FUTURE THERAPEUTIC STRATEGIES FOR DAAs

FUTURE THERAPEUTIC
STRATEGIES FOR DAAs
Nezam H. Afdhal M.D
Professor of Medicine,
Harvard Medical School,
Beth Israel Deaconess Medical Center, Boston
Yves Benhamou MD,
Assoc. Professor of Medicine,
University Paris 6
Current Issues
Efficacy: 90 – 95%
Duration: 6, 8, 12 or 24 weeks
Relapse approaches – salvage therapy
Special populations – are there any?
Future Research
Properties of DAAs of Clinical Importance
Genotype
coverage
Potency
Resistance
barrier
Safety/
tolerability
Half-life:
dosing interval
Metabolism
Metabolism
and
and elimination
elimination
Potential for
drug-drug
interactions
3
Highly Effective DAA Regimens for
Genotype 1a/b
No nucleotide
Nucleotide
NS5A
RBV
NNI
± RBV
NS5A
NNI
± RBV
NS5A
Nuc
PI / NNI
4
Abbreviations: NNI, nonnucleoside inhibitor; NS5A, nucleoside 5A inhibitor; Nuc, nucleotide; PI, protease inhibitor; RBV, ribavirin.
Less Effective DAA Regimens focus
on Genotype 1b only
No nucleotide
Outcomes
Hallmark Study
Asunaprevir / Daclatasvir
Tx-naive
PI
NS5A
± RBV
SVR12 (%)
89,7
182/
203
81
73
Non-responder
Ineligible/intolerant
82,4
80,3
90,8
98/
119
68/
84
Null Partial
57/ 79/
56/
71
87
77
/
/
ion mia a osis
s
s
ne eni ibr osis
re
A
p
p F rh
De
ro
t
cir
u
e
n
5
Abbreviations: NNI, nonnucleoside inhibitor; NS5A, nucleoside 5A inhibitor; Nuc, nucleotide; PI, protease inhibitor; RBV, ribavirin.
Highly Effective DAA Regimens for
Genotype 1a/b
No nucleotide
Outcomes and Regimens
% SVR AbbVie 3D regimen
RBV
NNI
NS5A
100
80
60
40
20
0
NAIVE
96
95
98
PEG/RBV Failure
100
95
100
95
PEG/RBV
Failure
80
R – ABT450
Ombitasvir
Dasabuvir
Ribavirin
60
40
20
0
REL
PR
NR
Abbreviations: NNI, nonnucleoside inhibitor; NS5A, nucleoside 5A inhibitor; PI, protease inhibitor; RBV, ribavirin.
6
Highly Effective DAA Regimens for
Genotype 1a/b
Nucleotide Backbone Treatment
ION TRIALS
SOF / LED
8, 12 and 24 weeks
SVR 94 – 100%
± RBV
COSMOS TRIAL
SOF / SIM
12 and 24 weeks
SVR 95%
7
Abbreviations: NNI, nonnucleoside inhibitor; NS5A, nucleoside 5A inhibitor; Nuc, nucleotide; PI, protease inhibitor; RBV, ribavirin.
Treatment of HCV Special Populations
REGIMEN / SVR
•
•
•
•
•
Cirrhosis 85 – 99%
SOF-LED
Pre-transplant
Childs B / C
Post-Transplant
PI Failures
AbbVie 3D /
SOF/RBV
SOF-LED
SOF-LED
SOF-LED
70%
90%
90%
94%
• Renal Disease remains only major subgroup needing study
• Clinical Outcomes needed in advanced liver disease patients
Shortening Treatment Duration

Convenience

Compliance

Cost

Cannot sacrifice SVR

Must be predictable for different patient
populations – kinetic / immunological
predictors

Must have a real clinical rationale
9
treatment
with ACH-3102 and SOF in G1 treatment-naive patients:
A Phase 2 ‘proxy’ study
ACH-3102: ‘2nd generation’ NS5A inhibitor
SOF used as ‘proxy’ for ACH-3422 (NI)
Two cohorts of treatment-naive G1:
Cohort 1: ACH-3012 50 mg +
SOF 400 mg QD 8 weeks
(n=12) and 6 controls
– Cohort 2: ACH-3102 + SOF 6 weeks
(n=12) and 6 controls
Patients (%)
–
Virologic response (n=12)
<LLOQ
<LLOD
●
100
100
100
100
8/8 thus far have ETR; no SVR data
No SAEs
No discontinuations for AEs
(EOT)
Promising clinical results consistent with preclinical profiles of both
drugs
Potential in long-term for new combinations of NS5A/nucleotide ± other
DAA to enter the HCV treatment space
Gane EJ, et al. AASLD 2014, Boston. #LB-23
C-SWIFT: MK-5172 (grazoprevir)+ MK-8742 (elbasvir) + SOF in
treatment-naive G1 pts with/without cirrhosis, for 4, 6, or 8
weeks
HCV RNA
<15IU/mL
83
81
97 100
100 100
85
68
n=30
n=21
n=20
n=15
25
Primary
endpoint
:
SVR12
n=10
TW4 TW8 TW12
G1a 76–87%
Viral load >6 million IU/mL in 17–
19% non-cirrhotics and 0–5% in
cirrhotics
Safety
HA, fatigue, nausea (3–10%)
No anemia, no bili >5x BL;
no AST/ALT
>5x2014,
ULN
Lawitz
E, et al. AASLD
Boston. #LB-33
100 100
60
45
50
n=20
90
75
0
TW
32
25
16
20
5/ 21/ 25/ 31/
31 31 31 31
6/ 18/ 25/ 29/ 30/ 5/ 9/ 17/ 20/ 20/
30 30 30 30 30 20 20 20 20 20
1
2 4 FU2 1
4 wks
2 4 6 FU2 1
6 wks
100
80
60
40
20
0
Breakthrough
Relapse
All relapse
Relapse at FU4
Relapse at FU8
86,7
10
2/ 6/ 17/ 19/ 19/
19 19 19 19 19
2 4 6 FU2 1
6 wks
Non-cirrhotic
SVR4/8 (%)
D1
100
100
n=31
Cirrhoti
c
NonNoncirrhoti Cirrhot cirrhot
c
ic
ic
G3
G1
102 G1 ± cirrhosis treated with
grazoprevir 100 mg/elbasvir 50 mg
FDC QD + SOF 400 mg QD
Cirrhotic
80
2 4 8 FU2
8 wks
94,7
38,7
12/31
26/30
16/20
18/19
0
0
0
0
19
10
9
4
4
0
4
2
2
1
1
0
C-SWIFT: MK-5172 (grazoprevir)+ MK-8742 (elbasvir) + SOF in
treatment-naive G1 pts with/without cirrhosis, for 4, 6, or 8
weeks
8 pts with BL NS5A RAVs:
SVR in pts
No BL
SVR in pts
Tx
with NS5A
NS5A RAV, with no NS5A
group
RAVs,
n
RAVs, n (%)
n (%)
4-wk
3
0 (0)
28
12 (43)
6-wk
3
2 (66)
47
40 (85)
8-wk
2
1 (50)
17
17 (100)
 NS5A BL RAVs: 8 pts; 3 SVR and 5 relapsed
Total
8
3 (38)
92
69 (75)
●
3 pts from 4-wk Tx: 3 VFs
●
3 pts from 6-wk Tx: 2 SVR, 1 VF
●
2 pts from 8-wk Tx: 1 SVR, 1 VF
 NS3 BL RAV: 1 pt (this pt achieved SVR)
 NS5B BL RAV: None
BL
NS5A
RAV, n
First trial to cure patients with designed 4-wk
duration but reaches limits of biologic plausibility
with current generation of antivirals as high
relapse seen
High viral load and non CC predictive of failure with
4-week duration
Optimal duration of 8 weeks should be studied in
Lawitz E, et al. AASLD 2014, Boston. #LB-33
diverse populations
Pharmacokinetics: Non-cirrhotic G1 pts (6-week)
Grazoprevir/elbasvir Ctrough
Phase 1/2a study assessing 7-day dosing of MK3682 (formerly IDX21437) in HCV-infected subjects
MK-3682 is a uridine nucleotide polymerase inhibitor
Genotype
8:2
1
8:2
1
8:2
1
*Active:PBO
Dose
Study drug administration
MK-3682 or PBO QD x 7
50 mg
days
MK-3682 or PBO QD x 7
150 mg
days
MK-3682 or PBO QD x 7
300 mg
days
G1
MK-3682 dose x 7 days
Mean
maximum
PBO QD x7
HCV RNA
days (n=5) 50 mg QD 150 mg QD 300 mg QD
reduction
(n=6)
(n=5)
(n=8)
†
0.74
Mean (SE) 0.31 (0.102)
(0.081)
Median
0.36
0.78
SD
0.197
†log10
IU/mL 0.227
25%, 75% 0.20, 0.44 0.63, 0.90
Min, Max -0.02, 0.57 0.42, 0.96
N (G2/3) Dose
0/5
50 mg
1/4
150 mg
300
3/7
mg
Mean change from baseline
(log10 IU/mL)
N*
2.61
4.23
(0.431)
(0.277)
2.46
4.29
0.964
0.782
1.98, 2.84 3.57, 4.82
1.65, 4.13
G1a 3.12, 5.36
G1b
n=3
n=5
4.8 log10
3.9 log10
Gane EJ, et al. AASLD 2014, Boston. #1974
1
Drug administration
MK-3682 QD x 7 days
MK-3682 QD x 7 days
MK-3682 QD x 7 days
G1a
G1b
0
-1
-2
-3
-4
-5
-6
0 2 4 6 8 10 12 0 2 4 6 8 10 12
Day
Dose
0 mg
50 mg
150 mg
300 mg
G2/3
MK-3682 dose x7 days
Mean
maximum
HCV RNA
reduction†
50 mg QD
(n=5)
150 mg QD
(n=5)
300 mg QD
(n=10)
Mean (SE)
Median
SD
25%, 75%
Min, Max
†log10
IU/mL
1.01 (0.279)
1.14
0.624
1.00, 1.42
-0.03, 1.54
2.24 (0.308)
2.09
0.688
1.76, 2.51
1.55, 3.29
4.27 (0.144)
4.12
0.454
3.93, 4.78
3.68, 5.03
Safety:
No dose dependent AEs
HA 14%; diarrhea 11%
PK mostly dose proportional
G2
n=3
4.6 log
G3
n=7
4.1 log
Mean change from baseline
(log10 IU/mL)
Phase 1/2a study assessing 7-day dosing of MK3682 (formerly IDX21437) in HCV-infected subjects
1
G2
G3
0
-1
-2
-3
-4
-5
-6
0 2 4 6 8 10 12 0 2 4 6 8 10 12
Day
Dose
150 mg
50 mg
300 mg
New uridine nucleotide polymerase inhibitor achieves potent activity (>4
logs)
in G1–3 at 300 mg
No safety signals to date; await safety and efficacy data from longer
exposures
MK-3682
to pipeline
of MK-5172 (advanced PI) and two NS5A
Gane EJ,
et al. AASLDadded
2014, Boston.
#1974
inhibitors
Pangenotypic all oral regimen: Sofosbuvir/GS5816
Picomolar activity
in GT 1-6
High SVR rates in Phase 2 studies
–
12-week treatment
–
No RBV
100%
Phase 3 program underway
100%
2
1
100%
5
4
100%
Slide 15
6
3
86%
94%
Confidential

Download Report