2nd wave IFN-based triple therapy for HCV genotype 1: Simeprevir, Faldaprevir and Sofosbuvir.
Paris Hepatitis Conference
Pr Tarik Asselah
14 janvier 2014
MD, PhDService d’Hépatologie & INSERM U773
University Paris Diderot Hôpital Beaujon, Clichy
• Introduction
• New IFN-based triple therapy for HCV genotype 1Protease inhibitors
- Simeprevir (Quest-2, Promise)
- Faldaprevir (StartVerso 1, StartVerso 3)
- Other PI : MK5172, Asunaprevir, etc….
Polymerase inhibitor- Sofosbuvir (Neutrino)
• Summary and Conclusion
2nd wave IFN-based triple therapy for HCV genotype 1: Simeprevir, Faldaprevir and Sofosbuvir.
CapsidRNA
Polymerase
MetalloproteaseSerine protease
RNA helicase
EnvelopeGlycoproteins
E1C E2
Nonstructural proteinsStructural proteins5’NTR 3’NTR
NS1 NS2 NS3 NS4A NS4B
Cofactors
NS5A NS5B
Protease Inhibitors
TelaprevirBoceprevirSimeprevirFaldaprevirAsunaprevirABT-450MK-5172SovaprevirACH-2684
NS5A Inhibitors
DaclatasvirLedipasvirABT-267GS-5816ACH-3102PPI-668GSK-2336805SamatasvirMK-8742
Polymerase Inhibitors
Nucs Non-Nucs Sofosbuvir ABT-333VX-135 DeleobuvirIDX-20963 BMS-
791325ACH-3422 PPI-383
GS-9669TMC-647055
Direct-acting antivirals
Schinazi R, Halfon P, Marcellin P, Asselah T. Liver International 2014
Triple Therapy:1 DAA + PegIFN alfa/RBV IFN-Free Regimens
Simeprevir (PI)
Faldaprevir (PI)
Sofosbuvir (NI)
Daclatasvir (NS5A)
MK 5172 (PI)
Danoprevir (PI)
Alisporivir (CYP)
Sofosbuvir + RBV
Sofosbuvir + GS-5885 (FDC) ± RBV
Daclatasvir + asunaprevir
ABT-450/RTV + ABT-267 ± ABT-333 ± RBV
Faldaprevir + BI207127 + RBV
MK 5172 + MK 8742
Investigational HCV Regimens in Phase III Trials in 2014
Asselah and Marcellin P,. Liver International 2014
PI, 1stGeneration
PI, 2ndGeneration
NS5A Inhibitors, 1st
Generation
NS5A Inhibitors, 2nd
Generation
NS5BNucleosideInhibitors
NS5B Non NucleosideInhibitors
Efficacy
Resistance Profile
Pangenotypic Efficacy
Adverseevents
Drug-drug interactions
Good profile Average profile Least favorable profile
Schinazi R, Halfon P, Marcellin P, Asselah T. Liver International 2013
General Characteristics of Direct-Acting Antivirals
Potency
Genotype Coverage
Resistance Barrier
Safety/Tolerability
Half life & Pills burden
Treatment Duration
Drug-drug Interaction
Highest Importance
Secondary Priorities
Cost
Priorities for Direct-Acting Antivirals
Schinazi R, Halfon P, Marcellin P, Asselah T. Liver International 2013
2nd wave IFN-based triple therapy for HCV genotype 1: Simeprevir, Faldaprevir and Sofosbuvir.
• Introduction
• New IFN-based triple therapy for HCV genotype
1Protease inhibitors
- Simeprevir (Quest-2, Promise)
- Faldaprevir (StartVerso 1, StartVerso 3)
- Other PI : MK5172, Asunaprevir, etc….
Polymerase inhibitor- Sofosbuvir (Neutrino)
• Summary and Conclusion
SMV 150mg + PR
n=264Follow-up
0 12 24 48 72
n=130 Placebo + PRFollow-up
Follow-up
PR
Placebo + PRPR
PR
Response-guided treatment
12 24 48Week 720
Follow-upN=134 PRPlacebo + PR
Follow-upN=257PR
Follow-up
SMV 150mg +PR
PR
PR
12 24 48Week 720
N=133 PR PBO + PR
N=260PRSMV 150 mg
+ PRPR
PR
QUEST-1, naïve
QUEST-2, naïve
PROMISE, relapsers
Simeprevir (SMV) (PI): G1, phase III trial design
Follow-up
Follow-up
Follow-up
Pro
port
ion
of p
atie
nts,
%
*Based on the Cochran-Mantel-Haensze test controlling for type of PegIFN/ribavirin and stratification factors
209/25767/134
P<0.001*
SMV/PRPlacebo/PR
9
Simeprevir (SMV) (PI): G1 naïve, phase III (QUEST-2)
Manns et al. EASL 2013, Abstract 1413.
50
81,3SVR12 (%)
QUEST-2: Response-guided Treatment (RGT) allows shortened treatment duration with high SVR12
91.4% (235/257) of patients met
RGT criteria and were eligible for
24 weeks of treatment
202/235
Prop
ortio
n of
pati
ents
0
20
40
60
80
100
86
SVR12 in SMV/PR
• 8.6% (22/257) of patients did not meet RGT criteria – among them, 31.8% (7/22) achieved SVR12
202/235
RGT, response-guided therapy; RGT criteria: HCV RNA < 25 IU/mL detectable or undetectable at Week 4 and <25 IU/mL undetectable at Week 12
10
1105.03.2013
Quest-2: Changes in haemoglobin
Manns et al. EASL 2013, Abstract 1413.
Hemoglobin
0
Entire treatment phase – hemoglobin, µmol/L
Weeks
200
Mea
n va
lues
, ±S
E
180
160
140
120
100
4 8 24 36 482016122
SMV
Placebo
SMV/PR
Placebo/PR
75
58
84 85
4752
43
53
0
20
40
60
80
100
G1a G1awith Q80K
G1awithout Q80K
G1b
191/254 138/165 228/26762/131 23/44 36/83 70/13349/84
Simeprevir (SMV) (PI): G1 relapsers (Promise)
Lawitz et al. DDW 2013, Abstract 869b.
SVR12 (%)
QUEST-1 QUEST-2 PROMISE
Placebo + PR, %
(N = 130)
SMV + PR, %(N = 264)
Placebo + PR, % (N = 134)
SMV + PR, %(N = 257)
Placebo + PR, %
(N = 130)
SMV + PR, %(N = 264)
Serious AEs 4 3 2 2 4 3
Discontinuation due to AEs 3 3 1 2 3 3
Fatigue 38 40 39 35
Pruritus 11 21 15 19 28 28
Rash (any type) 25 27 11 24 23 23
Anaemia 11 16 14 16 20 17
Jacobson et al. DDW 2013, Abstract 1674582.Manns et al. EASL 2013, Abstract 1413.Lawitz et al. DDW 2013, Abstract 869b.
Simeprevir: adverse events (phase III trials)
PR: PegIFNα-2a 180 ug/wk + RBV 1000-1200mg/day
Week 12 Week 24 Week 36 Week 48
N=150 patients. Single arm, open-labelTriple TherapySMV + PR
Follow up
Continue PR to Wk 24
Ongoing trialResponse-guided therapy of 12 or 24 weeks guided by HCV-RNA measurements at treatment weeks 2, 4, and 8.
Week 4
Follow up
Clinicaltrials.gov: NCT01846832
Baseline
Simeprevir (PI): 12 weeks phase III trial (G1 naïve)
Faldaprevir (FDV) (PI): phase III trial, G1 naïve (StartVerso1)
PRPlacebo + PR Follow-up
Day 1 Week 12 Week 24 Week 48 Week 72
FDV 240 mg + PR
Follow-up
Placebo + PR
PR Follow-up
ETS
No ETS
Arm 2(n=261)
Arm 3(n=262)
Arm 1(n=133)
Follow-up
FDV 120 mg + PR
PR Follow-up
ETS
No ETS FDV 120 mg + PR
Placebo + PR
Ferenci et al. EASL 2013, abstract LB 1416.
SVR12 rates adjusted for race and genotypeITT, intention-to treat
204/259 210/26169/132
SV
R1
2 (%
)
(∆ = 28.6; 95% CI, 19.0–38.2; p<0.0001)
(∆ = 26.7; 95% CI, 17.1–36.3; p<0.0001)
Faldaprevir (FDV) (PI): G1 naïve, results (StartVerso1)
Faldaprevir (FDV): Early treatment success (ETS) allows shortened treatment duration with high SVR12
Pro
por
tion
of p
atie
nts
(%
)
ETS ETS + SVR12a
ETS, early treatment success: HCV RNA <25 IU/mL (detected or undetected) at Week 4 and <25 IU/mL (undetected) at Week 8. aDenominator = patients with ETS
226/259 194/226
FDV 120 mg FDV 120 mg
Changes in haemoglobin
FDV 120 mg + PR
FDV 240 mg + PR
Placebo + PR
16
14
12
10
80 4 8 12 24
Mea
n ha
em
oglo
bin
± S
D (
g/dL
)
Weeks
18
16 20
Placebo + PRN=264
FDV 120 mg + PR N=521
FDV 240 mg + PR N=524
AEs leading to discontinuation of all medication, n (%) 10 (4) 27 (5) 40 (8)
AEs leading to discontinuation of FDV or placebo only, n (%) 1 (<1) 6 (1) 14 (3)
Serious AEs, n (%) 16 (6) 39 (7) 43 (8)
AEs of at least moderate intensity (any)a, n (%)
RashPhotosensitivityGIAnemiaBilirubin associated
156 (59)
11 (4)0 (0)
19 (7)38 (14)
2 (1)
302 (58)
39 (7)0 (0)
58 (11)73 (14)18 (3)
332 (63)
50 (10)3 (1)
96 (18)70 (13)47 (9)
One patient with cirrhosis at baseline developed acute-on-chronic liver failure after 16 days of FDV (24 0mg) and PR, discontinued all treatment and died 12 days later. The event was considered not related to FDV but to pegylated interferon by investigator.aDAIDS Grade 2 to 4; protocol-defined AEs of special interest. DAIDS, Division of AIDS table for grading the severity of adult and pediatric adverse events; DC, discontinuation; GI, gastrointestinal.
Faldaprevir: adverse events (phase III trial results)
aStopping rule for RGT criteria: all relapsers, who did not achieve ETS (HCV RNA <25 IU/mL (detected or undetected) at week 4 and <25 IU/mL (undetected) at week 8, had extended PR treatment to week 48; bN=146 patients randomized, but N=145 patients treated. PR, pegylated interferon α-2a/ribavirin; QD, once daily; RGT, response-guided therapy.
PRPlacebo + PR
FDV 240 mg + PR Placebo + PR
Day 1 Week 12 Week 24 Week 48
FDV 240 mg + PR PR (RGT a)Placebo + PR
FDV 240 mg + PR PR (RGT a)
PRPlacebo + PR
FDV 240 mg + PR Placebo + PR
FDV 240 mg + PR
PR
PR
FDV 240 mg + PR PR
PR
Arm 1 (n=49)
Arm 2 (n=99)
Arm 3 (n=102)
Arm 1 (n=29)
Arm 2 (n=57)
Arm 3 (n=55)
Arm 1 (n=146)b
Arm 2 (n=141)
Relapser: Rebound from HCV RNA undetectable at end of 48 week treatmenta but detectable within 24 weeks of follow-up
Partial responder: HCV RNA drop by ≥2 log10 from baseline to week 12, but never undetectableBreakthrough: HCV RNA undetectable during treatment, but rebound to detected during ongoing treatment
Null responder: Absence of HCV RNA drop by ≥2 log10 from baseline to week 12
Prior relapse
Prior partial response
Prior null response
Faldaprevir (PI): phase III trial design, G1 experienced (StartVerso3)
Jacobson et al. AASLD 2013, abstract 1100.
14
70 70
0
20
40
60
80
100
7/49 69/99 71/102
Prior relapse
FDV 12 weeks
FDV 24 weeks
Placebo
3
58
47
1/29
FDV 12 weeks
FDV 24 weeks
Placebo
33/57 26/55
Prior partial response
33 33
48/145 46/141
FDV 12 weeks
FDV 24 weeks
Prior null response
Faldaprevir (FDV) (PI): SVR12, G1 experienced (StartVerso3)
71/102 26/55 46/141
Manns et al. EASL 2013, Abs. 66
0
25
50
75
10092 %
(61/66)
SV
R24
or
TN
D a
t la
st v
isit
(%
)
HCV RNA TND at last visit
96 %(64/67)
98 %(64/65)
86 %(55/64)
99 %(67/68)
92 %(61/66)
67 %(44/66)
91 %(58/64)
87 %(52/60)
54 %(31/57)
MK-5172100 mg + PR
MK-5172200 mg + PR
MK-5172400 mg + PR
MK-5172800 mg + PR
BOC + PR
SVR24
MK-5172 (PI) plus PEG-IFN/RBV: G1 naïve non-cirrhotic
SVR24 and HCV-RNA TND at Last Visit*
101/159 24/54 16/18 3/755/94 45/63
G1a G1b
Bronowicki et al. EASL 2013, Abs. 1420
Asunaprevir (PI) plus PEG-IFN/RBV: G1 naive
Final analysis
12 SVR12
N = 327
Post-therapy follow-up
Weeks
Sofosbuvir + PR
Sofosbuvir (NI): phase III trial design; G1 naïve (Neutrino)
Lawitz et al. N Engl J Med. 2013; 368(20):1878-87
90 %
0
20
40
60
80
100
TotalPopulation
295/327
SV
R12
(%
)92 %
80 %
SVR12
252/273 43/54
No cirrhosis
Cirrhosis
Sofosbuvir (NI): SVR12, G1 naïve, phase III trial (Neutrino)
Lawitz et al. N Engl J Med. 2013; 368(20):1878-87
89 %
Genotype 1
261/292
Sofosbuvir + PR, % (N = 327)
SAEs 1
Discontinuations due to AEs 2
Fatigue 59
Anaemia 21
Rash (any) 18
Pruritus 17
Neutropenia 17
Sofosbuvir : side effects (Neutrino)
Lawitz et al. N Engl J Med. 2013; 368(20):1878-87
2nd wave IFN-based triple therapy for HCV genotype 1: Simeprevir, Faldaprevir and Sofosbuvir.
• Introduction
• New IFN-based triple therapy for HCV genotype 1Protease inhibitors
- Simeprevir (Quest-2, Promise)
- Faldaprevir (StartVerso 1, StartVerso 3)
- Other PI : MK5172, Asunaprevir, etc….
Polymerase inhibitor- Sofosbuvir (Neutrino)
• Summary and Conclusion
DAA + PEG-IFN + RBV N SVR12DAA+PR vs. PR
Simeprevir QUEST-21 391 (7% F4)
81% vs. 50%
Faldaprevir StartVerso12 (120 vs. 240 mg)
652 (17% ≥ F3)
79-80% vs. 52%
Sofosbuvir3 292 (17% F4)
89 % vs no control arm
1Manns MP et al. Late breaker p1413 EASL 2013 2Ferenci P et al. Late breaker p. 1416, EASL 20133Lawitz E, et al. N Engl J Med 2013;368:1878-87.
Summary: 2nd wave IFN-based triple therapy for HCV G1
• The available data on second-generation IFN-based regimens
is very promising due to:● Higher proportion of patients candidates for short treatment duration
● Better safety profile when compared with first-generation PIs
● Less pill burden
• However, a proportion of patients remain difficult to cure and
more studies are needed in these populations. These include ● Cirrhotic patients
● Previous null responders
● Failure to triple therapy
● Patients infected with genotype 4
• Finally we need to explore cost effectiveness of DAA treatment strategies
DAAs in IFN-containing regimens : results, summary
Summary: 2nd wave IFN-based triple therapy for HCV G1
USA & Canada
4 M
SOUTH
AMERICA
10 M
AFRICA 32 M
EASTERNMEDITERRANEAN
21.3M
SOUTH EAST ASIA32.3 M
AUSTRALIA0.2 M
WHO, 1999
EUROPE
9 M
FAR EAST/ASIA60 M
170 Millions worldwide
HCV worldwide: Limited access to new treatment options in countries with the highest HCV prevalence
HCV worldwide: Limited access to new treatment options in countries with the highest HCV prevalence
Japan
2M
Majority of the WorldNo treatment or
Dual┃PegIFN/RBV
Majority of the WorldNo treatment or
Dual┃PegIFN/RBV
DAA + PR
Simeprevir
Faldaprevir
Sofosbuvir
IFN free
Sofosbuvir/ ledipasvir FDC ± RBV
ABT-450r/ABT-267 FDC + ABT-333 ± RBV
Daclastavir + asunaprevirG1b
Faldaprevir + Deleobuvir + RBVG1b
2015-20162014-2015
Off-label combinations
DaclatasvirOther IFN-free combinations
Other DAA + PR
Telaprevir
Boceprevir
Conclusion & Perspectives
Asselah and Marcellin P,. Liver International 2014
42/42
95
SVR12 (%)
0
20
40
60
80
100
G1bABT450/r ABT 267
40/42
Pearl-1, ABT450/r + ABT 267; Lawitz et al. AASLD 2013, A75.
96 100
89
24/25 24/27 13/13
G1MK-5172MK-8742 20 mgRBV
G1MK-5172MK-8742 50 mgRBV
G1bMK-5172MK-8742 50 mg
C-Worthy , MK-5172/MK-8742 + RBV; Lawitz et al. AASLD 2013, A76.
Cosmos : sofosbuvir (SOF)/simeprevir (SMV) + RBV; Jacobson et al. AASLD 2013, ALB3.
100
12/12
G1SMVSOFRBV
SVR4
Electron, SOF/ledipasvir (LDV) + RBV; Gane et al. AASLD 2013, A73
100
25/25
100
21/21
68
G1SOFLDVRBV12 W
G1SOFLDVRBV8 W
G1SOFLDVRBV6 W
95
19/20
100
21/21
95
G1SOFLDV
8 W
G1SOFLDVRBV8 W
G1SOFLDV
12 W
18/19
Daclatasvir (DCV) + asunaprevir (ASV) + BMS-791325; Everson et al. AASLD 2013, ALB1.
92
71/77
92
77/84
G1 G1DCV DCVASV ASV BMS-79132575 mg 150 mg
100
13/13
G1aFDVDBVPPI-668± RBVSVR4
Faldaprevir (FDV), deleobuvir (DBV) +PPI-668; Lalezari et al. AASLD 2013 ALB20.
Daclatasvir (DCV) + asunaprevir (ASV); Chayama et al. AASLD 2013, A211.
87
118/135
G1bDCVASV
Lonestar : sofosbuvir (SOF)/ledipasvir (LDV) + RBV; Lawitz et al. AASLD 2013, A215/1844.
17/25
Perspectives 1 (G1 naïves)
Schinazi R, Halfon P, Marcellin P, Asselah T. Liver International 2013
SVR12 (%)
0
20
40
60
80
100
Cosmos : sofosbuvir (SOF)/simeprevir (SMV) + RBV; Jacobson et al. AASLD 2013, ALB3.
92.9
13/14
G1SMVSOF
12 WF0-F2
Electron : sofosbuvir (SOF)/ledipasvir (LDV) + RBV; Gane et al. AASLD 2013, A73
100
25/25
100
26/26
70
G1SOFLDVRBV12 WF3/F4
G1SOFLDVGS-966912 WF3/F4
G1SOFLDV
12 WF4
95
18/19
100
21/21
G1 IPSOFLDV
12 W
G1 IPSOFLDVRBV12 W
Lonestar : sofosbuvir (SOF)/ledipasvir (LDV) + RBV; Lawitz et al. AASLD 2013, A215/1844.
G1SOFLDV
12 WF4
7/10
100
9/942/42
90
36/40
G1b NRABT450/r ABT 267
Pearl-1, ABT450/r + ABT 267; Lawitz et al. AASLD 2013, A75.
93.3
14/15
G1SMVSOF
24 WF0-F2
G1SMVSOFRBV12 WF0-F2
G1SMVSOFRBV24 WF0-F2
96.3
26/27
79.3
19/24
Perspectives 2 (G1 experienced)
Schinazi R, Halfon P, Marcellin P, Asselah T. Liver International 2013
SOF
ABTSMV
FDV
DCV
MK
APV
And the Winner is…………………….
The Patient.
