94.2%
•
Looking at GT1 only the results of LDV and DCV were similar, with the LDV result
again suffering from that breakthrough patient (S282T RAV)
#AIDS2016 | @AIDS_conference
Freemen J et al. EASL 2015
2
Innovation in HCV Treatment:
what the future holds
SVR > 95%
No Toxicity
Must haves
Excellent Tolerability
Short duration
High barrier to resistance
Helpful
One size fits all: pangenotypic
No drug–drug interactions????
Low pill burden
#AIDS2016 | @AIDS_conference
Nice
bonus